EMILIA Trial TDM1 Protocolo

Protocol
This trial protocol has been provided by the authors to give readers additional information about their work.
Protocol for: Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer.
N Engl J Med 2012;367:1783-91. DOI: 10.1056/NEJMoa1209124
Supplement to: Verma S, Miles D, Gianni L, et al. Trastuzumab Emtansine for HER2-positive
Advanced Breast Cancer
This supplement contains the following items:
Section 1: Original protocol, final protocol, summary of changes
Section 2: Original statistical analysis plan, final statistical analysis plan, summary of changes
Section 3: Statistical analysis plan amendment

Section 1: Original protocol, final protocol, summary of changes
PROTOCOL
TITLE: A RANDOMIZED, MULTICENTER, PHASE III OPEN LABEL STUDY
OF THE EFFICACY AND SAFETY OF TRASTUZUMAB MCC-DM1
VS. CAPECITABINE + LAPATINIB IN PATIENTS WITH HER2
POSITIVE LOCALLY ADVANCED OR METASTATIC BREAST
CANCER WHO HAVE RECEIVED PRIOR TRASTUZUMAB BASED
THERAPY
PROTOCOL NUMBER: TDM4370g/BO21977 VERSION NUMBER: A4
EUDRACT NUMBER: 2008-005 713-22 IND NUMBER: 71,072
TEST PRODUCT: Trastuzumab emtansine (RO5304020)
MEDICAL MONITOR: Ellie Guardino, M.D., Ph.D.
SPONSOR: Genentech, Inc.
F. Hoffmann-La Roche Ltd
DATE FINAL: Version 1: 8 October 2008
DATES AMENDED: Version A1: 19 February 2010
Version A2: 13 May 2010
Version A3: 4 October 2010
Version A4: See electronic date stamp below
PROTOCOL AMENDMENT APPROVAL
Name Reason for Signing Date and Time

(UTC)
Berger,Dietmar Company Signatory 30-May-2012 14:53:36
CONFIDENTIAL STATEMENT
The information contained in this document, especially any unpublished data, is the property of
F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as
an investigator, potential investigator, or consultant, for review by you, your staff, and an
applicable Ethics Committee or Institutional Review Board. It is understood that this information
will not be disclosed to others without written authorization from Roche except to the extent
necessary to obtain informed consent from persons to whom the drug may be administered.
Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

Protocol TDM4370g/BO21977, Version A4
PROTOCOL
THERAPY
DATE FINAL: Version 1: 8 October 2008
DATES AMENDED: Version A1: 19 February 2010
Version A2: 13 May 2010
Version A3: 4 October 2010
Version A4: See electronic date stamp below
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL STATEMENT
The information contained in this document, especially any unpublished data, is the property of
F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as
an investigator, potential investigator, or consultant, for review by you, your staff, and an
applicable Ethics Committee or Institutional Review Board. It is understood that this information
will not be disclosed to others without written authorization from Roche except to the extent
necessary to obtain informed consent from persons to whom the drug may be administered.

Protocol TDM4370g/BO21977, Version A4
PROTOCOL AMENDMENT, VERSION A4:
RATIONALE
Protocol TDM4370g/BO21977 has been amended to modify study activities that will be
performed after the final analysis of progression-free survival (PFS) that had occurred
based on a clinical data cutoff date of 14 January 2012. As a result of this important
milestone being reached, study administrative structures, procedures, and requirements
for investigators and patients will change. This protocol amendment is intended
primarily to clarify these changes, which include the following:
• The Data Monitoring Committee (DMC) and Cardiac Review Committee (CRC)
monitoring of patient safety data have been discontinued.
Prior to the final analysis of PFS, the DMC met every 6 months to monitor
accumulating patient safety data and reviewed data on serious adverse events
every 3 months. After completion of the final analysis of PFS, these reviews
will stop, as specified in the DMC charter.
The sole purpose of the CRC was to provide potential cardiac event information
to the DMC. Therefore, the CRC is also no longer required.
The Sponsor will now be exclusively responsible for monitoring overall study
safety.
• The Independent Review Committee (IRC) review of ECHO/MUGA scans has been
discontinued.
At the time of the final PFS analysis, the Sponsor also performed safety
analyses, including an evaluation of cardiac safety data. Upon review of both
central and local ECHO/MUGA left ventricular ejection fraction (LVEF) data, the
Sponsor determined that there were no qualitative differences between the
treatment arms or methods of assessment. Additionally, central LVEF results
are not reported to the investigators and are therefore not applicable for
individual patient treatment and care decisions (all investigator treatment and
care decisions are based on local LVEF results). For these reasons, after the
final PFS analysis, local LVEF evaluation will continue and the central review of
ECHO/MUGA scans will be discontinued. This change is consistent with recent
trastuzumab emtansine studies, which do not include a requirement of central
ECHO/MUGA review.
• The IRC review of tumor assessment data has been discontinued, and the conduct
of tumor assessments has been modified.
As stated in the protocol, the IRC was to evaluate tumor responses for all
patients until the time of the final PFS analysis. Now that the primary efficacy
endpoint of IRC-determined PFS has been analyzed, the IRC is no longer
needed, and the frequency, method, and evaluation criteria of tumor
assessments will be according to investigator standard clinical practice.
• Text allowing additional analyses of overall survival (OS) to be performed has been
included.

Protocol TDM4370g/BO21977, Version A4 2
Provision for additional interim analyses has been included in anticipation of
updated OS analyses being requested by some health authorities to facilitate
their review of the benefit−risk assessment for patients receiving trastuzumab
emtansine therapy. To preserve the statistical rigor at all future OS analyses,
the Type I error rate will be strictly controlled at the 0.05 level by the continued
use of the Lan-DeMets α-spending function with an O'Brien-Fleming boundary
that is prespecified in the protocol and Statistical Analysis Plan. The final
analysis for OS (at approximately 632 events) will still be conducted. If any
interim analysis of OS meets the criteria for statistical significance, the co-
primary endpoint of OS will be considered met at that interim; the final analysis
will therefore be considered descriptive only.
• Patients randomized to the control arm will be allowed to cross over to receive
trastuzumab emtansine if a statistically significant OS benefit in favor of trastuzumab
emtansine is demonstrated. The timing of which is to expedite patient access when
a statistically significant OS benefit is demonstrated. Eligibility criteria and an
additional appendix detailing assessments for these cross-over patients have been
provided.
The option allowing patients randomized to the control arm to cross over to
receive trastuzumab emtansine has been included in order to ensure that all
study patients have the opportunity to receive treatment with trastuzumab
emtansine if it is shown to result in an OS benefit. A significant amount of time
may have passed since an individual patient was originally screened for this
study (and the patient may have received subsequent non-protocol therapies).
Therefore, to ensure the safety of patients who wish to receive cross-over
therapy, specific criteria must be met prior to administration of their first dose of
trastuzumab emtansine.
• Protocol-defined events of special interest/non-serious expedited adverse events
have been updated.
Asymptomatic and transient elevations of liver enzymes (AST and/or ALT) are
an identified risk following treatment with trastuzumab emtansine, although the
association of trastuzumab emtansine with more severe liver injury has yet to
be established. Therefore, any potential case of drug-induced liver injury, as
assessed by laboratory criteria for Hy’s Law, has been added as a
protocol-defined event of special interest and will need to be reported to the
Sponsor expeditiously. The following laboratory abnormalities define potential
Hy’s Law cases:
AST or ALT elevations that are > 3 × the upper limit of normal (ULN)
Concurrent elevation (within 21 days of AST and/or ALT elevations) of total
bilirubin > 2 × ULN, except in patients with documented Gilbert syndrome
On the basis of the results of completed (Phase I and Phase II) and ongoing
(Phase III) trials with trastuzumab emtansine, symptomatic congestive heart
failure, asymptomatic declines in LVEF, and significant bleeding events
associated with thrombocytopenia that require a blood transfusion are no longer
considered protocol-defined events of special interest for trastuzumab
emtansine studies. These events will continue to be captured through the
standard reporting of serious and non-serious adverse events.
• Dose modification guidelines have been updated to better mitigate the
hepatotoxicity risk in patients.
Trastuzumab emtansine must be permanently discontinued in patients with ALT
> 3 × ULN and a subsequent increase in total bilirubin to > 2 × ULN within
21 days.
For patients with AST > 3 × ULN (without ALT > 3 × ULN) and a subsequent
increase of total bilirubin to > 2 × ULN within 21 days, treatment with
trastuzumab emtansine may be continued with one dose level reduction after
recovery of AST to ≤ 2.5 × ULN and total bilirubin to ≤ 1.5 × ULN only after
consultation with the Medical Monitor.
• Text describing the risks associated with trastuzumab emtansine has been updated
to include nodular regenerative hyperplasia (NRH) as a new identified risk for
trastuzumab emtansine.
Cases of NRH have been identified from liver biopsies. NRH is a rare liver
condition characterized by widespread benign transformation of hepatic
parenchyma into small regenerative nodules; diagnosis can be confirmed only
by histopathology. NRH may lead to non-cirrhotic portal hypertension. NRH
should be considered in all patients with clinical symptoms of portal
hypertension, but with normal transaminases and no manifestations of cirrhosis.
This condition may be reversible upon discontinuation of trastuzumab
emtansine therapy. Upon diagnosis of NRH, patients should be re-evaluated to
continue trastuzumab emtansine.
• The Day 8 and 15 study visits have been eliminated.
On the basis of the Sponsor review of the safety data at the time of the PFS
analysis, it was determined that the Day 8 and 15 assessments are not
essential to ensure patient safety. Laboratory assessments on Day 1 of each
cycle (and as clinically indicated) are sufficient to ensure patient safety. This
change is consistent with recent trastuzumab emtansine clinical studies.
Previously, Day 8 and 15 study visits were required for Cycles 1-4. This change
affects patients who cross over, since the last patient was enrolled in October
2011 and has already received Cycle 4 treatment.
Additional changes to the protocol are as follows:
• Text clarifying that the cycle of treatment is defined by the start of capecitabine
chemotherapy has been included.
• Instructions for dose administration of trastuzumab emtansine have been updated.
The dose of trastuzumab emtansine does not need to be recalculated unless the
body weight has changed by > 10% from the weight used to calculate the most
recent dose.
• Language pertaining to pregnancy and contraception has been updated.

• The schedule of FACT-B assessment for Day 1 (prior to any study procedures or
discussion of test results) of Cycle 1 and every two cycles thereafter until treatment
discontinuation has been modified. After treatment discontinuation for any reason,
the FACT–B assessment will be performed according to the same schedule as
during the survival follow-up.
• Text describing the risks associated with capecitabine and lapatinib has been
updated.
• Evaluations using the Diarrhea Assessment Scale (DAS) have been discontinued
now that the final analysis of the DAS has been completed at the time of PFS
analysis. Thus, no additional DAS data collection is needed.
• References to “trastuzumab-MCC-DM1” and “T-DM1” have been changed
throughout the document to “trastuzumab emtansine,” the recommended
International Nonproprietary Name.
Additional minor changes have been made to improve clarity and consistency.
Substantive new information appears in italics. This amendment represents cumulative
changes to the original protocol.

PROTOCOL AMENDMENT, VERSION A4:
SUMMARY OF CHANGES
GLOBAL CHANGES
Global changes that have been affected to the protocol are as follows:
• All instances of T-DM1 and trastuzumab MCC-DM1 have been revised to

trastuzumab emtansine
• Throughout the protocol, text to clarify procedures and assessments that were
performed prior to versus following the final PFS assessment was added
PROTOCOL SYNOPSIS
The protocol synopsis has been updated to reflect the changes to the protocol, where
applicable.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMSThe list of

abbreviations and definitions of terms has been updated to reflect the changes to the
protocol, where applicable.
SECTION 1.2.4: Study TDM4450g

Of the 137 patients randomized (n = 67 in the trastuzumab emtansine arm; n = 70 in the
control arm), all patients (n = 67; 100%) in the trastuzumab emtansine arm and 68 of
70 patients in the control arm (97.1%) received treatment as randomized. The primary
efficacy endpoint, PFS, was assessed based on a data cutoff date of 15 November 2010.
For patients treated with trastuzumab emtansine, median PFS was 14.2 months
compared with 9.2 months for patients treated with trastuzumab + docetaxel (hazard
ratio = 0.594; p = 0.0353) (Hurvitz et al. 2011). The ORR in the
trastuzumab emtansine arm was 64.2% (95% CI: 51.8%, 74.8%) compared with
58.0% (95% CI: 45.5%, 69.2%) in the trastuzumab + docetaxel arm. The CBR was
74.6% (95% CI: 63.2%, 84.2%) in the trastuzumab emtansine arm versus 81.2%
(95% CI: 70.7%, 89.1%) in the trastuzumab + docetaxel arm.
Preliminary evaluations of safety in the randomized study TDM4450g suggest that the
safety and tolerability of trastuzumab emtansine compares favorably with that of
trastuzumab plus docetaxel, with the overall incidence of Grade ≥ 3 adverse events
favoring the trastuzumab emtansine arm (46.4% vs. 89.4%, Hurvitz et al. 2011).
As of 1 November 2009, 98 patients of a planned 120 patients were enrolled into the
study. A preliminary safety analysis was concluded on 18 August 2009 on the basis of
available data involving 39 patients. The trastuzumab emtansine safety profile was
similar to that seen on the previous Phase I and II studies.

SECTION 3.1: DESCRIPTION OF THE STUDY
Prior to the final PFS analysis, tTumor assessments will be were conducted
approximately every 6 weeks from the date of randomization or Cycle 1 Day 1,
regardless of dose delays or dose interruptions, until 6 weeks after investigator-
assessed PD or until death, whichever occurs occurred first, even if study treatment has
had been discontinued as a result of patient or physician choice or unacceptable toxicity
(see Appendix B).
After the final PFS analysis, the frequency, method, and evaluation criteria of tumor
assessments will be according to routine clinical practice per investigator. However, it
is recommended that RECIST be used to evaluate tumor assessments (see Appendix B).
Patients may remain on study treatment until disease progression (as assessed by the
investigator), unmanageable toxicity, or study termination by Genentech and Roche (the
Sponsors).
All patients who are discontinued from study treatment will return for a Study Drug
Completion Visit approximately 30 days (± 7 days) after the last dose of study treatment,
as shown in Appendix A-1.
Patients who are discontinued from study treatment for any reason because of disease
progression will complete the Study Drug Completion Visit approximately 30 days after
the last dose of study treatment. and return for one additional tumor assessment visit
and complete the FACT-B approximately 6 weeks after disease progression.
After the Study Drug Completion Visit, the patient will be followed for survival every
3 months until study closure. In addition, the FACT-B will be completed according to the
same schedule as survival follow-up.
Patients who are discontinued for reasons other than disease progression will complete
the Study Drug Completion Visit approximately 30 days after the last dose of study
treatment. After the Study Drug Completion Visit, the patient will be followed for survival
every 3 months until study closure. Meanwhile, these patients will continue to undergo
tumor assessments, have concomitant medications collected (anti-cancer therapies
only), and complete the FACT-B approximately every 6 weeks until 6 weeks after
disease progression. After disease progression, the FACT-B will also be completed
according to the same schedule as survival follow-up.
After the Study Drug Completion Visit, all patients (regardless of reason for
discontinuation) will be followed for survival every 3 months until death, loss to follow-up,
withdrawal of consent, or study termination by the Sponsors.
Patient-reported outcomes (PROs) as assessed by the FACT-B (female patients only)

should be completed every two treatment cycles until 6 weeks after disease progression;

for patients who discontinue study treatment for reasons other than disease progression,
the FACT-B assessment should be performed every two treatment cycles until treatment
discontinuation and at the Study Drug Completion Visit. the same time of tumor
assessments thereafter, until 6 weeks after disease progression. After treatment
discontinuation for any reason, disease progression, the FACT-B assessment will be
performed according to the same schedule as during survival follow-up.
After patients discontinue from study treatment, subsequent anti-cancer therapies will be
collected according to the same schedule as survival follow-up.
An independent Data Monitoring Committee (DMC) will monitor monitored accumulating

patient safety data at least once every 6 months during the course of the study until the
final PFS analysis had been conducted. In addition, data on serious adverse events will
were monitored by the DMC at least once every 3 months until the final PFS analysis
had been conducted. An independent Cardiac Review Committee (CRC) will review
reviewed all potential cases of left ventricular systolic dysfunction prior to each DMC
review and reported their findings to the DMC until the final PFS analysis had been
conducted. An IRC will evaluate evaluated tumor responses through the review of all
radiographic and other tumor assessment data generated from all patients at until the
time of the final PFS analysis, with treatment arm information blinded to the IRC. After
the final PFS analysis, the IRC will discontinue the review of tumor assessment data.
No interim analysis of IRC-assessed PFS is planned for this study. The final analysis of
the primary efficacy endpoint of PFS will take took place when approximately 508 IRC
assessed PFS events have had occurred and enrollment is completed. One interim
analysis of OS is planned at the time of the final analysis of PFS as assessed by the IRC.
The final analysis of OS will be performed when approximately 632 deaths have
occurred. See Section 4.9.10 for further details.
If the study is not terminated per DMC recommendation or by the Sponsors for other
reasons beforehand, it will be closed when approximately 632 deaths have been
reported and the final analysis of OS has been completed.
Additional interim analyses of OS will be performed with the appropriate control of the
Type I error rate using the pre-specified Lan-DeMets function with O’Brien-Fleming
boundary (additional details to be outlined in the Statistical Analysis Plan). If an
analysis of OS demonstrates a statistically significant benefit in favor of trastuzumab
emtansine, the co-primary endpoint of OS will be considered as met and at that time
patients randomized to the control arm may cross over to receive trastuzumab
emtansine.
Patients who cross over to trastuzumab emtansine may remain on study treatment
until disease progression (as assessed by the investigator), unmanageable toxicity, or
study termination by Genentech and Roche (the Sponsors). All patients will be followed

until approximately 632 deaths have been reported and the final analysis of OS has been
completed.
SECTION 3.4: SAFETY PLAN

Overall safety will be assessed on an ongoing basis during the conduct of the study. An
independent DMC will monitor monitored cumulative safety data at least once every
6 months during the course of the study until the final PFS analysis was conducted. In
addition, data on serious adverse events will be were monitored by the DMC at least
once every 3 months until the final PFS analysis was conducted. An independent CRC
will review reviewed all potential cases of left ventricular systolic dysfunction prior to
each semi-annual DMC review and will report reported their findings to the DMC until
the final PFS analysis was conducted.
SECTION 3.4.1.1: Risks associated with Trastuzumab Emtansine

The following summarizes the experience with trastuzumab emtansine in multiple
breast cancer studies to date. Trastuzumab emtansine has demonstrated a favorable
toxicity and tolerability profile to date across multiple studies. Please refer to the
Trastuzumab Emtansine Investigator’s Brochure for further information.
Reversible thrombocytopenia has been commonly observed in completed and ongoing

studies with trastuzumab emtansine. Most events were Grade 1 or 2; Grade 3 and 4
thrombocytopenia has been observed less frequently. The incidence of Grade 1 and 2
thrombocytopenia gradually increased over successive cycles; there was no increase in
the proportion of Grade ≥ 3 abnormalities. The number of patients who experienced
platelet count recovery to normal levels by Day 1 of the subsequent cycle decreased with
successive cycles, suggesting a modest cumulative effect of trastuzumab emtansine on
platelet count. There was no clear association between thrombocytopenia and severe
hemorrhagic events; however, the use of platelet transfusions has been reported.
Transient increases in serum AST and ALT have been observed across the trastuzumab
emtansine studies. Grade 1 and 2 events have been observed frequently; Grade 3 and 4
events have been observed less commonly. The incidence of increased AST was
substantially higher than that for ALT. Increases in AST and ALT were commonly
observed by Day 8 of each cycle and generally returned to baseline by Day 21. The
proportion of patients with Grade 1 or 2 increases in transaminases increased with
successive cycles; however, no increase in the proportion of Grade 3 abnormalities over
time was observed. To date, there have been no cases meeting Hy’s Law criteria for
drug-induced liver injury with trastuzumab emtansine. Although significant
hepatotoxicity has been seen in clinical trials with trastuzumab emtansine to date, the
relationship to trastuzumab emtansine has not been established. Nevertheless, severe
liver injury remains an important potential risk.
Cases of nodular regenerative hyperplasia (NRH) of liver have been identified from
liver biopsies. NRH is a rare liver condition characterized by widespread benign

transformation of hepatic parenchyma into small regenerative nodules; diagnosis can
only be confirmed by histopathology. It may lead to non-cirrhotic portal hypertension.
NRH should be considered in all patients with clinical symptoms of portal hypertension,
but with normal transaminases and no manifestations of cirrhosis. This condition may
be reversible upon discontinuation of trastuzumab emtansine treatment. Upon
diagnosis of NRH, patients should be re-evaluated to continue trastuzumab emtansine.
Infusion-related reactions are known to occur with the administration of monoclonal

antibodies and have been reported with trastuzumab emtansine. Infusion reaction
adverse events occurred rarely and were mostly Grade 1 or 2. Non-specific symptoms
occurring on the first day of trastuzumab emtansine infusion that could be associated
with an infusion reaction included fatigue, nausea, chills, pyrexia, and less commonly,
headache, hypertension, vomiting, and cough.
Pneumonitis (including severe, life-threatening cases) has been rarely reported with
trastuzumab emtansine. Signs, symptoms, and clinical findings include dyspnea,
cough, fatigue, and pulmonary infiltrates. In some patients with multiple lung
metastases, ventilator support (mechanical ventilation) was required. Treatment
included administration of corticosteroids, oxygen, and study drug discontinuation.
In clinical trials with trastuzumab emtansine, peripheral neuropathy has been reported,
mainly as a Grade 1 toxicity. Hypokalemia and decreases in serum potassium have
been reported in completed and ongoing studies with trastuzumab emtansine. Most of
these adverse events were Grade 1 or 2.
Although significant cardiac events have been infrequent in clinical trials with
trastuzumab emtansine to date, severe cardiotoxicity remains an important potential
risk. Treatment with trastuzumab, a component of trastuzumab emtansine, has
resulted in subclinical and clinical cardiac failure manifesting as CHF, decreased LVEF,
and cardiac death. The incidence and severity of cardiac dysfunction was highest in
patients who received trastuzumab concurrently with anthracycline-containing
chemotherapy regimens. Cardiotoxicity, manifesting as a decline in LVEF or CHF, is
being closely monitored in the trastuzumab development program. Across Studies
TDM4258g, TDM4374g, and TDM4688g, approximately 273 patients were treated,
and a total of 8 patients recorded an asymptomatic decrease in baseline LVEF of
≥ 10 percentage points below baseline to an absolute value < 50%. Two patients had
trastuzumab emtansine treatment withdrawn owing to decreased LVEF. Rare cases of
Grade 3 cardiac dysrhythmias have been reported among patients receiving
trastuzumab emtansine, although a direct relationship to study drug remains unclear.
Importantly, preliminary evaluations of safety in the randomized study TDM4450g

suggest that the safety and tolerability of trastuzumab emtansine compares favorably
with that of trastuzumab plus docetaxel, with the overall incidence of Grade ≥ 3 adverse
events favoring the trastuzumab emtansine arm (46.4% vs. 89.4%) (data on file).

Full details regarding the clinical safety of trastuzumab emtansine are presented in
Sections 5 and 6 of the Trastuzumab Emtansine Investigator’s Brochure.
SECTION 3.4.1.2: Risks associated with Capecitabine

Risks associated with capecitabine include diarrhea, coagulopathy, cardiotoxicity,
hand-and-foot syndrome, hyperbilirubinemia, and hematologic toxicity. Please see the
Xeloda ® Package Insert/national prescribing information for more details.
SECTION 3.4.1.3: Risks associated with Lapatinib

Risks associated with lapatinib include decreases in LVEF, hepatotoxicity, diarrhea,
interstitial lung disease and pneumonitis, and QT prolongation. Please see the
Tykerb ®/Tyverb ® Package Insert/national prescribing information for more details.
SECTION 3.4.2: Trastuzumab Emtansine Safety Plan

{New Section Heading}
SECTION 4.1.4: Eligibility Criteria for Control Arm Patients Who Cross over
to Receive Trastuzumab Emtansine
For patients randomized to the control arm offered the possibility to receive trastuzumab
emtansine (see Section 3.1), the following eligibility criteria must be met in order to receive
treatment.
SECTION 4.1.4.1: Inclusion Criteria for Cross-Over Patients

1. Cardiac ejection fraction ≥ 50% by either ECHO or MUGA
2. ECOG performance status of 0, 1, or 2
3. Adequate organ function, evidenced by the following laboratory results within 30 days prior
to Cycle 1, Day 1:
Absolute neutrophil count > 1500 cells/mm3
Platelet count > 100,000 cells/mm3
Hemoglobin > 9.0 g/dL
Patients are allowed to be transfused red blood cells to this level.
Albumin ≥ 2.5 g/dL
Total bilirubin ≤ 1.5 × ULN
SGOT (AST), SGPT (ALT), and ALP ≤ 2.5 × ULN with the following exception:
patients with bone metastases: ALP ≤ 5 × ULN
INR and aPTT < 1.5 × ULN (unless on therapeutic coagulation)

4. For women of childbearing potential and men with partners of childbearing potential,
agreement to use a highly effective, non-hormonal form of contraception:
Acceptable forms of contraception should include two of the following:
Placement of non-hormonal IUD
Condom with spermicidal foam/gel/film/cream/suppository
Diaphragm or cervical/vault caps with spermicidal
foam/gel/film/cream/suppository
The above contraception is not a requirement in the case of any of the following:
Patient is surgically sterilized (i.e., who have undergone surgical sterilization with
a hysterectomy and/or bilateral oophorectomy)
Patient has had no menstrual period for 12 consecutive months, or
Patient truly abstains from sexual activity
Contraception use should continue for the duration of the study treatment and for at
least 6 months after the last dose of study treatment. Periodic abstinence (e.g., calendar
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable
methods of contraception. Postmenopausal is defined as ≥ 12 months of amenorrhea.
Specific country requirements will be followed (e.g., in the United Kingdom, women of
childbearing potential and male subjects and their partners of childbearing potential must use
two methods of contraception [one of which must be a barrier method] for the duration of the
study).
SECTION 4.1.4.2: Exclusion Criteria for Cross-Over Patients

Cancer-Related Criteria
1. History of treatment with trastuzumab emtansine

2. Peripheral neuropathy of Grade ≥ 3 per National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE) Version 3.0
3. History of receiving any anti-cancer drug/biologic or investigational treatment within
14 days prior to Cycle 1, Day 1 except hormone therapy, which can be given up to 7 days
prior to Cycle 1, Day 1; recovery of treatment-related toxicity consistent with other eligibility
criteria
4. History of radiation therapy within 14 days of Cycle 1, Day 1
The patient must have recovered from any resulting acute toxicity (to Grade ≤ 1) prior
of Cycle 1, Day 1.
Brain metastases that are untreated, symptomatic, or require therapy to control symptoms, as
well as a history of radiation, surgery, or other therapy, including corticosteroids, to control
symptoms from brain metastases within 2 months (60 days) before months of Cycle 1, Day 1

Cardiopulmonary Function
5. History of symptomatic CHF or serious cardiac arrhythmia requiring treatment

6. History of myocardial infarction or unstable angina within 6 months of Cycle 1, Day 1
7. Current dyspnea at rest due to complications of advanced malignancy or requirement for
continuous oxygen therapy
General Criteria
8. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular,

pulmonary, or metabolic disease)
9. Pregnancy or lactation
10. Currently known active infection with HIV, hepatitis B virus, or hepatitis C virus
11. History of intolerance (such as Grade 3−4 infusion reaction) to trastuzumab
12. Assessed by the investigator to be unable or unwilling to comply with the requirements of the
protocol
SECTION 4.2: Method of Treatment Assignment and Blinding

After written informed consent has been obtained and eligibility has been established
and approved, the study site will obtain the patient’s randomization number and
treatment assignment from the IVRS. Patients should receive their first dose of study
treatment the day of randomization if possible, but no later than 5 business days after
randomization. Patients will be randomized in a 1:1 ratio by a hierarchical randomization
scheme to one of the two treatment arms (trastuzumab emtansine or lapatinib and
capecitabine) through use of the IVRS.
Randomization will be stratified by the following criteria:
• World region (United States, Western Europe, Other)

• Prior chemotherapy regimens for unresectable, locally advanced or metastatic
disease (0−1, > 1)
• Visceral versus non-visceral disease
If an analysis of OS demonstrates a statistically significant benefit in favor of
trastuzumab emtansine, at that time patients randomized to the control arm may be
allowed to cross over to receive trastuzumab emtansine.
SECTION 4.3.1.2: Trastuzumab Emtansine Dosage and Administration

Trastuzumab emtansine will be given at a dose of 3.6 mg/kg IV every 21 days (unless
dose reduction and/or dose delays are required) until study drug discontinuation.
The total dose will depend on the patient’s weight on Day 1 (or up to 3 days before) of
each cycle. The dose administered at the previous cycle may be used at subsequent
cycles. However, in cases where there is a ≥ 10% relative change in weight from the
weight used to calculate the dose, the trastuzumab emtansine dose must be calculated
based on the current weight. The calculated total dose may be rounded to the nearest
milligram.
The initial dose will be administered over 90 minutes (± 10 minutes). Infusions may be
slowed or interrupted for patients experiencing infusion-associated symptoms.
Vital signs must be assessed pre-dose and post-dose. Following the initial dose,
patients will be observed for at least 90 minutes for fever, chills, or other
infusion-associated symptoms. If prior infusions were well tolerated (without any signs
or symptoms of infusion reactions), subsequent doses of trastuzumab emtansine may be
administered over 30 minutes (± 10 minutes), with a minimum 30-minute observation
period after infusion. Local health authority guidelines must be followed with regard to
further observation and monitoring, if applicable. Please refer to the
TDM4370g/BO21977 Study Pharmacy Binder or the most recent version of the
Trastuzumab Emtansine Investigator’s Brochure for the procedures for the preparation
and administration of trastuzumab emtansine.
SECTION 4.3.1.3.2: Dose Modification for Hepatotoxicity

Regardless of dose level, trastuzumab emtansine must be permanently discontinued in
patients with ALT > 3 × ULN and a subsequent increase of total bilirubin to > 2 × ULN
within 21 days. All relevant hepatic laboratory tests performed (including AST, ALT,
total bilirubin, alkaline phosphatase, PTT, INR, and albumin) will be entered into the
clinical database.
Regardless of dose level, for patients with AST > 3 × ULN (without ALT > 3 × ULN) and a
subsequent increase in total bilirubin to > 2 × ULN within 21 days, treatment with
trastuzumab emtansine may be continued with one dose level reduction after recovery
of AST to ≤ 2.5 × ULN and total bilirubin to ≤ 1.5 × ULN only after consultation with
the Medical Monitor. Please see Table 1 for instructions pertaining to dose reduction.
All relevant hepatic laboratory tests performed (including AST, ALT, total bilirubin,
alkaline phosphatase, PTT, INR, and albumin) will be entered into the clinical database.
Patients receiving trastuzumab emtansine at 3.6 mg/kg who experience a Grade 3 or 4

transaminase elevation and/or a Grade ≥ 2 total bilirubin elevation may, after adequate
recovery to Grade ≤ 2 (transaminase levels) and/or Grade ≤ 1 (total bilirubin level) or
baseline, continue treatment with T-DM1 at a dose of 3.0 mg/kg. Patients at the 3.0
mg/kg dose level who experience a Grade 3 or 4 transaminase elevation and/or a Grade
≥ 2 total bilirubin elevation may, after adequate recovery to Grade ≤ 2 (transaminase
levels) and/or Grade ≤ 1 (total bilirubin level) or baseline, continue treatment with
trastuzumab emtansine at a dose of 2.4 mg/kg. Patients at the 2.4 mg/kg dose level
who experience a Grade 3 or 4 transaminase elevation and/or a Grade ≥ 2 total bilirubin
elevation will be discontinued from study treatment. A dose delay of up to 42 days from
the patient’s last received dose is permitted.

SECTION 4.5: Study Assessment
If the timing of a protocol-mandated procedure coincides with a holiday and/or weekend that
precludes the procedure within the allotted window, the procedure should be performed on the
nearest following date. Visits are based on a 21-day cycle. In the control arm, the cycle is
defined by the start of capecitabine dosing. If a patient requires a delay in treatment on the
control arm (beyond Day 21), the restart of capecitabine will be Day 1 of the next cycle.
Study assessments are outlined in this section. Appendices A-1 and A-2 contain a
study flowchart for randomized patients and a flowchart of blood sample collection for
central laboratory assessments, respectively. Appendix A-3 contains a study
flowchart for control patients who cross over to receive trastuzumab emtansine. and in
Appendix A-1 (Study Flowchart).
SECTION 4.5.2.1: Screening Assessments for Control Patients Who Cross

over to Receive Trastuzumab Emtansine
Patients randomized to the control arm may have the option to cross over to receive trastuzumab
emtansine (see Section 3.1). These patients will be required to meet the eligibility criteria
described in Section 4.1.4; exceptions may be discussed with the Medical Monitor. Cross-over
patients will undergo the following assessments and procedures within 30 days prior to receiving
their first dose of trastuzumab emtansine on Day 1 of Cycle 1:
• Medical history
• Complete physical examination
• Weight
• Vital signs (blood pressure, pulse, temperature)
• ECOG performance status (see Appendix E)
• Concomitant medications
Record concomitant medications used within 14 days prior to the Cycle 1, Day 1
dose and record investigational and standard anti-cancer therapies used within 21 days
prior to the Cycle 1, Day 1 dose.
• Adverse events (see Section 5.1 for further details)
Prior to initiation of study medication, only serious adverse events considered to be
related to protocol-mandated procedures will be collected.
• 12-lead ECG
One set of all ECG tracings should be printed and kept with the patient’s record.
• ECHO or MUGA scan (ECHO is strongly preferred because of the anticipated
global Tc-99m shortage)
• Isotope bone scan and/or skeletal X-rays
Because of the anticipated Tc-99m shortage, skeletal X-rays should be obtained in
addition to an isotope bone scan. Skeletal X-rays should include areas of the body that
are not included by other radiographic modalities (CT scans of the chest, abdomen, and

pelvis) to accurately assess the existence of relevant non-target lesions (bony lesions).
Skeletal X-rays should also be performed to assess any suspicious bone lesions within
the appendicular skeleton if the screening CT scans of the chest, abdomen, and pelvis
warrant further evaluation.
• Tumor assessment (CT scans of the chest, abdomen, and pelvis with IV and oral
contrast; see Section 4.5.1 for additional details)
• CT or MRI scan of the brain
• Local laboratory assessments
CBC with platelet count and 3-part differential (hemoglobin, hematocrit, platelet count,
red blood cells, white blood cells; differentials: lymphocytes, monocytes, and
granulocytes)
Serum chemistries (sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine,
calcium, phosphorus, total and direct bilirubin, total protein, albumin, ALT, AST,
LDH, and ALP)
INR and aPTT
Serum pregnancy test (for women of childbearing potential, including premenopausal
women who have had a tubal ligation)
Must be performed within 7 days prior to the Cycle 1, Day 1 dose.
SECTION 4.5.4.2: Cycle 1, Day 8 ( ± 3 Days)

• Central laboratory assessments for patients receiving trastuzumab emtansine who
are participating in the PK sampling (see Appendix A-2 and the Central
Laboratory Manual)
• Assess capecitabine and lapatinib compliance with use of diary cards
• Local laboratory assessments: Day 8 of Cycles 1−4 and then optionally for
subsequent cycles
In the event of a Grade 3 or 4 toxicity (per CTCAE version 3.0),
pertinent laboratory assessments should be repeated at the Investigator’s
discretion until recovery to Grade 2 or less.
CBC with platelet count and 3-part differential (includes hemoglobin, hematocrit,
platelet count, red blood cells, white blood cells; differentials: lymphocytes,
monocytes, and granulocytes)
Serum chemistries (AST, ALT, and total bilirubin)
Patients on capecitabine who are receiving coumarin-derivative anticoagulant
therapy such as warfarin or phenprocoumen should have their PT or
INR monitored weekly.
SECTION 4.5.4.3: Cycle 1, Day 15 ( ± 3 Days)

Laboratory Manual)

subsequent cycles
therapy such as warfarin or phenprocoumen should have their PT or INR
monitored weekly.
SECTION 4.5.4.4: Cycle 2-34 + , Day 1 ( ± 3 Days)

• Limited physical examination
• Weight
• Adverse events
• Pre-dose (within 72 hours of visit) local laboratory assessments
All results except for alkaline phosphatase and LDH must be reviewed by
Principal Investigator or designee prior to study drug administration/distribution.
CBC with platelet count and 3-part differential (hemoglobin, hematocrit,
Serum chemistries (BUN, creatinine, total bilirubin, ALP, LDH, AST, and
ALT)
Urine pregnancy test (every third cycle, for women of childbearing potential;
a positive urine test must be confirmed with a serum test)
• FACT-B (see Appendix C)
For female patients only. Administer on Day 1 of Cycles 1, 3, 5, 7, 9, and every
two cycles thereafter. Administer prior to any other study procedure and
discussion of any test results
• DAS (see Appendix D)
Administer prior to any other study procedure and discussion of any test results.
• Central laboratory assessments for patients receiving trastuzumab emtansine
(see Appendix A-2 and the Central Laboratory Manual)
• Assessment of patient hospitalizations and/or hospital visits

• Study drug administration/distribution (see Section 4.3)
For patients assigned to the trastuzumab emtansine arm, take vital signs before
and after the trastuzumab emtansine infusion. This trastuzumab emtansine
infusion may be administered over approximately 30 minutes if the first infusion
was well tolerated. Subsequent infusions may continue to be administered over
approximately 30 minutes if the previous infusion was well tolerated. Monitor
patients for a minimum of 30 minutes in the absence of infusion-related events
at previous infusions.

Laboratory Manual)
subsequent cycles
therapy such as warfarin or phenprocoumen, should have their PT or INR
monitored weekly.
Laboratory Manual)
subsequent cycle
therapy such as warfarin or phenprocoumen, should have their PT or INR
monitored weekly.

SECTION 4.5.4.2: Weeks 6, 12, and Every 6 Weeks Thereafter ( ± 5 Days)
• Prior to the final PFS analysis, tumor assessments were performed according to the
following schedule:
Every 6 weeks (i.e., Weeks 6, 12, 18, 24, 30, 36, 42, 48, etc.) until disease
progression ( ± 5 days) and one additional assessment 6 weeks after disease
progression ( ± 7 days) regardless of delay in dosing
Visit date were always to be based on randomization or Cycle 1,
Day 1 regardless of delay in dosing.
Sites were instructed to submit all radiographic images to a central reading
facility within 2 weeks of the patient visit (please see the IRC Manual for
shipping details).
• After the final PFS analysis, the frequency, method, and evaluation criteria of
tumor assessments will be according to routine clinical practice per investigator.
It is recommended that the investigator continue using modified RECIST in tumor
assessments and for patient care decisions. The IRC will discontinue the review of
tumor assessment data following the final PFS analysis.
Refer to Section 4.5.1 for additional details.
SECTION 4.5.6: Follow-Up Assessments after Study Drug Completion

Visit/Survival Follow-Up
After the Study Drug Completion Visit, ongoing adverse events related to study
treatment or participation should be followed until the event has resolved to baseline
grade, the event is assessed by the investigator as stable, the patient is lost to follow-up,
the patient withdraws consent, or when it has been determined that the study treatment
or participation is not the cause of the adverse event.
The occurrence of serious adverse events will be collected until 30 days after the last
dose of study treatment. Thereafter, only serious adverse events felt by the investigator
to be related to the prior study treatment will be collected.
Patients who are discontinued from study treatment for any reason because of disease
progression will complete the Study Drug Completion Visit approximately 30 days after
the last dose of study treatment.
and return for one additional tumor assessment visit and complete the FACT-B
approximately 6 weeks after disease progression. After the Study Drug Completion Visit,
the patient will be followed for survival every 3 months until study closure. In addition,
the FACT-B will be completed according to the same schedule as survival follow-up.
Patients who are discontinued for reasons other than disease progression will complete
the Study Drug Completion Visit approximately 30 days after the last dose of study
treatment. After the Study Drug Completion Visit, the patient will be followed for survival
every 3 months until study closure. Meanwhile, these patients will continue to undergo

tumor assessments, have concomitant medications collected (anti-cancer therapies
only), and complete the FACT-B approximately every 6 weeks until 6 weeks after
disease progression. After disease progression, the FACT-B will also be completed

should be completed every two treatment cycles until 6 weeks after treatment
discontinuation for any reason disease progression; for patients who discontinue study
treatment for reasons other than disease progression, the FACT-B assessment should
be performed every two treatment cycles until treatment discontinuation, and at the
same time of tumor assessments thereafter, until 6 weeks after disease progression.
After treatment discontinuation, disease progression, the FACT-B assessment will be
performed according to the same schedule as survival follow-up. Completion of the
FACT-B is not required of patients who cross over form the control arm to receive trastuzumab
emtansine.
SECTION 4.8.6: HER2 Confirmatory Testing

HER2 gene amplification will be assessed on all archival tumor material with use of
HER2 FISH kit (DAKO pharmDx™) and select samples will be subject to HER2 gene
amplification using an FDA-approved HER2 FISH kit (e.g., Abbott Vysis PathVysion®
HER-2 DNA Probe Kit or DAKO HER2 FISH pharmDx™ Kit). Testing for HER2
gene amplification will be performed according to the manufacturer’s instructions. In
brief, tissue sections will be heated in formamide to denature the DNA. Dual-color DNA
probes for HER2 (red) and CEP17 (green) will be applied to the slide for hybridization.
The slides will then be washed to remove unbound probe. The average number of
HER2 and CEP17 copies per cell will be determined by counting signals in
approximately 20 tumor nuclei. The ratio of HER2 to CEP17 is then calculated. If the
ratio is ≥ 2.0, the sample is considered amplified.
SECTION 4.9.10: Interim Analysis

Prior to final analysis of PFS, aAn independent DMC will monitor monitored
accumulating safety data every 6 months. In addition, data on serious adverse events
will be were monitored by the DMC at least once every 3 months. An independent CRC
will review reviewed all potential cases of left ventricular systolic dysfunction prior to
each semi-annual DMC review and will report reported their findings to the DMC until
the final PFS analysis. Additional details are will be provided in the DMC and
CRC Charters.

There will be is no interim analysis of PFS. One An interim analysis of OS will be
conductedis planned to be , atconducted at the same time as the final analysis of PFS.
The final analysis of OS will be performed when 632 deaths have occurred. At the
interim analysis, OS will be tested at the significance level determined using the Lan-
DeMets alpha spending function with an O’Brien-Fleming boundary, so that the overall
two-sided Type I error rate will be maintained at the 5% level. The final analysis of
OS will be performed when 632 deaths have occurred. Additional interim analyses of
OS will be performed with the appropriate control of the Type I error rate using the
same alpha spending function specified above (additional details to those interim
analyses will be outlined in the Statistical Analysis Plan). If any interim analysis of
OS meets the criteria for statistical significance, the co-primary endpoint of OS will be
considered met at that interim and the final analysis will be considered descriptive only.
SECTION 5.1.4: Protocol-Defined Events of Special Interest/Non-Serious

Expedited Adverse Events
The following events are events of special interest for patients randomized to the
trastuzumab emtansine arm and will need to be reported to the Sponsors expeditiously
(see Section 5.4 for reporting instructions), irrespective of regulatory seriousness criteria
or causality:
o Symptomatic CHF (left ventricular systolic dysfunction Grade ≥ 3)

o Asymptomatic declines in LVEF that lead to permanent discontinuation of study drug:
a confirmed LVEF of < 40% or an LVEF of < 45% with a ≥ 10% points change from
baseline that is confirmed.
• Any significant bleeding events associated with thrombocytopenia that require a
blood transfusion
• Potential drug-induced liver injury

Any potential case of drug-induced liver injury as assessed by laboratory
criteria for Hy’s Law will be considered as a protocol-defined event of special
interest and will need to be reported to the Sponsor expeditiously. The
following laboratory abnormalities define potential Hy’s Law cases:
AST or ALT elevations that are > 3 × the ULN with
bilirubin > 2 × the ULN, except in patients with documented Gilbert syndrome
SECTION 5.1.5: Pregnancy and Contraception

ICH M3 guidance requires precautions to be taken to minimize risk to fetus or embryo
when including women of childbearing potential in clinical studies. These precautions
include the use of highly effective contraceptive measures, excluding pregnancy at
baseline (serum test) and continued pregnancy monitoring.

Trastuzumab, a component of trastuzumab emtansine, can cause fetal harm when
administered to a pregnant woman; postmarketing case reports indicate that its use
during pregnancy increases the risk for oligohydramnios during the second and third
trimester. Trastuzumab has also been associated with fetal pulmonary hypoplasia,
skeletal abnormalities, and neonatal death (see the Herceptin ® Package Insert).
There are no clinical studies of trastuzumab in pregnant women. IgGs are known to
cross the placental barrier. There are no adequate and well-controlled studies of
capecitabine or lapatinib in pregnant women. Capecitabine and lapatinib are listed as
drugs that have positive evidence of fetal risk based on adverse reaction data from
investigational or marketing experience or studies in humans, but potential benefits
may warrant use of the drug in pregnant women despite potential risks (in the United
States, Pregnancy Category D) in the Xeloda ® and Tykerb ®/Tyverb ® Product
Inserts/national prescribing information. Therefore, trastuzumab emtansine,
capecitabine, or lapatinib should not be used during pregnancy. Women of childbearing
potential (who have not undergone surgical sterilization with a hysterectomy and/or
bilateral oophorectomy, and are not postmenopausal, as defined as ≥ 12 months of
amenorrhea.) and men with partners of childbearing potential must agree to use a
highly effective non-hormonal form of contraception or two effective forms of
non-hormonal contraception by the patient and/or partner.
Highly Effective Birth Control

Methods of birth control that result in a low failure rate (i.e., < 1% per year)
when used consistently and correctly are considered highly effective forms of
contraception. The use of the following non-hormonal methods of contraception is
acceptable:
• True abstinence, when this is the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, and symptothermal post-ovulation
methods) and withdrawal are not acceptable methods of contraception.
• Male sterilization (with appropriate post-vasectomy documentation of the absence
of sperm in the ejaculate). For female patients, the vasectomized male partner
should be the sole partner.
Effective Birth Control
Alternatively, use of two of the following forms of contraception is acceptable:
• Placement of intrauterine device (IUD)
Consideration should be given to the type of device being used, as there are
higher failure rates for certain types (e.g., steel or copper wire).
• Condom with spermicidal foam/gel/film/cream/suppository
• Occlusive cap (diaphragm or cervical/vault caps) with spermicidal

The use of barrier contraceptives should always be supplemented with the use of a
spermicide. The following should be noted:
• Failure rates indicate that, when used alone, the diaphragm and condom are not
highly effective forms of contraception. Therefore the use of additional spermicides
does confer additional theoretical contraceptive protection.
• However, spermicides alone are ineffective at preventing pregnancy when the whole
ejaculate is spilled. Therefore, spermicides are not a barrier method of
contraception and should not be used alone.
It should be noted that two forms of effective contraception are required. A double
barrier method, defined as condom AND occlusive cap (diaphragm or cervical/vault
caps) with spermicidal foam/gel/film/cream/suppository, is acceptable.
Male Patients
For male patients with a female partner of childbearing potential, cooperation of female
partner is required (i.e., use of two forms of contraception as stated above) during the
study and for ≥ 6 months following the last dose of study treatment. Experimental
studies have reported that IgGs are present in both the pre-ejaculate and the seminal
plasma (Moldoveanu et al. 2005). To date, there have been no clinical studies to assess
the IgG profile in the pre-ejaculate and seminal plasma in male patients receiving
trastuzumab or trastuzumab emtansine. Therefore, as precaution male patients with
female partners of childbearing potential are also required to use highly effective form of
contraception or use two forms of contraception as outlined above. Similarly, vaginal
absorption of trastuzumab emtansine is unknown and therefore male patients with
pregnant partners are required to use condoms for the duration of the pregnancy, and
then revert to contraceptive methods as outlined above. This is to ensure that the fetus
is not exposed to the study medication through vaginal absorption.
Duration of Contraception
Based on PK considerations, contraception must continue for the duration of study
treatment and for at least 6 months after the last dose of study treatment.
Pregnancy and Nursing

A female patient who becomes pregnant during the study must be instructed to stop
taking the study medication and immediately inform the investigator. The investigator
should report all pregnancies within 24 hours to the Sponsor including the partners of
male patients. The investigator should counsel the patient/partner, and discuss the
risks of continuing with the pregnancy and the possible effects on the fetus.
Monitoring of the patient/partner should continue until conclusion of the pregnancy.
Pregnancies occurring up to 6 months after the completion of study medication must
also be reported to the investigator. Please refer to Sections 5.3.1.9 and 5.4.2 for
reporting procedures.

It is not known whether trastuzumab or trastuzumab emtansine are excreted in human
milk. Maternal IgG is excreted in milk and any of these monoclonal antibodies could
harm infant growth and development; therefore, women should be advised to
discontinue nursing during trastuzumab emtansine therapy and not to breastfeed for at
least 6 months following the last dose of either study drug.
In addition, sperm or blood donation should not occur for at least 6 months after the
last dose of study treatment.
APPENDIX A-1: Study Flowchart for Patients Receiving Randomized

Treatment
Study Flowchart was modified to indicate elimination of the Day 8 and Day 15
assessments.
APPENDIX A-3: Study Flowchart for Control Patients Who Cross over to
Receive Trastuzumab Emtansine
Appendix A-3 has been added to capture the assessments for cross-over patients.
APPENDIX G: Procedures for the Preparation and Administration of

Trastuzumab−MCC-DM1
Appendix G has been deleted and the relevant text was included in Section 4.3.1.2.
Subsequent appendices have been renumbered accordingly.
SAMPLE INFORMED CONSENT FORM

The sample Informed Consent Form has been revised to reflect the changes to the
protocol.

TABLE OF CONTENTS
1. BACKGROUND .......................................................................................... 44
1.1 HER2-Positive Metastatic Breast Cancer .............................. 44
1.2 Trastuzumab emtansine ........................................................ 45
1.2.1 Study TDM3569g ................................................................... 45
1.2.2 Study TDM4258g ................................................................... 46
1.2.3 Study TDM4374g ................................................................... 47
1.2.4 Study TDM4450g ................................................................... 48
1.3 Rationale for This Study ........................................................ 48
2. OBJECTIVES .............................................................................................. 49
2.1 Primary Objectives ................................................................ 49
2.2 Secondary Objectives ............................................................ 49
2.3 Exploratory Objectives ........................................................... 50
3. STUDY DESIGN ......................................................................................... 51

3.1 Description of the Study......................................................... 51
3.2 Rationale for Study Design .................................................... 53
3.2.1 Rationale for Patient Population ............................................ 53
3.2.2 Rationale for Dose and Regimen ........................................... 53
3.2.3 Rationale for Continued Dosing ............................................. 54
3.2.4 Rationale for Efficacy Assessments ...................................... 54
3.2.5 Rationale for Exploratory Diagnostic Studies......................... 54
3.2.6 Rationale for Pharmacogenomic Studies............................... 55
3.2.7 Rationale for the Pharmacokinetic Assessment
Plan (for the Trastuzumab Emtansine Arm)........................... 56
3.2.8 Rationale for Pharmacoeconomic Endpoints and
the Patient-Reported Outcomes Assessment
Plan ....................................................................................... 56
3.3 Outcome Measures ............................................................... 57
3.3.1 Primary Outcome Measures .................................................. 57
3.3.2 Secondary Outcome Measures ............................................. 57
3.3.3 Exploratory Outcome Measures ............................................ 59
3.4 Safety Plan ............................................................................ 59
3.4.1 Risks Associated with Study Treatment ...........................................59
3.4.1.1 Risks Associated with Trastuzumab Emtansine ....................... 59
3.4.1.2 Risks Associated with Capecitabine ..................................................61
3.4.1.3 Risks Associated with Lapatinib........................................................61
3.4.2 Trastuzumab Emtansine Safety Plan................................................61
3.4.2.1 Cardiotoxicity ......................................................................... 61
3.4.2.2 Hematologic Toxicity ............................................................. 62
3.4.2.3 Hepatotoxicity ........................................................................ 63
3.4.2.4 Infusion Reactions ................................................................. 63
3.4.2.5 Neurotoxicity .......................................................................... 63
3.4.3 Control Arm Safety Plan .......................................................... 63
3.5 Study Patients and Analysis Groups ..................................... 63
3.6 Control Groups ...................................................................... 63
3.7 Minimization of Bias ............................................................... 64
3.8 Ethical Considerations ........................................................... 64
3.9 Administrative Structure......................................................... 64
3.10 Compliance with Laws and Regulations ................................ 65
4. MATERIALS AND METHODS .................................................................... 65

4.1 Patients.................................................................................. 65
4.1.1 Patient Selection .................................................................... 65
4.1.2 Inclusion Criteria .................................................................... 65
4.1.2.1 Disease-Specific Criteria ....................................................... 66
4.1.2.2 General Criteria ..................................................................... 66
4.1.3 Exclusion Criteria ................................................................... 67
4.1.3.1 Cancer-Related Criteria ......................................................... 67
4.1.3.2 Cardiopulmonary Function..................................................... 68
4.1.3.3 General Criteria ..................................................................... 68
4.1.4 Eligibility Criteria for Control Arm Patients Who
Cross Over to Receive Trastuzumab Emtansine ...............................69
4.1.4.1 Inclusion Criteria for Cross-Over Patients .......................................69
4.1.4.2 Exclusion Criteria for Cross-Over Patients ......................................70
4.2 Method of Treatment Assignment and Blinding ..................... 70
4.3 Study Treatment .................................................................... 71
4.3.1 Trastuzumab Emtansine Arm ................................................ 71

4.3.1.1 Trastuzumab Emtansine Formulation,
Preparation, and Storage....................................................... 71
4.3.1.2 Trastuzumab Emtansine Dosage and
Administration ........................................................................ 71
4.3.1.3 Trastuzumab Emtansine Dose Modification .......................... 72
4.3.1.3.1 Dose Modification for Hematologic Toxicity ........................... 73
4.3.1.3.2 Dose Modification for Hepatotoxicity ..................................... 74
4.3.1.3.3 Dose Modification for Neurotoxicity ....................................... 74
4.3.1.3.4 Dose Modification for Cardiotoxicity ...................................... 74
4.3.2 Control Arm Drugs ................................................................. 75
4.3.2.1 Capecitabine.......................................................................... 75
4.3.2.1.1 Capecitabine Formulation ...................................................... 75
4.3.2.1.2 Capecitabine Dosage, Administration, and
Storage .................................................................................. 76
4.3.2.1.3 Capecitabine Dosage Modification ........................................ 76
4.3.2.2 Lapatinib ................................................................................ 77
4.3.2.2.1 Lapatinib Formulation ............................................................ 77
4.3.2.2.2 Lapatinib Dosage, Administration, and Storage..................... 78
4.3.2.2.3 Lapatinib Dosage Modification............................................... 78
4.3.2.3 Other Toxicities ...................................................................... 78
4.4 Concomitant and Excluded Therapies ................................... 79
4.4.1 Effects of Other Medicinal Products on
Capecitabine.......................................................................... 79
4.4.2 Effects of Other Medicinal Products on Lapatinib .................. 80
4.5 Study Assessments ............................................................... 81
4.5.1 Tumor Assessments .............................................................. 82
4.5.2 Screening and Pretreatment Assessments............................ 83
4.5.2.1 Screening Assessments for Control Patients Who
Cross over to Receive Trastuzumab Emtansine ................................85
4.5.3 Randomization ....................................................................... 86
4.5.4 Assessments during Treatment ............................................. 87
4.5.4.1 Cycles 1−34+, Day 1 (study treatment is to begin
≤ 5 days following randomization) ......................................... 87
4.5.4.2 Weeks 6, 12, and Every 6 Weeks Thereafter (± 5 Days)
...........................................................................................................88

4.5.4.3 Weeks 6, 12, and every 12 Weeks Thereafter
(± 5 days) until the Study Drug Completion Visit ................... 89
4.5.5 Study Drug Completion Visit .................................................. 89
4.5.6 Follow-Up Assessments after Study Drug
Completion Visit/Survival Follow-Up ...................................... 89
4.6 Patient Discontinuation .......................................................... 90
4.7 Study Discontinuation ............................................................ 90
4.8 Assay Methods ...................................................................... 91
4.8.1 Trastuzumab Emtansine ELISA ............................................. 91
4.8.2 Total Trastuzumab ELISA...................................................... 91
4.8.3 DM1 LC-MS/MS Assay .......................................................... 91
4.8.4 Anti-Trastuzumab Emtansine Antibody ELISA ...................... 91
4.8.5 HER2/NEU Serum Extracellular Domain ............................... 91
4.8.6 HER2 Confirmatory Testing ................................................... 91
4.8.7 Pharmacogenomic Studies .................................................... 92
4.8.8 Tissue Samples ..................................................................... 92
4.9 Statistical Methods ................................................................ 93
4.9.1 Analysis of the Conduct of the Study ..................................... 93
4.9.2 Analysis of Treatment Group Comparability .......................... 93
4.9.3 Efficacy Analyses .................................................................. 93
4.9.3.1 Primary Efficacy Endpoint...................................................... 93
4.9.3.2 Secondary Efficacy Endpoints ............................................... 95
4.9.3.2.1 Progression-Free Survival Based on Investigator
Tumor Assessment ................................................................ 95
4.9.3.2.2 Objective Response .............................................................. 95
4.9.3.2.3 Duration of Objective Response ............................................ 96
4.9.3.2.4 Clinical Benefit Rate .............................................................. 96
4.9.3.2.5 Time to Treatment Failure ..................................................... 96
4.9.4 Safety Analysis ...................................................................... 96
4.9.4.1 Study Drug Exposure............................................................. 97
4.9.4.2 Adverse Events ..................................................................... 97
4.9.4.3 Laboratory Data ..................................................................... 97
4.9.4.4 Left Ventricular Ejection Fraction ........................................... 97

4.9.5 Pharmacokinetic and Pharmacodynamic
Analyses ................................................................................ 97
4.9.6 Pharmacoeconomic and Patient-Reported
Outcomes Analyses ............................................................... 98
4.9.6.1 Time to Symptom Progression .............................................. 98
4.9.6.2 Pharmacoeconomic Endpoint ................................................ 98
4.9.7 Exploratory Analyses ............................................................. 98
4.9.7.1 Patient Self-Reported Diarrhea .............................................. 98
4.9.7.2 Proportion of Patients with a Significant
Improvement in Symptoms .................................................... 99
4.9.7.3 Concordance between IRC- and
Investigator-Assessed Tumor Assessments .......................... 99
4.9.8 Handling of Missing Data ....................................................... 99
4.9.9 Determination of Sample Size ............................................... 99
4.9.10 Interim Analysis ................................................................... 100
4.10 Data Quality Assurance ....................................................... 101
5. ASSESSMENT OF SAFETY ..................................................................... 102

5.1 Safety Parameters and Definitions ...................................... 102
5.1.1 Progression of the Underlying Malignancy .......................... 102
5.1.2 Adverse Event ..................................................................... 103
5.1.3 Serious Adverse Event ........................................................ 103
5.1.4 Protocol-Defined Events of Special Interest/Non-
Serious Expedited Adverse Events ..................................... 104
5.1.5 Pregnancy and Contraception .........................................................104
5.1.6 Diarrhea Adverse Events ..................................................... 106
5.2 Methods and Timing for capturing and Assessing
Safety Parameters ............................................................... 107
5.2.1 Adverse Event Reporting Period ......................................... 107
5.2.2 Eliciting Adverse Events ...................................................... 108
5.2.3 Assessment of Severity and Causality of Adverse
Events.................................................................................. 108
5.3 Procedures for Recording Adverse Events .......................... 110
5.3.1 Recording Adverse Events on the Electronic
Case Report Form ............................................................... 110
5.3.1.1 Diagnosis versus Signs and Symptoms............................... 110

5.3.1.2 Adverse Events Occurring Secondary to Other
Events.................................................................................. 110
5.3.1.3 Persistent or Recurrent Adverse Events .............................. 110
5.3.1.4 Abnormal Laboratory Values ............................................... 111
5.3.1.5 Deaths ................................................................................. 111
5.3.1.6 Preexisting Medical Conditions ............................................ 111
5.3.1.7 Progression of Breast Cancer.............................................. 112
5.3.1.8 Hospitalization ..................................................................... 112
5.3.1.9 Pregnancy ........................................................................... 112
5.4 Reporting Requirements for Serious
Adverse Events and Protocol-Defined Events of
Special Interest .................................................................... 112
5.4.1 Expedited Reporting Requirements ..................................... 112
5.4.2 Reporting Requirements for All Serious Adverse
Events.................................................................................. 113
5.4.2.1 If the EDC System Is Unavailable (U.S. Sites) .................... 113
5.4.2.2 If the EDC System Is Unavailable (Ex-U.S. Sites) ............... 114
5.5 Type and Duration of Follow-Up of Patients after
Adverse Events ................................................................... 114
5.6 Post-Study Adverse Events ................................................. 114
6. INVESTIGATOR REQUIREMENTS.......................................................... 115

6.1 Study Initiation ..................................................................... 115
6.2 Study Completion ................................................................ 116
6.3 Informed Consent Form ....................................................... 116
6.4 Communication with the Institutional Review
Board or Ethics Committee .................................................. 118
6.5 Study Monitoring Requirements .......................................... 118
6.6 Electronic Case Report Forms............................................. 118
6.7 Source Data Documentation................................................ 119
6.8 Use of Computerized Systems ............................................ 119
6.9 Study Medication Accountability .......................................... 120
6.10 Disclosure of Data ............................................................... 120
6.11 Retention of Records ........................................................... 120
7. REFERENCES ......................................................................................... 122

LIST OF TABLES
Table 1 Dose-Reduction for Trastuzumab Emtansine ............................. 73

Table 2 Summary of Planned Overall Survival Analyses Assuming
One Interim Analysis .................................................................. 101
Table 3 NCI CTCAE, Version 3.0, Grading Scale for Diarrhea .............. 107
Table 4 Adverse Event Grading (Severity) Scale ................................... 109
Table 5 Causal Attribution Guidance ..................................................... 109
LIST OF FIGURES
Figure 1 Algorithm for Continuation and Discontinuation of

Trastuzumab Emtansine Based on LVEF Assessments in
Patients ....................................................................................... 62
Figure 2 Adverse Event Collection .......................................................... 108

LIST OF APPENDICES
APPENDIX A-1 Study Flowchart for Patients Receiving Randomized Treatment .. 124
APPENDIX A-2 Exploratory Central Laboratory Blood Samples ..................... 128
APPENDIX A-3 Study Flowchart for Control Patients Who Cross over to Receive
Trastuzumab Emtansine .......................................................................129
APPENDIX B Modified Response Evaluation Criteria in Solid Tumors
(RECIST) .................................................................................. 132
APPENDIX C Functional Assessment of Cancer Therapy−Breast
Questionnaire............................................................................ 138
APPENDIX D Diarrhea Assessment Scale ...................................................... 141
APPENDIX E Eastern Cooperative Oncology Group Performance Status
Scale ......................................................................................... 142
APPENDIX F Child-Pugh Classification of the Severity of Liver Disease ........ 143
APPENDIX G New York Health Association Classification ............................. 144
APPENDIX H Capecitabine Dose Calculations According to Body Surface
Area .......................................................................................... 145

PROTOCOL AMENDMENT ACCEPTANCE FORM
THERAPY
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature Date
Please return a copy of the form to the Sponsors or their designee. Contact
details will be provided to the investigator prior to the study start. Please retain
the original for your study files.

PROTOCOL SYNOPSIS
TITLE: A RANDOMIZED, MULTICENTER, PHASE III OPEN-LABEL

STUDY OF THE EFFICACY AND SAFETY OF
TRASTUZUMAB-MCC-DM1 VS.
CAPECITABINE + LAPATINIB IN PATIENTS WITH
HER2-POSITIVE LOCALLY ADVANCED OR METASTATIC
BREAST CANCER WHO HAVE RECEIVED PRIOR
TRASTUZUMAB-BASED THERAPY
PROTOCOL NUMBERS: Genentech, Inc. TDM4370g
F. Hoffmann-La Roche Ltd BO21977
EUDRACT NUMBER: 2008-005 713-22
STUDY DRUG: Trastuzumab emtansine (RO5304020)
PHASE: III
INDICATION: Metastatic breast cancer
IND: 71,072
SPONSORS: Genentech, Inc.
1 DNA Way
South San Francisco, CA 94080-4990 U.S.A.
Grenzacherstrasse 124
4070 Basel, Switzerland
DATE FINAL: 8 October 2008
DATES AMENDED: 19 February 2010
13 May 2010
4 October 2010
25 May 2012
Objectives
The primary objectives for this study are as follows:
• To compare the efficacy of trastuzumab emtansine versus capecitabine plus lapatinib in
patients with HER2-positive unresectable, locally advanced or metastatic breast cancer
(MBC) as measured by progression-free survival (PFS) on the basis of an independent
review of tumor assessments
patients with HER2-positive, unresectable, locally advanced breast cancer or MBC as
measured by overall survival (OS) and to assess landmark (1-year and 2-year) survival
rates within each treatment group, as appropriate
• To assess the safety of trastuzumab emtansine relative to the safety of capecitabine plus
lapatinib
• The secondary objectives for this study are as follows:
• To compare PFS between the two treatment arms on the basis of investigator review of
tumor assessments
• To compare the overall objective response rate between the two treatment arms on the
basis of both investigator and independent review of tumor assessments
• To estimate the duration of objective response within each treatment arm on the basis of
both investigator and independent review of tumor assessments

• To compare the clinical benefit rate (the proportion of patients with complete response (CR),
partial response (PR), or stable disease (SD) at 6 months after randomization) between the
two treatment arms on the basis of both investigator and independent review of tumor
assessments
• To compare time to treatment failure (TTF) between the two treatment arms
TTF is defined as the time from randomization to discontinuation of treatment for any reason,
including treatment discontinuation without disease progression or treatment toxicity,
disease progression, treatment toxicity, starting another anti-cancer agent before
documented progressive disease (PD), and death on study from any cause.
• To compare the time to symptom progression between the two treatment arms as
measured by the FACT-Breast-Trial Outcome Index (FACT-B TOI)
• To compare resource expenditure between the two treatment arms
Resource expenditure due to hospitalizations and hospital visits for reasons other than
defined study evaluations will be compared between the two treatment arms.
Study Design
This is a Phase III, randomized, multicenter, international, two-arm, open-label clinical trial
designed to compare the safety and efficacy of trastuzumab emtansine with that of
capecitabine + lapatinib for HER2-positive unresectable, locally advanced breast cancer or MBC.
A total of 980 patients will be enrolled at more than 200 sites worldwide. Eligible patients will be
randomized in a 1:1 ratio to either trastuzumab emtansine or lapatinib + capecitabine as follows:
• Trastuzumab Emtansine Arm: trastuzumab emtansine 3.6 mg/kg intravenously (IV) over
30−90 minutes on Day 1 of a 21-day cycle
• Control Arm (lapatinib + capecitabine): lapatinib 1250 mg/day orally once per day of a
21-day cycle + capecitabine 1000 mg/m2 orally twice daily on Days 1−14 of a 21-day cycle
A hierarchical dynamic randomization scheme will be used to ensure an approximately equal
sample size for the two treatment arms 1) overall; 2) by world region (United States, Western
Europe, Other); and 3) within each of the four categories defined by the following two prognostic
factors: 1) the number of prior chemotherapeutic regimens for unresectable, locally advanced
or metastatic disease (0−1 vs. > 1) and 2) visceral versus non-visceral disease.
Prior to enrollment, patients will be confirmed for having HER2-positive adenocarcinoma of the
breast by immunohistochemical (IHC) and/or fluorescence in situ hybridization (FISH) in a
central laboratory specified by the Sponsors through use of archival paraffin-embedded tumor
tissue. A patient’s HER2 status will be considered positive if the central laboratory reports
Grade 3 + staining intensity (on a scale of 0 to 3 +) by means of IHC analysis and/or gene
amplification by FISH. Patients may have either measurable (per modified Response
Evaluation Criteria in Solid Tumors [RECIST]) and/or non-measurable unresectable, locally
advanced or metastatic disease. Locally advanced disease must not be amenable to resection
or other local therapy with curative intent.
Prior to the final PFS analysis, tumor assessments were conducted every 6 weeks from the
date of randomization or Cycle 1 Day 1, regardless of dose delays or dose interruptions, until
6 weeks after investigator-assessed PD or until death, whichever occurred first, even if study
treatment had been discontinued as a result of patient or physician choice or unacceptable
toxicity.
assessments will be according to routine clinical practice per investigator. However, it is
recommended that RECIST be used to evaluate tumor assessments.
Sponsors).
All patients who are discontinued from study treatment will return for a Study Drug Completion
Visit approximately 30 days (± 7 days) after the last dose of study treatment.
Patients who are discontinued from study treatment for any reason will complete the Study Drug
Completion Visit approximately 30 days after the last dose of study treatment.

After the Study Drug Completion Visit, all patients (regardless of reason for discontinuation) will
be followed for survival every 3 months until death, loss to follow-up, withdrawal of consent, or
study termination by the Sponsors.
Patient-reported outcomes (PROs) as assessed by the FACT-B (female patients only) should
be completed every two treatment cycles until treatment discontinuation and at the Study
Drug Completion Visit. After treatment discontinuation for any reason, the FACT-B
assessment will be performed according to the same schedule as during survival follow-up.
An independent Data Monitoring Committee (DMC) monitored accumulating patient safety data
at least once every 6 months during the course of the study until the final PFS analysis had
been conducted. In addition, data on serious adverse events were monitored by the DMC at
least once every 3 months until the final PFS analysis had been conducted. An independent
Cardiac Review Committee (CRC) reviewed all potential cases of left ventricular systolic
dysfunction prior to each DMC review and will report their findings to the DMC until the final
PFS analysis had been conducted. An IRC evaluated tumor responses through the review of all
tumor-assessment data generated from all patients at the time of the final PFS analysis with
treatment-arm information blinded to the IRC. After the final PFS analysis, the IRC will
discontinue the review of tumor assessment data.
No interim analysis of IRC-assessed PFS is planned for this study. The final analysis of the
primary efficacy endpoint of PFS took place when approximately 508 IRC-assessed PFS events
had occurred and enrollment was completed. One interim analysis of OS is planned at the time
of the final analysis of PFS as assessed by the IRC. The final analysis of OS will be performed
when approximately 632 deaths have occurred. If the study is not terminated per DMC
recommendation or by the Sponsors for other reasons beforehand, it will be closed when
approximately 632 deaths have been reported and the final analysis of OS has been completed.
Additional interim analyses of OS will be performed with the appropriate control of the Type
I error rate using the pre-specified Lan-DeMets function with O’Brien-Fleming boundary
(additional details to be outlined in the Statistical Analysis Plan). If an analysis of OS
demonstrates a statistically significant benefit in favor of trastuzumab emtansine, the co-
primary endpoint of OS will be considered as met and at that time patients randomized to the
control arm may cross over to receive trastuzumab emtansine.
Patients who cross over to trastuzumab emtansine may remain on study treatment until
disease progression (as assessed by the investigator), unmanageable toxicity, or study
termination by Genentech and Roche (the Sponsors). All patients will be followed until
approximately 632 deaths have been reported and the final analysis of OS has been completed.
Outcome Measures
Primary Outcome Measures
The primary outcome measures for this study are as follows:
• PFS by IRC assessment, defined as the time from randomization to the first occurrence of
progression, as determined by independent review of tumor assessments through use of
modified RECIST, or death from any cause
• OS, defined as the time from randomization to death from any cause, and landmark survival
rate, defined as the survival rate estimated using the Kaplan-Meier approach at pre-defined
timepoints from randomization (e.g., 1 year or 2 years)
• Incidence, nature, and severity of adverse events
Secondary Outcome Measures
The secondary outcome measures for this study are as follows:
• PFS by investigator assessment, defined as the time from randomization to the first
occurrence of disease progression, as determined by investigator review of tumor
assessments through use of modified RECIST, or death from any cause

• Objective response (PR plus CR) as determined by both investigator and independent
review of tumor assessments with use of modified RECIST
Objective responses must be confirmed at least 28 days after initial documentation of
response.
• Duration of objective response, defined as the first occurrence of a documented objective
response until the time of disease progression, as determined by both investigator and
independent review of tumor assessments with use of modified RECIST, or death from any
cause
• Clinical benefit rate (the proportion of patients with CR, PR, or SD at 6 months after
randomization between the two treatment arms based on both investigator and independent
review of tumor assessments)
• TTF, defined as the time from randomization to discontinuation of treatment for any reason,
disease progression, treatment toxicity, starting another anti-cancer agent before
documented PD, or death from any cause
• Time to symptom progression (defined as the time from randomization to the first
documentation of a ≥ 5-point decrease from baseline in the scoring of responses) between
the two treatment arms as measured by the FACT-B TOI
The FACT-B TOI is a subset of the FACT-B and includes the Physical, Functional,
and Breast subscales.
• Estimated resources for hospitalizations and/or hospital visits that occur within 30 days of
the last dose of study treatment for reasons other than those defined by the protocol
The number of hospital visits, number of days admitted, and type of visits (emergency
department vs. inpatient care) will be collected and compared between the two arms.
The reason for admission (disease progression vs. adverse event) will also be
assessed.
Safety Plan
Overall safety will be assessed on an ongoing basis during the conduct of the study. Prior to the
final PFS analysis, an independent DMC monitored cumulative safety data at least once every
6 months during the course of the study. In addition, data on serious adverse events were
monitored by the DMC at least once every 3 months. An independent CRC reviewed all potential
cases of left ventricular systolic dysfunction prior to each semi-annual DMC review and reported
their findings to the DMC until the final PFS analysis is had been conducted. Additional details
will be provided in the DMC and CRC Charters.
The safety plan for patients in the trastuzumab emtansine treatment arm is based on nonclinical
toxicities of trastuzumab emtansine, the clinical experience with this molecule in ongoing studies,
and clinical toxicities related to its components (trastuzumab and maytansine, the parent drug of
DM1).
The safety plan for patients receiving lapatinib and capecitabine is based on the national
prescribing guidelines, emphasizing the adverse event data reported for each drug.
Study Treatment
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg IV every 21 days.
Lapatinib plus Capecitabine
The total daily dose of capecitabine is 2000 mg/m2/day (administered as two oral doses
approximately 12 hours apart) on Days 1−14 in a repeating 21-day cycle.
The dose of lapatinib is 1250 mg (5 tablets) given orally once daily on Days 1−21, continually.
Concomitant Therapy and Clinical Practice
Trastuzumab emtansine, lapatinib, and capecitabine are the investigational medicinal products
in this study. All other concomitant medications and premedication therapies are considered
non-investigational medicinal products. Concomitant therapy (non-investigational products)
includes any prescription medication, over-the-counter preparation, herbal therapy, or

radiotherapy used by a patient between the 14 days preceding randomization and the study
survival follow-up or early discontinuation visit.
Premedication for lapatinib and capecitabine is allowed according to standard practice
guidelines.
Patients who use maintenance therapy should continue their use unless otherwise indicated
(see Section 4.4). Concomitant use of erythropoiesis-stimulating agents is allowed if clinically
indicated in accordance with proper prescribing guidelines.
No premedication for the first infusion of trastuzumab emtansine is specified or expected;
any planned premedication, specifically steroids, for the first infusion must be approved by the
Medical Monitor prior to administration. Premedication for nausea and anxiety has not been
generally necessary but is allowed.
Patients who experience trastuzumab emtansine infusion–related temperature elevations of
> 38.5°C or other minor infusion-related symptoms may be treated symptomatically with
acetaminophen and/or H1- and H2-receptor antagonists (e.g., diphenhydramine, ranitidine).
Serious infusion-related events manifested by dyspnea, hypotension, wheezing, bronchospasm,
tachycardia, reduced oxygen saturation, or respiratory distress should be managed with
supportive therapies as clinically indicated according to standard clinical practice
(e.g., supplemental oxygen, β2-agonists, and corticosteroids).
Use of the following therapies is prohibited during the study prior to discontinuation of study
treatment (collectively, these will be referred to as non-protocol therapy):
• Any therapies intended for the treatment of breast cancer, whether they are approved by
national health authorities or experimental, including cytotoxic chemotherapy (other than
that specified by the protocol), immunotherapy, hormonal therapy (other than megestrol
acetate), and biologic agents (other than granulocyte colony-stimulating factor and
erythropoiesis-stimulating agents)
• Radiotherapy
Palliative radiotherapy may be permitted to treat painful bone metastases. Please
contact the Medical Monitor for approval. If the Medical Monitor cannot be reached
because of time zone differences, radiotherapy may be administered, but the Medical
Monitor should still be informed.
Patients who require the use of any of these therapies described above will be discontinued
from study treatment but will be followed for disease progression and survival. Other
medications considered necessary for the patient’s safety and well-being may be given at the
discretion of the investigator. Use of bisphosphonates (e.g., pamidronate) for control of bone
pain, treatment of bony metastases, and treatment of osteoporosis, is permitted. If required for
the treatment of symptomatic malignancy-associated hypercalcemia, tumor assessments
should be performed to document PD radiographically.
Patients randomized to the control arm who are on warfarin need to have their prothrombin time
or international normalized ratio monitored weekly.
Statistical Methods
Primary Efficacy Analysis
To adjust for multiplicity due to having two primary endpoints, a fixed-sequence hypothesis
testing procedure will be implemented. The hypothesis test for PFS will be conducted at a one-
sided alpha of 2.5%. If the PFS is statistically different between the two arms, OS will be tested
at a one-sided alpha of 2.5% to determine if the two arms have significantly different OS.
The co-primary efficacy endpoint is PFS based on independent review of tumor assessment,
defined as the time from randomization to documented IRC-assessed disease progression or
death from any cause (whichever occurs earlier).
For the analysis of PFS, data for patients without disease progression or death will be censored
at the time of the last tumor assessment (or, if no tumor assessment was performed after the
baseline visit, at the time of randomization plus 1 day). Data from patients who are lost to
follow-up will be included in the analysis as censored observations on the last date of tumor
assessment that the patient was known to be progression free.

For patients who receive non-protocol therapy (defined as any treatment the patient receives
that is intended to treat his or her MBC) prior to documented PD, the primary PFS analysis will
not censor patients at the initiation of non-protocol therapy. A sensitivity analysis of PFS
censoring patients at the last tumor assessment before the initiation of non-protocol therapy will
also be performed.
The two-sided log-rank test, stratified by world region (United States, Western Europe, Other),
number of prior chemotherapeutic regimens for unresectable, locally advanced or metastatic
disease (0−1 vs. > 1), and visceral vs. non-visceral disease will be used as the primary analysis
to compare PFS between the two treatment arms. The results from the unstratified log-rank test
and the stratified and unstratified Wilcoxon test will also be provided.
The Kaplan-Meier approach will be used to estimate median PFS for each treatment arm.
Cox proportional-hazards models, stratified by world region (United States, Western Europe,
Other), number of prior chemotherapeutic regimens for unresectable, locally advanced or
metastatic disease (0−1 vs. > 1), and visceral vs. non-visceral disease will be used to estimate
the hazard ratio (HR) and its 95% confidence interval (CI).
OS, the co-primary endpoint, is defined as the time from the date of randomization to the date of
death from any cause. Patients who are alive at the time of the analysis data cutoff will be
censored at the last date they were known to be alive. Patients with no post-baseline
information will be censored at the date of randomization plus 1 day. Methods for OS analysis
are similar to those described for the PFS endpoint, with the stratified log-rank test being the
primary analysis and sensitivity analysis using the unstratified log-rank test and the stratified
and unstratified Wilcoxon test. In addition, 1-year and 2-year survival rates and corresponding
95% CIs will be estimated using the Kaplan−Meier approach, as appropriate. The final analysis
of OS will occur after 632 deaths have occurred.
Missing Data
For the primary analysis of PFS and duration of response, data from patients who are lost to
follow-up will be included in the analysis as censored observations on the last date that the
patient is known to be progression free, defined as the date of the last tumor assessment.
When disease progression occurs after two or more consecutive missed tumor assessments,
these events will not be counted; rather, the patient will be censored at the patient’s last tumor
assessment prior to the missing assessments. If disease progression occurs after one missed
tumor assessment, the event will be counted at the respective event date.
Determination of Sample Size
There are two primary efficacy endpoints of this Phase III trial: PFS based on independent
review of tumor assessments, and OS. The fixed-sequence testing procedure described above
will be used to control the overall two-sided Type I error rate at 5% for the primary efficacy
analyses.
The sample size of the study is determined by the analysis of OS. To detect an HR of 0.8 in OS
(a 25% improvement in median OS; i.e., from 17.2 months in the control arm to 21.5 months in
the treatment arm), approximately 632 deaths will be required to achieve 80% power at a two-
sided 5% alpha level. A total of 980 patients will be enrolled into the study.
The primary efficacy analysis will be event driven, and the primary analysis of PFS will take
place when approximately 508 IRC-assessed PFS events have occurred. This provides 90%
power to detect an HR of 0.75 in PFS (a 33% improvement in median PFS; i.e., from 6.2
months in the control arm to 8.3 months in the treatment arm), with a two-sided alpha of 5%.
It is expected that 980 patients will be enrolled over approximately 35 months. Assuming a
median PFS of 6.2 months in the control arm and an HR of 0.75, the date of data cutoff for the
final analysis of PFS will be approximately 32 months from when the first patient is enrolled
(FPI). However, the final analysis of PFS will not be conducted until the last patient is enrolled.
Assuming the median OS of 17.2 months in the control arm and an HR of 0.8, the data cutoff
date for the final analysis of OS is projected to be approximately 51 months from FPI.
The sample size was estimated using EAST software.

Interim Analysis
There is no interim analysis of PFS. An interim analysis of OS is planned to be conducted at
the same time as the final analysis of PFS. Additional statistical analyses of OS will be
performed with the appropriate control of the Type I error rate using the Lan-DeMets alpha
spending function with an O’Brien-Fleming boundary as prespecified in the protocol and
statistical analysis plan (SAP) (additional details to be outlined in the Statistical Analysis
Plan). See Section 4.9.10 for further details.

LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation Definition
ADC antibody-drug conjugate
AE adverse event
ALP alkaline phosphatase
ALT alanine aminotransferase
aPTT activated partial thromboplastin time
AST aspartate aminotransferase
AUC area under the curve
BUN blood urea nitrogen
Cmax maximum plasma concentration
CBC complete blood count
CBR clinical benefit rate
CHF congestive heart failure
CI confidence interval
CR complete response
CRO Clinical Research Organization
CRC Cardiac Review Committee
CT computed tomography
DAS Diarrhea Assessment Scale
DLT dose-limiting toxicity
DMC Data Monitoring Committee
EC ethics committee
ECD extracellular domain
ECG electrocardiogram
ECHO echocardiogram
ECOG Eastern Cooperative Oncology Group
eCRF electronic Case Report Form
EDC Electronic Data Capture
ESF Eligibility Screening Form
FACT-B Functional Assessment of Cancer Therapy−Breast
FDA U.S. Food and Drug Administration
FISH fluorescence in situ hybridization
GCP Good Clinical Practice
GFR glomerular filtration rate
HR hazard ratio
HIPAA U.S. Health Insurance Portability and Accountability Act
ICH International Conference on Harmonisation

ICF informed consent form
IHC immunohistochemistry
INR international normalized ratio
IRB Institutional Review Board
IRC Independent Review Committee
ITT intent to treat
IV intravenous
IVRS Interactive Voice Response System
LC-MS/MS liquid chromatography electrospray tandem mass spectrometry
LDH lactate dehydrogenase
LVEF left ventricular ejection fraction
MBC metastatic breast cancer
MCC N-maleimidomethyl cyclohexane-1-carboxylate
MRI magnetic resonance imaging
MTD maximum tolerated dose
MUGA multiple-gated acquisition
NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse
Events
ORR objective response rate
OS overall survival
PD progressive disease
PFS progression-free survival
PK pharmacokinetic
PR partial response
PRO patient-reported outcome
PT prothrombin time
PTT partial thromboplastin time
qRT-PCR quantitative RT-PCR
RECIST Response Evaluation Criteria in Solid Tumors
RT-PCR reverse-transcriptase polymerase chain reaction
SAE serious adverse event
SD stable disease
SDV source data verification
t1/2 elimination half-life
T-DM1 trastuzumab emtansine, trastuzumab-MCC-DM1
Tc99 technetium-99
TOI-PFB Trial Outcome Index⎯Physical Functional Breast

TTF time to treatment failure
ULN upper limit of normal
USP United States Pharmacopeia
Vss volume of distribution at steady state

1. BACKGROUND
1.1 HER2-POSITIVE METASTATIC BREAST CANCER
Breast cancer is the most common cancer in women. In 2007, approximately 1.3 million
women were diagnosed with breast cancer worldwide, and an estimated 465,000 breast
cancer−related deaths were expected (Garcia et al. 2007). Almost 100,000 of these
breast cancer-related deaths occur in patients who overexpress Human Epidermal
Growth Factor Receptor 2 (HER2) receptors. Metastatic breast cancer
(MBC) is incurable; the primary goal of treatment is to extend life and palliate symptoms
while preserving quality of life.
Overexpression of HER2 (also known as erbB2, neu, and p185HER2) is observed

in approximately 20% of human breast cancers. Several lines of scientific and
clinical evidence support a direct role for HER2 overexpression in the aggressive growth
and poor clinical outcomes associated with these tumors (Slamon et al. 1987).
The development of trastuzumab in the 1990s provided women with
HER2-overexpressing tumors a markedly better outcome than was possible
with chemotherapy alone. Increases in response rate, response duration,
and progression-free survival (PFS) were associated with a 5-month survival
advantage when given in the first-line metastatic setting as demonstrated in the
initial Phase III trials (Slamon et al. 2001).
For patients with HER2-positive MBC, the combination of trastuzumab and a taxane is a
globally accepted first-line treatment option of choice based on the survival advantage
demonstrated in two large pivotal trials (Studies H0648g and M77001). However,
virtually all patients with HER2-positive MBC develop progressive disease (PD) and
require additional therapies for palliation. These patients’ tumors continue to express
high levels of HER2 after progression on trastuzumab and a taxane (Spector et al. 2005).
On the basis of the magnitude of benefit when the HER2 pathway is targeted in
the first-line setting, as well as the clinical experience with HER2-directed agents beyond
first-line treatment, HER2 therapy is often given with chemotherapy in subsequent lines
of chemotherapy. Evidence of improved PFS with lapatinib, an inhibitor of HER1 and
HER2 receptor tyrosine kinases, has provided support for the frequent practice of
continued suppression of HER2 signaling. In a Phase III trial involving patients with
advanced HER2-positive breast cancer previously treated with an anthracycline, a
taxane, and trastuzumab, the addition of lapatinib to capecitabine resulted in
an increased response rate (24% vs. 14%) and time to disease progression (6.2 months
vs. 4.3 months) (see the Tykerb® Package Insert/Tyverb® Summary of Product
Characteristics). On the basis of this, lapatinib in combination with capecitabine has
been approved in the United States since March 2007 for the treatment of HER2-positive
MBC patients who have previously received an anthracycline, a taxane, and
trastuzumab. In June 2008, the European Commission granted conditional marketing
authorization for lapatinib in combination with capecitabine for the treatment of

HER2-positive advanced or MBC patients who have previously received and progressed
on an anthracycline, a taxane, and trastuzumab in the metastatic setting. For these
reasons, lapatinib in combination with capecitabine is an appropriate control arm to
compare with trastuzumab emtansine (trastuzumab-MCC-DM1 [T-DM1]) in patients who
have been exposed to a trastuzumab-containing chemotherapeutic regimen in the
metastatic setting.
1.2 TRASTUZUMAB EMTANSINE

Trastuzumab emtansine (T-DM1) is a novel antibody-drug conjugate (ADC). ADCs
represent a new approach to conferring selectivity to highly potent cytotoxic agents.
Linkage of a cytotoxic agent to highly specific monoclonal antibodies targeting unique
and/or overexpressed cell surface tumor antigens focuses the delivery of such agents to
tumor cells, creating a more favorable therapeutic window than could be achieved by
their administration as free drugs. Trastuzumab emtansine is specifically designed for
the treatment of HER2-positive MBC. It is composed of the cytotoxic agent DM1
(a thiol-containing maytansinoid anti-microtubule agent) conjugated to trastuzumab via
lysine side chains, with an average drug-to-antibody ratio (DAR) of approximately 3.5:1.
Trastuzumab emtansine binds to HER2 with an affinity similar to that of trastuzumab;

such binding is required for its anti-tumor activity. It is hypothesized that after binding to
HER2, trastuzumab emtansine undergoes receptor-mediated internalization, followed by
intracellular release of DM1 and subsequent cytotoxicity.
Completed and ongoing Phase I and II studies of trastuzumab emtansine have

demonstrated clinical activity when trastuzumab emtansine is given as a single agent to
patients with HER2 + MBC who have progressed on a trastuzumab-containing
chemotherapy regimen. Clinical trials of trastuzumab emtansine relevant to the design
of the current trial are listed below.
1.2.1 Study TDM3569g

Study TDM3569g was a Phase I, dose-escalation study that evaluated the safety and
efficacy of trastuzumab emtansine as a single agent in 52 patients with HER2-positive
MBC whose disease progressed on a trastuzumab-containing chemotherapy regimen.
The study was activated in March 2006, and enrollment was completed in May 2008.
The study was completed on 11 June 2009, with 52 patients receiving trastuzumab
emtansine therapy.
On the every-3-week (q3w) dosing schedule, the dose-limiting toxicity (DLT) was
observed in 2 of the 3 patients treated at the 4.8 mg/kg q3w dose level who developed
transient Grade 4 thrombocytopenia and a Grade 2 elevation in liver function tests.
The 3.6 mg/kg q3w dose level was subsequently expanded to 15 patients, and no DLTs
were observed. On the basis of these data, the recommended dose schedule for the
Phase II studies was 3.6 mg/kg q3w.

Treatment with trastuzumab emtansine was well tolerated. Toxicity was generally mild,
reversible, and non-cumulative. No drug-related cardiac toxicity has been noted. No
deaths were reported other than those due to PD. No clinically significant bleeding
events were observed. Two serious adverse events, one Grade 3 pulmonary
hypertension in patient receiving trastuzumab emtansine at 3.6 mg/kg q3w and one
Grade 1 pneumonitis 2.0 mg/kg every week) were considered possibly related to study
drug. All other reported serious adverse events were not considered to be study
drug-related.
Trastuzumab emtansine administration demonstrated significant activity in this Phase I

study. The confirmed objective response rate (ORR) in patients (n = 9) with measurable
disease at the 3.6-mg/kg dose level, q3w schedule was 44% (4 of 9 patients),
by investigator assessment, with a median duration of response of 10.5 months. The
clinical benefit rate (CBR) in the 15 patients treated at the maximum tolerated dose
(MTD) was 67% (10 of 15 patients), as assessed by the investigator.

Study TDM4258g was a Phase II study that evaluated the safety and efficacy of
trastuzumab emtansine administered at a dose of 3.6 mg/kg (IV) every 3 weeks in
HER2-positive MBC patients who had progressed on previous HER2-directed therapy
and conventional chemotherapy.
The primary objectives for this study were: 1) to assess the ORR by investigator and
independent radiologic review associated with trastuzumab emtansine 3.6 mg/kg IV
every 3 weeks, 2) to characterize the safety and tolerability of trastuzumab emtansine at
this dose, 3) to assess PFS of trastuzumab emtansine at this dose by independent
radiologic and investigator review, and 4) to characterize the pharmacokinetic (PK)
profile of trastuzumab emtansine at this dose.
The study was activated on 20 July 2007, and enrollment was completed (n = 112)
on 31 July 2008. The final analysis of ORR was performed with a data cut-off date
25 June 2009, 11 months after the last patient was enrolled. The reported ORR in
all patients was 37.5% (95% confidence interval [CI], 28.6%, 46.6%) by investigator
assessment and 25.9% (95% CI, 18.4%, 34.4%) by independent review. The CBR
(defined as complete response [CR], partial response [PR], or stable disease [SD]
for > 6 months) was 46.3% by investigator assessment [95% CI, 36.7%, 56.2%]
and 39.3% by independent review [95% CI, 30.3%, 48.3%]. The median PFS
was 4.6 months by both the investigators and the Independent Review Committee (IRC)
assessment.
The most common adverse events were Grade 1−2 fatigue (65.2%),
nausea (50.9%), headache (40.2%), epistaxis (35.7%), and pyrexia (34.8%). The most
common Grade 3−4 adverse events observed in this trial were hypokalemia (8.9%),
thrombocytopenia (8.0%), and fatigue (4.5%). Additionally, the following Grade 3

adverse events were each observed in at least 2 patients: epistaxis, dyspnea, anemia,
chest pain, neutropenia, dysphagia, pleural effusion, cellulitis, convulsion, confusional
state, and ascites. Grade 4 adverse events consisted of thrombocytopenia (4 patients)
and confusional state (2 patients). No Grade > 3 left ventricular systolic dysfunction
events (symptomatic congestive heart failure [CHF] and/or left ventricular ejection
fraction [LVEF] of < 40%) or elevations in serum troponin I levels were observed.
Study treatment was discontinued in 4 patients because of adverse events. Three of
these events were considered by the investigator to be possibly related to study
treatment: Grade 4 increase in transaminases, Grade 3 dehydration, and Grade 2
thrombocytopenia.

Study TDM4374g was a Phase II single-arm study of trastuzumab emtansine
administered at 3.6 mg/kg by IV infusion q3w to patients with HER2-positive MBC.
Patients must have received an anthracycline, trastuzumab, a taxane, lapatinib, and
capecitabine given in the neo-adjuvant, adjuvant, or metastatic setting or as treatment
for locally advanced disease. Patients must have been treated with two HER2-directed
therapies in the metastatic or locally advanced setting and have progressed on their
most recent treatment.
The primary objectives of this study were: 1) to assess the ORR as assessed by an IRC
utilizing Response Evaluation Criteria for Solid Tumors (RECIST) version 1.0,
2) to characterize the safety and tolerability of this trastuzumab emtansine regimen in
the aforementioned patient population. Efficacy and safety analyses reported herein
were based on study data collected through 17 September 2009, corresponding to
a minimum follow-up of 24 weeks after the last patient was enrolled in the study.
The study was activated on 2 May 2008, and enrollment was complete on 2 April 2009.
A total of 110 patients were enrolled and treated in the study. As of 17 September 2009,
40 patients continued to receive study treatment. On the basis of clinical data collected
as of 17 September 2009, the ORR among all treated patients was 32.7% (95% CI,
24.1%, 42.1%). No patient had CR, and 36 patients had PR.
The most common adverse events were fatigue (59.1%), nausea (37.3%),
and thrombocytopenia (29.1%). Forty-six patients (41.8%) experienced at least
one Grade ≥ 3 adverse event. The most common Grade ≥ 3 adverse events were
thrombocytopenia (5.5%) and back pain (3.6%).
There were two deaths reported on study within 30 days of trastuzumab emtansine
administration. One patient died following CNS progression. A second patient’s death
following Grade 5 hepatic function abnormality was reported to be possibly related to
trastuzumab emtansine. Although trastuzumab emtansine was reported to be related to
the hepatic event, confounding factors including the patient’s declining performance

status and her exposure to hepatotoxic drugs preclude making definitive conclusions
regarding trastuzumab emtansine causality.

TDM4450g is a randomized Phase II study in which the primary objectives are to
compare the efficacy and safety of single-agent trastuzumab emtansine with the
combination of trastuzumab and docetaxel (hereafter referred to as the control arm) in
patients with HER2-positive unresectable, locally advanced breast cancer or MBC and
who have not received prior chemotherapy for metastatic disease. PFS based on
investigator assessments is the primary efficacy endpoint. Trastuzumab emtansine will
be administered at a dose of 3.6 mg/kg every 3 weeks; trastuzumab 6 mg/kg (8 mg/kg
loading dose) and docetaxel (75-100 mg/m2) will be administered every 3 weeks.
Of the 137 patients randomized (n = 67 in the trastuzumab emtansine arm; n = 70 in the

control arm), all patients (n = 67; 100%) in the trastuzumab emtansine arm and 68 of
70 patients in the control arm (97.1%) received treatment as randomized. The primary
efficacy endpoint, PFS, was assessed based on a data cutoff date of 15 November 2010.
For patients treated with trastuzumab emtansine, median PFS was 14.2 months
compared with 9.2 months for patients treated with trastuzumab + docetaxel (hazard
ratio = 0.594; p = 0.0353) (Hurvitz et al. 2011). The ORR in the
trastuzumab emtansine arm was 64.2% (95% CI: 51.8%, 74.8%) compared with
58.0% (95% CI: 45.5%, 69.2%) in the trastuzumab + docetaxel arm. The CBR was
74.6% (95% CI: 63.2%, 84.2%) in the trastuzumab emtansine arm versus 81.2%
(95% CI: 70.7%, 89.1%) in the trastuzumab + docetaxel arm.
Preliminary evaluations of safety in the randomized study TDM4450g suggest that the
safety and tolerability of trastuzumab emtansine compares favorably with that of
trastuzumab plus docetaxel, with the overall incidence of Grade ≥ 3 adverse events
favoring the trastuzumab emtansine arm (46.4% vs. 89.4%, Hurvitz et al. 2011).
Please refer to the Trastuzumab Emtansine Investigator’s Brochure for further

information on all of the trastuzumab emtansine completed and ongoing studies.
1.3 RATIONALE FOR THIS STUDY

The intent of this Phase III trial is to support multinational approval of trastuzumab
emtansine for the treatment of patients with HER2-positive, unresectable, locally
advanced breast cancer or MBC with PD who have previously received a taxane and
trastuzumab.
A variety of treatment options are available for patients with HER2-positive, unresectable,
locally advanced breast cancer or MBC progressing on or following trastuzumab-based
therapy. On the basis of the clinical experience with HER2-directed agents, including
trastuzumab, HER2-directed treatment is often given with chemotherapy in subsequent

lines of chemotherapy; however, one approved regimen for this patient population is the
combination of lapatinib and capecitabine (see Section 1.1).
Results of the Phase I study (TDM3569g) and the Phase II studies (TDM4258g and
TDM4374g) suggest that trastuzumab emtansine has single-agent activity and
potentially an acceptable safety profile in the study population evaluated and, thus,
represents a reasonable treatment option in the setting of prior treatment with
trastuzumab and a taxane. Study TDM4370g/BO21977 is proposed to evaluate the
efficacy and safety of trastuzumab emtansine compared with a currently recognized
standard treatment option, capecitabine plus lapatinib, in this patient population.
2. OBJECTIVES
2.1 PRIMARY OBJECTIVES
• To compare the efficacy of trastuzumab emtansine versus capecitabine plus

lapatinib in patients with HER2-positive, unresectable, locally advanced breast
cancer or MBC as measured by PFS on the basis of an independent review of
tumor assessments
• To compare the efficacy of trastuzumab emtansine versus capecitabine plus
lapatinib in patients with HER2-positive, unresectable, locally advanced breast
cancer or MBC as measured by overall survival (OS) and to assess landmark
(1-year and 2-year) survival rates within each treatment group, as appropriate
• To assess the safety of trastuzumab emtansine relative to the safety of capecitabine
plus lapatinib
2.2 SECONDARY OBJECTIVES

The secondary objectives for this study are as follows:
• To compare PFS between the two treatment arms on the basis of investigator
• To compare the overall ORR between the two treatment arms on the basis of both
investigator and independent review of tumor assessments
• To estimate the duration of objective response within each treatment arm on the
basis of both investigator and independent review of tumor assessments
• To compare the CBR (the proportion of patients with CR, PR, or SD at 6 months
after randomization) between the two treatment arms on the basis of both

TTF is defined as the time from randomization to discontinuation of treatment
for any reason, including treatment discontinuation without disease progression
or treatment toxicity, disease progression, treatment toxicity, starting another
anti-cancer agent before documented PD, and death from any cause.
• To compare the time to symptom progression between the two treatment arms as
measured by the FACT-Breast-Trial Outcome Index (FACT-B TOI)
Resource expenditure due to hospitalizations and hospital visits for reasons
other than defined study evaluations will be compared between the two
treatment arms.
2.3 EXPLORATORY OBJECTIVES

The exploratory objectives for this study are as follows:
• To compare the proportion of patients with moderate to severe diarrhea,

as measured by the Diarrhea Assessment Scale (DAS), between the two treatment
arms
• To compare the proportion of patients with a clinically significant improvement in
symptoms between the two treatment arms as measured by the FACT-B TOI
(Brady et al. 1997)
• To determine whether the level of HER2 gene amplification (as assessed by
fluorescence in situ hybridization [FISH]) and/or mRNA expression (as assessed by
reverse-transcriptase polymerase chain reaction [RT-PCR]) in archival tumor tissue
correlates with efficacy
• To investigate whether the assessment of biomarkers that are related to the
mechanism of action of trastuzumab emtansine and/or HER2 signaling and/or
breast cancer will allow the identification of patient subgroups with differential
efficacy of trastuzumab emtansine
• To conduct an exploratory exposure-effect analysis to investigate the relationship
between the pharmacokinetics of trastuzumab emtansine and drug effect
(e.g., efficacy, safety)
• To investigate whether presence and/or levels of soluble HER2 extracellular domain
(ECD) at baseline correlate with efficacy

• To determine the population pharmacokinetics of trastuzumab emtansine and to
estimate the typical values for and inter-patient variability of PK parameters
(including covariate effects on inter-patient variability) in this population
• To assess the concordance between IRC-assessed and investigator-assessed PFS
in the two treatment arms
3. STUDY DESIGN
3.1 DESCRIPTION OF THE STUDY
This is a Phase III, randomized, multicenter, international, two-arm, open-label clinical
trial designed to compare the safety and efficacy of trastuzumab emtansine with that of
capecitabine + lapatinib for HER2-positive MBC. A total of 980 patients will be enrolled
at more than 200 sites worldwide. Eligible patients will be randomized in a 1:1 ratio to
either trastuzumab emtansine or lapatinib + capecitabine as follows:
• Trastuzumab Emtansine Arm: Trastuzumab emtansine 3.6 mg/kg intravenously

(IV) over 30−90 minutes on Day 1 of a 21-day cycle
• Control Arm (lapatinib + capecitabine): Lapatinib 1250 mg/day orally once per
day of a 21-day cycle + capecitabine 1000 mg/m2 orally twice daily on Days 1−14 of
a 21-day cycle
A hierarchical dynamic randomization scheme will be used to ensure an approximately
equal sample size for the two treatment arms 1) overall, 2) by world region (United
States, Western Europe, Other), and 3) within each of the four categories defined by the
following two prognostic factors: 1) the number of prior chemotherapeutic regimens for
unresectable, locally advanced or metastatic disease (0−1 vs. > 1) and 2) visceral versus
non-visceral disease. Patients with both visceral and non-visceral disease will be
counted as having visceral disease.
Prior to enrollment, patients will be confirmed for having HER2-positive adenocarcinoma

of the breast. Both immunohistochemical (IHC) and/or FISH will be performed in a
central laboratory with use of archival paraffin-embedded tumor tissue. A patient’s
HER2 status will be considered positive if the central laboratory reports Grade 3 +
staining intensity (on a scale of 0 to 3 +) by means of IHC analysis or gene amplification
by FISH. Patients may have either measurable (per modified RECIST) and/or
non-measurable, unresectable, locally advanced or metastatic disease.
Locally advanced disease must not be amenable to resection or other local therapy with
curative intent.
Prior to the final PFS analysis, tTumor assessments were conducted approximately
every 6 weeks from the date of randomization or Cycle 1 Day 1, regardless of dose
delays or dose interruptions, until 6 weeks after investigator-assessed PD or until death,
whichever occurs occurred first, even if study treatment has had been discontinued as a
result of patient or physician choice or unacceptable toxicity (see Appendix B).

assessments will be according to routine clinical practice per investigator. However, it
is recommended that RECIST be used to evaluate tumor assessments (see Appendix B).
Sponsors).
All patients who are discontinued from study treatment will return for a Study Drug
Completion Visit approximately 30 days (± 7 days) after the last dose of study treatment,
as shown in Appendix A-1 .
Patients who are discontinued from study treatment for any reason will complete the
Study Drug Completion Visit approximately 30 days after the last dose of study
treatment.

should be every two treatment cycles until treatment discontinuation and at the Study
Drug Completion Visit. After treatment discontinuation for any reason, the FACT-B
assessment will be performed according to the same schedule as during survival follow-
up.
An independent Data Monitoring Committee (DMC) monitored accumulating patient

safety data at least once every 6 months during the course of the study until the final
PFS analysis had been conducted. In addition, data on serious adverse events were
monitored by the DMC at least once every 3 months until the final PFS analysis had
been conducted. An independent Cardiac Review Committee (CRC) reviewed all
potential cases of left ventricular systolic dysfunction prior to each DMC review and
reported their findings to the DMC until the final PFS analysis had been conducted. An
IRC evaluated tumor responses through the review of all radiographic and other tumor
assessment data generated from all patients until the time of the final PFS analysis,
with treatment arm information blinded to the IRC. After the final PFS analysis, the IRC
will discontinue the review of tumor assessment data.
No interim analysis of IRC-assessed PFS is planned for this study. The final analysis of
the primary efficacy endpoint of PFS took place when approximately 508 IRC assessed
PFS events had occurred and enrollment is completed. An interim analysis of OS is

planned at the time of the final analysis of PFS (as assessed by the IRC). The final
analysis of OS will be performed when approximately 632 deaths have occurred. See
Section 4.9.10 for further details.
Additional interim analyses of OS will be performed with the appropriate control of the
Type I error rate using the pre-specified Lan-DeMets function with O’Brien-Fleming
boundary (additional details to be outlined in the Statistical Analysis Plan). If an
analysis of OS demonstrates a statistically significant benefit in favor of trastuzumab
emtansine, the co-primary endpoint of OS will be considered as met and at that time
patients randomized to the control arm may cross over to receive trastuzumab
emtansine.
Patients who cross over to trastuzumab emtansine may remain on study treatment
until disease progression (as assessed by the investigator), unmanageable toxicity, or
study termination by Genentech and Roche (the Sponsors). All patients will be followed
until approximately 632 deaths have been reported and the final analysis of OS has been
completed.
3.2 RATIONALE FOR STUDY DESIGN

3.2.1 Rationale for Patient Population
Nonclinical studies indicate that the sensitivity of cancer cells to trastuzumab emtansine
requires HER2 overexpression, and measurement of such expression is a standard of
care in determining eligibility for trastuzumab therapy (see the HERCEPTIN® Package
Insert). Measurement of HER2 gene amplification has traditionally been performed
using IHC measurement. HER2 gene amplification determined by FISH has also proven
to be a reliable method for demonstrating HER2-positive status (Press et al. 2005).
Patients with incurable MBC whose tumors are positive for HER2 overexpression
represent the patient population eligible for study enrollment.
3.2.2 Rationale for Dose and Regimen

In Study TDM3569g, the MTD of trastuzumab emtansine administered by IV infusion
every 3 weeks was 3.6 mg/kg. DLT consisted of Grade 4 thrombocytopenia in
2 of 3 patients treated at 4.8 mg/kg. Related Grade ≥ 2 adverse events at 3.6 mg/kg
were infrequent and manageable. Both treatment schedules (trastuzumab
emtansine given every week or every 3 weeks) appear to be well tolerated and
associated with significant clinical activity as described previously in Section 1.2 .
Patients in the ongoing Phase II study, TDM4258g, have shown similar tolerability at the
3.6 mg/kg dose level administered every 3 weeks. Thus, the trastuzumab emtansine
dose of 3.6 mg/kg given every 3 weeks has been selected for testing in this study on the
basis of 1) the comparable efficacy and safety of the two regimens and 2) the
convenience of a 3-week regimen for this patient population.

The control arm of capecitabine + lapatinib was selected. Lapatinib in combination with
capecitabine has been approved in the United States since March 2007 for the treatment
of HER2-positive MBC. The European Commission granted conditional marketing
authorization for lapatinib in combination with capecitabine for the treatment of
HER2-positive advanced breast cancer or MBC patients in June 2008. Therefore, it is
an appropriate control arm for a global study in a patient population that has progressed
on trastuzumab-based treatment for HER2-positive breast cancer. The doses and
schedules of both drugs in this study are the same as those in the lapatinib pivotal study,
as described in Section 1.1 .
3.2.3 Rationale for Continued Dosing

In the Phase I (TDM3569g) and Phase II (TDM4258g) studies of trastuzumab emtansine,
4 patients have received 12 + months of treatment with trastuzumab emtansine at the
MTD (3.6 mg/kg) on a q3w schedule, with 1 patient remaining on treatment for nearly 24
months. Patients who meet the criteria for ongoing clinical benefit will be allowed to
continue study treatment in the absence of disease progression or unacceptable toxicity
or until study closure.
3.2.4 Rationale for Efficacy Assessments

An assessment of PFS, a co-primary objective of this trial, will be based on modified
RECIST and will be determined by independent review of baseline and follow-up
assessments obtained every 6 weeks. An additional tumor assessment will be performed
after investigator-documented disease progression. This is to provide the IRC with an
additional opportunity to confirm investigator-assessed disease progression in an effort to
reduce discordance between investigator and independent assessments of PD.
While an improvement in time to progression in this disease setting served as the basis
for approval (approval in the United States and conditional approval in the European
Union) of lapatinib when given in combination with capecitabine in patients with MBC,
the co-primary endpoint, OS, is considered as the “gold standard” for the demonstration
of clinical benefit of an experimental therapy.
Therefore, OS is a co-primary endpoint for this study in addition to PFS. Accordingly, an

appropriate sample size has been calculated to ensure the study is adequately powered
to detect a clinically meaningful OS benefit. Based on clinical data in patients treated
with trastuzumab emtansine to date, no safety concerns are anticipated in this patient
population with this larger sample size.
3.2.5 Rationale for Exploratory Diagnostic Studies

Several diagnostic questions will be assessed in this study. The current determination of
HER2 status in breast cancer is made according to a semi-quantitative algorithm with a
binary result (positive or negative, amplified or non-amplified). An open question
remains as to whether levels of HER2 mRNA expression or gene amplification within the

positive range are correlated with degree of response to HER2-targeted therapies.
Patients will be classified into quartiles on the basis of the degree of HER2 gene
amplification and level of mRNA expression to assess the potential relationship between
response and these variables.
HER2 signaling is known to be modulated by expression levels of other HER family

members (e.g., HER1 and HER3) and ligands (e.g., amphiregulin, betacellulin,
neuregulin). Several studies have indicated that expression of these genes may
correlate with response or resistance to HER2-targeted therapies (Wiseman et al. 2005;
Robinson et al. 2006). As an exploratory study, the expression of other HER family
receptors or ligands will be assessed using quantitative RT-PCR (qRT-PCR) with use of
sections from the archival tumor block or from unstained slides.
The presence and/or levels of soluble HER2 ECD at baseline along with changes during
treatment have been correlated with treatment efficacy. In this study, baseline ECD
levels with clinical efficacy will be explored.
Other biomarker assessments that may be related to the method of action of

trastuzumab emtansine, HER2 signaling, or breast cancer may be performed in this
study on the archival tissue collected at study entry.
3.2.6 Rationale for Pharmacogenomic Studies

Both safety and efficacy questions will be explored with the pharmacogenomic studies.
In the initial Phase I study of trastuzumab emtansine, the DLT identified on a q3w
schedule was Grade 4 thrombocytopenia. The magnitude of this effect was dose related
but was milder in 1 of the 3 patients treated at the dose level that exceeded the MTD
(4.8 mg/kg). In addition, some patients receiving 3.6 mg/kg have experienced no
thrombocytopenia. There has been no commensurate effect observed on other marrow
constituents (neutrophils, red blood cells). One possible hypothesis to explain the
observation of trastuzumab emtansine-induced thrombocytopenia in some but not all
patients is differential ability of megakaryocytes and/or platelets to bind and internalize
the drug conjugate. Another hypothesis is the possible existence of a single nucleotide
polymorphism locus that could be related to the incidence or severity of
thrombocytopenia.
In relationship to efficacy, it has been hypothesized that the mechanism of action

of antibody therapeutics such as rituximab and trastuzumab could include Fc-mediated
attraction of immune effector cells known as antibody-dependent cell-mediated
cytotoxicity. Polymorphisms have been associated with differential affinity of natural
killer cells for the Fc portion of antibodies and differential efficacy in nonclinical models
(Clynes et al. 2000). A recent clinical study has suggested that such polymorphisms are
associated with efficacy of trastuzumab (Musolino et al. 2007). This study will further
explore whether such polymorphisms are associated with efficacy.

3.2.7 Rationale for the Pharmacokinetic Assessment Plan (for the
Trastuzumab Emtansine Arm)
The combination of PK data obtained in this study and in the Phase I and ongoing Phase
II studies will allow complete profiling of the distribution and elimination phases for this
molecule and its components (trastuzumab and DM1) and the investigation of potential
correlations between various PK parameters and efficacy and/or toxicity.
In this study, PK samples will be collected from approximately 160 patients treated with
trastuzumab emtansine as outlined in Appendix A-2. Sites will be informed when PK
sample collection on subsequently enrolled patients is no longer required. Patients who
begin PK sampling at study entry should continue to undergo PK sampling as specified
in Appendix A-2 until the study drug completion visit.
Serum concentration−time data collected throughout treatment in this study combined

with data from previous Phase I and Phase II studies can be modeled to estimate
population PK parameters (mean and inter-patient variability) as well as the relationship
between trastuzumab emtansine clearance and pathophysiologic covariates.
3.2.8 Rationale for Pharmacoeconomic Endpoints and the Patient-

Reported Outcomes Assessment Plan
As patients progress to second- and third-line treatment options, physicians and patients
must balance the costs, both financial and quality of life, with the benefits of available
cancer treatment options.
While on study treatment, hospitalizations and/or hospital visits for reasons other than
those defined by the protocol will be evaluated as an estimate of the resource utilization
required for patients in both treatment arms. The number of hospital visits, number of
days admitted, and type of visits (emergency department vs. inpatient care) will be
collected and compared between the two arms. The reason for admission (disease
progression vs. adverse event) will also be assessed.
PROs will be collected during the study. The goal of this collection is to evaluate the
patient’s health status and the impact that treatment with trastuzumab emtansine or
lapatinib plus capecitabine has on a patient’s reported health status.
With any oncologic treatment, it is important to ensure that gains in clinical outcomes
(e.g., prolongation of PFS) are not at the expense of a vastly increased symptom burden
on the patient. PROs provide a better understanding of the subjective impact a
treatment has on a patient (Wenzel et al. 2007).
Patients who progress may have a higher symptom burden that can be either disease or
treatment related. Extending PFS can delay this increase in disease-related symptom
burden. In an attempt to quantify the change in symptom burden that patients

experience during disease progression, patient-reported health status will continue to be
assessed after patients experience disease progression and discontinue study therapy.
Collecting PROs after progression will provide an exploratory assessment of the

changes in symptom burden that are seen because of disease progression.
The FACT-B (Version 4; see Appendix C) is a 37-item questionnaire that will be

administered to female patients only. The questionnaire should be administered
to patients before any other procedures are conducted at that study visit,
including informing the patient of any results of tumor assessments, if applicable.
The Trial Outcome Index ⎯ Physical Functional Breast (TOI-PFB) is a 24-item subscale
generated using three subsections from the FACT-B instrument (Physical Well-Being,
Functional Well-Being, and Additional Concerns) (Brady et al. 1997). The entire FACT-B
will be administered.
Treatment-induced diarrhea can negatively impact a patient’s health status and may
lead to dose reductions or dose delays. Prior to the final analysis of PFS, the DAS was
administered to patients on Day 1 of every cycle to assess diarrhea experienced by
patients in the two treatment arms (see Appendix D). The DAS consists of four
questions assessing the frequency, urgency, consistency of diarrhea as well as the
discomfort due to diarrhea (Casey and Zachariah 1993; Chambers and McMillan 1997;
Gwede et al. 2007). After the final PFS analysis, the DAS will no longer be
administered.
3.3 OUTCOME MEASURES

3.3.1 Primary Outcome Measures
• PFS by IRC assessment, defined as the time from randomization to the

first occurrence of progression, as determined by independent review of tumor
• OS, defined as the time from randomization to death from any cause, and landmark
survival rate, defined as the survival rate estimated using the Kaplan-Meier
approach at pre-defined timepoints from randomization (e.g., 1 year or 2 years)
3.3.2 Secondary Outcome Measures
• PFS by investigator assessment, defined as the time from randomization to the first
occurrence of disease progression, as determined by investigator review of tumor
• Objective response (PR or CR) as determined by both investigator and independent
review of tumor assessments through use of modified RECIST

Objective responses must be confirmed at least 28 days after
initial documentation of response
• Duration of objective response, defined as the first occurrence of a documented
objective response until the time of disease progression, as determined by
both investigator and independent review of tumor assessments through use
of modified RECIST, or death from any cause
• CBR (the proportion of patients with CR, PR, or SD at 6 months after randomization
between the two treatment arms based on both investigator and independent review
of tumor assessments)
• TTF, defined as the time from randomization to discontinuation of treatment for
any reason, including treatment discontinuation without disease progression
or treatment toxicity, disease progression, treatment toxicity, starting another
anti-cancer agent before documented PD, or death from any cause
documentation of a ≥ 5-point decrease from baseline in the scoring of responses)
between the two treatment arms as measured by the FACT-B TOI (see Appendix C)
The FACT-B TOI is a subset of the FACT-B and includes the Physical,
Functional, and Breast subscales.
• Estimated resource expenditures for hospitalizations and/or hospital visits that occur
within 30 days of the last dose of study treatment for reasons other than those
defined by the protocol
The number of hospital visits, number of days admitted, and type of visits
(emergency department vs. inpatient care) will be collected and compared
between the two arms. The reason for admission (disease progression vs.
adverse event) will also be assessed.

3.3.3 Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:
• The proportion of patients with moderate to severe diarrhea between the

two treatment arms as measured by the patient-completed DAS
• The proportion of patients with a clinically significant improvement in symptoms
between the two treatment arms as measured by the FACT-B TOI
(Brady et al. 1997)
• To determine the population pharmacokinetics of trastuzumab emtansine and to
estimate the typical values for and inter-patient variability of PK parameters
(including covariate effects on inter-patient variability) in this population
3.4 SAFETY PLAN

Overall safety will be assessed on an ongoing basis during the conduct of the study. An
independent DMC monitored cumulative safety data at least once every 6 months during
the course of the study until the final PFS analysis was conducted. In addition, data on
serious adverse events were monitored by the DMC at least once every 3 months until
the final PFS analysis was conducted. An independent CRC reviewed all potential
cases of left ventricular systolic dysfunction prior to each semi-annual DMC review and
reported their findings to the DMC until the final PFS analysis was conducted.
Additional details are provided in the DMC and CRC Charters.
3.4.1 Risks Associated with Study Treatment

3.4.1.1 Risks Associated with Trastuzumab Emtansine
The following summarizes the experience with trastuzumab emtansine in multiple
breast cancer studies to date. Trastuzumab emtansine has demonstrated a favorable
toxicity and tolerability profile to date across multiple studies. Please refer to the
Trastuzumab Emtansine Investigator’s Brochure for further information.
Reversible thrombocytopenia has been commonly observed in completed and ongoing

studies with trastuzumab emtansine. Most events were Grade 1 or 2; Grade 3 and 4
thrombocytopenia has been observed less frequently. The incidence of Grade 1 and 2
thrombocytopenia gradually increased over successive cycles; there was no increase in
the proportion of Grade ≥ 3 abnormalities. The number of patients who experienced
platelet count recovery to normal levels by Day 1 of the subsequent cycle decreased with
successive cycles, suggesting a modest cumulative effect of trastuzumab emtansine on
platelet count. There was no clear association between thrombocytopenia and severe
hemorrhagic events; however, the use of platelet transfusions has been reported.
Transient increases in serum AST and ALT have been observed across the trastuzumab
emtansine studies. Grade 1 and 2 events have been observed frequently; Grade 3 and 4
events have been observed less commonly. The incidence of increased AST was

substantially higher than that for ALT. Increases in AST and ALT were commonly
observed by Day 8 of each cycle and generally returned to baseline by Day 21. The
proportion of patients with Grade 1 or 2 increases in transaminases increased with
successive cycles; however, no increase in the proportion of Grade 3 abnormalities over
time was observed. To date, there have been no cases meeting Hy’s Law criteria for
drug-induced liver injury with trastuzumab emtansine. Although significant
hepatotoxicity has been seen in clinical trials with trastuzumab emtansine to date, the
relationship to trastuzumab emtansine has not been established. Nevertheless, severe
liver injury remains an important potential risk.
Cases of nodular regenerative hyperplasia (NRH) of liver have been identified from
liver biopsies. NRH is a rare liver condition characterized by widespread benign
transformation of hepatic parenchyma into small regenerative nodules; diagnosis can
only be confirmed by histopathology. It may lead to non-cirrhotic portal hypertension.
NRH should be considered in all patients with clinical symptoms of portal hypertension,
but with normal transaminases and no manifestations of cirrhosis. This condition may
be reversible upon discontinuation of trastuzumab emtansine treatment. Upon
diagnosis of NRH, patients should be re-evaluated to continue trastuzumab emtansine.
Infusion-related reactions are known to occur with the administration of monoclonal

antibodies and have been reported with trastuzumab emtansine. Infusion reaction
adverse events occurred rarely and were mostly Grade 1 or 2. Non-specific symptoms
occurring on the first day of trastuzumab emtansine infusion that could be associated
with an infusion reaction included fatigue, nausea, chills, pyrexia, and less commonly,
headache, hypertension, vomiting, and cough.
Pneumonitis (including severe, life-threatening cases) has been rarely reported with
trastuzumab emtansine. Signs, symptoms, and clinical findings include dyspnea,
cough, fatigue, and pulmonary infiltrates. In some patients with multiple lung
metastases, ventilator support (mechanical ventilation) was required. Treatment
included administration of corticosteroids, oxygen, and study drug discontinuation.
In clinical trials with trastuzumab emtansine, peripheral neuropathy has been reported,
mainly as a Grade 1 toxicity. Hypokalemia and decreases in serum potassium have
been reported in completed and ongoing studies with trastuzumab emtansine. Most of
these adverse events were Grade 1 or 2.
Although significant cardiac events have been infrequent in clinical trials with
trastuzumab emtansine to date, severe cardiotoxicity remains an important potential
risk. Treatment with trastuzumab, a component of trastuzumab emtansine, has
resulted in subclinical and clinical cardiac failure manifesting as CHF, decreased LVEF,
and cardiac death. The incidence and severity of cardiac dysfunction was highest in
patients who received trastuzumab concurrently with anthracycline-containing
chemotherapy regimens. Cardiotoxicity, manifesting as a decline in LVEF or CHF, is

being closely monitored in the trastuzumab development program. Across Studies
TDM4258g, TDM4374g, and TDM4688g, approximately 273 patients were treated,
and a total of 8 patients recorded an asymptomatic decrease in baseline LVEF of
≥ 10 percentage points below baseline to an absolute value < 50%. Two patients had
trastuzumab emtansine treatment withdrawn owing to decreased LVEF. Rare cases of
Grade 3 cardiac dysrhythmias have been reported among patients receiving
trastuzumab emtansine, although a direct relationship to study drug remains unclear.
Importantly, preliminary evaluations of safety in the randomized study TDM4450g

suggest that the safety and tolerability of trastuzumab emtansine compares favorably
with that of trastuzumab plus docetaxel, with the overall incidence of Grade ≥ 3 adverse
events favoring the trastuzumab emtansine arm (46.4% vs. 89.4%) (data on file).
Full details regarding the clinical safety of trastuzumab emtansine are presented in
Sections 5 and 6 of the Trastuzumab Emtansine Investigator’s Brochure.
3.4.1.2 Risks Associated with Capecitabine

Risks associated with capecitabine include diarrhea, coagulopathy, cardiotoxicity,
hand-and-foot syndrome, hyperbilirubinemia, and hematologic toxicity. Please see the
Xeloda ® Package Insert/national prescribing information for more details.
3.4.1.3 Risks Associated with Lapatinib

Risks associated with lapatinib include decreases in LVEF, hepatotoxicity, diarrhea,
interstitial lung disease and pneumonitis, and QT prolongation. Please see the
Tykerb ®/Tyverb ® Package Insert/national prescribing information for more details.
3.4.2 Trastuzumab Emtansine Safety Plan

The safety plan for patients in the trastuzumab emtansine treatment arm is based on
nonclinical toxicities of trastuzumab emtansine, the clinical experience with this molecule
in ongoing studies, and clinical toxicities related to its components (trastuzumab and
maytansine, the parent drug of DM1). The potential safety issues anticipated in this
treatment arm as well as measures intended to avoid or minimize such toxicities are
outlined below. Please refer to the Trastuzumab Emtansine Investigator’s Brochure for
the most recent information.
3.4.2.1 Cardiotoxicity
Patients without significant cardiac history and with an LVEF ≥ 50% determined by
echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan are eligible
for study participation. For an individual patient, the same modality should be used
throughout the study. ECHO is preferred because of the anticipated worldwide
Tc99 shortage. Ejection fractions will be monitored at screening, at 6 and 12 weeks
after first dose of study treatment, and every 12 weeks thereafter until the assessment at
the Study Drug Completion Visit. Patients with confirmed symptomatic cardiac
dysfunction (Grade ≥ 3 left ventricular systolic dysfunction) will be discontinued from

study treatment and will be followed as specified in Section 4.5. Asymptomatic declines
in LVEF will be handled as per the algorithm in Figure 1. Prior to the final PFS analysis,
an independent CRC reviewed all potential cases of left ventricular systolic dysfunction
prior to each 6-month DMC review and reported their findings to the DMC.
Figure 1 Algorithm for Continuation and Discontinuation of Trastuzumab

Emtansine Based on LVEF Assessments in Patients
a
LVEF <40% or LVEF 40% to ≤45% LVEF >45%
symptomatic CHF
Absolute decrease in Continue T-DM1

Discontinue T-DM1 % points from baseline
≥10% points <10% points
Hold T-DM1 and repeat Continue T-DM1 and

b
LVEF in 21 days repeat LVEF next cycle
CHF = congestive heart failure; LVEF = left ventricular ejection fraction; T-DM1 = trastuzumab
emtansine.
Note: LVEF assessment results must be reviewed before the next scheduled trastuzumab
emtansine infusion.
a
LVEF < 40% can be repeated within 21 days, and trastuzumab emtansine should be
discontinued if LVEF < 40% is confirmed. Trastuzumab emtansine should be held while the
repeat LVEF is obtained.
b
After a second consecutive confirmatory result, trastuzumab emtansine should be
discontinued if the LVEF is confirmed and if medical management was required in order to
correct the LVEF.
3.4.2.2 Hematologic Toxicity

Thrombocytopenia has been observed in ongoing studies with trastuzumab emtansine.
Patients must have adequate bone marrow function, as manifested by measurements of
blood granulocytes, hemoglobin, and platelets, for initial and continued dosing.
Evaluations of blood granulocytes, hemoglobin, and platelets will be performed regularly.
Use of erythropoiesis-stimulating agents will be allowed as consistent with prescribing
guidelines. Transfusion of either red blood cells or platelets will be according to and at
the discretion of the treating physician. Trastuzumab emtansine dose modifications are
described in Section 4.3.1.3 .

3.4.2.3 Hepatotoxicity
Transient liver-enzyme elevations have been observed in ongoing trastuzumab
emtansine studies. Patients must have adequate liver function, as manifested by
measurements of total bilirubin and hepatic transaminases, for initial and continued
dosing. Trastuzumab emtansine dose modifications are described in Section 4.3.1.3.
3.4.2.4 Infusion Reactions

Administration of trastuzumab emtansine will be performed in a setting with access to
emergency facilities and staff who are trained to monitor and respond to medical
emergencies. Patients will be monitored during and after each trastuzumab emtansine
infusion for a minimum of 90 minutes after the first infusion and for a minimum of
30 minutes after subsequent infusions in the absence of infusion-related adverse events.
Consistent with the Herceptin® Package Insert/national prescribing information, patients

should be made aware of the possibility of severe delayed infusion reactions associated
with trastuzumab emtansine, because of its trastuzumab component. Patients should be
instructed to contact their treating physician with any concerns after dosing.
3.4.2.5 Neurotoxicity
Trastuzumab emtansine, an anti-microtubule agent, can potentially cause peripheral
neuropathy. Patients must have Grade < 3 peripheral neuropathy to be eligible for study
participation. Patients should be examined for signs of peripheral neuropathy prior to
each dose of trastuzumab emtansine. Patients who experience Grade ≥ 3 neurotoxicity
in the form of peripheral neuropathy that does not resolve to Grade 2 or less within
42 days after last dose received will be discontinued from study treatment.
3.4.3 Control Arm Safety Plan

The safety plan for patients receiving lapatinib and capecitabine is based on the U.S.
and E.U. prescribing guidelines, emphasizing the adverse event data reported for each
drug. Measures intended to avoid or minimize such toxicities (including any special
monitoring, dose modification criteria, and/or prohibited concomitant medications) are
described in Section 4.3.2 . Eligibility criteria are outlined in Section 4.1 .
3.5 STUDY PATIENTS AND ANALYSIS GROUPS

The primary and secondary outcome measures will be analyzed according to the
appropriate analysis subgroups as defined in Section 4.9 .
3.6 CONTROL GROUPS

The most recently approved regimen for the patient population under investigation is the
combination of lapatinib (which received full approval in the United States and
conditional approval in the European Union) and capecitabine.

3.7 MINIMIZATION OF BIAS
To reduce potential bias in this open label trial, patients will be randomized to the
two treatment arms (trastuzumab emtansine or lapatinib + capecitabine) with use of an
Interactive Voice Response System (IVRS). The hierarchical randomization scheme is
designed to ensure approximately equal number of patients in the two arms, within the
following three categories: world region (United States, Western Europe, Other), the
number of prior chemotherapeutic regimens for unresectable, locally advanced or
metastatic disease (0−1 vs. > 1), and visceral versus non-visceral disease. In addition, in
order to guard against bias in this open-label trial, an IRC will be used to review the
tumor scans of the patients for the primary endpoint of PFS.
3.8 ETHICAL CONSIDERATIONS

Despite the advances that have been made, MBC is incurable. The primary goals of
treatment remain to extend life and palliate symptoms while preserving quality of life.
At present, no single chemotherapy regimen can be considered the global standard of
care for advanced breast cancer. However, for patients with HER2-positive MBC, the
combination of trastuzumab and chemotherapy is established as a standard treatment
option on the basis of positive results of two large pivotal trials (Studies H0648g and
M77001).
As demonstrated in Studies TDM3569g, TDM4258g, and TDM4374g, trastuzumab

emtansine has shown activity in heavily pretreated patients with HER2-overexpressing
MBC, possibly with less toxicity than that seen with currently used palliative regimens.
All patients enrolled in the trastuzumab emtansine arm of this study will receive
trastuzumab emtansine at 3.6 mg/kg every 3 weeks, the dose determined to be the MTD
of trastuzumab emtansine given on this schedule. Appropriate evaluations for disease
progression will be performed. Patients enrolled in the lapatinib + capecitabine arm of
the study will receive a current standard-of-care option for patients with
HER2-overexpressing MBC. The U.S. Food and Drug Administration (FDA) approved
this regimen in March 2007, and the European Union conditionally approved this
combination in June 2008.
3.9 ADMINISTRATIVE STRUCTURE

This study will be sponsored by Genentech and by F. Hoffmann-La Roche Ltd. More
than 200 sites globally will participate in the study and will enroll approximately
980 patients.
Randomization will occur through an IVRS. Central laboratories will be used for
laboratory assessments throughout the study. Accredited local laboratories will be used
for routine monitoring; all laboratory ranges will be collected.

An external independent DMC monitored safety. Prior to the final PFS analysis, the
DMC reviewed results from the analyses of accumulating safety data and made
recommendations regarding continuation of the study. An independent CRC reviewed
all potential cases of left ventricular systolic dysfunction before each DMC review prior to
the final PFS analysis. The CRC members reviewed patient data profiles and source
documents, if needed, from all potential cases of left ventricular systolic dysfunction, as
specified in the CRC Charter. The independent cardiac assessments were provided to
the DMC for review. The detailed review process, committee composition, and member
roles and responsibilities are documented in the CRC Charter.
An independent statistical research organization will perform statistical analysis of

accumulated safety data every 3 months during the trial and present these to the DMC
for review until the final PFS analysis is conducted.
Prior to the final PFS analysis, an IRC was utilized to assess response and disease
progression by modified RECIST and to process ECHO/MUGA assessments
independent of the site assessments.
3.10 COMPLIANCE WITH LAWS AND REGULATIONS

This study will be conducted in accordance with FDA regulations, the International
Conference on Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP), the
Declaration of Helsinki (October 1996), and applicable local, state, and federal laws, as
well as other applicable country laws.
4. MATERIALS AND METHODS

4.1 PATIENTS
4.1.1 Patient Selection
The population for this study is patients with HER2-positive unresectable,
locally advanced breast cancer or MBC who have progressed after treatment with
trastuzumab and a taxane, at the minimum, in any breast cancer disease setting.
A signed, written Informed Consent Form (ICF) (approved by the Institutional Review
Board [IRB] or Independent Ethics Committee [EC]) must be obtained prior to performing
any study-specific screening tests or evaluations unless the tests or evaluations are
performed as standard of care (see Appendix A-1).
4.1.2 Inclusion Criteria

Patients must meet the following inclusion criteria to be eligible for study entry.

4.1.2.1 Disease-Specific Criteria
1. Prospective centrally confirmed HER2-positive (i.e., immunohistochemistry [IHC] 3 +
and/or gene-amplified by FISH). Both IHC and FISH assays will be performed;
however, only one positive result is required for eligibility. If prior approval has been
granted by the Sponsors, centrally confirmed HER2 results (either IHC or FISH) from a
current or previous study identified by the Sponsors⎯for example, Studies BETH
(AVF4285s/BO20906), AVEREL (BO20231), HERA (BO16348), NEOSPHERE
(WO20697), MARIANNE (BO22589/TDM4788g), AVANT, HANNAH, PHEREXA,
or CLEOPATRA (WO20698/TOC4129g)⎯can be used to determine eligibility for this
study. Additional tissue samples will be required to perform all mandatory testing
(including qRT-PCR).
2. Histologically or cytologically confirmed invasive breast cancer: incurable,
unresectable, locally advanced breast cancer previously treated with multimodality
therapy or MBC
3. Prior treatment for breast cancer in the adjuvant, unresectable, locally advanced, or
metastatic setting must include both:
A taxane, alone or in combination with another agent, and trastuzumab, alone
or in combination with another agent in the adjuvant, unresectable, locally
advanced, or metastatic setting
4. Documented progression of incurable unresectable, locally advanced, or metastatic
breast cancer, defined by the investigator:
Progression must occur during or after most recent treatment for locally
advanced/MBC or within 6 months after completing adjuvant therapy.
5. Measurable and/or non-measurable disease. Patients with CNS-only disease
are excluded.
4.1.2.2 General Criteria

6. Age ≥ 18 years
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
9. Adequate organ function, evidenced by the following laboratory results
within 30 days prior to randomization:
Total bilirubin ≤ 1.5 upper limit of normal (ULN)

SGOT (aspartate aminotransferase [AST]), SGPT (alanine aminotransferase
[ALT]), and alkaline phosphatase (ALP) ≤ 2.5 × ULN with the following exception:
Creatinine clearance > 50 mL/min based on Cockroft-Gault glomerular filtration
rate (GFR) estimation:
(140 − Age) × (weight in kg) × (0.85 if female)/(72 × serum creatinine)
International normalized ratio (INR) and activated partial thromboplastin time (aPTT)
< 1.5 × ULN (unless on therapeutic coagulation)
Placement of non-hormonal intrauterine device (IUD)
Patient is surgically sterilized (i.e., who have undergone surgical sterilization
with a hysterectomy and/or bilateral oophorectomy)
Contraception use should continue for the duration of the study treatment and
for at least 6 months after the last dose of study treatment. Periodic abstinence
(e.g., calendar ovulation, symptothermal, post-ovulation methods) and
withdrawal are not acceptable methods of contraception. Postmenopausal is
defined as ≥ 12 months of amenorrhea.
Specific country requirements will be followed (e.g., in the United Kingdom,
women of childbearing potential and male subjects and their partners of
childbearing potential must use two methods of contraception [one of which
must be a barrier method] for the duration of the study).
4.1.3 Exclusion Criteria
4.1.3.1 Cancer-Related Criteria
2. Prior treatment with lapatinib or capecitabine
3. Peripheral neuropathy of Grade ≥ 3 per National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0

4. History of other malignancy within the previous 5 years, except for appropriately
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 1
uterine cancer, synchronous or previously diagnosed HER2-positive breast cancer,
or cancers with a similar curative outcome as those mentioned above.
21 days prior to randomization except hormone therapy, which can be given up to
7 days prior to randomization; recovery of treatment-related toxicity consistent with
other eligibility criteria
6. History of radiation therapy within 14 days of randomization
The patient must have recovered from any resulting acute toxicity (to Grade ≤ 1)
prior to randomization.
7. Brain metastases that are untreated, symptomatic, or require therapy to control
symptoms, as well as a history of radiation, surgery, or other therapy, including
corticosteroids, to control symptoms from brain metastases within 2 months (60 days)
before randomization
4.1.3.2 Cardiopulmonary Function

9. History of myocardial infarction or unstable angina within 6 months of randomization
10. Current dyspnea at rest due to complications of advanced malignancy or
requirement for continuous oxygen therapy
4.1.3.3 General Criteria

11. Current severe, uncontrolled systemic disease
(e.g., clinically significant cardiovascular, pulmonary, or metabolic disease)
14. Presence of conditions that could affect gastrointestinal absorption: malabsorption
syndrome, resection of the small bowel or stomach, and ulcerative colitis
16. Known hypersensitivity to 5-fluorouracil or known dihydropyrimidine dehydrogenase
deficiency
17. Current treatment with sorivudine or its chemically related analogs,
such as brivudine
18. Assessed by the investigator to be unable or unwilling to comply with
the requirements of the protocol (i.e., unable to swallow pills)

4.1.4 Eligibility Criteria for Control Arm Patients Who Cross Over to
Receive Trastuzumab Emtansine
For patients randomized to the control arm offered the possibility to receive trastuzumab
emtansine (see Section 3.1 ), the following eligibility criteria must be met in order to receive
treatment.
4.1.4.1 Inclusion Criteria for Cross-Over Patients

2. ECOG performance status of 0, 1, or 2
3. Adequate organ function, evidenced by the following laboratory results within 30 days prior
to Cycle 1, Day 1:
Total bilirubin ≤ 1.5 × ULN
SGOT (AST), SGPT (ALT), and ALP ≤ 2.5 × ULN with the following exception:
INR and aPTT < 1.5 × ULN (unless on therapeutic coagulation)
Placement of non-hormonal IUD
Patient is surgically sterilized (i.e., who have undergone surgical sterilization with
a hysterectomy and/or bilateral oophorectomy)
Contraception use should continue for the duration of the study treatment and for at
least 6 months after the last dose of study treatment. Periodic abstinence (e.g., calendar
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable
methods of contraception. Postmenopausal is defined as ≥ 12 months of amenorrhea.

Specific country requirements will be followed (e.g., in the United Kingdom, women of
childbearing potential and male subjects and their partners of childbearing potential
must use two methods of contraception [one of which must be a barrier method] for the
duration of the study).
4.1.4.2 Exclusion Criteria for Cross-Over Patients
Cancer-Related Criteria
14. Peripheral neuropathy of Grade ≥ 3 per National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE) Version 3.0
14 days prior to Cycle 1, Day 1 except hormone therapy, which can be given up to 7 days
prior to Cycle 1, Day 1; recovery of treatment-related toxicity consistent with other eligibility
criteria
16. History of radiation therapy within 14 days of Cycle 1, Day 1
The patient must have recovered from any resulting acute toxicity (to Grade ≤ 1) prior
of Cycle 1, Day 1.
17. Brain metastases that are untreated, symptomatic, or require therapy to control symptoms, as
well as a history of radiation, surgery, or other therapy, including corticosteroids, to control
symptoms from brain metastases within 2 months (60 days) before months of Cycle 1, Day 1
Cardiopulmonary Function
19. History of myocardial infarction or unstable angina within 6 months of Cycle 1, Day 1
20. Current dyspnea at rest due to complications of advanced malignancy or requirement for
continuous oxygen therapy
General Criteria
21. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular,
pulmonary, or metabolic disease)
25. Assessed by the investigator to be unable or unwilling to comply with the requirements of the
protocol
4.2 METHOD OF TREATMENT ASSIGNMENT AND BLINDING

After written informed consent has been obtained and eligibility has been established
and approved, the study site will obtain the patient’s randomization number and
treatment assignment from the IVRS. Patients should receive their first dose of study
treatment the day of randomization if possible, but no later than 5 business days after

randomization. Patients will be randomized in a 1:1 ratio by a hierarchical randomization
scheme to one of the two treatment arms (trastuzumab emtansine or lapatinib and
capecitabine) through use of the IVRS.
Randomization will be stratified by the following criteria:

• World region (United States, Western Europe, Other)
• Prior chemotherapy regimens for unresectable, locally advanced or metastatic
disease (0−1, > 1)
• Visceral versus non-visceral disease
If an analysis of OS demonstrates a statistically significant benefit in favor of
trastuzumab emtansine, at that time patients randomized to the control arm may be
allowed to cross over to receive trastuzumab emtansine.
4.3 STUDY TREATMENT

4.3.1 Trastuzumab Emtansine Arm
4.3.1.1 Trastuzumab Emtansine Formulation, Preparation, and Storage
Trastuzumab emtansine is provided as a single-use lyophilized formulation in a colorless
20-mL Type I glass vial closed by means of a FluroTec-coated stopper and an overseal
with a flip-off plastic cap.
Trastuzumab emtansine should be handled using appropriate procedures in place at the

clinical site for preparation of chemotherapeutic drugs.
Upon reconstitution, the resulting product contains 20 mg/mL trastuzumab emtansine,

10 mM sodium succinate, pH 5.0, 6% (w/v) (i.e., 60 mg/mL) sucrose, and 0.02% (w/v)
polysorbate 20. Each 20-mL vial contains enough trastuzumab emtansine to allow
delivery of 160 mg of trastuzumab emtansine.
Upon receipt of trastuzumab emtansine, vials should be refrigerated at 2°C−8°C

(36°F−46°F) until use. VIALS MUST NOT BE FROZEN OR SHAKEN. Trastuzumab
emtansine must be stored in the original carton to protect from light. Do not use beyond
the expiration date provided by the manufacturer. The reconstituted product contains no
preservative and is intended for single use only. Any remaining medication should be
discarded.
For further details regarding the formulation, storage, and preparation, please refer to
the Trastuzumab Emtansine Investigator Brochure and the Pharmacy Binder.
4.3.1.2 Trastuzumab Emtansine Dosage and Administration

Trastuzumab emtansine will be given at a dose of 3.6 mg/kg IV every 21 days (unless
dose reduction and/or dose delays are required) until study drug discontinuation.
The total dose will depend on the patient’s weight on Day 1 (or up to 3 days before) of
each cycle. The dose administered at the previous cycle may be used at subsequent

cycles. However, in cases where there is a ≥ 10% relative change in weight from the
weight used to calculate the dose, the trastuzumab emtansine dose must be calculated
based on the current weight. The calculated total dose may be rounded to the nearest
milligram.
The initial dose will be administered over 90 minutes (± 10 minutes). Infusions may be
slowed or interrupted for patients experiencing infusion-associated symptoms.
Vital signs must be assessed pre-dose and post-dose. Following the initial dose,
patients will be observed for at least 90 minutes for fever, chills, or other
infusion-associated symptoms. If prior infusions were well tolerated (without any signs
or symptoms of infusion reactions), subsequent doses of trastuzumab emtansine may be
administered over 30 minutes (± 10 minutes), with a minimum 30-minute observation
period after infusion. Local health authority guidelines must be followed with regard to
further observation and monitoring, if applicable. Please refer to the
TDM4370g/BO21977 Study Pharmacy Binder or the most recent version of the
Trastuzumab Emtansine Investigator’s Brochure for the procedures for the preparation
and administration of trastuzumab emtansine.
4.3.1.3 Trastuzumab Emtansine Dose Modification

Patients should be assessed for toxicity prior to each dose; dosing will occur only if the
clinical assessment and laboratory test values are acceptable.
Dose delays and reductions are designed to maximize treatment for those who derive
clinical benefit from treatment while ensuring patient safety. Dose delays for
trastuzumab emtansine−related toxicity other than the ones specified below
(i.e., infusion reactions, hematologic toxicity, hepatotoxicity, neurotoxicity,
and cardiotoxicity) are as follows:
• If significant trastuzumab emtansine–related toxicities (other than infusion reactions,

hematologic toxicity, hepatotoxicity, neurotoxicity, and cardiotoxicity) have not
recovered to Grade 1 or baseline, the next scheduled dose may be delayed for up to
42 days from the last dose received. “Significant” and “related” will be based on the
judgment of the investigator (in consultation with the Sponsors’ Medical Monitor or
designee when appropriate). For example, alopecia even if considered related
would most likely not be considered to be significant. Fatigue may or may not be
considered either related or significant.

• In general, when the significant and related toxicity (or any other toxicity that the
investigator chooses to delay dosing for) resolves to Grade 1 or baseline, the patient
may resume trastuzumab emtansine if the delay has not exceeded 42 days from the
last received dose. Patients should be re-evaluated weekly during the delay,
whenever possible. If dosing resumes, the patient may receive trastuzumab
emtansine either at the same dose level as before or at one dose level lower
(see Table 1 ), at the discretion of the investigator. If possible, subsequent cycles
should remain every 21 days.
• If a patient requires a dose reduction, dosing will be reduced by one dose level, per
Table 1. No dose re-escalation will be allowed.
Table 1 Dose-Reduction for Trastuzumab Emtansine
Dose Level Dose
0 3.6 mg/kg
−1 3 mg/kg
−2 2.4 mg/kg
Indication for further dose reduction Off study
If a toxicity does not resolve within 42 days from the last dose received, the patient will
be discontinued from study treatment and will be followed for disease progression and
survival outcome as described in Section 4.5 .
Protocol requirements for specific toxicities are outlined below.
4.3.1.3.1 Dose Modification for Hematologic Toxicity

Patients receiving trastuzumab emtansine who experience a first Grade 4
thrombocytopenia event may, after adequate recovery to a platelet count of Grade ≤ 1 or
baseline, continue treatment with trastuzumab emtansine at a dose of 3 mg/kg in
subsequent treatment cycles. Patients at the 3 mg/kg dose level who experience a
Grade 4 thrombocytopenia event may, after adequate recovery as defined above,
continue treatment with trastuzumab emtansine at a dose of 2.4 mg/kg in subsequent
treatment cycles. Patients who experience a Grade 4 thrombocytopenia event at the
2.4 mg/kg dose level will be discontinued from study treatment. A dose delay of up to
42 days from the patient’s last dose received is permitted.
Patients who experience a Grade 3 or 4 hematologic event should be checked twice

weekly for recovery of counts. If a patient’s platelet counts do not recover to baseline
or Grade ≤ 1 within 42 days from the patient’s last dose received, the patient will be
discontinued from study treatment.
No re-escalation of the trastuzumab emtansine dose is allowed.

4.3.1.3.2 Dose Modification for Hepatotoxicity
Regardless of dose level, trastuzumab emtansine must be permanently discontinued in
patients with ALT > 3 × ULN and a subsequent increase of total bilirubin to > 2 × ULN
within 21 days. All relevant hepatic laboratory tests performed (including AST, ALT,
total bilirubin, alkaline phosphatase, PTT, INR, and albumin) will be entered into the
clinical database.
Regardless of dose level, for patients with AST > 3 × ULN (without ALT > 3 × ULN) and a
subsequent increase in total bilirubin to > 2 × ULN within 21 days, treatment with
trastuzumab emtansine may be continued with one dose level reduction after recovery
of AST to ≤ 2.5 × ULN and total bilirubin to ≤ 1.5 × ULN only after consultation with
the Medical Monitor. Please see Table 1 for instructions pertaining to dose reduction.
All relevant hepatic laboratory tests performed (including AST, ALT, total bilirubin,
alkaline phosphatase, PTT, INR, and albumin) will be entered into the clinical database.
Patients receiving trastuzumab emtansine at 3.6 mg/kg who experience a Grade 3 or 4

transaminase elevation and/or a Grade ≥ 2 total bilirubin elevation may, after adequate
recovery to Grade ≤ 2 (transaminase levels) and/or Grade ≤ 1 (total bilirubin level) or
baseline, continue treatment with T-DM1 at a dose of 3 mg/kg. Patients at the 3 mg/kg
dose level who experience a Grade 3 or 4 transaminase elevation and/or a Grade ≥ 2
total bilirubin elevation may, after adequate recovery to Grade ≤ 2 (transaminase levels)
and/or Grade ≤ 1 (total bilirubin level) or baseline, continue treatment with trastuzumab
emtansine at a dose of 2.4 mg/kg. Patients at the 2.4 mg/kg dose level who experience
a Grade 3 or 4 transaminase elevation and/or a Grade ≥ 2 total bilirubin elevation will be
discontinued from study treatment. A dose delay of up to 42 days from the patient’s last
received dose is permitted.
Patients who experience a Grade 3 or 4 elevation of liver function should be checked

twice weekly for the recovery of transaminases and/or total bilirubin. If a patient’s
transaminases and/or total bilirubin do not recover to baseline or Grade ≤ 1 within
42 days from the patient’s last dose received, the patient will be discontinued from study
treatment.
No re-escalation of the trastuzumab emtansine dose is allowed.
4.3.1.3.3 Dose Modification for Neurotoxicity

Patients receiving trastuzumab emtansine who experience Grade 3 or 4 peripheral
neuropathy that does not resolve to Grade ≤ 2 within 42 days after the last dose received
will be discontinued from study treatment.
4.3.1.3.4 Dose Modification for Cardiotoxicity

Patients without significant cardiac history and with a baseline LVEF ≥ 50% as
determined by ECHO or MUGA scan are eligible for study participation.
Ejection fractions will be monitored at screening, at 6 and 12 weeks after first dose of

study treatment, and every 12 weeks thereafter until the assessment at the Study Drug
Completion Visit. Figure 1 in Section 3.4.2.1 summarizes the management of
trastuzumab emtansine on the basis of measured LVEF and changes in LVEF from
baseline in patients.
If the LVEF is reported as a range, the average should be taken. If an investigator is

concerned that an adverse event may be related to cardiac dysfunction, an additional
LVEF measurement may be performed. Trastuzumab emtansine will be discontinued in
any patient who develops confirmed CHF (i.e., Grade ≥ 3 left ventricular systolic
dysfunction as defined by NCI CTCAE, Version 3.0). CHF should be treated and
monitored according to standard medical practice.
Trastuzumab emtansine must be discontinued in all patients for whom a drop of LVEF to
below 40% is documented (unless it is not confirmed with a repeat assessment within
21 days). For patients whose LVEF drops to values between 40% and 45%,
the decision to stop or continue Trastuzumab emtansine should be based on the
algorithm shown in Figure 1 .
Trastuzumab emtansine should be held with a decrease in LVEF of ≥ 10% points from
absolute baseline for patients whose LVEF falls to ≤ 45%. For these patients, the LVEF
should be repeated in 21 days, and trastuzumab emtansine should be discontinued if the
LVEF has not recovered to within 10% points from absolute baseline. If clinically
significant cardiac dysfunction or cardiac failure develops or persists or if significant
medical management is required to maintain ejection fraction, the patient should be
discontinued from study treatment.
Please refer to Section 4.5 for assessments to be performed for patients who
discontinue study treatment but have not progressed.
4.3.2 Control Arm Drugs

4.3.2.1 Capecitabine
The following information has been obtained from the Xeloda® EU Summary of Product
Characteristics and U.S. Xeloda® Package Insert. National prescribing information
should be referred to for additional information.
4.3.2.1.1 Capecitabine Formulation

Capecitabine is available as biconvex, oblong, film-coated tablets, available as follows:
• 150-mg tablets: color, light peach; engraving, XELODA on one side, 150 on the
other; packs of 60
• 500-mg tablets: color, light peach; engraving, XELODA on one side, 500 on the
other; packs of 120

4.3.2.1.2 Capecitabine Dosage, Administration, and Storage
of 1000 mg/m2 approximately 12 hours apart) on Days 1−14 in a repeating 21-day cycle.
The cycle is defined by the start of capecitabine chemotherapy. If a patient requires a
delay in treatment on the control arm (beyond Day 21), the restart of capecitabine will
be Day 1 of the next cycle.
Capecitabine should be taken with food or within 30 minutes after food. If a dose is
missed, the patient should skip that dose. The patient should not double the dose the
next administration. Patients should record all doses on the diary card provided for the
study. Do not store capecitabine tablets above 30°C.
4.3.2.1.3 Capecitabine Dosage Modification

The following is to serve as a guideline for the investigator. It is up to the investigator’s
judgment to decide whether a toxicity is significant and/or related and would require a
dose modification and/or interruption. For example, diarrhea and hand-foot syndrome
are known side effects of capecitabine, and dose modifications should be made for
these toxicities as described below.
Please refer to Appendix H for reduction of capecitabine to 75% and 50% of the total
daily dose of 2000 mg/m2/day.
Patients should record all doses on the diary cards provided for the study.
Patients should be assessed for toxicity prior to initiating each new cycle of therapy;
dosing will be initiated only if the clinical assessment and laboratory test values
are acceptable.
Capecitabine may be held to allow Grade 2 to 4 adverse events to resolve to Grade 0 or

1, and future doses modified, as described below.
Grade 2. If a first occurrence of a Grade 2 adverse event felt to be significant

and/or related resolves, capecitabine may be resumed at 100% of the starting dose.
If a second occurrence of a Grade 2 adverse event felt to be significant and/or related

resolves, capecitabine may be resumed at 75% of the starting dose (or 50% if it is
already being given at 75% of the starting dose).
If a third occurrence of a Grade 2 adverse event felt to be significant and/or related

resolves, capecitabine may be resumed at 50% of the starting dose (or permanently
discontinued if it is already being given at 50% of the starting dose).
For any occurrence of a Grade 2 adverse event felt to be significant and/or related at
50% of the starting dose, capecitabine may be permanently discontinued.

Grade 3. If a first occurrence of a Grade 3 adverse event felt to be significant and/or
related resolves, capecitabine may be resumed at 75% of the starting dose (or 50% if it
is already being given at 75% of the starting dose).
If a second occurrence of a Grade 3 adverse event felt to be significant and/or related

resolves, capecitabine may be resumed at 50% of the starting dose (or permanently
discontinued if it is already being given at 50% of the starting dose).
Grade 4. If a first occurrence of a Grade 4 adverse event felt to be significant and/or

related resolves, capecitabine may be resumed at 50% of the starting dose if it is
thought by the investigator to be in the patient’s best interest or may be permanently
discontinued. Capecitabine may be permanently discontinued after a Grade 4 adverse
event if it is already being given at 50% of the starting dose.
If a second occurrence of a Grade 4 adverse event is felt to be significant and/or related

occurs, capecitabine should be permanently discontinued.
Capecitabine may be permanently discontinued for a Grade 2−4 adverse event felt to be
possibly related and significant that fails to resolve if deemed appropriate by the
investigator.
On the basis of the investigator’s judgment, patients may discontinue capecitabine and
remain on lapatinib alone and patients may also discontinue lapatinib and remain on
capecitabine alone.
If lapatinib and capecitabine are both delayed more than 42 consecutive days, the
patient should discontinue study treatment.
4.3.2.2 Lapatinib
The following information has been obtained from the Tykerb® Package Insert and the
E.U. Tyverb® Summary of Product Characteristics. National prescribing information
should be referred to for additional information.
4.3.2.2.1 Lapatinib Formulation

Lapatinib is available as oval, biconvex, orange/yellow, and film-coated 250-mg tablets,
with GS XJG debossed on one side.

4.3.2.2.2 Lapatinib Dosage, Administration, and Storage
The dose of lapatinib is 1250 mg (5 tablets) given orally once daily on Days 1−21,
continually. Lapatinib may be held when appropriate for toxicity, but the timing of
resumption or discontinuation of lapatinib dosing does not define, respectively, the
start or stop of a cycle.
Lapatinib should be taken once daily at least 1 hour before or 1 hour after a meal. If a
day’s dose is missed, the patient should skip that dose. The patient should not double
the dose the next day. Do not store lapatinib tablets above 30°C.
Patients should record all doses on the diary card provided for the study.
Patients should be assessed for toxicity prior to initiating each new cycle of therapy;
dosing will be initiated only if the clinical assessment and laboratory test values are
acceptable.
4.3.2.2.3 Lapatinib Dosage Modification

The following is to serve as a guideline for the investigator. It is up to the investigator’s
judgment to decide whether a toxicity is significant and/or related and would require a
dose modification and/or interruption.
Cardiac Events. Lapatinib administration should be interrupted in patients with a

decreased LVEF that is Grade ≥ 2 by NCI CTCAE and in patients with an LVEF that
drops below the institution’s lower limit of normal. Lapatinib may be restarted at a
reduced dose (1000 mg/day) after a minimum of 14 days if the LVEF recovers to normal
and the patient is asymptomatic.
Hepatic Impairment. Patients with severe hepatic impairment (Child-Pugh Class C;

see Appendix F) should have their dose of lapatinib reduced. A dose reduction to
750 mg/day in patients with severe hepatic impairment is predicted to adjust the area
under the curve (AUC) to the normal range and should be considered.
Effects of Other Medicinal Products on Lapatinib. Please refer to Section 4.4.
4.3.2.3 Other Toxicities

Decisions to discontinue, interrupt, or modify therapy should be based on the
investigator’s judgment of whether the toxicity is likely related and/or clinically significant.
Discontinuation or interruption of dosing with lapatinib may be considered when patients

develop Grade ≥ 2 toxicity that is deemed significant and/or related and may be restarted
at 1250 mg/day when the toxicity improves to Grade ≤ 1 or baseline. If the toxicity recurs,
lapatinib should be restarted at a lower dose (1000 mg/day).
Lapatinib may be permanently discontinued for any Grade 2−4 adverse event felt to be
possibly related and significant that fails to resolve, if deemed appropriate by the
investigator.

On the basis of the investigator’s judgment, patients may discontinue lapatinib and
remain on capecitabine alone, and patients may also discontinue capecitabine and
remain on lapatinib alone.
If lapatinib and capecitabine are both delayed more than 42 consecutive days, the
patient should discontinue study treatment.
4.4 CONCOMITANT AND EXCLUDED THERAPIES

Trastuzumab emtansine, lapatinib, and capecitabine are the investigational medicinal
products in this study. All other concomitant medications and premedication therapies
are considered non-investigational medicinal products. Concomitant therapy
(non-investigational products) includes any prescription medication, over-the-counter
preparation, herbal therapy, or radiotherapy used by a patient between the 14 days
preceding randomization and the study treatment discontinuation visit. Afterward, only
anti-cancer therapies will be collected.
Premedication for lapatinib and capecitabine is allowed according to standard practice

guidelines.
Patients who use maintenance therapy should continue their use unless proscribed.
Concomitant use of erythropoiesis-stimulating agents is allowed if clinically indicated in
accordance with proper prescribing guidelines.

any planned premedication with corticosteroids for the first infusion should be approved
by the Medical Monitor prior to administration. Premedication for nausea and anxiety
has not been generally necessary but is allowed.
Patients who experience trastuzumab emtansine infusion–related temperature

elevations of > 38.5°C or other minor infusion-related symptoms may be treated
symptomatically with acetaminophen and/or H1- and H2-receptor antagonists
(e.g., diphenhydramine, ranitidine). Serious infusion-related events manifested by
dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen
saturation, or respiratory distress should be managed with supportive therapies as
clinically indicated according to standard clinical practice (e.g., supplemental oxygen,
β2-agonists, and corticosteroids).
4.4.1 Effects of Other Medicinal Products on Capecitabine

Concomitant treatment with sorivudine or its chemically related analogs such as
brivudine should be avoided because it has been shown to have clinically significant
drug-drug interactions, including death.

Patients randomized to the control arm who are receiving coumarin-derivative
anticoagulant therapy such as warfarin or phenprocoumen should have their
prothrombin time (PT) or INR monitored weekly because of a potentially fatal drug
interaction between capecitabine and the anticoagulant.
Refer to the capecitabine prescribing guidelines for other potential drug-drug interactions.
4.4.2 Effects of Other Medicinal Products on Lapatinib

Concomitant treatment with inducers of CYP3A4 should be avoided because of a risk of
decreased exposure to lapatinib. Co-administration of lapatinib with known inducers of
CYP3A4 (e.g., rifampicin, rifabutin, carbamazepine, phenytoin, or Hypericum perforatum
[St John’s wort]) should be avoided.
Concomitant treatment with strong inhibitors of CYP3A4 should be avoided because of

the risk of increased exposure to lapatinib. Co-administration of lapatinib with strong
inhibitors of CYP3A4 (e.g., ritonavir, saquinavir, telithromycin, ketoconazole,
itraconazole, voriconazole, posaconazole, nefazodone) should be avoided.
The solubility of lapatinib is pH-dependent. Substances that increase gastric pH should

be avoided, because lapatinib solubility and absorption may decrease. Please refer to
lapatinib prescribing guidelines for more-detailed information.
Grapefruit juice should be avoided during treatment with lapatinib.
Co-administration of lapatinib with medicinal products with narrow therapeutic windows

that are substrates of CYP3A4 (e.g., cisapride, pimozide, and quinidine) or CYP2C8
(e.g., repaglinide) should be avoided. Lapatinib inhibits CYP3A4 and CYP2C8 in vitro at
clinically relevant concentrations.
Refer to the lapatinib national prescribing guidelines for other potential

drug-drug interactions.

Use of the following therapies is prohibited during the study prior to discontinuation
of study treatment (collectively, these will be referred to as non-protocol therapy):
• Any therapies intended for the treatment of breast cancer, whether they are
approved by national health authorities or experimental, including cytotoxic
chemotherapy (other than that specified by the protocol), immunotherapy, hormonal
therapy (other than megestrol acetate), and biologic agents (other than granulocyte
colony-stimulating factor and erythropoiesis-stimulating agents)
• Radiotherapy
Palliative radiotherapy may be permitted to treat painful bone metastases.
Please contact the Medical Monitor for approval. If the Medical Monitor
cannot be reached because of time zone differences, radiotherapy may be
administered, but the Medical Monitor should still be informed.
Patients who require the use of any of these therapies described above will be
discontinued from study treatment, unless approved by the Medical Monitor, but will be
followed for disease progression and survival (see Appendix A-1).
Other medications considered necessary for the patient’s safety and well-being may be
given at the discretion of the investigator. Use of bisphosphonates for other purposes,
including control of bone pain, prevention and/or treatment of bony metastases, and
treatment of osteoporosis, is permitted. If required for the treatment of symptomatic
malignancy-associated hypercalcemia, tumor assessments should be performed to
document PD radiographically.
4.5 STUDY ASSESSMENTS

All patients will be closely monitored for safety and tolerability during all cycles of therapy
and at the study drug completion visit. Patients should be assessed for toxicity prior to
each dose; dosing will occur only if the clinical assessment and local laboratory test
values are acceptable. Patients will be monitored during study drug administration as
described in Section 3.4 and 4.3 . Study drug will be administered in 21-day cycles if no
additional time is required for reversal of toxicity as discussed in Section 4.3. Dose
delays and dose reductions will be allowed for trastuzumab emtansine and
lapatinib + capecitabine as outlined in Section 4.3.
If the timing of a protocol-mandated procedure coincides with a holiday and/or weekend that
precludes the procedure within the allotted window, the procedure should be performed on the
nearest following date. Visits are based on a 21-day cycle. In the control arm, the cycle is
defined by the start of capecitabine dosing. If a patient requires a delay in treatment on the
control arm (beyond Day 21), the restart of capecitabine will be Day 1 of the next cycle.

Study assessments are outlined in this section. Appendices A-1 and A-2 contain a
study flowchart for randomized patients and a flowchart of blood sample collection for
central laboratory assessments, respectively. Appendix A-3 contains a study
flowchart for control patients who cross over to receive trastuzumab emtansine.
4.5.1 Tumor Assessments

Measurable and non-measurable disease must be documented at screening
(within 30 days of randomization) and must be re-assessed at each subsequent tumor
evaluation per modified RECIST (see Appendix B). Prior to the final PFS analysis,
tumor assessments were to be performed every 6 weeks until disease progression
regardless of drug delays or interruptions or early drug discontinuation. All patients must
have had one additional tumor assessment 6 weeks after the initial documentation of
investigator-assessed disease progression.
After completion of the final PFS analysis, the frequency, method, and evaluation
criteria of tumor assessments will be according to routine clinical practice per
investigator. It is recommended that the investigator continue using modified RECIST
in tumor assessments and for patient care decisions.
Tumor assessments should include an evaluation of all known and/or suspected sites of
disease, whenever possible. Patients should have lesions selected that can be
evaluated at every tumor assessment. Patients with non-measurable disease (including
patients with bone-only disease) whose non-target lesions are not assessed at a
follow-up visit will be considered unevaluable at that visit unless PD is assessed.
Tumor response (based on CT and bone scans, X-rays, MRIs, and/or physical exam
findings) should be assessed by the investigator using modified RECIST (see
Appendix B) and will be used for patient care decisions.
CT scans should include the chest, abdomen, and pelvis. Contrast agents (IV and oral)
should be used per standard practice. If the patient cannot undergo CT with contrast,
then the chest should be imaged via CT without contrast and the abdomen and pelvis
should be imaged using MRI with contrast. A bone scan and/or X-rays and a brain scan
are required 30 days prior to randomization and should be repeated if PD in the relevant
organ is suspected as outlined in this section and in Appendix A-1. At the investigator’s
discretion, radiographic imaging may be repeated at any time if PD is suspected.
In applying modified RECIST (see Appendix B), it is recommended that if bone lesions
are selected as index non-target lesions, they must be apparent on baseline CT scans or
X-rays (plain film or other radiographic modality) and can be repeated at every tumor
assessment. At the investigator’s discretion, additional baseline films may be obtained
to follow a clinically important or dominant lesion, in the femur for example, if not
visualized on pelvic CT scan.

In addition, radiographic imaging is preferable to physical examination findings whenever
possible. For example, in applying modified RECIST, it is recommended that lesions
identified at the baseline physical examination be selected as index non-target lesions
when considered by the investigator as clinically relevant and reproducibly evaluable on
baseline CT scan or other X-ray. Radiographic imaging (or photographic documentation)
is also preferred when there is unequivocal evidence of PD assessed by physical
examination.
4.5.2 Screening and Pretreatment Assessments

Written informed consent for participation in the study must be obtained before
performing any study-specific screening tests or evaluations. ICFs for patients who are
not subsequently enrolled will be maintained at the study site.
Once the patient has signed the ICF, a call to IVRS should be made prior to Cycle 1,
Day 1 to obtain the patient’s screening number.
Results of standard-of-care tests or examinations performed prior to obtaining informed

consent and within 30 days prior to randomization may be used; such tests do not need
to be repeated for screening.
The following screening and pretreatment tests and evaluations will be performed within
30 days prior to randomization unless indicated otherwise:
• Prospective HER2 central testing

Tumor cell blocks or unstained slides (at least 11 slides) are required to be sent
at any point prior to randomization to a central laboratory identified by the
Sponsors for confirmation of HER2 positivity (i.e., IHC 3 + and/or FISH +).
Both IHC and FISH assays will be performed; however, only one positive result
is required for downcrolling crollingcrolleligibility.
qRT-PCR will also be performed to assess HER2 expression levels.
Detailed procedures for collection, handling, and shipping of the samples to the
central laboratory will be provided in the Sampling Handling Manual.
If prior approval has been granted by the Sponsors or designee,
centrally confirmed HER2 results (IHC and/or FISH) from a current or
previous study identified by the Sponsors⎯for example, Studies BETH
(AVF4285s/BO20906), AVEREL (BO20231), HERA (BO16348),
NEOSPHERE (WO20697), MARIANNE (BO22589/TDM4788g, AVANT,
HANNAH, PHEREXA, or CLEOPATRA (WO20698/TOC4129g)⎯can be used
to determine eligibility for this study. Additional tissue samples will be required
to perform all mandatory testing (IHC, FISH, and qRT-PCR).

Optional tumor tissue
For patients who have provided appropriate consent, additional tumor tissue
samples (at least 5 unstained slides) will be collected at screening or at any
point during the study. Assessments may include the HER2 signaling pathway
and other related pathways. Analysis may also include mutation status of
genes in the HER2 signaling pathway. These assessments may be performed
by the Sponsors or at a central laboratory.
• Medical history and demographics
• Weight and height
Record concomitant medications used within 14 days prior to randomization
and record investigational and standard anti-cancer therapies used within 21
days of randomization.
Prior to initiation of study medication, only serious adverse events considered to
be related to protocol-mandated procedures will be collected.
• 12-lead electrocardiogram (ECG)
• ECHO or MUGA scan (ECHO is strongly preferred because of the anticipated global
Tc-99m shortage).
The same method used at screening should be used throughout the study
unless the Tc-99m shortage inhibits the ability to comply. Prior to the final
PFS analysis, all ECHO and MUGA scans were submitted for independent
central review. After the final PFS analysis, analysis of ECHO/MUGA results
will be performed locally without the need for central submission or review.
• Baseline isotope bone scan and/or skeletal X-rays
Because of the anticipated Tc-99m shortage, skeletal X-rays should be
obtained in addition to an isotope bone scan. Skeletal X-rays should include
areas of the body that are not included by other radiographic modalities (CT
scans of the chest, abdomen, and pelvis) to accurately assess the existence of
relevant non-target lesions (bony lesions). Skeletal X-rays should also be
performed to assess any suspicious bone lesions within the appendicular
skeleton if the screening CT scans of the chest, abdomen, and pelvis warrant
further evaluation.

• Baseline tumor assessment (CT scans of the chest, abdomen, and pelvis with IV
and oral contrast; see Section 4.5.1 for additional details)
The same radiographic procedure used at screening must be used throughout
the study (e.g., the same contrast protocol for CT scans). Technical imaging
parameters are defined in Appendix B. Prior to the final PFS analysis, all
radiographic images were to be submitted for central review. After the final
PFS analysis, submission of radiographs to the IRC for central review will no
longer be required.
• Baseline CT or MRI scan of the brain
• Urinalysis
Includes specific gravity, pH, protein, glucose, blood ketones, and bilirubin
Complete blood count (CBC) with platelet count and 3-part differential
(hemoglobin, hematocrit, platelet count, red blood cells, white blood cells;
differentials: lymphocytes, monocytes, and granulocytes)
Serum chemistries (sodium, potassium, chloride, bicarbonate, glucose, blood
urea nitrogen (BUN), creatinine, calcium, phosphorus, total and direct bilirubin,
total protein, albumin, ALT, AST, lactate dehydrogenase (LDH), ALP, and uric
acid)
INR and aPTT
Serum pregnancy test (for women of childbearing potential,
including premenopausal women who have had a tubal ligation)
Must be performed within 7 days prior to randomization.
4.5.2.1 Screening Assessments for Control Patients Who Cross over
to Receive Trastuzumab Emtansine
Patients randomized to the control arm may have the option to cross over to receive trastuzumab
emtansine (see Section 3.1 ). These patients will be required to meet the eligibility criteria
described in Section 4.1.4 . Cross-over patients will undergo the following assessments and
procedures within 30 days prior to receiving their first dose of trastuzumab emtansine on Day 1
of Cycle 1:
• Medical history
• Weight
Record concomitant medications used within 14 days prior to the Cycle 1, Day 1
dose and record investigational and standard anti-cancer therapies used within 21 days
prior to the Cycle 1, Day 1 dose.

Prior to initiation of study medication, only serious adverse events considered to be
related to protocol-mandated procedures will be collected.
• 12-lead ECG
• ECHO or MUGA scan (ECHO is strongly preferred because of the anticipated
global Tc-99m shortage)
• Isotope bone scan and/or skeletal X-rays
Because of the anticipated Tc-99m shortage, skeletal X-rays should be obtained in
addition to an isotope bone scan. Skeletal X-rays should include areas of the body that
are not included by other radiographic modalities (CT scans of the chest, abdomen, and
pelvis) to accurately assess the existence of relevant non-target lesions (bony lesions).
Skeletal X-rays should also be performed to assess any suspicious bone lesions within
the appendicular skeleton if the screening CT scans of the chest, abdomen, and pelvis
warrant further evaluation.
• Tumor assessment (CT scans of the chest, abdomen, and pelvis with IV and oral
contrast; see Section 4.5.1 for additional details)
• CT or MRI scan of the brain
CBC with platelet count and 3-part differential (hemoglobin, hematocrit, platelet count,
red blood cells, white blood cells; differentials: lymphocytes, monocytes, and
granulocytes)
Serum chemistries (sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine,
calcium, phosphorus, total and direct bilirubin, total protein, albumin, ALT, AST,
LDH, and ALP)
INR and aPTT
Serum pregnancy test (for women of childbearing potential, including premenopausal
women who have had a tubal ligation)
Must be performed within 7 days prior to the Cycle 1, Day 1 dose.
4.5.3 Randomization
For U.S. sites, once all required screening test results are available and eligibility has
been confirmed by the site, the study site will be required to fax information regarding
the patient’s eligibility for approval prior to enrollment. Please see details for faxing in
your Site Binder. Please allow up to 24 hours to obtain approval once a completed
package has been received. After receiving approval to enroll, the study site will obtain
the patient’s study randomization number and randomization assignment from the IVRS.
Randomization may occur on Cycle 1, Day 1; patients should receive their first dose of
study treatment no later than 5 days after randomization.

For non−U.S. sites, an Eligibility Screening Form (ESF) documenting the subject’s
fulfillment of the entry criteria for all patients considered for the study and subsequently
included or excluded is to be completed by the investigator/designee. Patients who are
considered for study entry but fail to meet the eligibility requirements should also have
an ESF completed with the reason for lack of eligibility given, since this provides
information on the selected trial population. This information will not be entered into the
clinical trial database but will be collected in the IVRS database via screen-failure calls
with the reason for screen failure. All ESFs should be kept in the study files at the sites.
4.5.4 Assessments during Treatment

All visits must occur within ± 3 days from the scheduled date, unless otherwise
noted. All assessments will be performed on the day of the specified visit unless
indicated otherwise. Assessments scheduled on the day of study drug administration
(Day 1) of each cycle should be performed prior to study drug administration,
unless otherwise noted.
4.5.4.1 Cycles 1−34+, Day 1 (study treatment is to begin ≤ 5 days

following randomization)
• Assignment of patient randomization numbers via the IVRS if not already performed
• Limited physical examination
For the purposes of this study, a limited physical is defined as a directed
physical rather than a thorough examination of all body systems. For example,
if the patient presents with a symptom, there should be a more comprehensive
assessment of the affected body system.
• Weight
• Adverse events
• FACT-B (see Appendix C)
For female patients only. Administer prior to any other study procedure or
discussion of any test results (not required for patients who cross over from the
control to trastuzumab emtansine)
• DAS (see Appendix D)
Administer prior to any other study procedure or discussion of any test results
(prior to the final PFS analysis)
• Pre-dose (within 96 hours of visit) local laboratory assessments
All results except for alkaline phosphatase and LDH must be reviewed by
Principal Investigator or designee prior to study drug administration/distribution.

CBC with platelet count and 3-part differential (hemoglobin, hematocrit, platelet
count, red blood cells, white blood cells; differentials: lymphocytes, monocytes,
and granulocytes)
Serum chemistries (BUN, creatinine, total bilirubin, ALP, LDH, AST, and ALT)
• Assessment of patient hospitalizations and/or hospital visits
• Central laboratory assessments for patients in both treatment arms
(see Appendix A-2 and the Central Laboratory Manual; review of results is not
required prior to study drug administration/distribution) (prior to the final PFS
analysis)
• Study drug administration/distribution (see Section 4.3 )
For patients assigned to the control arm. Treatment with lapatinib and
capecitabine will start as described in Section 4.3.2 .
For patients assigned to trastuzumab emtansine and for those who cross over
from the control arm to trastuzumab emtansine. Take vital signs before and
after the trastuzumab emtansine infusion. The first infusion of trastuzumab
emtansine will be administered over approximately 90 minutes. Patients will be
monitored for any untoward effects during the infusion and for at least 90
minutes after completion of the first trastuzumab emtansine infusion (see
Section 4.3.1 ).
4.5.4.2 Weeks 6, 12, and Every 6 Weeks Thereafter (± 5 Days)
• Prior to the final PFS analysis, tumor assessments were performed according to the
following schedule:
Every 6 weeks (i.e., Weeks 6, 12, 18, 24, 30, 36, 42, 48, etc.) until disease
progression ( ± 5 days) and one additional assessment 6 weeks after disease
progression ( ± 7 days) regardless of delay in dosing
Visit date were always to be based on randomization or Cycle 1,
Day 1 regardless of delay in dosing.
Sites were instructed to submit all radiographic images to a central reading
facility within 2 weeks of the patient visit (please see the IRC Manual for
shipping details).
• After the final PFS analysis, the frequency, method, and evaluation criteria of
tumor assessments will be according to routine clinical practice per investigator.
It is recommended that the investigator continue using modified RECIST in tumor
assessments and for patient care decisions. The IRC will discontinue the review of
tumor assessment data following the final PFS analysis.
Refer to Section 4.5.1 for additional details.

4.5.4.3 Weeks 6, 12, and every 12 Weeks Thereafter (± 5 days) until the
Study Drug Completion Visit
If a dose is delayed significantly because of cardiotoxicity, an additional scan should be
performed to have an accurate assessment of current cardiac function.
• ECHO or MUGA scan (ECHO is strongly preferred because of the anticipated global
Tc-99m shortage).
Results must be reviewed prior to next scheduled dose administration.
Additional scans are permitted if clinically indicated.
The same method used at screening should be used throughout the study
unless the Tc-99m shortage inhibits the ability to comply.
Prior to the final PFS analysis, sites were instructed to submit all ECHO and
MUGA scans to the central reading facility within 2 weeks of the patient visit
(please see the IRC Manual for shipping details). After the final PFS analysis,
the IRC will discontinue the review of left ventricular systolic dysfunction, so
further submission of ECHO/MUGA scans to the central facility is not
required.
4.5.5 Study Drug Completion Visit
Patients may remain on study treatment until disease progression (as assessed
by the investigator), unmanageable toxicity, or study termination by the Sponsors.
Patients who discontinue study treatment will be asked to return to the clinic
approximately 30 days (± 7 days) after the last study drug administration,
for the Study Drug Completion Visit. Please see the Study Flowchart provided in
Appendix A-1 for the assessments to be performed at the Study Drug Completion Visit.
4.5.6 Follow-Up Assessments after Study Drug Completion

Visit/Survival Follow-Up
After the Study Drug Completion Visit, ongoing adverse events related to study
treatment or participation should be followed until the event has resolved to baseline
grade, the event is assessed by the investigator as stable, the patient is lost to follow-up,
the patient withdraws consent, or when it has been determined that the study treatment
or participation is not the cause of the adverse event.
The occurrence of serious adverse events will be collected until 30 days after the last
dose of study treatment. Thereafter, only serious adverse events felt by the investigator
to be related to the prior study treatment will be collected.
Patients who are discontinued from study treatment for any reason will complete the
Study Drug Completion Visit approximately 30 days after the last dose of study
treatment.


should be completed every two treatment cycles until treatment discontinuation for any
reason. After treatment discontinuation, the FACT-B assessment will be performed
according to the same schedule as survival follow-up. Completion of the FACT-B is not
required of patients who cross over from the control arm to receive trastuzumab emtansine.
4.6 PATIENT DISCONTINUATION

The investigator has the right to discontinue a patient from study therapy a) for any
medical condition that the investigator determines may jeopardize the patient’s safety if
he or she continues in the study, b) for reasons of noncompliance (e.g., missed doses,
visits), c) if the patient becomes pregnant, or d) if the investigator determines it is in the
best interest of the patient.
Patients may withdraw from the study or from study therapy at any time. Any patient
who withdraws will be asked to return to the study center for a follow-up visit. Patients
who discontinue study treatment early should return approximately 30 days following the
last dose of study drug to complete the Study Drug Completion Visit. The primary
reason for discontinuation must be recorded on the appropriate electronic Case Report
Form (eCRF) page.
Patients must be withdrawn from study therapy if they experience either of the following:
• Disease progression (defined using modified RECIST; see Appendix B)
• Toxicity per the parameters specified in Section 3.4 or other unacceptable toxicity
All patients should be followed for survival follow-up in clinic or by phone until death.
See Sections 4.5.5 and 4.5.6 for assessments to be performed for patients who
prematurely withdraw from the study or from study therapy.
4.7 STUDY DISCONTINUATION

The study will be considered completed when approximately 632 deaths have been
reported and the final analysis of OS is completed. This is defined as the end of the
study. Prior to that, the Sponsors have the right to terminate this study at any time.
Reasons for terminating the study may include but are not limited to the following:
• The incidence or severity of adverse events in this or other studies indicates a
potential health hazard to patients.

• Patient enrollment is unsatisfactory.
• Data recording is inaccurate or incomplete.
4.8 ASSAY METHODS

4.8.1 Trastuzumab Emtansine ELISA
Serum samples will be assayed for trastuzumab emtansine in an indirect sandwich
ELISA. The assay will use an anti-DM1 monoclonal antibody in the capture phase of
the assay. The assay will use biotinylated recombinant HER2 ECD and horseradish
peroxidase conjugated to streptavidin for detection. The minimum quantifiable
concentration is 40 ng/mL.
4.8.2 Total Trastuzumab ELISA

Serum samples will be assayed for total trastuzumab (trastuzumab and trastuzumab
conjugated to DM1) in an indirect sandwich ELISA. The assay will use an
anti-complementarity determining region antibody against trastuzumab in the
capture phase of the assay and biotinylated anti-human IgG antibody, followed by
horseradish peroxidase avidin D for detection. The minimum quantifiable
concentration is 40 ng/mL.
4.8.3 DM1 LC-MS/MS Assay

Lithium–heparin plasma samples will be assayed using liquid chromatography
electrospray tandem mass spectrometry (LC−MS/MS). Prior to analysis, the samples
will be treated with a reducing agent to release any disulfide-bound DM1. The DM1 will
then be extracted from the plasma followed by treatment with n-ethyl maleimide to block
the free sulfhydryls. The derivative is then assayed by LC−MS/MS. The lower
and upper limits of quantification are 100 nmol/L and 500 nmol/L, respectively.
4.8.4 Anti-Trastuzumab Emtansine Antibody ELISA

Serum samples will be assayed for anti–trastuzumab emtansine antibodies in a bridging
antibody ELISA. Samples, biotinylated trastuzumab emtansine, and trastuzumab
emtansine conjugated to digoxigenin will be incubated together to form the antibody
bridge, which will be captured on a streptavidin-coated plate. Horseradish peroxidase-
conjugated mouse monoclonal anti-digoxigenen antibody will be added for detection.
The minimum dilution of serum samples is 1/50, resulting in the sensitivity of log1050
(equivalent to 1.70-log titer unit).
4.8.5 HER2/NEU Serum Extracellular Domain

Serum samples will be analyzed for HER2 ECD levels using an FDA-approved assay
method. Please refer to the laboratory manual for further details.
4.8.6 HER2 Confirmatory Testing

HER2 gene amplification will be assessed on all archival tumor material with use of
HER2 FISH kit (DAKO pharmDx™) and select samples will be subject to HER2 gene

amplification using an FDA-approved HER2 FISH kit (e.g., Abbott PathVysion® HER-2
DNA Probe Kit or DAKO HER2 FISH pharmDx™ Kit). Testing for HER2 gene
amplification will be performed according to the manufacturer’s instructions. In brief,
tissue sections will be heated in formamide to denature the DNA. Dual-color DNA
probes for HER2 (red) and CEP17 (green) will be applied to the slide for hybridization.
The slides will then be washed to remove unbound probe. The average number of
HER2 and CEP17 copies per cell will be determined by counting signals in
approximately 20 tumor nuclei. The ratio of HER2 to CEP17 is then calculated. If the
ratio is ≥ 2.0, the sample is considered amplified.
Tumor samples will also be tested for HER2 protein overexpression by IHC with use of
an FDA-approved HER2 IHC kit (e.g., DAKO HercepTest®) according to the
manufacturer’s instructions.
qRT-PCR analysis of HER2 and other HER family receptors and/or ligands will be
performed. Some samples may be enriched for tumor content by macrodissection of
histologically identifiable tumor. RNA will be extracted, and qRT-PCR for HER family
receptors and/or ligands and a reference gene will be performed using a standard
platform (e.g., LightCycler or TaqMan).
4.8.7 Pharmacogenomic Studies

Whole blood samples will be sent to a central laboratory for assay to find polymorphisms
that may be useful predictors of efficacy or safety.
4.8.8 Tissue Samples

For patients who have signed the Optional Research ICF, paraffin tissue blocks or
unstained tissue slides may be used for assessment of levels of expression of
HER family proteins, the HER2 signaling pathway, and other related pathways. Analysis
may also include mutation status of genes in the HER2 signaling pathway.
Any slides submitted from patients who sign the Optional Research ICF will be retained
by the Sponsors; paraffin block tumor tissue not required for exploratory analyses will be
returned to the referring institution.

4.9 STATISTICAL METHODS
This study is a randomized, multicenter, international, two-arm, open label trial designed
to compare the efficacy and safety of trastuzumab emtansine with
lapatinib + capecitabine for HER2-positive MBC. PFS and OS are co-primary efficacy
endpoints for this study. The date of data cutoff for the final analysis of PFS will be
when 508 IRC-assessed PFS events occur. However, the final analysis of PFS will not
be conducted until the last patient is enrolled. The final analysis of OS will be performed
when approximately 632 deaths have occurred.
4.9.1 Analysis of the Conduct of the Study

Patient enrollment, duration of follow-up, and discontinuation from the study
and discontinuation reasons will be summarized by treatment arm for all randomized
patients. In addition, protocol deviations and eligibility violations will be summarized by
treatment arm.
4.9.2 Analysis of Treatment Group Comparability

The evaluation of treatment group comparability between the two treatment arms will
include summaries of demographics, medical history, baseline disease characteristics,
and patient treatment history.
Descriptive statistics (mean, median, standard deviation, 25th percentile, 75th percentile,
and range) will be presented by treatment arm for continuous variables such as age,
time since initial breast cancer diagnosis, and time since metastatic diagnosis.
Frequency counts will be presented by treatment arm for categorical variables such as sex,
race, age category, ECOG performance status, estrogen receptor/progesterone receptor
status, HER2 (IHC 3 + and/or FISH positive) status, number of prior chemotherapy agents,
prior radiation therapy, and prior anthracycline therapy.
4.9.3 Efficacy Analyses

The intent-to-treat (ITT) population is the primary analysis population for the primary
endpoint. The ITT population consists of all patients who are randomized, regardless of
whether they received any study drug or complete a full course of treatment. A patient is
considered to be randomized to treatment when the study site is notified of the initial
randomization number assigned to that patient. The ITT population will be analyzed
according to the treatment assigned at randomization.
4.9.3.1 Primary Efficacy Endpoint

To adjust for multiplicity due to having two primary endpoints, a fixed-sequence
hypothesis testing procedure will be implemented. The hypothesis test for PFS will be
conducted at a one-sided alpha of 2.5%. If the PFS is statistically different between the
two arms, OS will be tested at a one-sided alpha of 2.5% to determine if the two arms
have significantly different OS.

The co-primary efficacy endpoint of PFS is based on independent review of tumor
assessment, defined as the time from randomization to documented IRC-assessed
disease progression or death from any cause (whichever occurs earlier).
For the analysis of PFS, data for patients without disease progression or death will
be censored at the time of the last tumor assessment (or, if no tumor assessment was
performed after the baseline visit, at the time of randomization plus 1 day). Data from
patients who are lost to follow-up will be included in the analysis as censored
observations on the last date of tumor assessment that the patient was known to be
progression free.
For patients who receive non-protocol therapy (defined as any treatment the patient
receives that is intended to treat his or her MBC) prior to documented PD, the primary
PFS analysis will not censor patients at the initiation of non-protocol therapy. A
sensitivity analysis of PFS censoring patients at the last tumor assessment before the
initiation of non-protocol therapy will also be performed.
The two-sided log-rank test, stratified by world region (United States, Western Europe,
Other), number of prior chemotherapeutic regimens for unresectable, locally advanced
or metastatic disease (0−1 vs. > 1), and visceral versus non-visceral disease will be
used as the primary analysis to compare PFS between the two treatment arms. The
results from the unstratified log-rank test and the stratified and unstratified Wilcoxon test
will also be provided.
Cox proportional-hazards models, stratified by world region (United States, Western
Europe, Other), number of prior chemotherapeutic regimens for unresectable, locally
advanced or metastatic disease (0−1 vs. > 1), and visceral versus non-visceral disease
will be used to estimate the hazard ratio (HR) and its 95% CI.
OS, the co-primary endpoint, is defined as the time from the date of randomization to the
date of death from any cause. Patients who are alive at the time of the analysis data
cutoff will be censored at the last date they were known to be alive. Patients with no
post-baseline information will be censored at the date of randomization plus 1 day.
Methods for OS analysis are similar to those described for the PFS endpoint, with the
stratified log-rank test being the primary analysis and sensitivity analysis using the
unstratified log-rank test and the stratified and unstratified Wilcoxon test. In addition,
1-year and 2-year survival rates and corresponding 95% CIs will be estimated using
the Kaplan−Meier approach, as appropriate.

The final analysis of OS will occur after 632 deaths have occurred. An interim analysis
of OS will be performed at the time of the primary efficacy analysis of PFS. Additional
interim analyses of OS may be performed with the appropriate control of the Type I
error rate using the pre-specified Lan-DeMets function with O’Brien-Fleming
boundary.
See Section 4.9.10 (Interim Analysis) for additional information.
4.9.3.2 Secondary Efficacy Endpoints

If the primary endpoints of PFS (based upon independent review of tumor assessments)
and OS are statistically significant, the secondary endpoints will be tested in the
following order: PFS (based upon investigator assessment), response rate (based upon
independent review of tumor assessments), time to treatment failure, and time to
symptom progression (see Section 4.9.6.1 ). Additional details on the testing procedure
will be provided in the Statistical Analysis Plan.
4.9.3.2.1 Progression-Free Survival Based on Investigator Tumor

Assessment
PFS based on investigator tumor assessment is defined as the time from randomization
to documented investigator-assessed disease progression or death from any cause
(whichever occurs earlier). Disease progression will be determined by investigator
assessment of tumor assessments with use of modified RECIST. The methods for data
censoring and analysis are similar to those described for the primary endpoint; however,
patients will not be censored at the initiation of non-protocol therapy.
4.9.3.2.2 Objective Response

Objective tumor response will be determined primarily by independent review of tumor
assessments through use of modified RECIST (an analysis based on investigator tumor
assessments will also be performed). Only patients with measurable disease at baseline
will be included in the analysis of objective response. Patients without a post-baseline
tumor assessment will be considered non-responders.
An estimate of the ORR and its 95% CI (Blyth-Still-Casella) will be calculated for each
treatment arm. The Mantel-Haenszel χ2 test stratified by world region (United States,
Western Europe, Other); number of prior chemotherapeutic regimens for unresectable,
locally advanced or metastatic disease (0−1 vs. >1); and visceral versus non-visceral
disease will be used to compare the response rate between the two treatment arms. An
unstratified analysis will also be performed. Finally, the difference in response rate will
also be provided with 95% CIs.

4.9.3.2.3 Duration of Objective Response
Only patients with an objective response will be included in the analysis of duration of
objective response. Duration of objective response is defined as the time from first
documented objective response to first documented disease progression or death from
any cause (whichever occurs earlier). Duration of objective response will be determined
primarily by independent review of tumor assessments through use of modified RECIST
(an analysis based on investigator tumor assessments will also be performed). The
censoring methods for this endpoint are similar to those described for PFS. Patients will
not be censored at the initiation of non-protocol therapy. The Kaplan−Meier approach
will be used to estimate the median duration of objective response for each treatment
group and the corresponding 95% CIs. Because of the non-randomized nature of these
data, the analysis of duration of objective response will be considered descriptive.
4.9.3.2.4 Clinical Benefit Rate

The CBR (the proportion of patients with CR, PR, or SD at 6 months from randomization)
will be compared between the two treatment arms on the basis of both investigator and
independent review of tumor assessments, separately. Patients without a post-baseline
tumor assessment will be considered to be non-responders.
An estimate of the CBR and its 95% CI (Blyth-Still-Casella) will be calculated for each
treatment arm. The Mantel-Haenszel χ2 test stratified by world region (United States,
Western Europe, Other); number of prior chemotherapeutic regimens for unresectable,
locally advanced or metastatic disease (0−1 vs. > 1); and visceral disease versus non-
visceral disease will be used to compare the CBR between the two treatment arms. An
unstratified analysis will also be performed. Finally, the difference in CBR will also be
provided with 95% CIs.
4.9.3.2.5 Time to Treatment Failure

TTF is defined as the time from randomization to discontinuation of treatment for any
reason, including disease progression, treatment toxicity, and death from any cause.
Patients who have not failed treatment (as defined above) will be censored at their last
study treatment date. The methods for analysis are similar to those described for PFS.
Patients who are on study treatment at the time of the analysis cutoff date will be
censored at the time of the last dose received.
4.9.4 Safety Analysis

Safety analyses will be performed on the treated population, which is defined as patients
who receive at least one dose of study medication, and will be based on the treatment
they actually receive.

4.9.4.1 Study Drug Exposure
The number of patients who experience a dose delay of > 1 week, dose modification,
and dose discontinuation and reasons for study treatment discontinuation will be
summarized for trastuzumab emtansine and the control regimen. Descriptive statistics
will be presented for total cumulative dose, number of cycles, dose intensity, and weeks
of exposure for trastuzumab emtansine and the control regimen.
4.9.4.2 Adverse Events

Safety will be assessed through summaries of adverse events, serious adverse events,
deaths, and changes in laboratory test results. Verbatim descriptions of adverse events
will be mapped to Medical Dictionary for Regulatory Activities thesaurus terms. All
adverse events occurring on or after the date of the first study treatment administered
will be summarized by mapped term, appropriate thesaurus levels, and NCI CTCAE
version 3.0 toxicity grade.
Deaths reported during the study treatment period and those reported during follow-up
after patient treatment discontinuation will be summarized by treatment arm. In addition,
the cause of death will be summarized (e.g., disease related, treatment related, other,
unknown).
4.9.4.3 Laboratory Data

Changes in laboratory data will be summarized by grade with use of the NCI CTCAE
version 3.0 toxicity grade by treatment arm.
4.9.4.4 Left Ventricular Ejection Fraction

Changes in LVEF from baseline and nadir over each scheduled visit will be summarized
by treatment arm. In particular, the median at baseline and at nadir will be summarized
for the two treatment arms. The number of patients who have an LVEF decrease to
below 40%, develop Grade 3 left ventricular dysfunction, or discontinue drug because of
cardiac function will be summarized. The number of patients who drop to below 50%
with an absolute decrease of ≥ 15 percentage points will also be summarized.
4.9.5 Pharmacokinetic and Pharmacodynamic Analyses

Blood and serum samples for measurement of trastuzumab emtansine, total
trastuzumab, and DM1 will be obtained from approximately 160 patients randomized to
the trastuzumab emtansine arm. Individual and mean trastuzumab emtansine and total
trastuzumab serum levels and DM1 plasma concentrations versus time data will be
tabulated and plotted. Serum and pharmacokinetics of trastuzumab emtansine will be
summarized by estimating total plasma exposure (AUC), maximum plasma
concentration (Cmax), total clearance, volume of distribution at a steady state (Vss), and
terminal elimination half-life (t1/2 where possible). Estimates for these parameters will be
tabulated and summarized (e.g., mean, standard deviation, coefficient of variation,
median, minimum, maximum, and range). Inter-patient variability and drug accumulation

after multiple dosing will be evaluated. Compartmental, noncompartmental,
and/or population approaches will be considered as appropriate.
Additional PK and pharmacodynamic analyses and exposure-efficacy analyses will be

conducted as appropriate.
4.9.6 Pharmacoeconomic and Patient-Reported Outcomes Analyses

4.9.6.1 Time to Symptom Progression
The time to symptom progression (defined as the time from randomization to the first
documentation of a ≥ 5-point decrease from baseline in the scoring of responses)
as measured by the FACT-B TOI will be measured between the two treatment arms.
The FACT-B TOI is a subset of the FACT-B and includes the Physical, Functional and
Breast subscales. A change of 5 points in the FACT-B TOI is considered clinically
significant. Only patients with a baseline assessment will be included in this analysis.
Analysis of time to symptom progression will be based on female patients only in the ITT
analysis population.
The analysis methods are similar to those described for the primary efficacy endpoint.
Data for patients who do not have an observed symptom progression at the time of data
cutoff will be censored at the last observed TOI-PFB assessment date. Patients without
TOI-PFB assessments after baseline will be censored at the time of randomization plus
1 day.
4.9.6.2 Pharmacoeconomic Endpoint

The resource expenditure due to hospitalizations that are not study-defined evaluations
while on study treatment will be evaluated. The number of hospital visits, number of
days admitted, and type of visits (emergency department vs. inpatient care) will be
collected and compared between the two arms. The reason for admission (disease
progression vs. adverse event) will also be assessed.
4.9.7 Exploratory Analyses

4.9.7.1 Patient Self-Reported Diarrhea
Patient self-reported diarrhea was measured by the DAS (see Appendix D) prior to the
final PFS analysis. The DAS has four questions that evaluate the frequency, urgency,
consistency, and discomfort of diarrhea experienced by a patient (summarized in
Section 4.9.6 ). Estimates of the proportion of patients with moderate or severe diarrhea
and the respective 95% CI (Blyth-Still-Casella) will be provided by treatment arm.
The Mantel-Haenszel χ2 test stratified by world region (United States, Western Europe,
Other); number of prior chemotherapeutic regimens for unresectable, locally advanced
or metastatic disease (0−1 vs. > 1); and visceral disease versus non-visceral disease will
be used to compare the proportion of patients with moderate or severe diarrhea between
the two treatment arms. The difference in the proportion of patients with moderate or
severe diarrhea between treatment arms and 95% CI will be provided.

After the final PFS analysis, the DAS will not be administered.
4.9.7.2 Proportion of Patients with a Significant Improvement in

Symptoms
The proportion of patients with a clinically significant improvement in symptoms, defined
as an increase in 5 points, between the two treatment arms as measured by the FACT-B
TOI, will be compared between the treatment arms. Estimates of the proportion of
patients with clinically significant symptom improvement and respective 95% CI
(Blyth-Still-Casella) will be provided by treatment arm. The Mantel-Haenszel χ2 test
stratified by world region, number of prior chemotherapeutic regimens in the metastatic
setting, and visceral versus non-visceral disease will be used to compare the proportions
of patients with clinically significant symptom improvement between the two treatment
arms. The difference in the proportion of patients with clinically significant symptom
improvement between treatment arms and 95% CI will be provided.
4.9.7.3 Concordance between IRC- and Investigator-Assessed Tumor

Assessments
The concordance between IRC- and investigator-assessed progression events will be
summarized. In addition, the concordance between the IRC- and investigator-assessed
PFS time will be summarized. The investigator-assessed PFS and IRC-assessed PFS
will be considered in agreement if both investigator and IRC assessments agree that a
PFS event has occurred and the absolute difference in between these two PFS event
dates are within one tumor assessment.
4.9.8 Handling of Missing Data

For the primary analysis of PFS and duration of response, data from patients who are
lost to follow-up will be included in the analysis as censored observations on the last
date that the patient is known to be progression free, defined as the date of the last
tumor assessment. When disease progression occurs after two or more consecutive
missed tumor assessments, these events will not be counted; rather, the patient will be
censored at the patient’s last tumor assessment prior to the missing assessments. If
disease progression occurs after one missed tumor assessment, the event will be
counted at the respective event date.
4.9.9 Determination of Sample Size

There are two primary efficacy endpoints of this Phase III trial: PFS based on
independent review of tumor assessments, and OS. The fixed-sequence testing
procedure described above will be used to control the overall two-sided Type I error rate
at 5% for the primary efficacy analyses.
The sample size of the study is determined by the analysis of OS. To detect an HR of
0.8 in OS (a 25% improvement in median OS; i.e., from 17.2 months in the control arm
to 21.5 months in the treatment arm), approximately 632 deaths will be required to

achieve 80% power at a two-sided 5% alpha level. A total of 980 patients will be
enrolled into the study.
The primary efficacy analysis will be event driven, and the primary analysis of PFS will
take place when approximately 508 IRC-assessed PFS events have occurred.
This provides 90% power to detect an HR of 0.75 in PFS (a 33% improvement in median
PFS; i.e., from 6.2 months in the control arm to 8.3 months in the treatment arm), with a
two-sided alpha of 5%.
It is expected that 980 patients will be enrolled over approximately 35 months.

Assuming a median PFS of 6.2 months in the control arm and an HR of 0.75, the date of
data cutoff for the final analysis of PFS will be approximately 32 months from when the
first patient is enrolled (FPI). However, the final analysis of PFS will not be conducted
until the last patient is enrolled. Assuming the median OS of 17.2 months in the control
arm and an HR of 0.8, the data cutoff date for the final analysis of OS is projected to be
approximately 51 months from FPI.
4.9.10 Interim Analysis

Prior to final analysis of PFS, an independent DMC monitored accumulating safety
data every 6 months. In addition, data on serious adverse events were monitored by
the DMC at least once every 3 months. An independent CRC reviewed all potential
cases of left ventricular systolic dysfunction prior to each semi-annual DMC review and
reported their findings to the DMC until the final PFS analysis. Additional details are
provided in the DMC and CRC Charters.
There is no interim analysis of PFS. An interim analysis of OS is planned to be
conducted at the same time as the final analysis of PFS. At the interim analysis, OS is
tested at the significance level determined using the Lan-DeMets alpha spending
function with an O’Brien-Fleming boundary, so that the overall two-sided Type I error
rate will be maintained at the 5% level. The final analysis of OS will be performed when
632 deaths have occurred. Additional interim analyses of OS will be performed with
the appropriate control of the Type I error rate using the same alpha spending function
specified above (additional details to those interim analyses will be outlined in the
Statistical Analysis Plan). If any interim analysis of OS meets the criteria for
statistical significance, the co-primary endpoint of OS will be considered met at that
interim and the final analysis will be considered descriptive only.
At each analysis time, the statistical methods for analyzing OS described in

Section 4.9.3 will be used to analyze OS data.
On the basis of data from the Tykerb® (lapatinib) U.S. package insert (2010), the median
OS was 17.2 months with the lapatinib and capecitabine combination treatment. Under
the assumption of an HR of 0.80 in OS between trastuzumab emtansine and lapatinib

plus capecitabine group, it is estimated that approximately 290 deaths would occur at
the time of the final analysis of PFS. It is estimated that 632 deaths would occur
approximately 51 months from start of study.
Table 2 presents a summary of the planned OS analyses, the efficacy stopping

boundary, and the estimated timing of these analyses.
Table 2 Summary of Planned Overall Survival Analyses Assuming One

Interim Analysis
No. of
Analysis of OS Deaths Efficacy Stopping Boundary a Estimated Timing b
Interim #1 290 p < 0.0019 or observed HR < 0.69 32 months c
Final analysis 632 p < 0.0494 or observed HR < 0.85 51 months
HR = hazard ratio; OS = overall survival; PFS = progression-free survival.
a
p-value will be based on two-sided log rank test.
b
Time from the enrollment of first patient to data cutoff.
c
At the same time as the final primary analysis of PFS.
The Sponsors will perform the interim analyses and the final analysis of OS. A survival
data sweep will be conducted prior to each OS analysis. In the event that the actual
number of deaths is different from the estimated 290 deaths when PFS data reaches
maturity (508 events by IRC assessment), the efficacy stopping boundary for the interim
OS analyses will be adjusted according to the aforementioned alpha spending function
and the actual number of deaths included in the analysis.
4.10 DATA QUALITY ASSURANCE

The data will be collected via Electronic Data Capture (EDC) through use of eCRFs. A
Clinical Research Organization (CRO) will be responsible for the data management of
this trial, including quality checking of the data. The site will be responsible for data
entry into the EDC system. In the event of discrepant data, the EDC system will either
ask for resolution online or the CRO responsible for data management activities will
request data clarification from the sites, which the sites will resolve electronically in the
EDC system.
Genentech or its designee will perform oversight of the data management of this trial.
The Sponsors will produce an EDC Study Specification document that describes the
quality checking to be performed on the data. Central Laboratory data and IRC data will
be sent directly to Genentech, with use of Genentech’s standard procedures to handle
and process the electronic transfer of these data. eCRFs and correction documentation
will be maintained in the EDC system’s audit trail. System backups for data stored at
Genentech and records retention for the study data will be consistent with Genentech’s
standard procedures.

5. ASSESSMENT OF SAFETY
5.1 SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording protocol-defined adverse
events (AEs) and serious adverse events (SAEs); measurement of protocol-specified
hematology and clinical chemistry; measurement of protocol-specified vital signs; and
other protocol-specified tests that are deemed critical to the safety evaluation of the
study drug(s).
The Sponsors or their designee are responsible for reporting relevant SAEs to the
Competent Authority, other applicable regulatory authorities, and participating
investigators, in accordance with ICH guidelines, FDA regulations, European Clinical
Trials Directive (Directive 2001/20/EC), and/or local regulatory requirements.
The Sponsors or their designee are responsible for reporting unexpected fatal or
life-threatening events associated with the use of the study drug to the regulatory
agencies and competent authorities within 7 calendar days after being notified of the
event. The Sponsors or their designee will report other relevant SAEs associated with
the use of the study medication to the appropriate competent authorities (according to
local guidelines), investigators, and central IRBs/ECs (except in countries where
investigators are responsible for reporting to their IRBs/ECs per local requirements) by a
written safety report within 15 calendar days of notification.
5.1.1 Progression of the Underlying Malignancy

Progression of underlying malignancy will not be reported as an adverse event if it is
clearly consistent with the suspected progression of the underlying cancer as defined by
modified RECIST, or other criteria as determined by protocol. Hospitalization due solely
to the progression of underlying malignancy should NOT be reported as a serious
adverse event. Clinical symptoms of progression may be reported as adverse events if
the symptom cannot be determined as exclusively due to the progression of the
underlying malignancy or does not fit the expected pattern of progression for the disease
under study.
Symptomatic deterioration may occur in some patients. Symptomatic deterioration is

when progression is evident in the patient’s clinical symptoms but is not supported by
the tumor measurements or disease progression is so evident that the investigator may
elect not to perform further disease assessments.
If there is any uncertainty about an adverse event being due only to the disease under
study, it should be reported as an adverse event or serious adverse event.

5.1.2 Adverse Event
An AE is any unfavorable and unintended sign, symptom, or disease temporally
associated with the use of an investigational medicinal product (IMP) or other
protocol-imposed intervention, regardless of attribution.
This includes the following:

• AEs not previously observed in the patient that emerge during the protocol-specified
AE reporting period, including signs or symptoms associated with breast cancer that
were not present prior to the AE reporting period (see Section 5.2.1 )
• Complications that occur as a result of protocol-mandated interventions
(e.g., invasive procedures such as biopsies)
• AEs that occur prior to assignment of study treatment that are related to a protocol-
mandated intervention (e.g., invasive procedures such as biopsies, medication
washout, or no treatment run-in).
• Preexisting medical conditions other than breast cancer judged by the investigator to
have worsened in severity or frequency or changed in character during the protocol-
specified AE reporting period
5.1.3 Serious Adverse Event

An SAE is any AE that is any of the following:
• Fatal (i.e., the AE actually causes or leads to death)

• Life threatening (i.e., the AE, in the view of the investigator, places the patient at
immediate risk of death)
• Requires or prolongs inpatient hospitalization
• Results in persistent or significant disability/incapacity (i.e., the AE results in
substantial disruption of the patient’s ability to conduct normal life functions)
• A congenital anomaly/birth defect in a neonate/infant born to a mother exposed to
the investigational product(s)
• Considered a significant medical event by the investigator (e.g., may jeopardize the
patient or may require medical/surgical intervention to prevent one of the outcomes
listed above)
All AEs that do not meet any of the criteria for serious should be regarded as non-
serious AEs.
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of
an AE (as in mild, moderate, or severe pain); the event itself may be of relatively minor
medical significance (such as severe headache). “Serious” is a regulatory definition and
is based on patient or event outcome or action criteria usually associated with events
that pose a threat to a patient’s life or vital functions. Seriousness (not severity) serves
as the guide for defining regulatory reporting obligations.

Severity and seriousness should be independently assessed when recording AEs and
SAEs on the eCRF.
5.1.4 Protocol-Defined Events of Special Interest/Non-Serious

Expedited Adverse Events
The following events are events of special interest for patients randomized to the
trastuzumab emtansine arm and will need to be reported to the Sponsors expeditiously
(see Section 5.4 for reporting instructions), irrespective of regulatory seriousness criteria
or causality:
• Potential drug-induced liver injury
Any potential case of drug-induced liver injury as assessed by laboratory
criteria for Hy’s Law will be considered as a protocol-defined event of special
interest and will need to be reported to the Sponsor expeditiously. The
following laboratory abnormalities define potential Hy’s Law cases:
AST or ALT elevations that are > 3 × the ULN with
bilirubin > 2 × the ULN, except in patients with documented Gilbert syndrome
5.1.5 Pregnancy and Contraception
ICH M3 guidance requires precautions to be taken to minimize risk to fetus or embryo
when including women of childbearing potential in clinical studies. These precautions
include the use of highly effective contraceptive measures, excluding pregnancy at
baseline (serum test) and continued pregnancy monitoring.
Trastuzumab, a component of trastuzumab emtansine, can cause fetal harm when

administered to a pregnant woman; postmarketing case reports indicate that its use
during pregnancy increases the risk for oligohydramnios during the second and third
trimester. Trastuzumab has also been associated with fetal pulmonary hypoplasia,
skeletal abnormalities, and neonatal death (see the Herceptin ® Package Insert).
There are no clinical studies of trastuzumab in pregnant women. IgGs are known to
cross the placental barrier. There are no adequate and well-controlled studies of
capecitabine or lapatinib in pregnant women. Capecitabine and lapatinib are listed as
drugs that have positive evidence of fetal risk based on adverse reaction data from
investigational or marketing experience or studies in humans, but potential benefits
may warrant use of the drug in pregnant women despite potential risks (in the United
States, Pregnancy Category D) in the Xeloda ® and Tykerb ®/Tyverb ® Product
Inserts/national prescribing information. Therefore, trastuzumab emtansine,
capecitabine, or lapatinib should not be used during pregnancy. Women of childbearing
potential (who have not undergone surgical sterilization with a hysterectomy and/or
bilateral oophorectomy, and are not postmenopausal, as defined as ≥ 12 months of
amenorrhea.) and men with partners of childbearing potential must agree to use a
highly effective non-hormonal form of contraception or two effective forms of
non-hormonal contraception by the patient and/or partner.

Highly Effective Birth Control
Methods of birth control that result in a low failure rate (i.e., < 1% per year)
when used consistently and correctly are considered highly effective forms of
contraception. The use of the following non-hormonal methods of contraception is
acceptable:
• True abstinence, when this is the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, and symptothermal post-ovulation
methods) and withdrawal are not acceptable methods of contraception.
• Male sterilization (with appropriate post-vasectomy documentation of the absence
of sperm in the ejaculate). For female patients, the vasectomized male partner
should be the sole partner.
Effective Birth Control
Alternatively, use of two of the following forms of contraception is acceptable:
• Placement of intrauterine device (IUD)
Consideration should be given to the type of device being used, as there are
higher failure rates for certain types (e.g., steel or copper wire).
• Condom with spermicidal foam/gel/film/cream/suppository
• Occlusive cap (diaphragm or cervical/vault caps) with spermicidal
The use of barrier contraceptives should always be supplemented with the use of a
spermicide. The following should be noted:
• Failure rates indicate that, when used alone, the diaphragm and condom are not
highly effective forms of contraception. Therefore the use of additional spermicides
does confer additional theoretical contraceptive protection.
• However, spermicides alone are ineffective at preventing pregnancy when the whole
ejaculate is spilled. Therefore, spermicides are not a barrier method of
contraception and should not be used alone.
It should be noted that two forms of effective contraception are required. A double
barrier method, defined as condom AND occlusive cap (diaphragm or cervical/vault
caps) with spermicidal foam/gel/film/cream/suppository, is acceptable.
Male Patients
For male patients with a female partner of childbearing potential, cooperation of female
partner is required (i.e., use of two forms of contraception as stated above) during the
study and for ≥ 6 months following the last dose of study treatment. Experimental
studies have reported that IgGs are present in both the pre-ejaculate and the seminal
plasma (Moldoveanu et al. 2005). To date, there have been no clinical studies to assess
the IgG profile in the pre-ejaculate and seminal plasma in male patients receiving
trastuzumab or trastuzumab emtansine. Therefore, as precaution male patients with
female partners of childbearing potential are also required to use highly effective form of
contraception or use two forms of contraception as outlined above. Similarly, vaginal

absorption of trastuzumab emtansine is unknown and therefore male patients with
pregnant partners are required to use condoms for the duration of the pregnancy, and
then revert to contraceptive methods as outlined above. This is to ensure that the fetus
is not exposed to the study medication through vaginal absorption.
Duration of Contraception
Based on PK considerations, contraception must continue for the duration of study
treatment and for at least 6 months after the last dose of study treatment.
Pregnancy and Nursing

A female patient who becomes pregnant during the study must be instructed to stop
taking the study medication and immediately inform the investigator. The investigator
should report all pregnancies within 24 hours to the Sponsor including the partners of
male patients. The investigator should counsel the patient/partner, and discuss the
risks of continuing with the pregnancy and the possible effects on the fetus.
Monitoring of the patient/partner should continue until conclusion of the pregnancy.
Pregnancies occurring up to 6 months after the completion of study medication must
also be reported to the investigator. Please refer to Sections 5.3.1.9 and 5.4.2 for
reporting procedures.
It is not known whether trastuzumab or trastuzumab emtansine are excreted in human

milk. Maternal IgG is excreted in milk and any of these monoclonal antibodies could
harm infant growth and development; therefore, women should be advised to
discontinue nursing during trastuzumab emtansine therapy and not to breastfeed for at
least 6 months following the last dose of either study drug.
In addition, sperm or blood donation should not occur for at least 6 months after the
last dose of study treatment.
5.1.6 Diarrhea Adverse Events

Prior to the final PFS analysis,patients were instructed to verbally report any diarrhea
events to the investigator during the study visit AE assessment.
Additionally, prior to the final PFS analysis, investigators may have learned of diarrhea
events from patient-completed DAS questionnaires. Patient-reported diarrhea severity
scores on the DAS (each symptom scores 0−3) do not correlate to NCI CTCAE version
3.0 diarrhea severity (Grades 1−5; see Table 3). Any diarrhea event assessed as a
worsening from baseline, whether or not identified by the DAS, should be reported as an
AE or SAE on the AE/SAE eCRF, with grading in accordance with NCI CTCAE version
3.0. DAS scores are recorded on a separate eCRF.
Please refer to Section 5.3.1 for additional guidance.

Table 3 NCI CTCAE, Version 3.0, Grading Scale for Diarrhea
Grade Symptoms
1 Increase of < 4 stools per day over baseline;
mild increase in ostomy output compared with baseline
2 Increase of 4−6 stools per day over baseline; IV fluids indicated
< 24 hours; moderate increase in ostomy output compared with baseline;
not interfering with ADL
3 Increase of ≥ 7 stools per day over baseline; incontinence; IV fluids
≥ 24 hours; hospitalization; severe increase in ostomy output compared
with baseline; interfering with ADL
4 Life-threatening consequences (e.g., hemodynamic collapse)
5 Death
ADL = activities of daily living; IV = intravenous; NCI CTCAE = National Cancer Institute Common
Terminology Criteria for Adverse Events.
5.2 METHODS AND TIMING FOR CAPTURING AND ASSESSING

SAFETY PARAMETERS
The investigator is responsible for ensuring that all AEs and SAEs (as defined in
Section 5.1 ) are recorded on the eCRF and reported to the Sponsors in accordance
with protocol instructions.
5.2.1 Adverse Event Reporting Period

After informed consent, but prior to initiation of study medications, only SAEs caused by
a protocol-mandated intervention will be collected (e.g., SAEs related to invasive
procedures such as biopsies, medication washout or no treatment run-in).
After initiation of study medications (trastuzumab emtansine or lapatinib and

capecitabine), all AEs and SAEs, regardless of attribution, will be collected until 30 days
following the last administration of study treatment. After this period, investigators
should report only SAEs that are felt to be related to prior study treatment (see Figure 2 ).

Figure 2 Adverse Event Collection
5.2.2 Eliciting Adverse Events

A consistent methodology of non-directive questioning for eliciting AEs at all
patient evaluation time points should be adopted. Examples of non-directive
questions include:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?”
5.2.3 Assessment of Severity and Causality of Adverse Events
Investigators will seek information on AEs and SAEs at each patient contact. All AEs
and SAEs, whether reported by the patient or noted by authorized study personnel, will
be recorded in the patient’s medical record and on the appropriate AE/SAE eCRF page.
For each AE and SAE recorded on the applicable eCRF, the investigator will make an
assessment of seriousness (see Section 5.1.3 for seriousness criteria), severity and
causality.
Table 4 provides guidance for grading AE severity and Table 5 provides guidance for
assessing the causal relationship to the investigational product(s).
The AE grading (severity) scale found in the NCI CTCAE version 3.0 will be used for AE
reporting. Events of symptomatic LVEF decrease or CHF (left ventricular systolic
dysfunction Grade ≥ 3) should also be graded using the NYHA classification
(see Appendix G).

Table 4 Adverse Event Grading (Severity) Scale
Grade Severity Alternate Description a
1 Mild (apply event-specific Transient or mild discomfort
NCI CTCAE grading criteria) (< 48 hours); no interference
with the patient’s daily
activities; no medical
intervention/therapy required
2 Moderate (apply event-specific Mild to moderate interference
NCI CTCAE grading criteria) with the patient’s daily activities;
no or minimal medical
intervention/therapy required
3 Severe (apply event-specific Considerable interference with
NCI CTCAE grading criteria) the patient’s daily activities;
medical intervention/therapy
required; hospitalization possible
4 Very severe, life threatening, Extreme limitation in activity;
or disabling (apply event-specific significant medical
NCI CTCAE grading criteria) intervention/therapy required,
hospitalization probable
5 Death related to AE
The National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) version 3.0 can be found at
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
Note: Regardless of severity, some events may also meet regulatory serious criteria.
Refer to definitions of an SAE (see Section 5.1.2 ).
a
Use these alternative definitions for Grade 1, 2, 3, and 4 events when the
observed or reported AE is not in the NCI CTCAE listing.
To ensure consistency of causality assessments, investigators should apply the

following general guidelines outlined in Table 5:
Table 5 Causal Attribution Guidance

Is the AE/SAE suspected to be caused by the investigational product on the basis of
facts, evidence, science-based rationales, and clinical judgment?
YES The temporal relationship of the AE/SAE to investigational product
administration makes a causal relationship possible, AND other drugs,
therapeutic interventions or underlying conditions do not provide sufficient
explanation for the AE/SAE.
NO The temporal relationship of the AE/SAE to investigational product
administration makes a causal relationship unlikely, OR other drugs,
therapeutic interventions or underlying conditions provide a sufficient
explanation for the AE/SAE.
Note: The investigator’s assessment of causality for individual AE reports is part of the
study documentation process. Regardless of the “Yes” or “No” causality assessment for
individual AE reports, the Sponsors will promptly evaluate all reported SAEs against

cumulative product experience to identify and expeditiously communicate possible new
safety findings to investigators and applicable regulatory authorities.
5.3 PROCEDURES FOR RECORDING ADVERSE EVENTS

5.3.1 Recording Adverse Events on the Electronic Case Report Form
Investigators should use correct medical terminology/concepts when recording AEs or
SAEs on the eCRF. Avoid colloquialisms and abbreviations.
AEs should be recorded either as an AE (if no serious criteria are met and the AE does
not qualify for expedited reporting) or an SAE on the eCRF page, but not both.
Only one medical concept should be recorded in the event field on the AE/SAE eCRF
page.
5.3.1.1 Diagnosis versus Signs and Symptoms

If known, a diagnosis should be recorded on the eCRF rather than individual signs and
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and
elevated transaminases). However, if a constellation of signs and/or symptoms cannot
be medically characterized as a single diagnosis or syndrome at the time of reporting,
each individual event should be recorded as an AE or SAE on the eCRF. If a diagnosis
is subsequently established, it should be reported as follow-up information.
5.3.1.2 Adverse Events Occurring Secondary to Other Events

In general, AEs occurring secondary to other events (e.g., cascade events or clinical
sequelae) should be identified by their primary cause. For example, if severe diarrhea is
known to have resulted in dehydration, it is sufficient to record only diarrhea as an AE or
SAE on the eCRF.
However, medically significant AEs occurring secondary to an initiating event that are
separated in time should be recorded as independent events on the eCRF. For example,
if a severe gastrointestinal hemorrhage leads to renal failure, both events should be
recorded separately on the eCRF.
5.3.1.3 Persistent or Recurrent Adverse Events

A persistent AE is one that extends continuously, without resolution between patient
evaluation time points. Such events should be recorded only once in the eCRF unless
their severity increases. If a persistent AE becomes more severe, it should be recorded
again on an AE/SAE eCRF page.
A recurrent AE is one that occurs and resolves between patient evaluation time points
and subsequently recurs. All recurrent AEs should be recorded on an AE/SAE eCRF
page.

5.3.1.4 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management
should be recorded as AEs or SAEs on the eCRF (e.g., abnormalities that require study
drug dose modification, discontinuation of study treatment, more frequent follow-up
assessments, further diagnostic investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g.,

ALP and bilirubin 5 × the ULN associated with cholecystitis), only the diagnosis (e.g.,
cholecystitis) needs to be recorded on the AE/SAE eCRF page.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome,

the abnormality itself should be recorded as an AE or SAE on the eCRF. If the
laboratory abnormality can be characterized by a precise clinical term, the clinical term
should be recorded as the AE or SAE. For example, an elevated serum potassium level
of 7.0 mEq/L should be recorded as “hyperkalemia.”
Observations of the same clinically significant laboratory abnormality from visit to visit
should not be repeatedly recorded as AEs or SAEs on the eCRF, unless their severity,
seriousness, or etiology changes.
5.3.1.5 Deaths
Deaths that occur during the protocol-specified AE reporting period (see Section 5.2.1 )
that are attributed by the investigator solely to progression of breast cancer will be
recorded only on the Study Discontinuation eCRF. All other on-study deaths (i.e.,
deaths occurring within 30 days of the last study treatment), regardless of attribution, will
be recorded on an SAE eCRF and expeditiously reported to the Sponsors.
When recording a death on the AE/SAE eCRF, the event or condition that caused or
contributed to the fatal outcome should be recorded as the single medical concept on
the AE/SAE eCRF and should be recorded as an SAE. If the cause of death is unknown
and cannot be ascertained at the time of reporting, record “Unexplained Death” on the
SAE eCRF.
During post-study survival follow-up, deaths attributed to progression of breast cancer

will be recorded on the Survival eCRF.
5.3.1.6 Preexisting Medical Conditions

A preexisting medical condition is one that is present at the start of the study.
A preexisting medical condition should be recorded as an AE or SAE only if the
frequency, severity, or character of the condition worsens during the study. When
recording such events on an AE/SAE eCRF page, it is important to convey the concept
that the preexisting condition has changed by including applicable descriptors
(e.g., “more frequent headaches”).

5.3.1.7 Progression of Breast Cancer
Progression and/or worsening of breast cancer should not be recorded as an AE or SAE.
These data will be captured as efficacy assessment data only (see Section 5.1.1 ).
5.3.1.8 Hospitalization
Any AE that results in hospitalization or prolonged hospitalization should be documented
and reported as an SAE except for progression of breast cancer as described in
Section 5.1.1 and 5.3.1.7 . Any condition responsible for surgery should be documented
as an AE if the condition meets the definition of an AE.
Some hospitalization scenarios do not require reporting as an SAE when there is no

occurrence of an AE. These scenarios include a planned hospitalization or prolonged
hospitalization to:
• Perform an efficacy measurement for the study
• Undergo a diagnostic or elective surgical procedure for a preexisting medical
condition that has not changed
• Receive scheduled therapy for breast cancer
5.3.1.9 Pregnancy
If a female patient becomes pregnant while receiving investigational therapy
(trastuzumab emtansine or control treatment) or within 6 months after the last dose of
investigational product, a Pregnancy Report eCRF should be completed and
expeditiously submitted to the Sponsors within 24 hours of learning of the pregnancy, to
facilitate outcome follow-up.
Abortion, whether accidental, therapeutic, or spontaneous, should always be recorded

as serious (because the Sponsors consider these medically significant), recorded on an
SAE eCRF page, and expeditiously reported to the Sponsors. Similarly, any congenital
anomaly/birth defect in a child born to a female patient exposed to the investigational
therapy (trastuzumab emtansine, capecitabine, or lapatinib) or female partner of a male
exposed to the investigational therapy (trastuzumab emtansine, capecitabine,
or lapatinib) should be recorded and reported as an SAE.
5.4 REPORTING REQUIREMENTS FOR SERIOUS

ADVERSE EVENTS AND PROTOCOL-DEFINED EVENTS OF
SPECIAL INTEREST
5.4.1 Expedited Reporting Requirements
Immediate telephone contact (contact information is provided below) is required for any
life-threatening (i.e., imminent risk of death) or fatal AE that is attributed, as determined
by the investigator, to one or more of the investigational products (trastuzumab
emtansine, capecitabine, or lapatinib).

For patients randomized to the trastuzumab emtansine arm only, please refer to
Section 5.1.4 for protocol-defined events of special interest, which need to be reported
expeditiously, irrespective of regulatory seriousness criteria or causality.
CONTACT INFORMATION
During regular business hours (Pacific Standard Time/Pacific Daylight Time):
Genentech Medical Monitor: Ellie Guardino, M.D., Ph.D.

Telephone No.: +1 (650) 467-9281
Alternate Telephone No.: +1 (888) 835-2555
During regular business hours (Central European Time/Central European Summer Time):
Medical Monitor: Fabrice Branle, M.D.

Telephone No.: + 41 79 865 89 19
Alternate Telephone No.: + 41 61 688 31 93
Outside regular business hours for Pacific Standard Time/Pacific Daylight Time and
Central European Time/Central European Summer Time or if contacts listed above cannot
be reached:
Roche Emergency Medical Call Center Help Desk. Refer to contact list with local
toll-free numbers provided by the Monitor.
Electronic submission of case details on an SAE eCRF is also required within 24 hours,
as described in the next section (Section 5.4.2 ).
5.4.2 Reporting Requirements for All Serious Adverse Events

Investigators will submit reports of all SAEs, regardless of attribution, to the Sponsors,
using the eCRF, within 24 hours of learning of the events. For initial SAE reports,
investigators should record all case details that can be gathered within 24 hours on an
SAE eCRF page and submit the report via the EDC system. A report will be generated
and sent to Genentech Drug Safety by the EDC system.
5.4.2.1 If the EDC System Is Unavailable (U.S. Sites)

For sites in the United States, in the event the EDC system is unavailable, a completed
SAE paper reporting form and fax coversheet should be faxed immediately upon
completion to the Sponsors’ Drug Safety Departments or their designee at the fax
numbers indicated below. Once the EDC system is available, all information will need to
be entered and submitted via the EDC system.
Sites in the United States:

Fax No.: +1 (650) 225-4682
Alternate Fax No.: +1 (650) 225-5288

Relevant follow-up information should be submitted to the Sponsors’ Drug Safety
Departments or their designee as soon as it becomes available and/or upon request.
5.4.2.2 If the EDC System Is Unavailable (Ex-U.S. Sites)

For sites outside the United States, if the EDC system is unavailable, serious adverse
events and pregnancies occurring during this study, or that come to the attention of the
investigator during the protocol-defined follow-up period, should be reported immediately
to the Sponsors or their designee, the Roche SAE responsible person, who will send a
scanned copy of the paper SAE form to the Sponsors’ Drug Safety Department. Contact
details will be provided to the investigator prior to study start. The investigator will
complete and submit one SAE Case Report Form (CRF) for each SAE experienced by
the patient.
Once the EDC system is working again, the SAE eCRF must be completed to ensure
that all SAEs are captured in the database.
Relevant follow-up information should be submitted to the Sponsors’ Drug Safety

Departments or their designee as soon as it becomes available and/or upon request.
5.5 TYPE AND DURATION OF FOLLOW-UP OF PATIENTS AFTER

ADVERSE EVENTS
The investigator should follow all unresolved AEs and SAEs until the events are resolved
or stabilized, the patient is lost to follow-up, or it has been determined that the study
treatment or participation is not the cause of the AE/SAE. Resolution of AEs and SAEs
(with dates) should be documented on the appropriate AE/SAE eCRF page and in the
patient’s medical record to facilitate source data verification (SDV).
For some SAEs, the Sponsors or their designee may follow-up by telephone, fax,
electronic mail, and/or a monitoring visit to obtain additional case details deemed
necessary to appropriately evaluate the SAE report (e.g., hospital discharge summary,
consultant report, or autopsy report).
5.6 POST-STUDY ADVERSE EVENTS

The investigator should follow all unresolved study-emergent AEs and SAEs until the
events are resolved, stabilized, the patient is lost to follow-up, or until it has been
determined that the study treatment or participation is not the cause of the AE/SAE. At
the last scheduled visit, the investigator should instruct each patient to report any
subsequent serious and/or severe adverse events that the patient’s personal physician
believes might reasonably be related to participation in this study. The investigator
should notify the study Sponsors of any death or other SAE occurring at any time after a
patient has discontinued or terminated study participation that may reasonably be
related to this study. The Sponsors should also be notified if the investigator should
become aware of the development of cancer or of a congenital anomaly in a
subsequently conceived offspring of a patient who has participated in this study.

The investigator should report these events to the Sponsors’ Drug Safety Department on
the study SAE eCRF. If the study SAE eCRF is no longer available, the investigator
should report the event directly to Genentech Drug Safety via phone at 1-888-835-2555
for sites in the United States.
For sites outside the United States, AE/SAEs should be reported to the Sponsors or their
designee, the Roche SAE responsible person. Contact details will be provided to the
investigator prior to study start. The investigator will complete and submit one SAE CRF
for each SAE experienced by the patient.
During the post-study survival follow-up, deaths attributed to progression of breast

cancer will be recorded on the Survival eCRF.
6. INVESTIGATOR REQUIREMENTS
6.1 STUDY INITIATION
Before the start of this study and any study-related procedures at a specific site,
the following documents must be on file with the Sponsors or their representative:
• FDA Form 1572 for each site (for all studies conducted under U.S. Investigational
New Drug [IND] regulations), signed by the Principal Investigator
The names of any co-investigators or subinvestigators must appear on this form.
Investigators must also complete all regulatory documentation as required by local
and national regulations.
• Current curricula vitae and evidence of licensure of the Principal Investigator and all
co-investigators or subinvestigators
• Complete financial disclosure forms for the Principal Investigator and all
co-investigators or subinvestigators listed on the FDA Form 1572
• Federalwide Assurance number (U.S. only) or IRB/EC statement of compliance or
evidence of compliance to local laws in accordance with local regulations
• Written documentation of IRB/EC approval of the protocol (identified by protocol
number or title and date of approval) and ICFs (identified by protocol number or title
and date of approval)
• A copy of the IRB/EC-approved ICFs
The Sponsors or their designee must review any proposed deviations from the
sample ICF.
• Current laboratory certification of the laboratory performing the analysis (if other
than a Sponsor-approved central laboratory), as well as current references ranges
for all laboratory tests
• A Clinical Research Agreement signed and dated by the appropriate signatories at
the study site
• Investigator Brochure Receipt signed and dated by the Principal Investigator

• Certified translations of approved ICFs and any other written information to be given
to the patient (when applicable), IRB/EC approval letters, and pertinent
correspondence
• A Protocol Acceptance Form signed and dated by the Principal Investigator and,
additionally, for sites outside the United States, a signed Roche PD01 Form
• Canada only when applicable: original Qualified Investigator Undertaking Form,
signed by each Canadian investigator involved in the study
• Any other documentation in accordance with the individual country’s local laws or
regulatory obligations
6.2 STUDY COMPLETION

The following data and materials are required by the Sponsors before a study can be
considered complete or terminated:
• Laboratory findings, clinical data, and all special test results from screening through
the end of the study follow-up period
• All laboratory certifications for laboratories performing the analysis (if other than the
Sponsor-approved central laboratory), as well as current normal laboratory ranges
for all laboratory tests
• eCRFs (including queries) properly completed by appropriate study personnel and
electronically signed and dated by the investigator
• Completed Drug Accountability Records (Retrieval Record, Drug Inventory Log, and
Inventory of Returned Clinical Material forms)
• Copies of protocol amendments and IRB/EC approval/notification, if appropriate
• A summary of the study prepared by the Principal Investigator (IRB/EC summary
close letter is acceptable)
• All essential documents (e.g., curriculum vitae for each Principal Investigator and
subinvestigator, FDA Form 1572 for each site)
• A signed and dated Protocol Amendment Acceptance Form(s) (if applicable)
• Updated financial disclosure forms for the Principal Investigator and all
subinvestigators listed on the FDA Form 1572 (applicable for 1 year after the last
patient has completed the study)
6.3 INFORMED CONSENT FORM

The Sponsors’ Sample ICF will be provided to each site. The Sponsors or
their designee must review and approve any proposed deviations from the Sample ICFs
or any alternate consent forms proposed by the site (collectively, the “Consent Forms”)
before IRB/EC submission. Patients must be re-consented to the most current version
of the Consent Forms during their participation in the study. The final IRB/EC-approved
Consent Forms must be provided to the Sponsors for regulatory purposes.

The Consent Forms must be signed by the patient or the patient’s legally authorized
representative before his or her participation in the study. The case history for each
patient shall document the informed consent process and that written informed consent
was obtained prior to participation in the study. A copy of each signed Consent Form
must be provided to the patient or the patient’s legally authorized representative. If
applicable, it will be provided in a certified translation of the local language.
All signed and dated Consent Forms must remain in each patient’s study file and must
be available for verification by study monitors at any time.
The ICF should be revised whenever there are changes to procedures outlined in the
informed consent or when new information becomes available that may affect the
willingness of the patient to participate.
For any updated or revised Consent Forms, the case history for each patient shall
document the informed consent process and that written informed consent was obtained
for the updated/revised Consent Form for continued participation in the study. The final
revised IRB/EC−approved ICF must be provided to the Sponsors for regulatory purposes.
If the site utilizes a separate Authorization Form for patient authorization to use and
disclose personal health information (e.g., the U.S. Health Insurance Portability and
Accountability Act [HIPAA] regulations), the review, approval, and other processes
outlined above apply except that IRB/IEC review and approval may not be required per
study site policies or in accordance with local laws.
Optional Research Informed Consent

If archival tissue for optional research described in Section 4.8.8 is approved by the
IRB/EC, the Consent Form entitled “Sample Research Informed Consent Form” will be
provided by the Sponsors to each study site. This form gives patients the option to
authorize the collection and use of these samples and personal health information for
additional research purposes. Signing of this separate consent form is not required for
enrollment in the trial but is required prior to any optional research sample collection. All
procedures outlined above for review, approval, processing, and use of Consent Forms
also apply to this optional research form.
If the site utilizes a separate Authorization Form for patient authorization to use and
disclose personal health information (e.g., in the United States, each ICF may also
include authorization allowing the institution, investigator, subinvestigator, and the
Sponsor(s) to use and disclose Personal Health information in compliance with
the HIPAA of 1996), this may also be included in the Sample Research ICF. Local laws
and regulations apply.
Signed and dated ICFs must remain in each patient’s study file and must be available for
verification by study monitors at any time.

6.4 COMMUNICATION WITH THE INSTITUTIONAL REVIEW BOARD
OR ETHICS COMMITTEE
This protocol, the ICFs, any information to be given to the patient, and relevant
supporting information must be submitted to the IRB/EC by the Principal Investigator for
review and approval before the study is initiated. In addition, any patient recruitment
materials must be approved by the IRB/EC.
The Principal Investigator is responsible for providing written summaries of the status of
the study to the IRB/EC annually or more frequently in accordance with the regulatory
requirements and policies and procedures established by the IRB/EC. Investigators are
also responsible for promptly informing the IRB/EC of any protocol changes or
amendments and of any unanticipated problems involving risk to human patients
or others.
In addition to the requirements to report protocol-defined AEs to the Sponsors,

investigators are required to promptly report to their respective IRB/EC all unanticipated
problems involving risk to human patients. Some IRBs/ECs may want prompt
notification of all SAEs, whereas others require notification only about events that are
serious, assessed to be related to study treatment, and are unexpected. Investigators
may receive written IND/SUSAR safety reports or other safety-related communications
from the Sponsors. Investigators are responsible for ensuring that such reports are
reviewed and processed in accordance with regulatory requirements and with the
policies and procedures established by their IRB/EC and archived in the site’s Study File.
6.5 STUDY MONITORING REQUIREMENTS

Site visits will be conducted by an authorized Sponsor representative to inspect study
data, patients’ medical records, and eCRFs. The Principal Investigator will permit the
Sponsors’ monitors/representatives and collaborators, the FDA, other regulatory
agencies, IRBs/ECs, and the respective national or local health authorities to inspect
facilities and records relevant to this study.
6.6 ELECTRONIC CASE REPORT FORMS

eCRFs are to be completed using the Medidata Solutions EDC system. Sites will
receive training and a manual for appropriate eCRF completion. eCRFs will be
submitted electronically to the Sponsors and should be handled in accordance with
instructions from the Sponsors.
All eCRFs should be completed by designated, trained examining personnel or the study
coordinator as appropriate. The eCRF should be reviewed and electronically signed and
dated by the investigator.
In addition, at the end of the study, the investigator will receive patient data for his or her
site in a readable format on a compact disc that must be archived with the study records.

6.7 SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing SDV to confirm that critical protocol data (i.e.,
source data) entered into the eCRFs by authorized site personnel are accurate,
complete, and verifiable from source documents.
Source documents are where patient data are recorded and documented for the first
time. They include but are not limited to hospital records, clinical and office charts,
laboratory notes, memoranda, patient diaries or evaluation checklists, pharmacy
dispensing records, recorded data from automated instruments, copies of transcriptions
that are certified after verification as being accurate and complete, microfiche,
photographic negatives, microfilm or magnetic media, X-rays, patient files, and records
kept at the pharmacy, laboratories, and medico-technical departments involved in a
clinical trial.
Source documents that are required to verify the validity and completeness of data
entered into the eCRFs must never be obliterated or destroyed.
To facilitate SDV, the investigator(s) and institution(s) must provide the Sponsors or their
designee direct access to applicable source documents and reports for trial-related
monitoring, Sponsor audits, and IRB/EC review. The investigational site must also allow
inspection by applicable regulatory authorities.
6.8 USE OF COMPUTERIZED SYSTEMS

When clinical observations are entered directly into an investigational site’s
computerized medical record system (i.e., in lieu of original hardcopy records), the
electronic record can serve as the source document if the system has been validated in
accordance with FDA and/or local health authority requirements pertaining to
computerized systems used in clinical research. An acceptable computerized data
collection system (for clinical research purposes) would be one that 1) allows data entry
only by authorized individuals, 2) prevents the deletion or alteration of previously entered
data and provides an audit trail for such data changes (e.g., modification of file), 3)
protects the database from tampering, and 4) ensures data preservation.
In collaboration with the study monitor, the Sponsors’ Quality Assurance groups may
assist in assessing whether electronic records generated from computerized medical
record systems used at investigational sites can serve as source documents for the
purposes of this protocol.
If a site’s computerized medical record system is not adequately validated for

the purposes of clinical research (as opposed to general clinical practice), applicable
hardcopy source documents must be maintained to ensure that critical protocol data
entered into the eCRFs can be verified.

6.9 STUDY MEDICATION ACCOUNTABILITY
Trastuzumab emtansine required for completion of this study will be provided by the
Sponsors. Genentech/Roche will provide control-arm study drug to sites. The recipient
will acknowledge receipt of the drug by returning the appropriate documentation form
indicating shipment content and condition and/or by calling into the IVRS. Damaged
supplies will be replaced.
Accurate records of all study drug received at, dispensed from, returned to, and
disposed of by the study site should be recorded using the Drug Inventory Log.
Vials of trastuzumab emtansine and control-arm drug will either be disposed of at the
study site if authorized by the Sponsors to do so or returned to the Sponsors with the
appropriate documentation. If the study site chooses to destroy study drug, the method
of destruction must be approved and documented.
The Sponsors must evaluate and approve the study site’s drug destruction standard
operating procedure prior to the initiation of drug destruction by the study site.
6.10 DISCLOSURE OF DATA

Patient medical information obtained by this study is confidential and may be disclosed
to third parties only as permitted by the ICFs (or separate authorization to use and
disclose personal health information) signed by the patient or unless permitted or
required by law.
Medical information may be given to a patient’s personal physician or

other appropriate medical personnel responsible for the patient’s welfare for
treatment purposes.
Data generated by this study must be available for inspection upon request by
representatives of the FDA and other regulatory agencies, national and local health
authorities, the Sponsors’ monitors/representatives and collaborators, and the IRB/EC
for each study site, if appropriate.
6.11 RETENTION OF RECORDS

For studies conducted outside the United States under a U.S. IND, the Principal
Investigator must comply with the record retention requirements set forth in the FDA IND
regulations and the relevant national and local health authorities, whichever is longer.
FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see Section 4.9 of
the guideline) require that records and documents pertaining to the conduct of this study
and the distribution of investigational drug, including eCRFs, consent forms, laboratory
test results, and medication inventory records, be retained by the Principal Investigator
for 2 years after the last marketing application approval in an ICH region or after at least

2 years have elapsed since formal discontinuation of clinical development of the
investigational product.
No records should be disposed of without the written approval of the Sponsors. Written
notification should be provided to the Sponsors for transfer of any records to another
party or moving them to another location.

7. REFERENCES
1. Brady MJ, Cella DF, Mo F, et al. Reliability and validity of the Functional
Assessment of Cancer Therapy-Breast quality-of-life instrument. J Clin Oncol
1997;15:974−86.
2. Casey L, Zachariah B. A pilot study to develop a diarrhea assessment scale.
Unpublished study, 1993.
3. Chambers KK, McMillan SC. Measuring bowel elimination. In: Instruments for
Clinical Healthcare Research. Jones & Bartlett Publishers; 2nd edition
(January 15, 1997):494.
4. Clynes RA, Towers TL, Presta LG, et al. Inhibitory Fc receptors modulate in
vivo cytotoxicity against tumor targets. Nat Med 2000;6:443−6.Garcia M,
Jemal A, Ward EM, et al. Global Cancer Facts & Figures 2007. Atlanta, GA:
American Cancer Society, 2007.
5. Gwede CK, James JL, Zachariah B, et al. Quality of life (QOL), bowel
symptoms and function assessments in patients undergoing chemoradiation
for anal or rectal cancer: RTOG 0315 [poster]. 2007 International Society for
Quality of Life Research Meeting Abstracts
[www.isoqol.org/2007mtgabstracts.pdf];Poster 3/1597.
6. HERCEPTIN® (trastuzumab) Package Insert, Genentech, Inc.
7. Hurvitz S, Dirix L, Kocsis J, et al. Trastuzumab emtansine (T-DM1) versus
trastuzumab plus docetaxel in previously untreated HER2-positive
metastatic breast cancer. ECCO-ESMO Meeting 2011;Abstract 5001
8. Moldoveanu Moldoveanu Z, Huang WQ, Kulhavy R, et al. Human male genital
tract secretions: both mucosal and systemic immune compartments contribute to the
humoral immunity. J Immunol 2005;175:4127−36.
9. Musolino A, Bella MA, Bortesi B, et al. BRCA mutations, molecular markers,
and clinical variables in early-onset breast cancer: a population-based study.
Breast 2007;16:280−92.
10. Press MF, Sauter G, Bernstein L, et al. Diagnostic evaluation of HER-2 as a
molecular target: an assessment of accuracy and reproducibility of laboratory
testing in large, prospective, randomized clinical trials. Clin Cancer Res
2005;11:6598−607.
11. Robinson AG, Turbin D, Thomson T. Molecular predictive factors in patients
receiving trastuzumab-based chemotherapy for metastatic disease.
Clin Breast Cancer 2006;7:254−61.
12. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of
relapse and survival with amplification of the HER-2/neu oncogene. Science
1987;235:177–82.

13. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a
monoclonal antibody against HER2 for metastatic breast cancer that
overexpresses HER2. N Engl J Med 2001;344:783−92.
14. Spector NL, Xia W, Burris H III, et al. Study of the biologic effects of lapatinib,
a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth
and survival pathways in patients with advanced malignancies. J Clin Oncol
2005;23:2502−12.
15. Therasse P, Arbuck S, Eisenhauer E, et al. New guidelines to evaluate the
response to treatment in solid tumors. J Natl Ca Inst 2000; 92:205−16.
16. Tykerb® (lapatinib) Package Insert, GlaxoSmithKline, April 2010.
17. Tyverb® (lapatinib) Summary of Product Characteristics, GlaxoSmithKline.
18. Wenzel LB, Huang HQ, Armstrong DK, et al. Health-related quality of life
during and after intraperitoneal versus intravenous chemotherapy for
optimally debulked ovarian cancer: a Gynecologic Oncology Group Study. J
Clin Oncol 2007;25:437−43.
19. Wiseman SM, Makretsov N, Nielsen TO, et al. Coexpression of the type 1
growth factor receptor family members HER-1, HER-2, and HER-3 has a
synergistic negative prognostic effect on breast carcinoma survival.
Cancer 2005;103:1770−7.
20. Xeloda® (capecitabine) E.U. Summary of Product Characteristics, Roche
Laboratories Inc.
21. Xeloda® (capecitabine) U.S. Package Insert, Roche Laboratories Inc.

APPENDIX A-1
Study Flowchart for Patients Receiving Randomized Treatment
Study Drug
Screening a Cycles 1–34 + Completion Visit
Survival
30 days (± 7) Follow-Up b
after Last Dose (Every 3
Day – 30 to – 1 Day 1 of Study Drug Months)
Informed consent xc
HER2 testing d x
Medical history and demographics x
Complete physical exam xe
Limited physical exam x x
FACT-B (female patients only) Day 1 (prior to any study procedures or x x
discussion of test results) of Cycle 1 and
every two cycles thereafter until treatment
discontinuation
Weight and height f x x x
ECOG performance status x x
Concomitant medications xg x x x
Adverse events xh x x x
12-lead electrocardiogram i x xv
ECHO or MUGA j (ECHO preferred) Weeks 6, 12 and every 12 weeks thereafter
x xv
until discontinuation of study drug
Tumor assessment k x Frequency, method, and evaluation criteria
of tumor assessments will be according to
routine clinical practice per investigator.
Bone scan/skeletal X-ray l x Per clinical indication
CT or MRI of brain x Per clinical indication
Central laboratory tests See Appendix A-2
CBC with platelet and 3-part differential m, n x x x
n
Serum chemistries xo xp xp

APPENDIX A-1 (cont’d)
Study Drug
Screening a
Cycles 1–34 + Completion Visit
Survival
INR and aPTT q x x
Serum/urine pregnancy test r x
Laboratory urinalysis s x x
Assessment of patient hospitalizations x x
and/or hospital visits
Evaluation of capecitabine and lapatinib
compliance t
Study drug administration/distribution u x

aPTT = activated partial thromboplastin time; CBC = complete blood count; CT = computed tomography; ECHO = echocardiogram; INR = international
normalized ratio; IHC = immunohistochemistry; MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition; SAE = serious adverse event.
Notes: Visits are based on a 21-day cycle. If the timing of a protocol-mandated procedure coincides with a holiday and/or weekend that preclude
the procedure within the allotted window, the procedure must be performed on the nearest following date.
a
Results of screening tests or examinations performed as standard of care prior to obtaining informed consent and within 30 days prior to
randomization may be used rather than repeating required tests.
b
Only SAEs considered to be related to study medication should be reported. Patients will also be followed for survival, patient-reported
outcomes as assessed by the FACT-B, and subsequent anti-cancer therapies (not all concomitant meds) approximately every 3 months starting
from the Study Drug Completion Visit until death, loss to follow-up, withdrawal of consent, or study discontinuation by the Sponsors.
c
Informed consent must be obtained prior to performance of any screening assessments unless the assessments were performed as standard of
care prior to obtaining informed consent. Informed consent does not need to be obtained within 30 days of randomization; however, patients
who fail screening and are rescreened will need to be reconsented.
d
HER2 status must be centrally confirmed any time prior to randomization (result must be IHC 3 + and/or gene amplified by FISH) by the Sponsor-
selected central laboratory. IHC, FISH, qRT-PCR will be performed. See Section 4.5.2 for further details.
e
Includes assessment of vital signs (blood pressure, pulse, temperature).
f
Height at screening only.
g
Record concomitant medications used within 14 days prior to randomization and investigational and/or anti-cancer therapies used within 21 days
of randomization.
h
Prior to initiation of study medication, only serious adverse events considered related to protocol-mandated procedures are collected.
i
ECGs for each patient should be obtained from the same machine whenever possible. One set of all ECG tracings should be printed and kept
with the patient’s record.
j
Because of a potential worldwide Tc-99 shortage, ECHO is preferred; however, the same method used at screening should be used throughout
the study. Additional scans may be performed at any point if clinically indicated. Refer to Section 3.4 for further information on cardiac safety
surveillance.
k
Response should be assessed using modified RECIST. Assessments should include an evaluation of all known or suspected sites of disease,
whenever possible. The same radiographic procedure used at baseline must be used throughout the study (e.g., the same contrast protocol for
CT scans). If the patient cannot undergo CT with contrast, then the chest should be imaged via CT without contrast and the abdomen and pelvis
should be imaged using MRI with contrast. See Section 4.5.1 for further details.

l
An isotope bone scan and/or skeletal X-rays will be performed at screening and should be repeated in the event of clinical suspicion of
progression of existing bone lesions and/or the development of new bone lesions.
m
CBC includes hemoglobin, hematocrit, platelet count, red blood cells, white blood cells; 3-part differential includes lymphocytes, monocytes,
and granulocytes.
n
Local laboratory assessments performed within 72 hours preceding study drug administration may be used as the Day 1 evaluations
(up to 96 hours for Cycle 1, Day 1). Results of these local laboratory assessments must be reviewed (except alkaline phosphatase and lactate
dehydrogenase) prior to study drug administration. In the event of a Grade 3 or 4 toxicity (per CTCAE version 3.0), pertinent laboratory
assessments should be repeated at the investigator’s discretion until recovery to Grade ≤ 2.
o
Sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, total and direct bilirubin, total protein, albumin, ALT,
AST, LDH, ALP, and uric acid.
p
BUN, creatinine, total bilirubin, ALP, LDH, AST, and ALT.
q
Patients on capecitabine who are receiving coumarin-derivative anticoagulant therapy, such as warfarin or phenprocoumen, should have the PT
or INR monitored weekly.
r
For women of childbearing potential, including premenopausal women who have had a tubal ligation. Screening assessment must be performed
on serum within 7 days prior to randomization. Afterward, perform every third cycle on urine. A positive urine test must be confirmed with a
serum test.
s
Includes specific gravity, pH, protein, glucose, blood ketones, and bilirubin.
t
Patients randomized to the lapatinib plus capecitabine arm will be assessed for their daily compliance by checking the completion of the patients’
diaries, and the information will be entered into the EDC system.
u
Cycle 1, Day 1 must occur within 5 days of randomization. For patients assigned to trastuzumab emtansine therapy, trastuzumab emtansine
should be administered over approximately 90 minutes for the first dose and, in the absence of infusion-related adverse events, over
approximately 30 minutes in subsequent doses. Vital signs should be taken before and after the trastuzumab emtansine infusion. Patients will
be monitored for any untoward effects for at least 90 minutes after completion of the first trastuzumab emtansine infusion and, in the absence of
infusion-related events, for a minimum of 30 minutes at subsequent infusions. For patients assigned to the control arm, therapy will be given
according to standard prescribing guidelines as described in Section 4.3.2 .
v
If the most recent assessments were performed less than 30 days from the Study Drug Completion Visit, these assessments do not need to be
repeated.

APPENDIX A-2
Exploratory Central Laboratory Blood Samples
Study Drug
Cycle 1 1 1 2 3 4 4 4 6 8 12 16 Completion Visit
30 days
( ± 7 days) after
Day 1 8 15 1 1 1 8 15 1 1 1 1 last dose
All Randomized Patients
Pre-dose whole blood a x
a
Pre-dose serum (HER2 ECD) x
Patients Randomized to T-DM1 Only
Pre-dose serum (anti-T-DM1 antibody) x x x x x
Pre-dose plasma PK plasma x x x x x x x x
Pre-dose serum PK serum x x x x x x x x
Post-dose (30 min) plasma PK x x x x x x x x
Post-dose (30 min) serum PK x x x x x x x x
Plasma PK (any point during visit) x x x x x
Serum PK (any point during visit) x x x x x
ECD = extracellular domain; PK = pharmacokinetic. T-DM1 = trastuzumab emtansine
Note: The shaded area indicates PK sampling for a subset of approximately 160 patients in the T-DM1 arm (PK sampling
does not apply to control arm patients who cross over to receive trastuzumab emtansine). Sites will be informed when
subsequently enrolled patients will not require PK sampling. Patients who begin PK sampling at study entry should continue
to undergo PK sampling as specified above until the study drug completion visit.
On days of study drug administration, pre-infusion laboratory samples should be drawn 0–4 hours before the start
of infusion, and post-infusion laboratory samples should be drawn 30 (± 10) minutes after the end of infusion,
unless otherwise specified.
a
These samples should be obtained for all patients in both arms of the study.

APPENDIX A-3
Study Flowchart for Control Patients Who Cross over to Receive Trastuzumab Emtansine
Study Drug
Survival
30 days (± 7) after Last Follow-Up b
Dose of Trastuzumab (Every 3
Day – 30 to – 1 1 (± 3) Emtansine Months)
Informed consent xc
Medical history x
Complete physical exam xd
Weight x x x
Concomitant medications xe x x x
Adverse events x x x x
12-lead electrocardiogram f x xg
ECHO or MUGA h (ECHO preferred) Weeks 6, 12, and every
12 weeks thereafter until
x xg
discontinuation of
Tumor assessment i x Frequency, method, and
evaluation criteria of
tumor assessments will
be according to routine
clinical practice per
investigator.
Bone scan/skeletal X-ray j x Per clinical indication
CBC with platelet and 3-part differential k, l x x x
Serum chemistries l xm xn xn
INR and aPTT x x
Study Drug
Survival
Serum/urine pregnancy test o x
Assessment of patient hospitalizations and/or
x x
hospital visits
Trastuzumab emtansine administration p x
aPTT = activated partial thromboplastin time; CT = computed tomography; ECHO = echocardiogram; MRI = magnetic resonance imaging;
MUGA = multiple-gated acquisition; SAE = serious adverse event.
Notes: Visits are based on a 21-day cycle. If the timing of a protocol-mandated procedure coincides with a holiday and/or weekend that
preclude the procedure within the allotted window, the procedure must be performed on the nearest following date.
a Screening tests or examinations must be performed within 30 days prior to Cycle 1, Day 1 unless noted otherwise.
b Only SAEs considered to be related to study medication should be reported. Patients will also be followed for survival and subsequent
anti-cancer therapies (not all concomitant meds) approximately every 3 months starting from the Study Drug Completion Visit until death,
loss to follow-up, withdrawal of consent, or study discontinuation by the Sponsors.
c Informed consent must be obtained prior to performance of any screening assessments unless the assessments were performed as standard
of care prior to obtaining informed consent. Informed consent does not need to be obtained within 30 days of Cycle 1, Day 1; however,
patients who fail screening and are rescreened will need to be reconsented.
d Includes assessment of vital signs (blood pressure, pulse, temperature).
e Record concomitant medications used within 21 days prior to Cycle 1, Day 1 and investigational and/or anti-cancer therapies used within
14 days of Cycle 1, Day 1.

f ECGs for each patient should be obtained from the same machine whenever possible. One set of all ECG tracings should be printed and
kept with the patient’s record.
g If the most recent assessments were performed less than 30 days from the Study Drug Completion Visit, these assessments do not need to
be repeated.

Study Flowchart for Control Patients Who Cross over to Receive Trastuzumab Emtansine
h Because of a potential worldwide Tc-99 shortage, ECHO is preferred; however, the same method used at screening should be used
throughout the study. Additional scans may be performed at any point if clinically indicated. Refer to Section 3.4 for further information
on cardiac safety surveillance.
i Response should be assessed using modified RECIST. Assessments should include an evaluation of all known or suspected sites of
disease, whenever possible. The same radiographic procedure used at baseline must be used throughout the study (e.g., the same contrast
protocol for CT scans). If the patient cannot undergo CT with contrast, then the chest should be imaged via CT without contrast and the
abdomen and pelvis should be imaged using MRI with contrast. See Section 4.5.1 for further details.
j An isotope bone scan and/or skeletal X-rays will be performed at screening and should be repeated in the event of clinical suspicion of
progression of existing bone lesions and/or the development of new bone lesions or for confirmation of complete response.
k CBC includes hemoglobin, hematocrit, platelet count, red blood cells, white blood cells; 3-part differential includes lymphocytes,
monocytes, and granulocytes.
l Local laboratory assessments performed within 72 hours preceding trastuzumab emtansine administration may be used as the Day 1
evaluations (up to 96 hours for Cycle 1, Day 1). Results of these local laboratory assessments must be reviewed (except alkaline
phosphatase and lactate dehydrogenase) prior to trastuzumab emtansine administration. In the event of a Grade 3 or 4 toxicity (per
CTCAE version 3.0), pertinent laboratory assessments should be repeated at the Investigator’s discretion until recovery to Grade ≤ 2.
Refer to Section 4.5 for further details.
m Sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, total and direct bilirubin, total protein,
albumin, ALT, AST, LDH, and ALP.
n BUN, creatinine, total bilirubin, ALP, LDH, AST, and ALT.
o For women of childbearing potential, including premenopausal women who have had a tubal ligation. Screening assessment must be
performed on serum within 7 days prior to randomization. Afterward, perform every third cycle on urine. A positive urine test must be
confirmed with a serum test.
p Trastuzumab emtansine should be administered over approximately 90 minutes for the first dose and, in the absence of infusion-related
adverse events, over approximately 30 minutes in subsequent doses. Vital signs should be taken before and after the trastuzumab
emtansine infusion. Patients will be monitored for any untoward effects for at least 90 minutes after completion of the first trastuzumab
emtansine infusion and, in the absence of infusion-related events, for a minimum of 30 minutes at subsequent infusions.

APPENDIX B
Modified Response Evaluation Criteria in Solid Tumors (RECIST)
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST) are
below.1
2. MEASURABILITY OF TUMOR LESIONS AT BASELINE

2.1. Definitions
At baseline, tumor lesions will be categorized as follows: measurable (lesions that can
be accurately measured in at least one dimension [longest diameter to be recorded] as
20 mm with conventional techniques or as 10 mm with spiral CT scan [see section 2.2 ])
or nonmeasurable (all other lesions, including small lesions [longest diameter < 20 mm
with conventional techniques or < 10 mm with spiral CT scan] and truly nonmeasurable
lesions).
The term "evaluable" in reference to measurability is not recommended and will not be
used because it does not provide additional meaning or accuracy.
All measurements should be recorded in metric notation by use of a ruler or calipers. All
baseline evaluations should be performed as closely as possible to the beginning of
treatment and never more than 4 weeks (approximately 30 days) before the beginning of
treatment.
Lesions considered to be truly nonmeasurable include the following: bone lesions,

leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast
disease, lymphangitis cutis/pulmonis, abdominal masses that are not confirmed and
followed by imaging techniques, and cystic lesions.
(Note: Tumor lesions that are situated in a previously irradiated area might or might not
be considered measurable, and the conditions under which such lesions should be
considered must be defined in the protocol when appropriate.)
2.2. Specifications by Methods of Measurements

The same method of assessment and the same technique should be used to
characterize each identified and reported lesion at baseline and during follow-up.
Imaging-based evaluation is preferred to evaluation by clinical examination when both

methods have been used to assess the anti-tumor effect of a treatment.
1
Therasse P, Arbuck SG, Eisenhauser EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to
evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205−16.
APPENDIX B (cont’d)
2.2.1. Clinical Examination
Clinically detected lesions will be considered measurable only when they are superficial
(e.g., skin nodules and palpable lymph nodes). For the case of skin lesions,
documentation by color photography—including a ruler to estimate the size of the
lesion—is required.
2.2.2. Chest X-ray

Lesions on chest X-rays are not acceptable as measurable lesions when they are clearly
defined and surrounded by aerated lung. More details concerning the use of this
method of assessment for objective tumor response evaluation are provided in Appendix
I. 2
2.2.3. CT and MRI

CT and MRI are the best currently available and most reproducible methods for
measuring target lesions selected for response assessment. Conventional CT and MRI
should be performed with contiguous cuts of 10 mm or less in slice thickness. Spiral CT
should be performed by use of a 5-mm or less contiguous reconstruction algorithm; this
specification applies to the tumors of the chest, abdomen, and pelvis, whereas head and
neck tumors and those of the extremities usually require specific protocols. More details
concerning the use of these methods of assessment for objective tumor response
evaluation are provided in Appendix I. 2
2.2.4. Ultrasound
When the primary endpoint of the study is objective response evaluation,
ultrasound should not be used to measure tumor lesions that are clinically not easily
accessible. It may be used as a possible alternative to clinical measurements for
superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules.
Ultrasound might also be useful to confirm the complete disappearance of superficial
lesions usually assessed by clinical examination.
Justifications for not using ultrasound to measure tumor lesions for objective response
evaluation are provided in Appendix I. 3
2.2.5. Endoscopy and Laparoscopy

The utilization of these techniques for objective tumor evaluation has not yet been fully
or widely validated. Their uses in this specific context require sophisticated equipment
and a high level of expertise that may be available only in some centers. Therefore,
utilization of such techniques for objective tumor response should be restricted to
2
See Appendix I of the Therasse et al. article.
3
See Appendix I of the Therasse et al. article.
validation purposes in specialized centers. However, such techniques can be useful in
confirming complete histopathologic response when biopsy specimens are obtained.
2.2.6. Tumor Markers

Tumor markers alone cannot be used to assess response. However, if markers are
initially above the upper normal limit, they must return to normal levels for a patient to be
considered in complete clinical response when all tumor lesions have disappeared.
Specific additional criteria for standardized usage of prostate-specific antigen and CA
(cancer antigen) 125 response in support of clinical trials are being validated.
3. Tumor Response Evaluation

3.1. Baseline Evaluation
3.1.1 Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response, it is necessary to estimate the overall tumor burden at
baseline to which subsequent measurements will be compared. Only patients with
measurable disease at baseline should be included in protocols where objective tumor
response is the primary endpoint. Measurable disease is defined by the presence of at
least one measurable lesion (as defined in Section 2.1). If the measurable disease is
restricted to a solitary lesion, its neoplastic nature should be confirmed by
cytology/histology.
3.1.2 Baseline Documentation of “Target” and “Nontarget” Lesions

All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total,
representative of all involved organs, should be identified as target lesions and recorded
and measured at baseline. Target lesions should be selected on the basis of their size
(those with the longest diameter) and their suitability for accurate repeated
measurements (either by imaging techniques or clinically). A sum of the longest
diameter for all target lesions will be calculated and reported as the baseline sum
longest diameter. The baseline sum longest diameter will be used as the reference by
which to characterize the objective tumor response.
All other lesions (or sites of disease) should be identified as nontarget lesions and
should be recorded at baseline. Measurements of these lesions are not required, but
the presence or absence of each should be noted throughout follow-up.
3.2 Response Criteria

3.2.1 Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor
response for target lesions. The criteria have been adapted from the original WHO
Handbook, taking into account the measurement of the longest diameter only for all

target lesions: CR—the disappearance of all target lesions; PR—at least a
30% decrease in the sum of the longest diameter of target lesions, taking as reference
the baseline sum longest diameter; PD—at least a 20% increase in the sum of the
longest diameter of target lesions, taking as reference the smallest sum longest diameter
recorded since the treatment started or the appearance of one or more new lesions;
stable disease—neither sufficient shrinkage to qualify for PR nor sufficient increase to
qualify for PD, taking as reference the smallest sum longest diameter since the
treatment started.
3.2.2 Evaluation of Nontarget Lesions

This section provides the definitions of the criteria used to determine the objective tumor
response for nontarget lesions: CR—the disappearance of all nontarget lesions and
normalization of tumor marker level; incomplete response/SD—the persistence of one or
more nontarget lesion(s) and/or the maintenance of tumor marker level above the normal
limits; and PD—the appearance of one or more new lesions and/or unequivocal
progression of existing nontarget lesions.
(Note: Although a clear progression of “nontarget” lesions only is exceptional, in such

circumstances, the opinion of the treating physician should prevail and the progression
status should be confirmed later by the review panel [or study chair]).
3.2.3 Evaluation of Best Overall Response

The best overall response is the best response recorded from the start of treatment until
disease progression/recurrence (taking as reference for PD the smallest measurements
recorded since the treatment started). In general, the patient's best response
assignment will depend on the achievement of both measurement and confirmation
criteria (see Section 3.3.1). 4 Table B1 provides overall responses for all possible
combinations of tumor responses in target and nontarget lesions with or without the
appearance of new lesions.
4
Refer to the Therasse et al. article.
Table B1
Overall Responses for All Possible Combinations of Tumor Responses
in Target and Nontarget Lesions
With or Without the Appearance of New Lesions
Target Lesions Nontarget Lesions New Lesions Overall Response
CR CR No CR
CR Incomplete response/SD No PR
PR Non-PD No PR
SD Non-PD No SD
PD Any Yes or No PD
Any PD Yes or No PD
Any Any Yes PD
CR = complete response; PR = partial response; SD = stable disease; PD = progressive
disease. See text for more details.
a. Conditions that may define early progression, early death, and inevaluability are
study specific and should be clearly defined in each protocol (depending on
treatment duration and treatment periodicity).
b. In some circumstances, it may be difficult to distinguish residual disease

from normal tissue. When the evaluation of CR depends on this determination,
it is recommended that the residual lesion be investigated (fine-needle
aspiration/biopsy) before confirming the CR status).
3.2.4 Frequency of Tumor Re-Evaluation

Frequency of tumor re-evaluation while on treatment should be protocol specific and
adapted to the type and schedule of treatment. However, in the context of Phase II
studies where the beneficial effect of therapy is not known, follow-up of every other cycle
(i.e., 6–8 weeks) seems a reasonable norm. Smaller or greater time intervals than these
could be justified in specific regimens or circumstances.
After the end of the treatment, the need for repetitive tumor evaluations depends on
whether the Phase II trial has, as a goal, the response rate or the time to an event
(disease progression/death). If time to an event is the main endpoint of the study, then
routine re-evaluation is warranted of those patients who went off the study for reasons
other than the expected event at frequencies to be determined by the protocol. Intervals
between evaluations twice as long as on study are often used, but no strict rule can be
made.

3.3 Confirmatory Measurement/Duration of Response
3.3.1 Confirmation
The main goal of confirmation of objective response in clinical trials is to avoid
overestimating the response rate observed. This aspect of response evaluation is
particularly important in nonrandomized trials where response is the primary endpoint.
In this setting, to be assigned a status of PR or CR, changes in tumor measurements
must be confirmed by repeat assessments that should be performed no less than
4 weeks after the criteria for response are first met. Longer intervals as determined by
the study protocol may also be appropriate.
In the case of stable disease, measurements must have met the stable disease criteria
at least once after study entry at a minimum interval (in general, not less than 6–8 weeks)
that is defined in the study protocol (see Section 3.3.3 of Therasse et al. 2000 5).
(Note: Repeat studies to confirm changes in tumor size may not always be feasible or
may not be part of the standard practice in protocols where PFS and OS are the key end
points. In such cases, patients will not have "confirmed response." This distinction
should be made clear when reporting the outcome of such studies.)
5
Refer to the Therasse et al. article.
APPENDIX C
Functional Assessment of Cancer Therapy−Breast
Questionnaire
Below is a list of statements that other people with your illness have said are
important. By circling one (1) number per line, please indicate how true each
statement has been for you during the past 7 days.
Not A Some- Quite Very
PHYSICAL WELL-BEING at little what a bit much
all bit
GP1 I have a lack of energy .................................................. 0 1 2 3 4

GP2 I have nausea ................................................................ 0 1 2 3 4
GP3 Because of my physical condition, I have trouble
meeting the needs of my family ..................................... 0 1 2 3 4
GP4 I have pain ..................................................................... 0 1 2 3 4
GP5 I am bothered by side effects of treatment .................... 0 1 2 3 4
GP6 I feel ill ........................................................................... 0 1 2 3 4
GP7 I am forced to spend time in bed ................................... 0 1 2 3 4
SOCIAL/FAMILY WELL-BEING Not A Some- Quite Very
at little what a bit much
all bit
GS1 I feel close to my friends ................................................ 0 1 2 3 4

GS2 I get emotional support from my family .......................... 0 1 2 3 4
GS3 I get support from my friends ......................................... 0 1 2 3 4
GS4 My family has accepted my illness ................................ 0 1 2 3 4
GS5 I am satisfied with family communication about my
illness ............................................................................ 0 1 2 3 4
GS6 I feel close to my partner (or the person who is my
main support) ................................................................ 0 1 2 3 4
Q1 Regardless of your current level of sexual activity, please
answer the following question. If you prefer not to answer
it, please mark this box and go to the next section.
GS7 I am satisfied with my sex life ......................................... 0 1 2 3 4

APPENDIX C (cont’d)
Questionnaire
By circling one (1) number per line, please indicate how true each
EMOTIONAL WELL-BEING Not A Some- Quite Very

at little what a bit much
all bit
GE1 I feel sad ..................................................................... 0 1 2 3 4

GE2 I am satisfied with how I am coping with my illness .... 0 1 2 3 4
GE3 I am losing hope in the fight against my illness ........... 0 1 2 3 4
GE4 I feel nervous .............................................................. 0 1 2 3 4
GE5 I worry about dying ..................................................... 0 1 2 3 4
GE6 I worry that my condition will get worse ...................... 0 1 2 3 4
FUNCTIONAL WELL-BEING Not A little Some- Quite Very

at all bit what a bit much
GF1 I am able to work (include work at home) .................. 0 1 2 3 4

GF2 My work (include work at home) is fulfilling................ 0 1 2 3 4
GF3 I am able to enjoy life ................................................. 0 1 2 3 4
GF4 I have accepted my illness......................................... 0 1 2 3 4
GF5 I am sleeping well ...................................................... 0 1 2 3 4
GF6 I am enjoying the things I usually do for fun............... 0 1 2 3 4
GF7 I am content with the quality of my life right now ....... 0 1 2 3 4

Questionnaire
By circling one (1) number per line, please indicate how true each
ADDITIONAL CONCERNS Not A little Some- Quite Very

at all bit what a bit much
B1 I have been short of breath ........................................ 0 1 2 3 4

B2 I am self-conscious about the way I dress ................. 0 1 2 3 4
B3 One or both of my arms are swollen or tender........... 0 1 2 3 4
B4 I feel sexually attractive ............................................. 0 1 2 3 4
B5 I am bothered by hair loss ......................................... 0 1 2 3 4
B6 I worry that other members of my family might
someday get the same illness I have ......................... 0 1 2 3 4
B7 I worry about the effect of stress on my illness .......... 0 1 2 3 4
B8 I am bothered by a change in weight ......................... 0 1 2 3 4
B9 I am able to feel like a woman ................................... 0 1 2 3 4
P2 I have certain parts of my body where I experience 0 1 2 3 4
pain ............................................................................

APPENDIX D
Diarrhea Assessment Scale

APPENDIX E
Eastern Cooperative Oncology Group Performance Status Scale
Grade Description
0 Fully active, able to carry on all pre-disease performance
without restriction
1 Restricted in physically strenuous activity but ambulatory and
able to carry out work of a light or sedentary nature; e.g., light
housework or office work
2 Ambulatory and capable of all self-care but unable to carry
out any work activities. Up and about > 50% of waking hours
3 Capable of only limited self-care, confined to a bed or chair
> 50% of waking hours
4 Completely disabled. Cannot carry on any self-care.
Totally confined to bed or chair
5 Dead

APPENDIX F
Child-Pugh Classification of the Severity of Liver Disease
Modified Child-Pugh classification of severity of liver disease according to the degree of
ascites, the plasma concentrations of bilirubin and albumin, the prothrombin time, and
the degree of encephalopathy.
Points Assigned
Parameter 1 2 3
Ascites Absent Slight Moderate
Bilirubin, mg/dL ≤ 2 2−3 >3
Albumin, g/dL >3.5 2.8−3.5 <2.8
Prothrombin time
* Seconds over control 1−3 4−6 >6
* INR <1.8 1.8−2.3 >2.3
Encephalopathy None Grade 1−2 Grade 3−4
A total score of 5−6 is considered Grade A (well-compensated disease); 7−9 is Grade B

(significant functional compromise); and 10−15 is Grade C (decompensated disease).
These grades correlate with 1- and 2-year patient survival.
One-year patient Two-year patient

Grade Points survival (%) survival (%)
A: well-compensated disease 5−6 100 85
B: significant functional 7−9 80 60
compromise
C: decompensated disease 10−15 45 35

APPENDIX G
New York Health Association Classification
Class I Patients with cardiac disease but without resulting limitations of physical activity.
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea,
or anginal pain.
Class II Patients with cardiac disease resulting in slight limitation of physical activity.
They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation,
dyspnea, or anginal pain.
Class III Patients with cardiac disease resulting in marked limitation of physical activity.
They are comfortable at rest. Less than ordinary physical activity causes fatigue,
palpitation, dyspnea, or anginal pain.
Class IV Patients with cardiac disease resulting in inability to carry on any physical
activity without discomfort. Symptoms of cardiac insufficiency or of the anginal
syndrome may be present even at rest. If any physical activity is undertaken,
discomfort is increased.
Oxford Textbook Of Medicine. Oxford University Press, 1997;2:2228

APPENDIX H
Capecitabine Dose Calculations According to Body Surface Area
No. of Tablets to be Taken at
100% Dose Level = 2000 mg/m2/day Each Dose
(Twice Daily 1000 mg/m2) (Morning and Evening)
Total Daily Twice Daily
Body Surface Area (m2) Dose (mg) Dose (mg) 150mg 500mg
≤1.26 2300 1150 1 2
1.27–1.38 2600 1300 2 2
1.39–1.52 2900 1450 3 2
1.53–1.66 3200 1600 4 2
1.67–1.78 3500 1750 5 2
1.79–1.92 3600 1800 2 3
1.93–2.06 4000 2000 0 4
2.07–2.18 4300 2150 1 4
≥ 2.19 4600 2300 2 4
No. of Tablets to Be Taken at

(Twice Daily 750 mg/m2) (Morning and Evening)
Surface Area (m2) Dose (mg)* Dose (mg) 150 mg 500 mg
≤ 1.26 1600 800 2 1
1.27–1.38 2000 1000 0 2
1.39–1.52 2200 1100 4 1
1.53–1.66 2400 1200 8 0
1.67–1.78 2600 1300 2 2
1.79–1.92 2800 1400 6 1
1.93–2.06 3000 1500 0 3
2.07–2.18 3200 1600 4 2
≥ 2.19 3500 1750 5 2

APPENDIX H (Cont’d)
Capecitabine Dose Calculations According to Body Surface Area
No. of Tablets to Be Taken at

(Twice Daily 500 mg/m2) (Morning And Evening)
Surface Area (m2) Dose (mg)* Dose (mg) 150 mg 500 mg
≤ 1.26 1200 600 4 0
1.27–1.38 1200 600 4 0
1.39–1.52 1500 750 5 0
1.53–1.66 1600 800 2 1
1.67–1.78 1600 800 2 1
1.79–1.92 1800 900 6 0
1.93–2.06 2000 1000 0 2
2.07–2.18 2100 1050 7 0
≥ 2.19 2200 1100 4 1

Section 2: Original statistical analysis plan, final statistical analysis plan,
summary of changes
STATISTICAL ANALYSIS PLAN
TITLE: A RANDOMIZED, MULTICENTER, PHASE III,

OPEN-LABEL STUDY OF THE EFFICACY AND
SAFETY OF TRASTUZUMAB-MCC-DM1 VS.
CAPECITABINE + LAPATINIB IN PATIENTS WITH
HER2-POSITIVE LOCALLY ADVANCED OR
METASTATIC BREAST CANCER WHO HAVE
RECEIVED PRIOR TRASTUZUMAB-BASED
THERAPY
PROTOCOL NUMBER: TDM4370g/BO21977
STUDY DRUG: Trastuzumab-MCC-DM1
IND NUMBER: 71,072

1 DNA Way
PLAN PREPARED BY: Liang Fang, Ph.D.
RECORDS RETENTION: Genentech Central Records
DATE FINAL: 11 November 2008
DATE AMENDED: 11 May 2011
CONFIDENTIAL
This is a Genentech, Inc. document that contains confidential information. Nothing herein is to be
disclosed without written consent from Genentech, Inc.
Statistical Analysis Plan: T-DM1—Genentech, Inc.

TDM4370g/BO21977 (Amendment 1)
TABLE OF CONTENTS
Page
STATISTICAL ANALYSIS PLAN AMENDMENT SUMMARY:

11 MAY 2011 AMENDMENT ……………………………………………………………. 4
1. STUDY DESIGN ............................................................................................... 5
2. RANDOMIZATION ISSUES .............................................................................. 5
3. STATISTICAL METHODS ................................................................................. 5
3.1 General Considerations .............................................................................. 5
3.2 Analysis of Study Conduct ...................................................................... 6
3.3 Analysis of Treatment Group Comparability ........................................... 6
3.4 Efficacy Analyses.................................................................................... 7
3.4.1 Primary Efficacy Endpoint ......................................................... 8
3.4.2 Secondary Efficacy Endpoints................................................... 9
3.4.3 Exploratory Endpoints ............................................................. 12
3.4.4 Sensitivity Analyses for the Primary Efficacy
Endpoint .................................................................................. 14
3.4.5 Subgroup Analyses to Assess Consistency of
the Treatment Benefit .............................................................. 15
3.5 Pharmacokinetic and Pharmacodynamic Analyses .............................. 15
3.6 Safety Analyses .................................................................................... 16
3.6.1 Study Drug Exposure .............................................................. 17
3.6.2 Adverse Events ....................................................................... 17
3.6.3 Laboratory Data ...................................................................... 17
3.6.4 Assessments of Left Ventricular Ejection
Fraction as Measured by ECHO or MUGA................................. 18
3.7 Additional Analyses to Demonstrate Clinical Utility of
Companion Diagnostics ........................................................................... 18
3.8 Missing Data and Underrepresented Strata .......................................... 18
3.9 Interim Analyses ................................................................................... 19
4. DETERMINATION OF SAMPLE SIZE ............................................................ 20
5. REFERENCES.................................................................................................. 21
TABLES
Table 1: Summary of Planned Overall Survival Analyses..................................... 20

2/TDM4370g/BO21977 (Amendment 1)
TABLE OF CONTENTS (cont’d)
APPENDICES
Appendix A: TDM4370g Protocol Synopsis
(from Protocol Amendment 3; 4 October 2010)
Appendix B: TDM4370g Study Flowchart
(from Protocol Amendment 3; 4 October 2010)
Appendix C: Hierarchical Dynamic Randomization Algorithm

11 MAY 2011 AMENDMENT
RATIONALE
The primary rationale for this amendment to the Statistical Analysis Plan (SAP) is
to harmonize it with the most recent protocol amendment for Study TDM4370g
(Amendment 3), which incorporated overall survival (OS) as a co-primary
endpoint, thereby creating a more robust trial. While an improvement in time to
progression in this disease setting served as the basis for approval (approval in
the United States and conditional approval in the European Union) of lapatinib
when given in combination with capecitabine in patients with metastatic breast
cancer (MBC), OS is considered the ‘gold standard’ for the demonstration of
clinical benefit of an experimental therapy. Consequently, the sample size was
increased from 580 to 980 to ensure that the study is properly powered to detect
an OS benefit of 4.3 months.
Also, analyses to demonstrate the clinical utility of companion diagnostics and

exploratory analyses of biomarkers have been specified.
Additional minor changes have been made to improve clarity and consistency
within the document and with the protocol and to reflect a change in study
personnel. Substantive new information appears in italics. This amendment
represents cumulative changes to the original SAP.

1. STUDY DESIGN
Study TDM4370g/BO21977 is a Phase III, randomized, multicenter, international,
two-arm, open-label clinical trial designed to compare the safety and efficacy
of trastuzumab-MCC-DM1 (T-DM1) with that of capecitabine + lapatinib
for HER2-positive locally advanced and metastatic breast cancer (MBC). A total of
980 patients will be enrolled at over 200 sites worldwide. Eligible patients will be
randomized in a 1:1 ratio to either T-DM1 or lapatinib + capecitabine.
2. RANDOMIZATION ISSUES
Upon verification of inclusion and exclusion criteria, eligible patients will be
randomized to either T-DM1 or lapatinib + capecitabine, using a hierarchical
dynamic randomization procedure (see Appendix C). The randomization scheme
is designed to ensure approximately equal sample sizes for the treatment arms,
within each category of world region (United States, Western Europe, Other),
number of prior chemotherapeutic regimens for locally advanced or metastatic
disease (0−1 vs. > 1), visceral vs. non-visceral disease, and overall. The order of
the stratification factors for the hierarchical randomization will be as follows:
1) world region, 2) number of prior chemotherapeutic regimens for locally
advanced or metastatic disease, and 3) visceral vs. non-visceral disease.
3. STATISTICAL METHODS
3.1 GENERAL CONSIDERATIONS

The primary objectives of the study are 1) to compare the efficacy of T-DM1 with
lapatinib + capecitabine in patients with HER2-positive locally advanced or
metastatic breast cancer who have received prior trastuzumab-based therapy as
measured by progression-free survival (PFS) based on independent review (by
an IRC) of tumor assessments; 2) to compare the efficacy of T-DM1 versus
capecitabine plus lapatinib in patients with HER2-positive, unresectable, locally
advanced breast cancer or MBC as measured by overall survival (OS) and to assess
landmark (1-year and 2-year) survival rates within each treatment group, as
appropriate; and 3) to assess the safety of T-DM1 compared with the safety of
lapatinib + capecitabine.

To avoid underestimation of the safety and tumor response rate due to an insufficient
follow-up period, data from all patients who were randomized into the study ≥ 3 months
prior to the data cutoff date for the primary PFS analysis will form the basis for all
analyses to be conducted at this time; all analyses will use the same data cutoff date as for
the primary PFS analysis. The date of the data cutoff for the primary analysis of PFS
will be when both the full enrollment of the 980 patients is completed and approximately
508 IRC-assessed PFS events have occurred for all patients who have been randomized
into the study for ≥ 3 months. At the time of the primary analysis of PFS, an interim
analysis of OS will be performed, as well as safety and all other protocol-specified
secondary and exploratory analyses.
The data cutoff date for the final analysis of OS will be when approximately 632 deaths
have occurred for all randomized patients. Only the OS and safety analyses will be
updated when the final OS analysis is conducted. Data from all randomized patients will
form the basis for all analyses to be performed at the time of the final OS analysis. The
analyses related to tumor assessments, such as PFS and objective response, will not be
repeated at the time of the final OS analysis.
Please see the sections below for detailed analysis methods and considerations for each
endpoint.
3.2 ANALYSIS OF STUDY CONDUCT

Patient enrollment, duration of follow-up, discontinuation from the study,
and discontinuation reasons will be summarized by treatment arm to which the
patients were randomized. In addition, protocol deviations and eligibility violations
will be summarized by treatment arm to which the patients were randomized.
At the time of the primary PFS analysis, all patients who were randomized into the study
≥ 3 months prior to the data cutoff date will be included in the analyses; at the time of the
final OS analysis, all patients randomized into the study will be included in the update of
these analyses.
3.3 ANALYSIS OF TREATMENT GROUP COMPARABILITY

The evaluation of treatment group comparability between the two treatment arms
will include summaries of demographics, medical history, baseline disease
characteristics, and patient treatment history. Data will be summarized by treatment

arm to which patients were randomized. All patients who were randomized ≥ 3 months
prior to the data cutoff date will be included in the analyses.
Descriptive statistics (mean, median, standard deviation, 25th percentile,

75th percentile, and range) will be presented for continuous variables such as
age, time since initial breast cancer diagnosis, and time since metastatic
diagnosis.
Frequency counts will be presented for categorical variables such as gender,

race, age category, Eastern Cooperative Oncology Group (ECOG) performance
score, estrogen receptor/progesterone receptor status, central HER2 status,
number of prior chemotherapy agents, prior radiation therapy, and prior
anthracycline therapy.
3.4 EFFICACY ANALYSES

The following section outlines the planned analyses of the efficacy outcomes of
the study.
The analysis population used for the primary analysis of PFS will be the randomized
population, defined as all patients who were randomized into the study ≥ 3 months prior
to the clinical data cutoff date for the final PFS analysis, regardless of whether they
received any study treatment.
All other efficacy endpoints will be analyzed using the randomized population with two
exceptions: 1) the analysis of objective response rate will only include patients in the
randomized population who have measurable disease at baseline; and 2) the analysis of
duration of response will include only patients who are in the randomized population and
also achieve an objective response to study treatment.
At the time of the final OS analysis, only the OS and safety analyses will be updated.
These analyses will include data from all patients randomized in the study.
For all efficacy analysis, patients will be counted towards the treatment group to which
they were randomized.

3.4.1 Primary Efficacy Endpoint
a. Progression-Free Survival
The primary efficacy endpoint of PFS, based on independent review of tumor

assessments, is defined as the time from randomization to the first documented
IRC-assessed disease progression using modified Response Evaluation Criteria
in Solid Tumors (RECIST 1.0) or death from any cause, whichever occurs earlier.
Data for patients without disease progression or death as of the data cutoff date will
be censored at the time of the last tumor assessment with an outcome other than
‘unevaluable’, or, if no tumor assessment was performed after the baseline visit, at
the time of randomization plus 1 day. Data from patients who are lost to follow-
up will be included in the analysis as censored observations on the last tumor
assessment date that the patient was known to be progression-free. Data from
patients whose disease progression or death occurs after two or more
consecutive missed tumor assessments will be handled by the approach
described in Section 3.8 (Missing Data).
For patients who receive non-protocol anti-cancer therapy prior to documented

progressive disease, the primary analysis of PFS will not censor patients at the
initiation of non-protocol anti-cancer therapy. A sensitivity analysis of PFS censoring
patients at their last tumor assessment before the initiation of non-protocol anti-
cancer therapy will also be provided. Although an analysis of PFS censoring for non-
protocol anti-cancer therapy has been used as the primary analysis in many oncology trials,
it could potentially lead to additional bias due to dependent censoring (Fleming et al.
2009). Therefore, the PFS analysis censoring for non-protocol anti-cancer therapy is
proposed as a sensitivity analysis rather than the primary analysis.
The two-sided log-rank test, stratified by world region (United States, Western
Europe, Other), number of prior chemotherapeutic regimens for locally advanced
or metastatic disease (0−1 vs. > 1), and visceral vs. non-visceral disease, will be
used as the primary test to compare PFS between the two treatment arms. The
results from an unstratified log-rank test and stratified and unstratified Wilcoxson tests
will also be provided as sensitivity analyses.
The Kaplan−Meier approach will be used to estimate median PFS for each
treatment arm. Cox proportional-hazards models, stratified by world region (United

States, Western Europe, Other), number of prior chemotherapeutic regimens for
locally advanced or metastatic disease (0−1 vs. > 1), and visceral vs. non-visceral
disease, will be used to estimate the hazard ratio and its 95% confidence interval
(CI).
b. Overall Survival
The co-primary endpoint, OS, is defined as the time from the date of randomization to the
date of death from any cause. Patients who are alive at the time of the data cutoff date
will be censored at the last known date they were alive. Patients with no post-baseline
information will be censored at the date of randomization plus 1 day. The methods for
data analysis are similar to those described for PFS, with the stratified log-rank test being
the primary analysis and sensitivity analysis using the unstratified log-rank test and the
stratified and unstratified Wilcoxon test. In addition, 1-year and 2-year survival rates
and the associated 95% CIs will be estimated using the Kaplan−Meier approach, as
appropriate.
The final analysis of OS will occur after approximately 632 deaths have occurred.
The results from the interim analysis of OS will be provided at the time the PFS analysis
results are reported.
To control the Type I error rate due to having two primary efficacy endpoints, a fixed-
sequence testing procedure will be implemented. The hypothesis testing for OS will be
conducted only when the test for PFS is statistically significant at a two-sided 5% alpha
level. For the purposes of controlling the Type I error associated with multiple looks at
the OS data, the O’Brien−Fleming method as implemented by Lan−DeMets will be used.
Additional information on the interim analysis of OS is provided in Section 3.9 of this
document.
3.4.2 Secondary Efficacy Endpoints

At the time of the primary PFS analysis, the secondary endpoints will be tested
sequentially at a two-sided 5% significance level in the following order: PFS per
investigator assessment, objective response rate per IRC assessment, time to treatment
failure, and time to symptom progression. However, these analyses will be considered as
conclusive only if the primary PFS and final OS analyses show that PFS and OS
endpoints are both statistically signficiant at a two-sided 5% significance level.
Otherwise, these analyses will be considered as descriptive in nature.

a. Progression-Free Survival Based on Investigator Tumor Assessment
PFS based on investigator tumor assessment is defined as the time from
randomization to first documented investigator-assessed disease progression or
death from any cause, whichever occurs earlier. Disease progression will be
determined by investigator review of tumor assessments using RECIST 1.0.
The methods for data censoring and analysis are similar to those described for
the primary endpoint of IRC-assessed PFS.
b. Objective Response
Objective tumor response will be determined primarily by independent review of
tumor assessments using RECIST 1.0. Only patients with measurable disease at
baseline will be included in the analysis of objective response. Patients without
a post-baseline tumor assessment will be considered non-responders.
An estimate of the objective response rate and its 95% CI (Blyth-Still-Casella)
will be calculated for each treatment arm. The Mantel-Haenszel chi-squared test
stratified by world region (United States, Western Europe, Other), number of
prior chemotherapeutic regimens for locally advanced or metastatic disease
(0−1 vs. > 1), and visceral vs. non-visceral disease, will be used to compare the
response rate between the two treatment arms. An unstratified χ2 test will also be
provided. Finally, the difference in response rate will also be provided with
95% CIs.
Separate analyses of objective response will be performed based on IRC assessment and
investigator assessment, respectively.
c. Duration of Objective Response

Only patients with an objective response will be included in the analysis of
duration of objective response. Duration of objective response will be
determined primarily by independent review of tumor assessments using
RECIST 1.0. Duration of response is defined as the period of time from the date
of initial confirmed partial response (PR) or complete response (CR) until the
date of progressive disease or death from any cause (whichever occurs earlier).
Patients will not be censored at initiation of non-protocol therapy. The
Kaplan−Meier approach will be used to estimate the median duration of objective
response for each treatment group and the corresponding 95% CIs. Because of the
non-randomized nature of the subgroup of patients who achieve an objective response, the
analysis of duration of objective response will be considered descriptive.

Separate analyses of duration of objective response will be performed based on IRC and
investigator assessment.
d. Clinical Benefit Rate

The clinical benefit rate, defined as the proportion of patients who achieve an
objective response (CR or PR per RECIST 1.0) any time during the study or who
maintain stable disease [SD] for at least 6 months from randomization, will be
compared between the two treatment arms based on both investigator and
independent review of tumor assessments, separately. Patients without a post-
baseline tumor assessment will be considered as not having experienced clinical
benefit from study treatment.
An estimate of the clinical benefit rate and its 95% CI (Blyth-Still-Casella) will be
calculated for each treatment arm. The Mantel-Haenszel chi-squared test
stratified by world region (United States, Western Europe, Other), number of
prior chemotherapeutic regimens for locally advanced or metastatic disease
(0−1 vs. > 1), and visceral disease vs. non-visceral disease, will be used to
compare the clinical benefit rate between the two treatment arms. An unstratified
χ2 test will also be provided. Finally, the difference in clinical benefit rate will also
be provided with 95% CIs.
e. Time to Treatment Failure

Time to treatment failure is defined as the time from randomization to
discontinuation of treatment for any reason, including (but not limited to) disease
progression per investigator assessment, treatment toxicity, or death. Patients
who are on study treatment at the time of the analysis cutoff date will be censored at
the time of the last dose received. The analysis methods are similar to those
described for the primary endpoint of PFS.
f. Time to Symptom Progression

The time to symptom progression (defined as the time from randomization to
the first documentation of a ≥ 5-point decrease from baseline in the scoring of
responses) as measured by the Functional Assessment of Cancer Therapy
Breast Trial Outcome Index (FACT-B TOI) will be measured between the
two treatment groups. The FACT-B TOI is a subset of the FACT-B and includes
the Physical, Functional and Breast subscales. A change of 5 points in the

FACT-B TOI is considered clinically significant. Only patients with a baseline
assessment and at least one follow-up assessment will be included in this analysis.
Analysis of time to symptom progression will be based on female patients only in
the randomized population as defined in Section 3.4.
The analysis methods are similar to those described for the primary efficacy
endpoint. Data for patients who do not have an observed symptom progression
at the time of data cutoff will be censored at the last observed Trial Outcome
Index-Physical Functional Breast (TOI-PFB) assessment date. Patients without
TOI-PFB assessments post-baseline will be censored at the time of
randomization plus 1 day.
g. Pharmacoeconomic Endpoint
The resource expenditure due to hospitalizations that are not study-defined
evaluations while on study treatment will be evaluated. The number of hospital
visits, number of days admitted, and type of visits (emergency room vs. inpatient
care) will be collected and compared between the two arms. An estimate of
the proportion of patients with hospital visits and its 95% CI (Blyth-Still-Casella)
will be calculated for each treatment arm. The Fisher’s exact test will be used to
compare the proportion of patients with hospital visits between the two treatment
arms. In addition, the difference in proportions will be provided with 95% CIs.
Similar methods will be used to compare the type of visits between the two arms.
Estimates of the mean and median number of days admitted to the hospital will
be calculated for each treatment arm. The t test will be used to compare the
mean number of days admitted between the two arms. Finally, the reason for
admission (disease progression vs. adverse event) will be summarized.
3.4.3 Exploratory Endpoints

The following exploratory endpoints will be assessed:
• Patient self-reported diarrhea will be measured by the Diarrhea Assessment
Scale (DAS; see Protocol TDM4370g, Appendix D).
The DAS has four questions that evaluate the frequency, urgency,
consistency, and discomfort of diarrhea experienced by a patient (see
Appendix D of Protocol TDM4370g). Estimates of the proportion of
patients with moderate or severe diarrhea and the respective 95% CI
(Blyth-Still-Casella) will be provided by treatment arm. The Mantel-

Haenszel chi-squared test stratified by world region (United States,
Western Europe, other), number of prior chemotherapeutic regimens for
locally advanced or metastatic disease (0−1 vs. > 1), and visceral disease
vs. non-visceral disease will be used to compare the proportion of patients
with moderate or severe diarrhea between the two treatment arms. The
difference in the proportion of patients with moderate or severe diarrhea
between treatment arms and 95% CI will be provided.
• The proportion of patients with a clinically significant improvement in
symptoms, defined as an increase in 5 points, as measured by the FACT-B
TOI, will be compared between the treatment arms.
Estimates of the proportion of patients with clinically significant symptom
improvement and respective 95% CI (Blyth-Still-Casella) will be provided
by treatment arm. The Mantel-Haenszel chi-squared test stratified by
world region (United States, Western Europe, other), number of prior
chemotherapeutic regimens for locally advanced or metastatic disease
(0−1 vs. > 1), and visceral disease vs. non-visceral disease will be used to
compare the proportions of patients with clinically significant symptom
improvement between the two treatment arms. The difference in the
proportion of patients with clinically significant symptom improvement
between treatment arms and 95% CI will be provided.
• Descriptive statistics (mean, standard error, minimum, and maximum) of change
from baseline in FACT-B TOI scores will be provided for each visit for each
treatment arm. An analysis of covariance (mixed model) will be used to compare
change from baseline in TOI score. In the mixed model, change from baseline in TOI
score will be the response variable; treatment, visit, and treatment by visit
interaction terms will be the fixed effects; baseline TOI score will be the covariate;
and patient will be the random effect.
• Two sensitivity analyses will be performed for the analysis of time to symptom
progression endpoint:
1. If a patient has a symptom progression event (i.e., a ≥ 5-point decrease from
baseline in FACT-B TOI score) after one or more missing FACT-B
assessments, the patient’s symptom progression event will be recorded as an
event on the last non-missing FACT-B assessment date, plus 1 day. This
sensitivity analysis is to assess the impact of missing assessments on the
results of the analysis of time to symptom progression.

baseline in FACT-B TOI score), the patient’s symptom progression event will
be back-dated by 6 weeks. This sensitivity analysis is to assess the impact of
the potential bias due to delayed reporting of symptom progression.

• Investigator and IRC tumor assessment:
The patient-level concordance between IRC and investigator-assessed
progression events will be summarized.
In addition, the concordance between the IRC and investigator-assessed
PFS time will be summarized.
The investigator-assessed PFS and IRC-assessed PFS will be
considered in agreement if both investigator and IRC assessments
agree that a PFS event has occurred and the absolute difference in
between these two PFS event dates is within one tumor assessment.
3.4.4 Sensitivity Analyses for the Primary Efficacy Endpoint

Several sensitivity analyses are planned for the primary efficacy analysis of PFS
to account for the potential impact of differences in IRC and investigator tumor
assessments, potential bias introduced by missed visits, timing of death,
non-protocol anti-cancer therapy, and loss to follow-up.
a. IRC and Investigator Tumor Assessment

A sensitivity analysis will be performed on the primary endpoint of IRC-assessed
PFS. In this analysis, PFS will be defined as time from randomization to the earliest
PFS event on the basis of progression by either the IRC or investigator tumor
assessment or death. For patients without a PFS event, PFS will be censored on
the date of the last IRC or last investigator tumor assessment with an assessment
other than ‘unevaluable’ or ‘unknown’, whichever is later. PFS for patients with no
post-baseline tumor assessments will be censored on the date of randomization
plus 1 day.
b. Missed Assessments
A sensitivity analysis will be performed on the primary endpoint of IRC-assessed
PFS to account for the potential impact of missing tumor assessments. Specifically, if a
patient has a documented IRC-assessed progression after two or more missing
or unevaluable assessments, the patient’s progression event will be recorded as
an event at the documented IRC-assessed progression date, after the missing
assessments.
In addition, if a patient has a documented IRC-assessed progression after one or

more missing assessments, the patient’s progression event will be back-dated to
the date of the last non-missing assessment, plus 1 day.

c. Non-Protocol Anti-Cancer Therapy
A sensitivity analysis of the primary endpoint of IRC-assessed PFS will be performed
in which patients are censored at the last tumor assessment before the initiation of
non-protocol anti-cancer therapy.
d. Loss to Follow-up
Patients who are lost to follow-up with regards to tumor assessment (i.e., alive but
without any tumor assessments for >84 days [two tumor assessment cycles] prior to data
cutoff) are counted as events at the last time they were known to be progression free.
3.4.5 Subgroup Analyses to Assess Consistency of the Treatment Benefit

In order to assess the consistency of treatment benefit with respect to the
primary efficacy endpoints of IRC-assessed PFS and OS across important
subgroups, forest plots (including estimated hazard ratios) will be provided for the
following variables: race, age, geographical region, ECOG, gender, number of
prior chemotherapeutic regimens for locally advanced or metastatic disease,
number of prior trastuzumab for locally advanced or metastatic disease, presence of
visceral disease, prior anthracycline, prior anti-cancer therapy for locally advanced or
metastatic disease, and key biomarkers. The forest plots will be created for IRC-
assessed PFS and OS.
In addition, a multivariate Cox regression on IRC-assessed PFS and OS will be run

that includes all the aforementioned baseline characteristics. A stepwise backward
regression or the fractional polynoms approach will be applied to obtain a final
multivariate model as appropriate.
3.5 PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES

Blood samples for measurement of serum T-DM1, total trastuzumab, and plasma
DM1 will be obtained from 160 patients randomized to the T-DM1 arm until sites
are notified that samples have been collected from 160 pharmacokinetic
(PK)-evaluable patients. A patient will be considered to be PK evaluable if they
remain on therapy through four or more cycles of study therapy. Individual and
mean concentration profiles of serum T-DM1, serum total trastuzumab, and plasma
DM1 versus time data will be tabulated and plotted. The following
pharmacokinetics parameters will be estimated for all PK-evaluable patients for Cycle 1

and Cycle 4: AUC, maximum concentration (Cmax), half-life (t1/2, where possible),
clearance (CL), and volume of distribution (Vss). Estimates for these parameters will
be tabulated and summarized (e.g., mean, standard deviation, coefficient of
variation, median, minimum, maximum, and range). Inter-patient variability and
drug accumulation after multiple dosing will be evaluated. Compartmental,
noncompartmental, and/or population approaches will be considered as
appropriate.
A population PK model for serum T-DM1 will be explored with concentration data from
this study and from previous internal T-DM1 studies (TDM3569g,TDM 4258g, and
TMD4374g) to further examine the interpatient variability of pharmacokinetics among
the different patient populations.
Additional exploratory PK and pharmacodynamic analyses and exposure-efficacy

analyses will be conducted as appropriate.
3.6 SAFETY ANALYSES

The safety-evaluable population is defined as randomized patients who received any
amount of study treatment. Safety analyses will be based on the actual treatment
received. Specifically, a patient will be included in the T-DM1 arm in safety analyses if
that patient receives any amount of T-DM1, regardless of the patient’s initial treatment
assignment by IVRS.
At the time of the primary analysis of PFS, two sets of safety analyses will be provided,
each based on a separate set of analysis populations:
1. All safety analyses, as detailed in Sections 3.6.1−3.6.4, based on data from
safety-evaluable patients who have been randomized to the study ≥ 3 months prior to
the data cutoff date.
2. Serious adverse events and deaths among the safety-evaluable patients who were
randomized to the study < 3 months prior to the data cutoff date. Unexpected
adverse events reported during this period will also be presented, as appropriate.
At the time of the final analysis of OS, all safety analyses will be updated to include
all safety-evaluable patients.

3.6.1 Study Drug Exposure
The number of patients who experience any dose interruption, including dose
delay, dose intensity, dose modification, dose discontinuation, and reasons for
study treatment discontinuation will be summarized for T-DM1 and the control
regimens. Descriptive statistics will be presented for total cumulative dose,
number of cycles, dose intensity, and weeks of exposure for T-DM1 and the
control regimens.
3.6.2 Adverse Events

Verbatim descriptions of adverse events will be mapped to Medical Dictionary for
Regulatory Activities (MedDRA) thesaurus terms and graded according to the National
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0.
The following events occurring on or after the first dose of study drug (i.e., treatment-
emergent adverse events) will be summarized by NCI CTCAE grade:
• All adverse events
• Serious adverse events
• Adverse events leading to death
• Adverse events leading to study drug discontinuation
For events of varying severity, the highest grade will be used in the summaries. Deaths
and causes of death will be summarized.
Selected adverse events of interest will be summarized by NCI CTCAE grade for each
treatment arm based on pre-specified category definitions, including (but not limited to)
hepatotoxicity, cardiac dysfunction, and thrombocytopenia. In addition, adverse events
occurring within 1 day of the first dose of each treatment cycle will be summarized to
help characterize potential infusion-related reactions.
3.6.3 Laboratory Data

Changes in laboratory data will be summarized by grade using the
NCI CTCAE v3.0 toxicity grade by treatment group.

3.6.4 Assessments of Left Ventricular Ejection Fraction as Measured by ECHO or
MUGA
Changes in left ventricular ejection fraction (LVEF) from baseline and nadir over
each scheduled visit will be summarized by treatment group. In particular, the
median at baseline and at nadir will be summarized for the two treatment arms.
The number of patients who have an LVEF decline to below 40%, develop
Grade 3 left ventricular dysfunction, or discontinue drug due to cardiac function
will be summarized. The number of patients who drop to below 50% with an
absolute decrease of ≥ 15 percentage points will also be summarized.
3.7 ADDITIONAL ANALYSES TO DEMONSTRATE CLINICAL UTILITY OF

COMPANION DIAGNOSTICS
Analysis of the primary endpoint of IRC-assessed PFS will be provided for the following
patient subgroups, using the same methods described in Section 3.4.5:
• Patients who are determined to be IHC 3+ by HercepTest™ and FISH+ by DAKO
HER2 FISH pharmDx™
• Patients who are determined to be IHC 3+ by HercepTest and FISH− by DAKO
HER2 FISH pharmDx
• Patients who are determined to be IHC 1 or 2 by HercepTest and FISH+ by DAKO
HER2 FISH pharmDx
In addition, concordance rates and 95% CIs will be provided for the following assays
using a kappa method:
• PathVysion® and DAKO HER2 FISH pharmDx
3.8 MISSING DATA AND UNDER-REPRESENTED STRATA

For the primary analysis of PFS and duration of response, data from patients who
are lost to follow-up will be included in the analysis as censored observations on
the last date that the patient is known to be progression free, defined as the date
of the last tumor assessment. When disease progression occurs after two or more
consecutive missed tumor assessments, these events will not be counted; rather,
the patient will be censored at the patient’s last tumor assessment prior to the
missing assessments. If disease progression occurs after one missed tumor
assessment, the event will be counted at the respective event date.

For the primary analysis of PFS and OS, a prospective pooling algorithm will be
applied in the event that there are underrepresented strata. If a given stratum
(e.g., world region of Western Europe, one prior chemotherapy for metastatic
disease, and visceral disease) has fewer than 10 PFS/OS events, it will be pooled
with its nearest stratum defined by the following hierarchy of variables: visceral
disease status, number of prior chemotherapeutic regimens for locally advanced
or metastatic disease, and world region. For example, the given stratum
mentioned above will be pooled with the stratum of world region of Western
Europe, one prior chemotherapy for metastatic disease, and non-visceral disease.
If the combined stratum has less than 10 PFS/OS events, the stratum will be
pooled over the respective prior chemotherapy level. This pooling procedure will
ensure that all remaining strata have greater or equal to 10 PFS/OS events for the
analysis.
Missing data in FACT-B TOI scores will not be imputed. However, the impact of missing
data will be assessed using the sensitivity analyses and mixed model described in Section
3.4.3.
3.9 INTERIM ANALYSES

An independent Data Monitoring Committee (DMC) will monitor accumulating safety
data every 6 months. In addition, data on serious adverse events will be monitored
by the DMC at least once every 3 months. An independent Cardiac Review
Committee (CRC) will review all potential cases of left ventricular systolic dysfunction
prior to each semi-annual DMC review and will report their findings to the DMC.
Additional details will be provided in the DMC and CRC Charters.
There will be no interim analysis of PFS. One interim analysis of OS will be conducted
at the same time as the primary analysis of PFS. The final analysis of OS will be
performed when 632 deaths have occurred. At the interim analysis, OS will be tested at
the significance level determined using the Lan-DeMets alpha spending function with an
O’Brien-Fleming boundary, so that the overall two-sided Type I error rate will be
maintained at the 5% level.
At each analysis, the statistical methods for analyzing OS described in Section 3.4.1 will
be used to analyze OS data.

On the basis of data from the Tykerb® (lapatinib) U.S. package insert (2010), the median
OS was 17.2 months with the lapatinib and capecitabine combination treatment. Under
the assumption of a hazard ratio [HR] of 0.80 in OS between the T-DM1 and
lapatinib + capecitabine groups, it is estimated that approximately 290 deaths would have
occurred at the time of data cutoff for the primary analysis of PFS. It is estimated that
632 deaths would occur approximately 51 months from the start of the study.
Table 1 presents a summary of the planned OS analyses, the efficacy stopping boundary,
and the estimated timing of these analyses.
Table 1
Summary of Planned Overall Survival Analyses
Analysis of OS No. of Deaths Efficacy Stopping Boundary a Estimated Timing b
Interim #1 290 c p < 0.0019 or observed HR < 0.69 32 months d
HR = hazard ratio; OS = overall survival.
a p-value will be based on two-sided log rank test.
b Time from the enrollment of first patient to data cutoff.
c Estimated number.
d At the same time as the final primary analysis of PFS.
The Sponsors will perform the interim and final analyses of OS. A survival data sweep
will be conducted prior to each OS analysis. In the event the actual number of deaths is
different from the estimated 290 deaths when PFS data reach maturity (508 events by
IRC assessment), the efficacy stopping boundary for this interim OS analysis will be
adjusted according to the aforementioned alpha spending function and the actual number
of deaths included in the analysis.
4. DETERMINATION OF SAMPLE SIZE

There are two primary efficacy endpoints of this Phase III trial: PFS, based on
independent review of tumor assessments, and OS. The fixed-sequence testing procedure
described above will be used to control the overall two-sided Type I error rate at 5% for
the primary efficacy analyses.
The sample size of the study was determined to ensure the final analysis of OS would be
appropriately powered. To detect an HR of 0.8 in OS (a 25% improvement in median
OS; i.e., from 17.2 months in the control arm to 21.5 months in the treatment arm),

approximately 632 deaths will be required to achieve 80% power at a two-sided 5% alpha
level. A total of 980 patients will be enrolled into the study.
The primary efficacy analysis will be event driven, and the primary analysis of PFS will
take place when approximately 508 IRC-assessed PFS events have occurred for patients
who have been randomized into the study for ≥ 3 months. This provides 90% power to
detect an HR of 0.75 in PFS (a 33% improvement in median PFS; i.e., from 6.2 months
in the control arm to 8.3 months in the treatment arm), with a two-sided alpha of 5%.

Assuming a median PFS of 6.2 months in the control arm and an HR of 0.75, the data
cutoff date for the primary analysis of PFS will be approximately 32 months from when
the first patient is enrolled (FPI). However, the primary analysis of PFS will not be
conducted until the study completes full enrollment of 980 patients. Assuming the
median OS of 17.2 months in the control arm and an HR of 0.8, the data cutoff date for
the final analysis of OS is projected to be approximately 51 months from FPI.
The sample size was estimated using EAST® software.
5. REFERENCES
Fleming TR, Rothmann MD, Lu HL. Issues in using progression-free survival when
evaluating oncology products. J Clin Oncol 2009;27:2874−80.

APPENDIX A
TDM4370g Protocol Synopsis (from Protocol Amendment 3; 4 October 2010)
PROTOCOL SYNOPSIS
TITLE: A RANDOMIZED, MULTICENTER, PHASE III OPEN-LABEL

STUDY OF THE EFFICACY AND SAFETY OF
TRASTUZUMAB-MCC-DM1 VS. CAPECITABINE + LAPATINIB
IN PATIENTS WITH HER2-POSITIVE LOCALLY ADVANCED
OR METASTATIC BREAST CANCER WHO HAVE RECEIVED
PRIOR TRASTUZUMAB-BASED THERAPY
PROTOCOL NUMBERS: Genentech, Inc. TDM4370g
F. Hoffmann-La Roche Ltd. BO21977
STUDY DRUG: Trastuzumab-MCC-DM1 (T-DM1)
PHASE: III
INDICATION: Metastatic breast cancer
IND: 71,072
SPONSORS: Genentech, Inc.
1 DNA Way
F. Hoffmann-La Roche Ltd.
Grenzacherstrasse 124
4070 Basel, Switzerland
DATE FINAL: 8 October 2008
DATES AMENDED: 19 February 2010
13 May 2010
4 October 2010
OBJECTIVES
• To compare the efficacy of Trastuzumab-MCC-DM1 (T-DM1) versus capecitabine plus
lapatinib in patients with HER2-positive unresectable, locally advanced or metastatic breast
cancer (MBC) as measured by progression-free survival (PFS) on the basis of an independent
• To compare the efficacy of T-DM1 versus capecitabine plus lapatinib in patients with HER2-
positive, unresectable, locally advanced breast cancer or MBC as measured by overall survival
(OS) and to assess landmark (1-year and 2-year) survival rates within each treatment group, as
appropriate
• To assess the safety of T-DM1 relative to the safety of capecitabine plus lapatinib
The secondary objectives for this study are as follows:
tumor assessments
• To compare the overall objective response rate between the two treatment arms on the basis of

1/TDM4370g/BO21977–A1 Signoff Draft
APPENDIX A (cont’d)
• To estimate the duration of objective response within each treatment arm on the basis of both
two treatment arms on the basis of both investigator and independent review of tumor assessments
disease progression, treatment toxicity, starting another anti-cancer agent before documented
progressive disease (PD), and death on study from any cause.
• To compare the time to symptom progression between the two treatment arms as measured by
the FACT-Breast-Trial Outcome Index (FACT-B TOI)
Resource expenditure due to hospitalizations and hospital visits for reasons other than defined
study evaluations will be compared between the two treatment arms.
STUDY DESIGN
This is a Phase III, randomized, multicenter, international, two-arm, open-label clinical trial designed
to compare the safety and efficacy of T-DM1 with that of capecitabine + lapatinib for HER2-positive
unresectable, locally advanced breast cancer or MBC. A total of 980 patients will be enrolled at
more than 200 sites worldwide. Eligible patients will be randomized in a 1:1 ratio to either T-DM1 or
lapatinib + capecitabine as follows:
• T-DM1 Arm: T-DM1 3.6 mg/kg intravenously (IV) over 30−90 minutes on Day 1 of a 21-day cycle
A hierarchical dynamic randomization scheme will be used to ensure an approximately equal sample
size for the two treatment arms 1) overall; 2) by world region (United States, Western Europe,
Other); and 3) within each of the four categories defined by the following two prognostic factors:
1) the number of prior chemotherapeutic regimens for unresectable, locally advanced or metastatic
disease (0−1 vs. > 1) and 2) visceral versus non-visceral disease.
Prior to enrollment, patients will be confirmed for having HER2-positive adenocarcinoma of the breast
by immunohistochemical (IHC) and/or fluorescence in situ hybridization (FISH) in a central laboratory
specified by the Sponsors through use of archival paraffin-embedded tumor tissue. A patient’s
HER2 status will be considered positive if the central laboratory reports Grade 3 + staining intensity
(on a scale of 0 to 3 +) by means of IHC analysis and/or gene amplification by FISH. Patients may
have either measurable (per modified Response Evaluation Criteria in Solid Tumors [RECIST])
and/or nonmeasurable unresectable, locally advanced or metastatic disease. Locally advanced
disease must not be amenable to resection or other local therapy with curative intent.
Tumor assessments will be conducted every 6 weeks from the date of randomization or Cycle 1
Day 1, regardless of dose delays or dose interruptions, until 6 weeks after investigator-assessed
PD or until death, whichever occurs first, even if study treatment has been discontinued as a result
of patient or physician choice or unacceptable toxicity.
Patients may remain on study treatment until disease progression (as assessed by the investigator),
unmanageable toxicity, or study termination by Genentech and Roche (the Sponsors).
Patients who are discontinued from study treatment because of disease progression will complete the
Study Drug Completion Visit approximately 30 days after the last dose of study treatment and return for
one additional tumor assessment visit and complete the FACT-B approximately 6 weeks after disease

progression. After the Study Drug Completion Visit, the patient will be followed for survival every
3 months until study closure. In addition, the FACT-B will be completed according to the same schedule
as survival follow-up.
Patients who are discontinued for reasons other than disease progression will complete the Study Drug
Completion Visit approximately 30 days after the last dose of study treatment. After the Study Drug
Completion Visit, the patient will be followed for survival every 3 months until study closure. Meanwhile,
these patients will continue to undergo tumor assessments, have concomitant medications collected
(anti-cancer therapies only), and complete the FACT-B approximately every 6 weeks until 6 weeks after
disease progression. After disease progression, the FACT-B will also be completed according to the
same schedule as survival follow-up.
After the Study Drug Completion Visit, all patients (regardless of reason for discontinuation) will be
followed for survival every 3 months until death, loss to follow-up, withdrawal of consent, or study
termination by the Sponsors.
Patient-reported outcomes (PROs) as assessed by the FACT-B (female patients only) should be
completed every two treatment cycles until 6 weeks after disease progression; for patients who
discontinue study treatment for reasons other than disease progression, the FACT-B assessment
should be performed every two treatment cycles until treatment discontinuation, and at the same time
of tumor assessments thereafter, until 6 weeks after disease progression. After disease progression,
the FACT-B assessment will be performed according to the same schedule as survival follow-up.
After patients discontinue from study treatment, subsequent anti-cancer therapies will be collected
An independent Data Monitoring Committee (DMC) will monitor accumulating patient safety data at
least once every 6 months during the course of the study. In addition, data on serious adverse events
will be monitored by the DMC at least once every 3 months. An independent Cardiac Review
Committee (CRC) will review all potential cases of left ventricular systolic dysfunction prior to each
DMC review and will report their findings to the DMC. An IRC will evaluate tumor responses through
the review of all tumor-assessment data generated from all patients at the time of the final PFS
analysis with treatment-arm information blinded to the IRC.
No interim analysis of IRC-assessed PFS is planned for this study. The final analysis of the primary
efficacy endpoint of PFS will take place when approximately 508 IRC-assessed PFS events have
occurred and enrollment is completed. One interim analysis of OS is planned at the time of the final
analysis of PFS as assessed by the IRC. The final analysis of OS will be performed when
approximately 632 deaths have occurred.
If the study is not terminated per DMC recommendation or by the Sponsors for other reasons
beforehand, it will be closed when approximately 632 deaths have been reported and the final
analysis of OS has been completed.
OUTCOME MEASURES


• PFS by investigator assessment, defined as the time from randomization to the first occurrence
of disease progression, as determined by investigator review of tumor assessments through use
• Objective response (PR plus CR) as determined by both investigator and independent review of
tumor assessments with use of modified RECIST
Objective responses must be confirmed at least 28 days after initial documentation of response.
independent review of tumor assessments with use of modified RECIST, or death from any cause
including treatment discontinuation without disease progression or treatment toxicity, disease
progression, treatment toxicity, starting another anti-cancer agent before documented PD,
or death from any cause
• Time to symptom progression (defined as the time from randomization to the first documentation
of a ≥ 5-point decrease from baseline in the scoring of responses) between the two treatment
arms as measured by the FACT-B TOI
• Estimated resources for hospitalizations and/or hospital visits that occur within 30 days of the
last dose of study treatment for reasons other than those defined by the protocol
The number of hospital visits, number of days admitted, and type of visits (emergency department
vs. inpatient care) will be collected and compared between the two arms. The reason for
admission (disease progression vs. adverse event) will also be assessed.
SAFETY PLAN
Overall safety will be assessed on an ongoing basis during the conduct of the study. An independent
DMC will monitor cumulative safety data at least once every 6 months during the course of the study.
In addition, data on serious adverse events will be monitored by the DMC at least once every
3 months. An independent CRC will review all potential cases of left ventricular systolic dysfunction
prior to each semi-annual DMC review and will report their findings to the DMC. Additional details will
be provided in the DMC and CRC Charters.
The safety plan for patients in the T-DM1 treatment arm is based on nonclinical toxicities of T-DM1,
the clinical experience with this molecule in ongoing studies, and clinical toxicities related to its
components (trastuzumab and maytansine, the parent drug of DM1).
The safety plan for patients receiving lapatinib and capecitabine is based on the national prescribing
guidelines, emphasizing the adverse event data reported for each drug.
STUDY TREATMENT
T-DM1
T-DM1 will be given at a dose of 3.6 mg/kg IV every 21 days.
Lapatinib Plus Capecitabine

CONCOMITANT THERAPY AND CLINICAL PRACTICE

T-DM1, lapatinib, and capecitabine are the investigational medicinal products in this study. All other
concomitant medications and premedication therapies are considered non-investigational medicinal
products. Concomitant therapy (non-investigational products) includes any prescription medication,
over-the-counter preparation, herbal therapy, or radiotherapy used by a patient between the
14 days preceding randomization and the study survival follow-up or early discontinuation visit.
Premedication for lapatinib and capecitabine is allowed according to standard practice guidelines.
(see Section 4.4 of the protocol). Concomitant use of erythropoiesis-stimulating agents is allowed if
clinically indicated in accordance with proper prescribing guidelines.
No premedication for the first infusion of T-DM1 is specified or expected; any planned premedication,
specifically steroids, for the first infusion must be approved by the Medical Monitor prior to administration.
Premedication for nausea and anxiety has not been generally necessary but is allowed.
Patients who experience T-DM1 infusion–related temperature elevations of > 38.5°C or other minor
infusion-related symptoms may be treated symptomatically with acetaminophen and/or H1- and
H2-receptor antagonists (e.g., diphenhydramine, ranitidine). Serious infusion-related events
manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen
saturation, or respiratory distress should be managed with supportive therapies as clinically indicated
according to standard clinical practice (e.g., supplemental oxygen, β2-agonists, and corticosteroids).
• Any therapies intended for the treatment of breast cancer, whether they are approved by national
health authorities or experimental, including cytotoxic chemotherapy (other than that specified by
the protocol), immunotherapy, hormonal therapy (other than megestrol acetate), and biologic agents
(other than granulocyte colony-stimulating factor and erythropoiesis-stimulating agents)
• Radiotherapy
Palliative radiotherapy may be permitted to treat painful bone metastases. Please contact the
Medical Monitor for approval. If the Medical Monitor cannot be reached because of time zone
differences, radiotherapy may be administered, but the Medical Monitor should still be informed.
Patients who require the use of any of these therapies described above will be discontinued from
study treatment but will be followed for disease progression and survival. Other medications
considered necessary for the patient’s safety and well-being may be given at the discretion of the
investigator. Use of bisphosphonates (e.g., pamidronate) for control of bone pain, treatment of
bony metastases, and treatment of osteoporosis, is permitted. If required for the treatment of
symptomatic malignancy-associated hypercalcemia, tumor assessments should be performed to
Patients randomized to the control arm who are on warfarin need to have their prothrombin time or
international normalized ratio monitored weekly.
STATISTICAL METHODS
To adjust for multiplicity due to having two primary endpoints, a fixed-sequence hypothesis testing
procedure will be implemented. The hypothesis test for PFS will be conducted at a one-sided alpha of
2.5%. If the PFS is statistically different between the two arms, OS will be tested at a one-sided alpha
of 2.5% to determine if the two arms have significantly different OS.
The co-primary efficacy endpoint is PFS based on independent review of tumor assessment, defined as
the time from randomization to documented IRC-assessed disease progression or death from any
cause (whichever occurs earlier).
For the analysis of PFS, data for patients without disease progression or death will be censored at
the time of the last tumor assessment (or, if no tumor assessment was performed after the baseline

visit, at the time of randomization plus 1 day). Data from patients who are lost to follow-up will be
included in the analysis as censored observations on the last date of tumor assessment that the
patient was known to be progression free.
For patients who receive non-protocol therapy (defined as any treatment the patient receives that is
intended to treat his or her MBC) prior to documented PD, the primary PFS analysis will not censor
patients at the initiation of non-protocol therapy. A sensitivity analysis of PFS censoring patients at
the last tumor assessment before the initiation of non-protocol therapy will also be performed.
disease (0−1 vs. > 1), and visceral vs. non-visceral disease will be used as the primary analysis to
compare PFS between the two treatment arms. The results from the unstratified log-rank test and
the stratified and unstratified Wilcoxon test will also be provided.
Cox proportional-hazards models, stratified by world region (United States, Western Europe, Other),
disease (0−1 vs. > 1), and visceral vs. non-visceral disease will be used to estimate the hazard ratio
(HR) and its 95% confidence interval (CI).
OS, the co-primary endpoint, is defined as the time from the date of randomization to the date of death
from any cause. Patients who are alive at the time of the analysis data cutoff will be censored at
the last date they were known to be alive. Patients with no post-baseline information will be censored
at the date of randomization plus 1 day. Methods for OS analysis are similar to those described for the
PFS endpoint, with the stratified log-rank test being the primary analysis and sensitivity analysis using
the unstratified log-rank test and the stratified and unstratified Wilcoxon test. In addition, 1-year and
2-year survival rates and corresponding 95% CIs will be estimated using the Kaplan−Meier approach,
as appropriate.
The final analysis of OS will occur after 632 deaths have occurred. One interim analysis of OS will be
performed at the time of the primary efficacy analysis of PFS. See Section 4.9.10 of the protocol (Interim
Analysis) for additional information.
Missing Data
follow-up will be included in the analysis as censored observations on the last date that the patient
is known to be progression free, defined as the date of the last tumor assessment. When disease
progression occurs after two or more consecutive missed tumor assessments, these events will not
be counted; rather, the patient will be censored at the patient’s last tumor assessment prior to the
missing assessments. If disease progression occurs after one missed tumor assessment, the event
will be counted at the respective event date.
There are two primary efficacy endpoints of this Phase III trial: PFS based on independent review
of tumor assessments, and OS. The fixed-sequence testing procedure described above will be
used to control the overall two-sided Type I error rate at 5% for the primary efficacy analyses.
(a 25% improvement in median OS; i.e., from 17.2 months in the control arm to 21.5 months in the
treatment arm), approximately 632 deaths will be required to achieve 80% power at a two-sided 5%
alpha level. A total of 980 patients will be enrolled into the study.
The primary efficacy analysis will be event driven, and the primary analysis of PFS will take place
when approximately 508 IRC-assessed PFS events have occurred. This provides 90% power to
detect an HR of 0.75 in PFS (a 33% improvement in median PFS; i.e., from 6.2 months in the
control arm to 8.3 months in the treatment arm), with a two-sided alpha of 5%.
It is expected that 980 patients will be enrolled over approximately 35 months. Assuming a median
PFS of 6.2 months in the control arm and an HR of 0.75, the date of data cutoff for the final analysis
of PFS will be approximately 32 months from when the first patient is enrolled (FPI). However, the

final analysis of PFS will not be conducted until the last patient is enrolled. Assuming the median
OS of 17.2 months in the control arm and an HR of 0.8, the data cutoff date for the final analysis of
OS is projected to be approximately 51 months from FPI.
Interim Analysis
There will be no interim analysis of PFS. One interim analysis of OS will be conducted, at the same
time as the final analysis of PFS. See Section 4.9.10 of the protocol for further details.

APPENDIX B
TDM4370g Study Flowchart (from Protocol Amendment 3; 4 October 2010)
Study Drug
Completion
Screening a Cycle 1 Cycles 2–34 + Visit
30 days (± 7)
8 15 1 8 after last dose Survival
Day – 30 to – 1 1 (± 3) (± 3) (± 3) (± 3) 15 (± 3) of study drug Follow-Up b
Informed consent xc
HER2 testing d x
Limited physical exam x x x
every two cycles thereafter until 6 weeks post
disease progression
Diarrhea Assessment Scale Day 1 (prior to any study procedures or x
discussion of test results) of every cycle
Weight and height f x x x x
Concomitant medications xg x x x x
Adverse events xh x x x x x x x x
12-lead electrocardiogram i x xw
x xw
Tumor assessment k x Every 6 weeks(± 5 days) regardless of dose
delay or early discontinuation until 6 weeks
post disease progression
Bone scan/skeletal X-ray l x Per clinical indication or to confirm a
complete response
CT or MRI of brain x Per clinical indication or to confirm a
complete response
Central laboratory tests See Appendix A-2 of the protocol
CBC with platelet and 3-part differential m, n x x x x x x x x
APPENDIX B
Study Drug
Completion
Screening a Cycle 1 Cycles 2–34 + Visit
30 days (± 7)
8 15 1 8 after last dose Survival
Day – 30 to – 1 1 (± 3) (± 3) (± 3) (± 3) 15 (± 3) of study drug Follow-Up b
Serum chemistries n xo xp xq xq xp xq xq xp
INR and aPTT r x x
Serum/urine pregnancy test s x x
t
Laboratory urinalysis x x
Assessment of patient hospitalizations x x x
Evaluation of capecitabine and lapatinib x x x
compliance u
Study drug administration/distribution v x x
aPTT = activated partial thromboplastin time; CBC = complete blood count; CT = computed tomography; ECHO = echocardiogram;
INR = international normalized ratio; IVRS = interactive voice response system; MRI = magnetic resonance imaging;
MUGA = multiple-gated acquisition.
a
b
outcomes as assessed by the FACT-B, and subsequent anti-cancer therapies (not all concomitant meds) approximately every 3 months
starting from the Study Drug Completion Visit until death, loss to follow-up, withdrawal of consent, or study discontinuation by the Sponsors.
c
Informed consent must be obtained prior to performance of any screening assessments unless the assessments were performed as
standard of care prior to obtaining informed consent. Informed consent does not need to be obtained within 30 days of randomization;
however, patients who fail screening and are rescreened will need to be reconsented.
d
HER2 status must be centrally confirmed any time prior to randomization (result must be IHC 3 + and/or gene amplified by FISH) by the
Sponsor-selected central laboratory. IHC, FISH, qRT-PCR will be performed. See Section 4.5.2 of the protocol for further details.
e
f

APPENDIX B
g
Record concomitant medications used within 14 days prior to randomization and investigational and/or anti-cancer therapies used within 21 days of
randomization.
h
i
Electrocardiograms for each patient should be obtained from the same machine whenever possible. One set of all ECG tracings should be printed
and kept with the patient’s record.
j
Because of a potential worldwide Tc-99 shortage, ECHO is preferred; however, the same method used at screening should be used throughout the
study. Additional scans may be performed at any point if clinically indicated. Refer to Section 3.4 of the protocol for further information on cardiac
safety surveillance. All ECHO and MUGA scans should be submitted to an IRC for central review within 2 weeks after the visit, if possible.
k
Response must be assessed using modified RECIST. Assessments should include an evaluation of all known or suspected sites of disease,
whenever possible. The same radiographic procedure used at baseline must be used throughout the study (e.g., the same contrast protocol for CT
scans). If the patient cannot undergo CT with contrast, then the chest should be imaged via CT without contrast and the abdomen and pelvis should
be imaged using MRI with contrast. See Section 4.5.1 of the protocol for further details. Technical imaging parameters are defined in Appendix B.
All radiographic images should be submitted to the IRC within 2 weeks after the visit, if possible. Patients who are discontinued from study treatment
for reasons other than disease progression will continue to undergo tumor assessments approximately every 6 weeks until 6 weeks post disease
progression.
l
An isotope bone scan and/or skeletal X-rays will be performed at screening and should be repeated in the event of clinical suspicion of progression
of existing bone lesions and/or the development of new bone lesions or for confirmation of complete response.
m
and granulocytes.
n
Local laboratory assessments performed within 72 hours preceding study drug administration may be used as the Day 1 evaluations (up to 96 hours
for Cycle 1, Day 1). Results of these local laboratory assessments must be reviewed (except alkaline phosphatase and lactate dehydrogenase) prior
to study drug administration. In the event of a Grade 3 or 4 toxicity (per CTCAE version 3.0), pertinent laboratory assessments should be repeated
at the Investigator’s discretion until recovery to Grade 2 or less. Refer to Section 4.5 of the protocol for further details. CBC and serum chemistry
are required for Day 8 and 15 for Cycles 1−4. At Day 8 and Day 15 for subsequent cycles, they are optional.
o
Sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, creatinine, calcium, phosphorus, total and direct bilirubin, total protein,
albumin, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, and uric acid.
p
Blood urea nitrogen, creatinine, total bilirubin, alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase,
and alanine aminotransferase.
q
Aspartate aminotransferase, alanine aminotransferase, and total bilirubin only.
r
Patients on capecitabine who are receiving coumarin-derivative anticoagulant therapy, such as warfarin or phenprocoumen, should have the
prothrombin time (PT) or INR monitored weekly.

APPENDIX B
s
For women of childbearing potential, including premenopausal women who have had a tubal ligation. Screening assessment must be performed on
serum within 7 days prior to randomization. Afterward, perform every third cycle on urine. A positive urine test must be confirmed with a serum test.
t
u
v
Cycle 1, Day 1 must occur within 5 days of randomization. For patients assigned to T-DM1 therapy, T-DM1 should be administered over
approximately 90 minutes for the first dose and, in the absence of infusion-related adverse events, over approximately 30 minutes in subsequent
doses. Vital signs should be taken before and after the T-DM1 infusion. Patients will be monitored for any untoward effects for at least 90 minutes
after completion of the first T-DM1 infusion and, in the absence of infusion-related events, for a minimum of 30 minutes at subsequent infusions. For
patients assigned to the control arm, therapy will be given according to standard prescribing guidelines as described in Section 4.3.2 of the protocol.
w
repeated.

APPENDIX C
Hierarchical Dynamic Randomization Algorithm
The dynamic randomization scheme attempts to produce a 1:1 ratio of sample sizes
for the two treatment arms (T-DM1 vs. lapatinib + capecitabine) within each category
of world region (US, Western Europe, Other), prior chemotherapy for metastatic or
locally advanced disease (0-1, >1), and visceral disease status (yes, no).
Step A:
Identify the strata (world region, number of prior chemotherapeutic regimens for
locally advanced or metastatic disease, and visceral disease status) for the subject
who will be randomized.
Step B:
Calculate the following statistics:
1. The number of subjects previously randomized to each treatment group overall:
O1, O2, and the absolute difference O12 = abs(O1−O2)
2. The number of subjects previously randomized to each treatment group within
world region levels: S1, S2, and the absolute difference S12 = abs(S1−S2)
prior chemotherapy levels: C1, C2, and the absolute difference
C12 = abs(C1−C2)
visceral disease levels: V1, V2, and the absolute difference V12 = abs(V1−V2)
Step C:
Check the following criteria to see which allocation probabilities are used:
• If O12 ≥ 4:
Select treatment with probability 0.75 from the treatment arm that satisfies
O = min(O1,O2) and with probability 0.25 from the other treatment arm.
• Otherwise, if S12 ≥ 4:
S = min(S1,S2) and with probability 0.25 from the other treatment arm.

• Otherwise, if C12 ≥ 4:
C = min(C1,C2) and with probability 0.25 from the other treatment arm.
• Otherwise, if V12 ≥ 4:
V = min(V1,V2) and with probability 0.25 from the other treatment arm.
• Otherwise, randomly assign treatment among the two treatment arms using
probabilities (0.5, 0.5).

Section 3: Statistical analysis plan amendment
STATISTICAL ANALYSIS PLAN
TITLE: A RANDOMIZED, MULTICENTER, PHASE III, OPEN-LABEL STUDY

OF THE EFFICACY AND SAFETY OF TRASTUZUMAB-MCC-DM1
VS. CAPECITABINE + LAPATINIB IN PATIENTS WITH
HER2-POSITIVE LOCALLY ADVANCED OR METASTATIC BREAST
CANCER WHO HAVE RECEIVED PRIOR TRASTUZUMAB-BASED
THERAPY
PROTOCOL NUMBER: TDM4370g/BO21977
STUDY DRUG: Trastuzumab-MCC-DM1
IND NUMBER: 71,072
1 DNA Way
PLAN PREPARED BY: Liang Fang, Ph.D.
DATE FINAL: 11 November 2008
DATES AMENDMEND: A1: 11 May 2011
A2: See electronic date stamp below
SAP APPROVAL
Plan Number / Version: 3
Date: See last date in electronic signature manifestation below.
Plan approved by: See electronic signature manifestation below.
Name Reason for Signing Date and Time

(UTC)
Burger,Hans_Ulrich Project Statistician 22-Jun-2012 08:43:19
Statistical Analysis Plan: Trastuzumab EmtansineGenentech, Inc.

TDM4370g/BO21977–A2
TABLE OF CONTENTS
1. STUDY DESIGN ........................................................................................... 5
2. RANDOMIZATION ISSUES .......................................................................... 5
3. STATISTICAL METHODS............................................................................. 5
3.1 General Considerations ........................................................... 5
3.2 Analysis of Study Conduct ....................................................... 6
3.3 Analysis of Treatment Group Comparability............................. 6
3.4 Efficacy Analyses..................................................................... 7
3.4.1 Primary Efficacy Endpoints ...................................................... 7
3.4.2 Secondary Efficacy Endpoints ................................................. 8
3.4.3 Exploratory Endpoints ............................................................ 11
3.4.4 Sensitivity Analyses for the Progression-Free
Survival Primary Efficacy Endpoint ........................................ 12
3.4.5 Subgroup Analyses to Assess Consistency of
Treatment Benefit .................................................................. 13
3.5 Pharmacokinetic and Pharmacodynamic Analyses ............... 14
3.6 Safety Analyses ..................................................................... 14
3.6.1 Study Drug Exposure............................................................. 15
3.6.2 Adverse Events...................................................................... 15
3.6.3 Laboratory Data ..................................................................... 15
3.6.4 Assessments of Left Ventricular Ejection Fraction as
Measured by Echocardiogram or Multigated
Acquisition Scan .................................................................... 15
3.7 Additional Analyses to Demonstrate Clinical Utility of
Companion Diagnostics ......................................................... 16
3.8 Exploratory Biomarker Analyses ............................................ 16
3.9 Missing Data and Under-Represented Strata ........................ 16
3.10 Interim Analyses .................................................................... 17
4. DETERMINATION OF SAMPLE SIZE ........................................................ 19
5. REFERENCES............................................................................................ 20

2/TDM4370g/BO21977–A2
TABLE OF CONTENTS (cont’d)
LIST OF TABLES
Table 1: Planned Timing and Stopping Boundary of Overall

Survival Analyses ........................................................................ 18
LIST OF APPENDICES
Appendix A: Protocol TDM4370g/BO21977, Version A4 Synopsis

Appendix B: Protocol TDM4370g/BO21977 Study Flowchart for Patients
Receiving Randomized Treatment
Appendix C: Protocol TDM4370g/BO21977 Study Flowchart for Control
Patients Who Cross over to Receive Trastuzumab Emtansine
Appendix D: Hierarchical Dynamic Randomization Algorithm

3/TDM4370g/BO21977–A2
The primary rationale for this second amendment is to harmonize this Statistical Analysis
Plan (SAP) with the most recent amendment (Amendment 4) to
Protocol TDM4370g/BO21977, which added additional interim analyses for overall
survival (OS). Provisions for additional interim analyses have been included in
anticipation of updated OS analyses being requested by some health authorities to
facilitate their review of the benefit−risk for patients receiving trastuzumab emtansine
therapy and to allow patients in the lapatinib and capecitabine arm the opportunity for
earlier access to trastuzumab emtansine in the event that the OS boundary is crossed
and the trial can be considered to have demonstrated statistically and clinically
significant survival benefit. To preserve the statistical rigor at all future OS analyses, the
type I error rate will be strictly controlled at the 0.05 level by the continued use of the
Lan-DeMets alpha-spending function with an O'Brien-Fleming boundary that is
prespecified in the protocol and in the SAP. The final analysis for OS (at approximately
632 events) will still be conducted. If any interim analysis of OS meets the criteria for
statistical significance, the co-primary endpoint of OS will be considered met at that
interim and the final OS analysis will therefore be considered descriptive only.
Additional minor changes have been made to improve clarity and consistency.

4/TDM4370g/BO21977–A2
1. STUDY DESIGN
Study TDM4370g/BO21977 is a Phase III, randomized, multicenter, international,
two-arm, open-label clinical trial designed to compare the safety and efficacy
of trastuzumab emtansine with those of capecitabine + lapatinib for human epidermal
growth factor−2 (HER2)−positive locally advanced and metastatic breast cancer. A total
of 980 patients will be enrolled at over 200 sites worldwide. Eligible patients will be
randomized in a 1:1 ratio to either trastuzumab emtansine or lapatinib + capecitabine.
2. RANDOMIZATION ISSUES
Upon verification of inclusion and exclusion criteria, eligible patients will be randomized
to either trastuzumab emtansine or lapatinib + capecitabine using a hierarchical dynamic
randomization procedure (see Appendix D). The randomization scheme is designed to
ensure approximately equal sample sizes for the treatment arms within each category of
world region (United States, Western Europe, other), number of prior chemotherapeutic
regimens for locally advanced or metastatic disease (0−1 vs. > 1), visceral vs.
non-visceral disease, and overall. The order of the stratification factors for the
hierarchical randomization will be as follows: 1) world region, 2) number of prior
chemotherapeutic regimens for locally advanced or metastatic disease, and 3) visceral
vs. non-visceral disease.
3. STATISTICAL METHODS
3.1 GENERAL CONSIDERATIONS
The primary objectives of the study are 1) to compare the efficacy of trastuzumab
emtansine with lapatinib + capecitabine in patients with HER2-positive locally advanced
or metastatic breast cancer who have received prior trastuzumab-based therapy as
measured by progression-free survival (PFS) based on independent review
(by an Independent Review Committee [IRC]) of tumor assessments; 2) to compare
the efficacy of trastuzumab emtansine versus lapatinib + capecitabine in patients with
HER2-positive, unresectable, locally advanced breast cancer or metastatic breast
cancer as measured by overall survival (OS) and to assess landmark (1-year and
2-year) survival rates within each treatment group, as appropriate; and 3) to assess
the safety of trastuzumab emtansine compared with the safety of
lapatinib + capecitabine.
To avoid the underestimation of the safety and tumor response rate due to an insufficient
follow-up period, data from all patients who were randomized into the study ≥ 3 months
prior to the data cutoff date for the primary PFS analysis will form the basis for all
analyses to be conducted at this time; all analyses will use the same data cutoff date as
for the primary PFS analysis. The data cutoff date for the primary analysis of PFS will
be when both the full enrollment of the 980 patients is completed and approximately
508 IRC-assessed PFS events have occurred for all patients who have been

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randomized into the study for ≥ 3 months. At the time of the primary analysis of PFS, an
interim analysis of OS will be performed, as well as safety and all other
protocol-specified secondary and exploratory analyses.
The data cutoff date for the final analysis of OS will be when approximately 632 deaths
have occurred for all randomized patients. Only the OS and safety analyses will be
updated when the final OS analysis is conducted. Data from all randomized patients will
form the basis for all analyses to be performed at the time of the final OS analysis.
The analyses related to tumor assessments, such as PFS and objective response, will
not be repeated at the time of the final OS analysis.
Please see the sections below for detailed analysis methods and considerations for each
endpoint.
3.2 ANALYSIS OF STUDY CONDUCT

Patient enrollment, duration of follow-up, discontinuation from the study,
and discontinuation reasons will be summarized by the treatment arm to which the
patients were randomized. In addition, protocol deviations and eligibility violations will
be summarized by the treatment arm to which the patients were randomized.
At the time of the primary PFS analysis, all patients who were randomized into the study
≥ 3 months prior to the data cutoff date will be included in the analyses; at the time of the
final OS analysis, all patients randomized into the study will be included in the update of
these analyses.
3.3 ANALYSIS OF TREATMENT GROUP COMPARABILITY

The evaluation of treatment group comparability between the two treatment arms will
include summaries of demographics, medical history, baseline disease characteristics,
and patient treatment history. Data will be summarized by the treatment arm to which
patients were randomized. All patients who were randomized ≥ 3 months prior to the
data cutoff date will be included in the analyses.
Descriptive statistics (mean, median, standard deviation, 25th percentile, 75th percentile,
and range) will be presented for continuous variables such as age, time since initial
breast cancer diagnosis, and time since metastatic diagnosis.
Frequency counts will be presented for categorical variables such as sex, race, age
category, Eastern Cooperative Oncology Group (ECOG) performance score, estrogen
receptor/progesterone receptor status, central HER2 status, number of prior
chemotherapy agents, prior radiation therapy, and prior anthracycline therapy.

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3.4 EFFICACY ANALYSES
The following section outlines the planned analyses of the study.
The analysis population to be used for the primary analysis of PFS will be the
randomized population, defined as all patients who were randomized into the study
≥ 3 months prior to the clinical data cutoff date for the final PFS analysis, regardless of
whether they received any study treatment.
All other efficacy endpoints will be analyzed using the randomized population with
two exceptions: 1) the analysis of objective response rate will only include patients in
the randomized population who have measurable disease at baseline and 2) the
analysis of duration of response will include only patients who were in the randomized
population and who also achieved an objective response to study treatment.
At the time of the final OS analysis, only the OS and safety analyses will be updated.
These analyses will include data from all patients randomized in the study.
For all efficacy analyses, patients will be counted towards the treatment group to which
they were randomized.
3.4.1 Primary Efficacy Endpoints

a. Progression-Free Survival
The primary efficacy endpoint of PFS, based on independent review of tumor
assessments, is defined as the time from randomization to the first documented
IRC-assessed disease progression using modified Response Evaluation Criteria in Solid
Tumors, Version 1.0 (RECIST v1.0) or death from any cause, whichever occurs earlier.
Data for patients without disease progression or death as of the data cutoff date will be
censored at the time of the last tumor assessment with an outcome other than
“unevaluable,” or, if no tumor assessment was performed after the baseline visit, at the
time of randomization plus 1 day. Data from patients who were lost to follow-up will be
included in the analysis as censored observations on the last tumor assessment date
that the patient was known to be progression free. Data from patients whose disease
progression or death occurred after two or more consecutive missed tumor assessments
will be handled by the approach described in Section 3.9 (Missing Data).
For patients who received non-protocol anti-cancer therapy (NPT) prior to documented
progressive disease, the primary analysis of PFS will not censor patients at the initiation of
NPT. A sensitivity analysis of PFS censoring patients at their last tumor assessment
before the initiation of NPT will also be provided. Although an analysis of PFS censoring
for NPT has been used as the primary analysis in many oncology trials, it could potentially
lead to additional bias due to dependent censoring (Fleming et al. 2009). Therefore, the

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PFS analysis censoring for NPT is proposed as a sensitivity rather than as the primary
analysis.
The two-sided log-rank test, stratified by world region (United States, Western Europe,
other), number of prior chemotherapeutic regimens for locally advanced or metastatic
disease (0−1 vs. > 1), and visceral vs. non-visceral disease, will be used as the primary
test to compare PFS between the two treatment arms. The results from an unstratified
log-rank test and stratified and unstratified Wilcoxon tests will also be provided as
sensitivity analyses.
The Kaplan-Meier approach will be used to estimate median PFS for each treatment
arm. Cox proportional hazards models, stratified by world region (United States,
Western Europe, other), number of prior chemotherapeutic regimens for locally
advanced or metastatic disease (0−1 vs. > 1), and visceral vs. non-visceral disease, will
be used to estimate the hazard ratio and its 95% CI.
b. Overall Survival
The co-primary endpoint, OS, is defined as the time from the date of randomization to
the date of death from any cause. Patients who were alive at the time of the data cutoff
date will be censored at the last known date they were alive. Patients with no
post-baseline information will be censored at the date of randomization plus 1 day. The
methods for OS data analysis are similar to those described for PFS, with the stratified
log-rank test being the primary analysis and sensitivity analysis using the unstratified
log-rank test and the stratified and unstratified Wilcoxon test. In addition, 1-year and
2-year survival rates and the associated 95% CIs will be estimated using the
Kaplan-Meier approach, as appropriate.
The final analysis of OS will occur after approximately 632 deaths have occurred.
The results from the first interim analysis of OS will be provided at the time the PFS
analysis results are reported.
To control the type I error rate due to having two primary efficacy endpoints, a
fixed-sequence testing procedure will be implemented. The hypothesis testing for OS
will be conducted only when the test for PFS is statistically significant at a two-sided
5% alpha level. For the purposes of controlling the type I error associated with multiple
looks at the OS data, the O’Brien-Fleming method as implemented by Lan-DeMets will
be used. Additional information on the interim analyses of OS is provided in
Section 3.10.
3.4.2 Secondary Efficacy Endpoints

At the time of the primary PFS analysis, the secondary endpoints will be tested
sequentially at a two-sided 5% significance level in the following order: PFS per
investigator assessment, objective response rate per IRC assessment, time-to-treatment

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failure, and time-to-symptom progression. However, these analyses will be considered
as conclusive only if the primary PFS and final OS analyses show that PFS and OS
endpoints are both statistically significant at a two-sided 5% significance level.
Otherwise, these analyses will be considered as descriptive in nature.
a. Progression-Free Survival Based on Investigator Tumor Assessment

PFS based on investigator tumor assessment is defined as the time from randomization
to first documented investigator-assessed disease progression or death from any cause,
whichever occurs earlier. Disease progression will be determined by investigator review
of tumor assessments using RECIST v1.0. The methods for data censoring and
analysis are similar to those described for the primary endpoint of IRC-assessed PFS.
b. Objective Response
Objective tumor response will be determined primarily by independent review of tumor
assessments using RECIST v1.0. Only patients with measurable disease at baseline
will be included in the analysis of objective response. Patients without a post-baseline
tumor assessment will be considered non-responders.
An estimate of the objective response rate and its 95% CI (Blyth-Still-Casella) will be
calculated for each treatment arm. The Mantel-Haenszel χ2 test stratified by world
region (United States, Western Europe, other), number of prior chemotherapeutic
regimens for locally advanced or metastatic disease (0−1 vs. > 1), and visceral vs.
non-visceral disease will be used to compare the response rate between the
two treatment arms. An unstratified χ2 test will also be provided. Finally, the difference
in response rates will also be provided with 95% CI.
Separate analyses of objective response will be performed based on IRC assessment

and investigator assessment, respectively.
c. Duration of Objective Response

Only patients with an objective response will be included in the analysis of duration of
objective response. Duration of objective response will be determined primarily by
independent review of tumor assessments using RECIST v1.0. Duration of response is
defined as the period of time from the date of the initial confirmed partial response or
complete response until the date of progressive disease or death from any cause
(whichever occurs earlier). Patients will not be censored at the initiation of NPT. The
Kaplan−Meier approach will be used to estimate the median duration of objective
response for each treatment group and the corresponding 95% CI. Because of the
non-randomized nature of the subgroup of patients who achieve an objective response,
the analysis of duration of objective response will be considered descriptive.
Separate analyses of duration of objective response will be performed based on IRC and
investigator assessments.

9/TDM4370g/BO21977–A2
d. Clinical Benefit Rate
The clinical benefit rate, defined as the proportion of patients who achieve an objective
response (complete response or partial response per RECIST v1.0) any time during the
study or who maintain stable disease (SD) for at least 6 months from randomization, will
be compared separately between the two treatment arms based on both investigator and
independent review of tumor assessments. Patients without a post-baseline tumor
assessment will be considered as not having experienced clinical benefit from study
treatment.
An estimate of the clinical benefit rate and its 95% CI (Blyth-Still-Casella) will be
calculated for each treatment arm. The Mantel-Haenszel χ2 test stratified by world
regimens for locally advanced or metastatic disease (0−1 vs. > 1), and visceral disease
vs. non-visceral disease will be used to compare the clinical benefit rate between the
two treatment arms. An unstratified χ2 test will also be provided. Finally, the difference
in clinical benefit rate will also be provided with 95% CI.
e. Time-to-Treatment Failure
Time-to-treatment failure is defined as the time from randomization to discontinuation of
treatment for any reason, including (but not limited to) disease progression per
investigator assessment, treatment toxicity, or death. Patients who were on study
treatment at the time of the analysis cutoff date will be censored at the time of the last
study treatment dose received. The analysis methods are similar to those described for
the primary endpoint of PFS.
f. Time-to-Symptom Progression
The time to symptom progression, defined as the time from randomization to the first
documentation of a ≥ 5-point decrease from baseline in the scoring of responses
as measured by the Functional Assessment of Cancer Therapy Breast Trial Outcome
Index (FACT-B TOI), will be measured between the two treatment groups. The FACT-B
TOI is a subset of the FACT-B and includes the physical, functional, and breast
subscales. A change of 5 points in the FACT-B TOI is considered clinically significant.
Only patients with a baseline assessment and at least one follow-up assessment will be
included in this analysis. Analysis of time to symptom progression will be based on
female patients only in the randomized population as defined in Section 3.4.
The analysis methods are similar to those described for the primary efficacy endpoint.
Data for patients who do not have an observed symptom progression at the time of data
cutoff will be censored at the last observed Trial Outcome Index−Physical Functional
Breast (TOI-PFB) assessment date. Patients without TOI-PFB assessments
post-baseline will be censored at the time of randomization plus 1 day.

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g. Pharmacoeconomic Endpoint
The resource expenditure due to hospitalizations that are not study-defined evaluations
while on study treatment will be assessed. The number of hospital visits, number of
days admitted, and type of visits (emergency room vs. inpatient care) will be collected
and compared between the two arms. An estimate of the proportion of patients with
hospital visits and its 95% CI (Blyth-Still-Casella) will be calculated for each treatment
arm. Fisher’s exact test will be used to compare the proportion of patients with hospital
visits between the two treatment arms. In addition, the difference in proportions will be
provided with 95% CI. Similar methods will be used to compare the type of visits
between the two arms. Estimates of the mean and median number of days admitted to
the hospital will be calculated for each treatment arm. The t test will be used to compare
the mean number of days admitted between the two arms. Finally, the reason for
admission (disease progression vs. adverse event) will be summarized.
3.4.3 Exploratory Endpoints

The following exploratory endpoints will be assessed:
• Patient self-reported diarrhea will be measured by the Diarrhea Assessment Scale
(DAS; see Protocol TDM4370g/BO21977 Appendix D).
The DAS has four questions that evaluate the frequency, urgency, consistency,
and discomfort of diarrhea experienced by a patient (see Appendix D of
Protocol TDM4370g/BO21977). Estimates of the proportion of patients with
moderate or severe diarrhea and the respective 95% CI (Blyth-Still-Casella) will
be provided by treatment arm. The Mantel-Haenszel χ2 test stratified by world
regimens for locally advanced or metastatic disease (0−1 vs. > 1), and visceral
disease vs. non-visceral disease will be used to compare the proportion of
patients with moderate or severe diarrhea between the two treatment arms. The
difference in the proportion of patients with moderate or severe diarrhea between
treatment arms and the 95% CI will be provided.
• The proportion of patients with a clinically significant improvement in symptoms,
defined as an increase in 5 points as measured by the FACT-B TOI, will be
compared between the treatment arms.
Estimates of the proportion of patients with clinically significant symptom
improvement and respective 95% CI (Blyth-Still-Casella) will be provided by
treatment arm. The Mantel-Haenszel χ2 test stratified by world region
(United States, Western Europe, other), number of prior chemotherapeutic
regimens for locally advanced or metastatic disease (0−1 vs. > 1), and visceral
disease vs. non-visceral disease will be used to compare the proportions of
patients with clinically significant symptom improvement between the
two treatment arms. The difference in the proportion of patients with clinically
significant symptom improvement between treatment arms and 95% CI will
be provided.

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• Descriptive statistics (mean, standard error, minimum, and maximum) of change
from baseline in FACT-B TOI scores will be provided for each visit for each
treatment arm. An analysis of covariance (mixed model) will be used to compare
change from baseline in TOI score. In the mixed model, change from baseline in
TOI score will be the response variable; treatment, visit, and treatment by visit
interaction terms will be the fixed effects; baseline TOI score will be the covariate;
and patient will be the random effect.
• Two sensitivity analyses will be performed for the analysis of time-to-symptom
progression endpoint:
baseline in FACT-B TOI score) after one or more missing FACT-B
assessments, the patient’s symptom progression event will be recorded as
an event on the last non-missing FACT-B assessment date plus 1 day. This
sensitivity analysis is to assess the impact of missing assessments on the
results of the analysis of time-to-symptom progression.

baseline in FACT-B TOI score), the patient’s symptom progression event will
be backdated by 6 weeks. This sensitivity analysis is to assess the impact of
the potential bias due to delayed reporting of symptom progression.
• Investigator and IRC tumor assessment:

The patient-level concordance between IRC- and investigator-assessed
progression events will be summarized.
In addition, the concordance between the IRC- and investigator-assessed PFS
time will be summarized.
The investigator-assessed PFS and the IRC-assessed PFS will be considered
in agreement if both investigator and IRC assessments agree that a PFS
event has occurred and the absolute difference in between these two PFS
event dates is within one tumor assessment.
3.4.4 Sensitivity Analyses for the Progression-Free Survival Primary

Efficacy Endpoint
Several sensitivity analyses are planned for the primary efficacy analysis of PFS to
account for the potential impact of differences in IRC and investigator tumor
assessments, the potential bias introduced by missed visits, timing of death, NPT, and
loss to follow-up.
a. IRC and Investigator Tumor Assessments

A sensitivity analysis will be performed on the primary endpoint of IRC-assessed PFS.
In this analysis, PFS will be defined as time from randomization to the earliest PFS event
on the basis of progression by either the IRC or investigator tumor assessment or death.

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For patients without a PFS event, PFS will be censored on the date of the last IRC or
last investigator tumor assessment with an assessment other than “unevaluable” or
“unknown,” whichever is later. PFS for patients with no post-baseline tumor
assessments will be censored on the date of randomization plus 1 day.
b. Missed Assessments
A sensitivity analysis will be performed on the primary endpoint of IRC-assessed PFS to
account for the potential impact of missing tumor assessments. Specifically, if a patient
has a documented IRC-assessed progression after two or more missing or unevaluable
assessments, the patient’s progression event will be recorded as an event at the
documented IRC-assessed progression date, after the missing assessments.
In addition, if a patient has a documented IRC-assessed progression after one or more

missing assessments, the patient’s progression event will be backdated to the date of
the last non-missing assessment plus 1 day.
c. Non-Protocol Anti-Cancer Therapy

A sensitivity analysis of the primary endpoint of IRC-assessed PFS will be performed in
which patients are censored at the last tumor assessment before the initiation of NPT.
d. Loss to Follow-Up
Patients who are lost to follow-up with regards to tumor assessment (i.e., alive but without
any tumor assessments for > 84 days [two tumor assessment cycles] prior to data cutoff)
are counted as events at the last time they were known to be progression free.
3.4.5 Subgroup Analyses to Assess Consistency of Treatment

Benefit
In order to assess the consistency of treatment benefit with respect to the primary
efficacy endpoints of IRC-assessed PFS and OS across important subgroups, forest
plots (including estimated hazard ratios) will be provided for the following variables:
race, age, geographical region, ECOG, sex, number of prior chemotherapeutic regimens
for locally advanced or metastatic disease, number of prior trastuzumab regimens for
locally advanced or metastatic disease, presence of visceral disease, prior
anthracycline, prior anti-cancer therapy for locally advanced or metastatic disease, and
key biomarkers. The forest plots will be created for IRC-assessed PFS and OS.
In addition, a multivariate Cox regression on IRC-assessed PFS and OS will be run that
includes all the aforementioned baseline characteristics. A stepwise backward
regression or the fractional polynoms approach will be applied to obtain a final
multivariate model as appropriate.

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3.5 PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Blood samples for the measurement of serum trastuzumab emtansine, serum total
trastuzumab, and plasma DM1 will be obtained from 160 patients randomized to the
trastuzumab emtansine arm until sites are notified that samples have been collected
from 160 pharmacokinetic (PK)-evaluable patients. A patient will be considered to be
PK evaluable if they remain on therapy through four or more cycles of study therapy.
Individual and mean concentration profiles of serum trastuzumab emtansine, serum total
trastuzumab, and plasma DM1 versus time data will be tabulated and plotted. The
following PK parameters will be estimated for all PK-evaluable patients for Cycle 1 and
Cycle 4: area under the concentration−time curve (AUC), maximum concentration
(Cmax), half-life (t1/2, where possible), clearance (CL), and volume of distribution (Vss).
Estimates for these parameters will be tabulated and summarized (e.g., mean, standard
deviation, coefficient of variation, median, minimum, maximum, and range). Interpatient
variability and drug accumulation after multiple dosing will be evaluated.
Compartmental, noncompartmental, and/or population approaches will be considered as
appropriate.
A population PK model for serum trastuzumab emtansine will be explored with

concentration data from this study and from previous internal trastuzumab emtansine
studies (3569g, 4258g, and 4374g) to further examine the interpatient variability of
pharmacokinetics among the different patient populations.
Additional exploratory PK and pharmacodynamic analyses and exposure-efficacy

analyses will be conducted as appropriate.
3.6 SAFETY ANALYSES

The safety-evaluable population is defined as randomized patients who received any
amount of study treatment. Safety analyses will be based on the actual treatment
received. Specifically, a patient will be included in the trastuzumab emtansine arm in
safety analyses if that patient received any amount of trastuzumab emtansine,
regardless of the patient’s initial treatment assignment by the interactive voice response
system.
At the time of the primary analysis of PFS, two sets of safety analyses will be provided,
each based on a separate set of analysis populations:
1. All safety analyses, as detailed in Sections 3.6.1−3.6.4, based on data from
safety-evaluable patients who were randomized to the study ≥ 3 months prior to the
data cutoff date
2. Serious adverse events and deaths among the safety-evaluable patients who were
randomized to the study < 3 months prior to the data cutoff date; unexpected
adverse events reported during this period will also be presented, as appropriate.

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At the time of the final analysis of OS, all safety analyses will be updated to include
all safety-evaluable patients.
3.6.1 Study Drug Exposure

The number of patients who experienced any dose interruption, including dose delay,
dose intensity, dose modification, dose discontinuation, and reasons for study treatment
discontinuation will be summarized for trastuzumab emtansine and the control regimen.
Descriptive statistics will be presented for total cumulative dose, number of cycles, dose
intensity, and weeks of exposure for trastuzumab emtansine and the control regimen.
3.6.2 Adverse Events

Verbatim descriptions of adverse events will be mapped to Medical Dictionary for
Regulatory Activities (MedDRA) thesaurus terms and graded according to the National
Cancer Institute Common Terminology Criteria for Adverse Events, Version 3
(NCI CTCAE v3.0). The following events occurring on or after the first dose of study
drug (i.e., treatment-emergent adverse events) will be summarized by NCI CTCAE
grade:
• All adverse events
• Serious adverse events
• Adverse events leading to death
• Adverse events leading to study drug discontinuation
For events of varying severity, the highest grade will be used in the summaries. Deaths
and causes of death will be summarized.
Selected adverse events of interest will be summarized by NCI CTCAE grade for each
treatment arm based on prespecified category definitions including (but not limited to)
hepatotoxicity, cardiac dysfunction, and thrombocytopenia. In addition, adverse events
occurring within 1 day of the first dose of each treatment cycle will be summarized to
help characterize potential infusion-related reactions.
3.6.3 Laboratory Data

Changes in laboratory data will be summarized by grade, using the NCI CTCAE v3.0
toxicity grade, and by treatment group.
3.6.4 Assessments of Left Ventricular Ejection Fraction as

Measured by Echocardiogram or Multigated
Acquisition Scan
Changes in left ventricular ejection fraction (LVEF) from baseline and nadir over each
scheduled visit will be summarized by treatment group. In particular, the median at
baseline and at nadir will be summarized for the two treatment arms. The number of
patients with an LVEF decline to below 40%, who developed Grade 3 left ventricular

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dysfunction, or who discontinued drug due to cardiac function will be summarized.
The number of patients who dropped to below 50% with an absolute decrease of
≥ 15 percentage points will also be summarized.
3.7 ADDITIONAL ANALYSES TO DEMONSTRATE CLINICAL

UTILITY OF COMPANION DIAGNOSTICS
Analysis of the primary endpoint of IRC-assessed PFS will be provided for the following
patient subgroups using the same methods as those described in Section 3.4.5:
• Patients who are determined to be IHC 3 + by HercepTest and FISH + by DAKO
HER2 FISH pharmDx
• Patients who are determined to be IHC 3 + by HercepTest and FISH− by DAKO
• Patients who are determined to be IHC 1 or 2 by HercepTest and FISH + by DAKO
In addition, concordance rates and 95% CIs will be provided for the following assays
using a kappa method:
• PathVysion and DAKO HER2 FISH pharmDx
3.8 EXPLORATORY BIOMARKER ANALYSES

Exploratory analyses of the primary endpoint of IRC-assessed PFS will be provided for
subgroups of the following biomarkers, using the same methods as those described in
Section 3.4.5:
• Fcγ receptor
• HER1 qRT-PCR concentration ratio
• Amphiregulin qRT-PCR concentration ratio
• Betacellulin qRT-PCR concentration ratio
• PI3K mutation status
• PTEN status
In addition, treatment-emergent thrombocytopenia adverse events will be summarized

by Fcγ receptor and β1-tubulin polymorphisms for the safety-evaluable patients.
3.9 MISSING DATA AND UNDER-REPRESENTED STRATA

For the primary analysis of PFS and duration of response, data from a patient lost to
follow-up will be included in the analysis as censored observations on the last date that
the patient was known to be progression free, defined as the date of the last tumor
assessment. When disease progression occurs after two or more consecutive missed

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tumor assessments, these events will not be counted; rather, the patient will be censored
at the patient’s last tumor assessment prior to the missing assessments. If disease
progression occurs after one missed tumor assessment, the event will be counted at the
respective event date.
For the primary analyses of PFS and OS, a prospective pooling algorithm will be
applied in the event that there are under-represented strata. If a given stratum
(e.g., world region of Western Europe, one prior chemotherapy for metastatic disease,
and visceral disease) has fewer than 10 PFS/OS events, it will be pooled with its nearest
stratum defined by the following hierarchy of variables: visceral disease status, number
of prior chemotherapeutic regimens for locally advanced or metastatic disease, and world
region. For example, the given stratum mentioned above will be pooled with the stratum
of world region of Western Europe, one prior chemotherapy for metastatic disease, and
non-visceral disease. If the combined stratum has fewer than 10 PFS/OS events,
the stratum will be pooled over the respective prior chemotherapy level. This pooling
procedure will ensure that all remaining strata have greater or equal to 10 PFS/OS events
for the analyses.
Missing data in FACT-B TOI scores will not be imputed. However, the impact of missing
data will be assessed using the sensitivity analyses and mixed model described in
Section 3.4.3.
3.10 INTERIM ANALYSES

An independent Data Monitoring Committee (iDMC) will monitor accumulating safety
data every 6 months until the primary PFS analysis occurs. In addition, data on serious
adverse events will be monitored by the iDMC at least once every 3 months. An
independent Cardiac Review Committee (CRC) will review all potential cases of left
ventricular systolic dysfunction prior to each semi-annual iDMC review and will report
their findings to the iDMC. Additional details will be provided in the iDMC and CRC
Charters.
There will be no interim analysis of PFS. An interim analysis of OS will be conducted at

the same time as the primary analysis of PFS. A second interim analysis of OS will be
conducted when approximately 316 OS events (i.e., 50% of the 632 events targeted for
the final analysis) have occurred. Additional interim analyses may be conducted to
satisfy regulatory and/or health care agency requirements. The decision for additional
analyses was made after database closure for the primary PFS analysis in order to allow
patients in the lapatinib and capecitabine arm the opportunity for earlier access to
trastuzumab emtansine in the event that the OS boundary is crossed and the trial can
be considered to have demonstrated statisticially and clinically significant survival
benefit. The final analysis of OS will be performed when 632 deaths have occurred. At
the interim analyses, OS will be tested at the significance level determined using the

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Lan-DeMets alpha spending function with an O’Brien-Fleming boundary so that the
overall two-sided type I error rate will be maintained at the 5% level.
At each interim analysis, the statistical methods for analyzing OS described in

Section 3.4.1 will be used to analyze OS data.
On the basis of data from the Tykerb (lapatinib) U.S. Package Insert, the median OS
was 17.2 months with the lapatinib and capecitabine combination treatment. Under the
assumption of a hazard ratio of 0.80 in OS between the trastuzumab emtansine and
lapatinib + capecitabine groups, it is estimated that approximately 290 deaths would have
occurred at the time of the data cutoff for the primary analysis of PFS. It is estimated
that 316 deaths would occur approximately 41 months and 632 deaths would occur
approximately 51 months from the start of the study.
Table 1 presents a summary of the OS analyses, the efficacy stopping boundary, and
the estimated timing of these analyses assuming two interim analyses and a final
analysis.
Table 1 Timing and Stopping Boundary of Overall Survival Analyses

Analysis of No. of
OS Deaths Efficacy Stopping Boundary a Estimated Timing b
Interim #1 290 c p < 0.0019 or observed HR < 0.69 32 months d
Interim #2 316 c p < 0.0025 or observed HR < 0.71 41 months e
HR = hazard ratio; OS = overall survival.
a
p-value will be based on two-sided log-rank test.
b
Time from the enrollment of first patient to data cutoff.
c
Estimated number.
d
At the same time as the final primary analysis of PFS.
e Based on observed enrollment rates and updated event projections.
The Sponsor will perform the interim and final analyses of OS. A survival data sweep
will be conducted prior to each OS analysis. In the event the actual number of deaths is
different from those specified in Table 1, the efficacy stopping boundary for the interim
OS analyses will be calculated using the aforementioned Lan-DeMets alpha spending
function and the actual number of deaths included in the analyses. If the efficacy
boundary is crossed at any interim analysis, the OS endpoint will be considered met at
that analysis. The trial will still continue until the final OS analysis when 632 deaths
occur and the results of the final analysis will be considered descriptive only.

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4. DETERMINATION OF SAMPLE SIZE
There are two primary efficacy endpoints for this Phase III trial: PFS, based on
independent review of tumor assessments, and OS. The fixed-sequence testing
procedure described above will be used to control the overall two-sided type I error rate
at 5% for the primary efficacy analyses.
The sample size of the study was determined to ensure that the final analysis of OS
would be appropriately powered. To detect a hazard ratio of 0.8 in OS
(a 25% improvement in median OS; i.e., from 17.2 months in the control arm to
21.5 months in the treatment arm), approximately 632 deaths will be required to achieve
80% power at a two-sided 5% alpha level. A total of 980 patients will be enrolled into the
study.
The primary efficacy analyses will be event driven, and the primary analysis of PFS will
take place when approximately 508 IRC-assessed PFS events have occurred for
patients who have been randomized into the study for ≥ 3 months. This provides
90% power to detect a hazard ratio of 0.75 in PFS (a 33% improvement in median PFS;
i.e., from 6.2 months in the control arm to 8.3 months in the treatment arm), with a
two-sided alpha of 5%.

Assuming a median PFS of 6.2 months in the control arm and a hazard ratio of 0.75, the
data cutoff date for the primary analysis of PFS will be approximately 32 months from
when the first patient is enrolled (FPI). However, the primary analysis of PFS will not be
conducted until the study completes the full enrollment of 980 patients. Assuming the
median OS of 17.2 months in the control arm and a hazard ratio of 0.8, the data cutoff
date for the final analysis of OS is projected to be approximately 51 months from FPI.
The sample size was estimated using EAST software.

19/TDM4370g/BO21977–A2
5. REFERENCES
Fleming TR, Rothmann MD, Lu HL. Issues in using progression-free survival when
evaluating oncology products. J Clin Oncol 2009;27:2874−80.
Tykerb (lapatinib) U.S. Package Insert, GlaxoSmithKline.

20/TDM4370g/BO21977–A2
APPENDIX A
Protocol TDM4370g/BO21977, Version A4 Synopsis
Objectives
patients with HER2-positive unresectable, locally advanced or metastatic breast cancer (MBC)
as measured by progression-free survival (PFS) on the basis of an independent review of tumor
assessments
patients with HER2-positive, unresectable, locally advanced breast cancer or MBC as
measured by overall survival (OS) and to assess landmark (1-year and 2-year) survival rates
within each treatment group, as appropriate
• To assess the safety of trastuzumab emtansine relative to the safety of capecitabine plus
lapatinib
• The secondary objectives for this study are as follows:
tumor assessments
• To compare the overall objective response rate between the two treatment arms on the basis of
• To estimate the duration of objective response within each treatment arm on the basis of both
two treatment arms on the basis of both investigator and independent review of tumor
assessments
disease progression, treatment toxicity, starting another anti-cancer agent before documented
progressive disease (PD), and death on study from any cause.
• To compare the time to symptom progression between the two treatment arms as measured by
the FACT-Breast-Trial Outcome Index (FACT-B TOI)
Resource expenditure due to hospitalizations and hospital visits for reasons other than defined
study evaluations will be compared between the two treatment arms.
Study Design
This is a Phase III, randomized, multicenter, international, two-arm, open-label clinical trial designed
to compare the safety and efficacy of trastuzumab emtansine with that of capecitabine + lapatinib
for HER2-positive unresectable, locally advanced breast cancer or MBC. A total of 980 patients will
be enrolled at more than 200 sites worldwide. Eligible patients will be randomized in a 1:1 ratio to
either trastuzumab emtansine or lapatinib + capecitabine as follows:
• Trastuzumab Emtansine Arm: trastuzumab emtansine 3.6 mg/kg intravenously (IV) over
30−90 minutes on Day 1 of a 21-day cycle
A hierarchical dynamic randomization scheme will be used to ensure an approximately equal
sample size for the two treatment arms 1) overall; 2) by world region (United States, Western
Europe, Other); and 3) within each of the four categories defined by the following two prognostic
factors: 1) the number of prior chemotherapeutic regimens for unresectable, locally advanced or
metastatic disease (0−1 vs. > 1) and 2) visceral versus non-visceral disease.

1/TDM4370g/BO21977–A2
Prior to enrollment, patients will be confirmed for having HER2-positive adenocarcinoma of the
breast by immunohistochemical (IHC) and/or fluorescence in situ hybridization (FISH) in a central
laboratory specified by the Sponsors through use of archival paraffin-embedded tumor tissue.
A patient’s HER2 status will be considered positive if the central laboratory reports Grade 3 +
staining intensity (on a scale of 0 to 3 +) by means of IHC analysis and/or gene amplification by
FISH. Patients may have either measurable (per modified Response Evaluation Criteria in Solid
Tumors [RECIST]) and/or non-measurable unresectable, locally advanced or metastatic disease.
Locally advanced disease must not be amenable to resection or other local therapy with curative
intent.
Prior to the final PFS analysis, tumor assessments were conducted every 6 weeks from the date of
randomization or Cycle 1 Day 1, regardless of dose delays or dose interruptions, until 6 weeks after
investigator-assessed PD or until death, whichever occurred first, even if study treatment had been
discontinued as a result of patient or physician choice or unacceptable toxicity.
After the final PFS analysis, the frequency, method, and evaluation criteria of tumor assessments
will be according to routine clinical practice per investigator. However, it is recommended that
RECIST be used to evaluate tumor assessments.
Patients may remain on study treatment until disease progression (as assessed by the investigator),
unmanageable toxicity, or study termination by Genentech and Roche (the Sponsors).
Patients who are discontinued from study treatment for any reason will complete the Study Drug
Completion Visit approximately 30 days after the last dose of study treatment.
After the Study Drug Completion Visit, all patients (regardless of reason for discontinuation) will be
followed for survival every 3 months until death, loss to follow-up, withdrawal of consent, or study
termination by the Sponsors.
Patient-reported outcomes (PROs) as assessed by the FACT-B (female patients only) should be
completed every two treatment cycles until treatment discontinuation and at the Study Drug
Completion Visit. After treatment discontinuation for any reason, the FACT-B assessment will be
performed according to the same schedule as during survival follow-up.
After patients discontinue from study treatment, subsequent anti-cancer therapies will be collected
An independent Data Monitoring Committee (DMC) monitored accumulating patient safety data at
least once every 6 months during the course of the study until the final PFS analysis had been
conducted. In addition, data on serious adverse events were monitored by the DMC at least once
every 3 months until the final PFS analysis had been conducted. An independent Cardiac Review
Committee (CRC) reviewed all potential cases of left ventricular systolic dysfunction prior to each
DMC review and will report their findings to the DMC until the final PFS analysis had been
conducted. An IRC evaluated tumor responses through the review of all tumor-assessment data
generated from all patients at the time of the final PFS analysis with treatment-arm information
blinded to the IRC. After the final PFS analysis, the IRC will discontinue the review of tumor
assessment data.
No interim analysis of IRC-assessed PFS is planned for this study. The final analysis of the primary
efficacy endpoint of PFS took place when approximately 508 IRC-assessed PFS events had
occurred and enrollment was completed. One interim analysis of OS is planned at the time of the
final analysis of PFS as assessed by the IRC. The final analysis of OS will be performed when
approximately 632 deaths have occurred. If the study is not terminated per DMC recommendation
or by the Sponsors for other reasons beforehand, it will be closed when approximately 632 deaths
have been reported and the final analysis of OS has been completed.
Additional interim analyses of OS will be performed with the appropriate control of the Type I error
rate using the pre-specified Lan-DeMets function with O’Brien-Fleming boundary (additional details
to be outlined in the Statistical Analysis Plan). If an analysis of OS demonstrates a statistically
significant benefit in favor of trastuzumab emtansine, the co-primary endpoint of OS will be

2/TDM4370g/BO21977–A2
considered as met and at that time patients randomized to the control arm may cross over to
receive trastuzumab emtansine.
Patients who cross over to trastuzumab emtansine may remain on study treatment until disease
progression (as assessed by the investigator), unmanageable toxicity, or study termination by
Genentech and Roche (the Sponsors). All patients will be followed until approximately 632 deaths
have been reported and the final analysis of OS has been completed.
Outcome Measures
• PFS by investigator assessment, defined as the time from randomization to the first occurrence
of disease progression, as determined by investigator review of tumor assessments through use
• Objective response (PR plus CR) as determined by both investigator and independent review of
tumor assessments with use of modified RECIST
Objective responses must be confirmed at least 28 days after initial documentation of
response.
independent review of tumor assessments with use of modified RECIST, or death from any
cause
including treatment discontinuation without disease progression or treatment toxicity, disease
progression, treatment toxicity, starting another anti-cancer agent before documented PD,
or death from any cause
documentation of a ≥ 5-point decrease from baseline in the scoring of responses) between the
two treatment arms as measured by the FACT-B TOI
• Estimated resources for hospitalizations and/or hospital visits that occur within 30 days of the
last dose of study treatment for reasons other than those defined by the protocol
The number of hospital visits, number of days admitted, and type of visits
(emergency department vs. inpatient care) will be collected and compared between the
two arms. The reason for admission (disease progression vs. adverse event) will also be
assessed.

3/TDM4370g/BO21977–A2
Safety Plan
Overall safety will be assessed on an ongoing basis during the conduct of the study. Prior to the final
PFS analysis, an independent DMC monitored cumulative safety data at least once every 6 months
during the course of the study. In addition, data on serious adverse events were monitored by the
DMC at least once every 3 months. An independent CRC reviewed all potential cases of left
ventricular systolic dysfunction prior to each semi-annual DMC review and reported their findings to
the DMC until the final PFS analysis is had been conducted. Additional details will be provided in the
DMC and CRC Charters.
The safety plan for patients in the trastuzumab emtansine treatment arm is based on nonclinical
toxicities of trastuzumab emtansine, the clinical experience with this molecule in ongoing studies,
and clinical toxicities related to its components (trastuzumab and maytansine, the parent drug of
DM1).
The safety plan for patients receiving lapatinib and capecitabine is based on the national prescribing
guidelines, emphasizing the adverse event data reported for each drug.
Study Treatment
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg IV every 21 days.
Lapatinib plus Capecitabine
Concomitant Therapy and Clinical Practice
Trastuzumab emtansine, lapatinib, and capecitabine are the investigational medicinal products in
this study. All other concomitant medications and premedication therapies are considered non-
investigational medicinal products. Concomitant therapy (non-investigational products) includes any
prescription medication, over-the-counter preparation, herbal therapy, or radiotherapy used by a
patient between the 14 days preceding randomization and the study survival follow-up or early
discontinuation visit.
Premedication for lapatinib and capecitabine is allowed according to standard practice guidelines.
(see Section 4.4 of Protocol TDM4370g/BO21977). Concomitant use of erythropoiesis-stimulating
agents is allowed if clinically indicated in accordance with proper prescribing guidelines.
any planned premedication, specifically steroids, for the first infusion must be approved by the
Medical Monitor prior to administration. Premedication for nausea and anxiety has not been
generally necessary but is allowed.
Patients who experience trastuzumab emtansine infusion–related temperature elevations of
> 38.5°C or other minor infusion-related symptoms may be treated symptomatically with
acetaminophen and/or H1- and H2-receptor antagonists (e.g., diphenhydramine, ranitidine).
Serious infusion-related events manifested by dyspnea, hypotension, wheezing, bronchospasm,
tachycardia, reduced oxygen saturation, or respiratory distress should be managed with supportive
therapies as clinically indicated according to standard clinical practice (e.g., supplemental oxygen,
β2-agonists, and corticosteroids).
• Any therapies intended for the treatment of breast cancer, whether they are approved by
national health authorities or experimental, including cytotoxic chemotherapy (other than that
specified by the protocol), immunotherapy, hormonal therapy (other than megestrol acetate),
and biologic agents (other than granulocyte colony-stimulating factor and
erythropoiesis-stimulating agents)

4/TDM4370g/BO21977–A2
• Radiotherapy
Palliative radiotherapy may be permitted to treat painful bone metastases. Please contact
the Medical Monitor for approval. If the Medical Monitor cannot be reached because of
time zone differences, radiotherapy may be administered, but the Medical Monitor should
still be informed.
Patients who require the use of any of these therapies described above will be discontinued from
study treatment but will be followed for disease progression and survival. Other medications
considered necessary for the patient’s safety and well-being may be given at the discretion of the
investigator. Use of bisphosphonates (e.g., pamidronate) for control of bone pain, treatment of bony
metastases, and treatment of osteoporosis, is permitted. If required for the treatment of
symptomatic malignancy-associated hypercalcemia, tumor assessments should be performed to
Patients randomized to the control arm who are on warfarin need to have their prothrombin time or
international normalized ratio monitored weekly.
Statistical Methods
To adjust for multiplicity due to having two primary endpoints, a fixed-sequence hypothesis testing
procedure will be implemented. The hypothesis test for PFS will be conducted at a one-sided alpha
of 2.5%. If the PFS is statistically different between the two arms, OS will be tested at a one-sided
alpha of 2.5% to determine if the two arms have significantly different OS.
The co-primary efficacy endpoint is PFS based on independent review of tumor assessment,
defined as the time from randomization to documented IRC-assessed disease progression or death
from any cause (whichever occurs earlier).
For the analysis of PFS, data for patients without disease progression or death will be censored at
the time of the last tumor assessment (or, if no tumor assessment was performed after the baseline
visit, at the time of randomization plus 1 day). Data from patients who are lost to follow-up will be
included in the analysis as censored observations on the last date of tumor assessment that the
patient was known to be progression free.
For patients who receive non-protocol therapy (defined as any treatment the patient receives that is
intended to treat his or her MBC) prior to documented PD, the primary PFS analysis will not censor
patients at the initiation of non-protocol therapy. A sensitivity analysis of PFS censoring patients at
the last tumor assessment before the initiation of non-protocol therapy will also be performed.
disease (0−1 vs. > 1), and visceral vs. non-visceral disease will be used as the primary analysis to
compare PFS between the two treatment arms. The results from the unstratified log-rank test and
the stratified and unstratified Wilcoxon test will also be provided.
Cox proportional-hazards models, stratified by world region (United States, Western Europe, Other),
disease (0−1 vs. > 1), and visceral vs. non-visceral disease will be used to estimate the hazard ratio
(HR) and its 95% confidence interval (CI).
OS, the co-primary endpoint, is defined as the time from the date of randomization to the date of
death from any cause. Patients who are alive at the time of the analysis data cutoff will be censored
at the last date they were known to be alive. Patients with no post-baseline information will be
censored at the date of randomization plus 1 day. Methods for OS analysis are similar to those
described for the PFS endpoint, with the stratified log-rank test being the primary analysis and
sensitivity analysis using the unstratified log-rank test and the stratified and unstratified Wilcoxon
test. In addition, 1-year and 2-year survival rates and corresponding 95% CIs will be estimated
using the Kaplan−Meier approach, as appropriate. The final analysis of OS will occur after
632 deaths have occurred.

5/TDM4370g/BO21977–A2
Missing Data
follow-up will be included in the analysis as censored observations on the last date that the patient
is known to be progression free, defined as the date of the last tumor assessment. When disease
progression occurs after two or more consecutive missed tumor assessments, these events will not
be counted; rather, the patient will be censored at the patient’s last tumor assessment prior to the
missing assessments. If disease progression occurs after one missed tumor assessment, the event
will be counted at the respective event date.
There are two primary efficacy endpoints of this Phase III trial: PFS based on independent review
of tumor assessments, and OS. The fixed-sequence testing procedure described above will be
used to control the overall two-sided Type I error rate at 5% for the primary efficacy analyses.
(a 25% improvement in median OS; i.e., from 17.2 months in the control arm to 21.5 months in the
treatment arm), approximately 632 deaths will be required to achieve 80% power at a two-sided
5% alpha level. A total of 980 patients will be enrolled into the study.
The primary efficacy analysis will be event driven, and the primary analysis of PFS will take place
when approximately 508 IRC-assessed PFS events have occurred. This provides 90% power to
detect an HR of 0.75 in PFS (a 33% improvement in median PFS; i.e., from 6.2 months in the
control arm to 8.3 months in the treatment arm), with a two-sided alpha of 5%.
It is expected that 980 patients will be enrolled over approximately 35 months. Assuming a median
PFS of 6.2 months in the control arm and an HR of 0.75, the date of data cutoff for the final analysis
of PFS will be approximately 32 months from when the first patient is enrolled (FPI). However, the
final analysis of PFS will not be conducted until the last patient is enrolled. Assuming the median
OS of 17.2 months in the control arm and an HR of 0.8, the data cutoff date for the final analysis of
OS is projected to be approximately 51 months from FPI.
Interim Analysis
There is no interim analysis of PFS. An interim analysis of OS is planned to be conducted at the
same time as the final analysis of PFS. Additional statistical analyses of OS will be performed with
the appropriate control of the Type I error rate using the Lan-DeMets alpha spending function with
an O’Brien-Fleming boundary as prespecified in the protocol and statistical analysis plan (SAP)
(additional details to be outlined in the Statistical Analysis Plan). See Section 4.9.10 of
Protocol TDM4370g/BO21977for further details.

6/TDM4370g/BO21977–A2
APPENDIX B
Protocol TDM4370g/BO21977 Study Flowchart for Patients Receiving Randomized Treatment
Study Drug
Survival
Informed consent xc
HER2 testing d x
every two cycles thereafter until treatment
discontinuation
Weight and height f x x x
Concomitant medications xg x x x
Adverse events xh x x x
12-lead electrocardiogram i x xv
x xv
Tumor assessment k x Frequency, method, and evaluation criteria
of tumor assessments will be according to
routine clinical practice per investigator.
Bone scan/skeletal X-ray l x Per clinical indication
Central laboratory tests See Appendix A-2 of Protocol TDM4370g/BO21977

1/TDM4370g/BO21977–A2
Study Drug
Survival
m, n
CBC with platelet and 3-part differential x x x
n p
Serum chemistries x o
x xp
INR and aPTT q x x
Serum/urine pregnancy test r x
Laboratory urinalysis s x x
Assessment of patient hospitalizations x x
Evaluation of capecitabine and lapatinib
compliance t
Study drug administration/distribution u x
aPTT = activated partial thromboplastin time; CBC = complete blood count; CT = computed tomography; ECHO = echocardiogram;
INR = international normalized ratio; IHC = immunohistochemistry; MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition;
SAE = serious adverse event.
a
b
outcomes as assessed by the FACT-B, and subsequent anti-cancer therapies (not all concomitant meds) approximately every 3 months
starting from the Study Drug Completion Visit until death, loss to follow-up, withdrawal of consent, or study discontinuation by the
Sponsors.
c
Informed consent must be obtained prior to performance of any screening assessments unless the assessments were performed as
standard of care prior to obtaining informed consent. Informed consent does not need to be obtained within 30 days of randomization;
however, patients who fail screening and are rescreened will need to be reconsented.

2/TDM4370g/BO21977–A2
d
HER2 status must be centrally confirmed any time prior to randomization (result must be IHC 3 + and/or gene amplified by FISH) by the Sponsor-
selected central laboratory. IHC, FISH, qRT-PCR will be performed. See Section 4.5.2 of Protocol TDM4370g/BO21977 for further details.
e
f
g
Record concomitant medications used within 14 days prior to randomization and investigational and/or anti-cancer therapies used within 21 days
of randomization.
h
i
ECGs for each patient should be obtained from the same machine whenever possible. One set of all ECG tracings should be printed and kept
with the patient’s record.
j
Because of a potential worldwide Tc-99 shortage, ECHO is preferred; however, the same method used at screening should be used throughout
the study. Additional scans may be performed at any point if clinically indicated. Refer to Section 3.4 of Protocol TDM4370g/BO21977 for
further information on cardiac safety surveillance.
k
Response should be assessed using modified RECIST. Assessments should include an evaluation of all known or suspected sites of disease,
whenever possible. The same radiographic procedure used at baseline must be used throughout the study (e.g., the same contrast protocol for
CT scans). If the patient cannot undergo CT with contrast, then the chest should be imaged via CT without contrast and the abdomen and pelvis
should be imaged using MRI with contrast. See Section 4.5.1 of Protocol TDM4370g/BO21977 for further details.
l
An isotope bone scan and/or skeletal X-rays will be performed at screening and should be repeated in the event of clinical suspicion of
progression of existing bone lesions and/or the development of new bone lesions.
m
and granulocytes.
n
Local laboratory assessments performed within 72 hours preceding study drug administration may be used as the Day 1 evaluations
(up to 96 hours for Cycle 1, Day 1). Results of these local laboratory assessments must be reviewed (except alkaline phosphatase and lactate
dehydrogenase) prior to study drug administration. In the event of a Grade 3 or 4 toxicity (per CTCAE version 3.0), pertinent laboratory
assessments should be repeated at the investigator’s discretion until recovery to Grade ≤ 2.
o
Sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, total and direct bilirubin, total protein, albumin, ALT,
AST, LDH, ALP, and uric acid.
p
q
Patients on capecitabine who are receiving coumarin-derivative anticoagulant therapy, such as warfarin or phenprocoumen, should have the PT
or INR monitored weekly.

3/TDM4370g/BO21977–A2
r
For women of childbearing potential, including premenopausal women who have had a tubal ligation. Screening assessment must be performed
on serum within 7 days prior to randomization. Afterward, perform every third cycle on urine. A positive urine test must be confirmed with a
serum test.
s
t
u
Cycle 1, Day 1 must occur within 5 days of randomization. For patients assigned to trastuzumab emtansine therapy, trastuzumab emtansine
should be administered over approximately 90 minutes for the first dose and, in the absence of infusion-related adverse events, over
approximately 30 minutes in subsequent doses. Vital signs should be taken before and after the trastuzumab emtansine infusion. Patients will
be monitored for any untoward effects for at least 90 minutes after completion of the first trastuzumab emtansine infusion and, in the absence of
infusion-related events, for a minimum of 30 minutes at subsequent infusions. For patients assigned to the control arm, therapy will be given
according to standard prescribing guidelines as described in Section 4.3.2 of Protocol TDM4370g/BO21977.
v
repeated.

4/TDM4370g/BO21977–A2
APPENDIX C
Protocol TDM4370g/BO21977 Study Flowchart for Control Patients
Who Cross over to Receive Trastuzumab Emtansine
Study Drug
Screening a Cycles 1–34 + Completion Visit Survival
Informed consent xc
Medical history x
Complete physical exam xd
Weight x x x
Concomitant medications xe x x x
Adverse events x x x x
12-lead electrocardiogram f x xg
ECHO or MUGA h (ECHO preferred) Weeks 6, 12, and every
12 weeks thereafter until
x xg
discontinuation of
Tumor assessment i x Frequency, method, and
evaluation criteria of
tumor assessments will
be according to routine
clinical practice per
investigator.
Bone scan/skeletal X-ray j x Per clinical indication
CBC with platelet and 3-part differential k, l x x x
l
Serum chemistries xm xn xn
INR and aPTT x x

1/TDM4370g/BO21977–A2
Study Drug
Screening a
Cycles 1–34 + Completion Visit
30 days (± 7) after Survival
Last Dose of Follow-Up b
Trastuzumab (Every
Day – 30 to – 1 1 (± 3) Emtansine 3 Months)
Serum/urine pregnancy test o x
Assessment of patient hospitalizations
x x
p
Trastuzumab emtansine administration x
aPTT = activated partial thromboplastin time; CT = computed tomography; ECHO = echocardiogram; MRI = magnetic resonance
imaging; MUGA = multiple-gated acquisition; SAE = serious adverse event.
Notes: Visits are based on a 21-day cycle. If the timing of a protocol-mandated procedure coincides with a holiday and/or
weekend that preclude the procedure within the allotted window, the procedure must be performed on the nearest following date.
a
Screening tests or examinations must be performed within 30 days prior to Cycle 1, Day 1 unless noted otherwise.
b
Only SAEs considered to be related to study medication should be reported. Patients will also be followed for survival and
subsequent anti-cancer therapies (not all concomitant meds) approximately every 3 months starting from the Study Drug
Completion Visit until death, loss to follow-up, withdrawal of consent, or study discontinuation by the Sponsors.
c
Informed consent must be obtained prior to performance of any screening assessments unless the assessments were
performed as standard of care prior to obtaining informed consent. Informed consent does not need to be obtained within
30 days of Cycle 1, Day 1; however, patients who fail screening and are rescreened will need to be reconsented.
d
e
Record concomitant medications used within 21 days prior to Cycle 1, Day 1 and investigational and/or anti-cancer therapies
used within 14 days of Cycle 1, Day 1.
f
ECGs for each patient should be obtained from the same machine whenever possible. One set of all ECG tracings should be
printed and kept with the patient’s record.
g
If the most recent assessments were performed less than 30 days from the Study Drug Completion Visit, these assessments
do not need to be repeated.

2/TDM4370g/BO21977–A2
h
Because of a potential worldwide Tc-99 shortage, ECHO is preferred; however, the same method used at screening should be
used throughout the study. Additional scans may be performed at any point if clinically indicated. Refer to Section 3.4 of
Protocol TDM4370g/BO21977for further information on cardiac safety surveillance.
i
Response should be assessed using modified RECIST. Assessments should include an evaluation of all known or
suspected sites of disease, whenever possible. The same radiographic procedure used at baseline must be used throughout
the study (e.g., the same contrast protocol for CT scans). If the patient cannot undergo CT with contrast, then the chest
should be imaged via CT without contrast and the abdomen and pelvis should be imaged using MRI with contrast.
See Section 4.5.1 of Protocol TDM4370g/BO21977for further details.
j
An isotope bone scan and/or skeletal X-rays will be performed at screening and should be repeated in the event of clinical
suspicion of progression of existing bone lesions and/or the development of new bone lesions or for confirmation of complete
response.
k
CBC includes hemoglobin, hematocrit, platelet count, red blood cells, white blood cells; 3-part differential includes
lymphocytes, monocytes, and granulocytes.
l
Local laboratory assessments performed within 72 hours preceding trastuzumab emtansine administration may be used as
the Day 1 evaluations (up to 96 hours for Cycle 1, Day 1). Results of these local laboratory assessments must be reviewed
(except alkaline phosphatase and lactate dehydrogenase) prior to trastuzumab emtansine administration. In the event of a
Grade 3 or 4 toxicity (per CTCAE version 3.0), pertinent laboratory assessments should be repeated at the Investigator’s
discretion until recovery to Grade ≤ 2. Refer to Section 4.5 of Protocol TDM4370g/BO21977for further details.
m
Sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, total and direct bilirubin,
total protein, albumin, ALT, AST, LDH, and ALP.
n
o
For women of childbearing potential, including premenopausal women who have had a tubal ligation. Screening assessment
must be performed on serum within 7 days prior to randomization. Afterward, perform every third cycle on urine. A positive
urine test must be confirmed with a serum test.
p
Trastuzumab emtansine should be administered over approximately 90 minutes for the first dose and, in the absence of
infusion-related adverse events, over approximately 30 minutes in subsequent doses. Vital signs should be taken before and
after the trastuzumab emtansine infusion. Patients will be monitored for any untoward effects for at least 90 minutes after
completion of the first trastuzumab emtansine infusion and, in the absence of infusion-related events, for a minimum of
30 minutes at subsequent infusions.

3/TDM4370g/BO21977–A2
APPENDIX D
The dynamic randomization scheme attempts to produce a 1:1 ratio of sample sizes for the
two treatment arms (trastuzumab emtansine vs. lapatinib + capecitabine) within each
category of world region (US, Western Europe, Other), prior chemotherapy for metastatic or
locally advanced disease (0-1, >1), and visceral disease status (yes, no).
Step A:
Identify the strata (world region, number of prior chemotherapeutic regimens for locally
advanced or metastatic disease, and visceral disease status) for the subject who will be
randomized.
Step B:
Calculate the following statistics:
1. The number of subjects previously randomized to each treatment group overall: O1,
O2, and the absolute difference O12 = abs(O1−O2)
2. The number of subjects previously randomized to each treatment group within world
region levels: S1, S2, and the absolute difference S12 = abs(S1−S2)
3. The number of subjects previously randomized to each treatment group within prior
chemotherapy levels: C1, C2, and the absolute difference C12 = abs(C1−C2)
4. The number of subjects previously randomized to each treatment group within visceral
disease levels: V1, V2, and the absolute difference V12 = abs(V1−V2)
Step C:
Check the following criteria to see which allocation probabilities are used:
• If O12 ≥ 4:
O = min(O1,O2) and with probability 0.25 from the other treatment arm.
• Otherwise, if S12 ≥ 4:
S = min(S1,S2) and with probability 0.25 from the other treatment arm.
• Otherwise, if C12 ≥ 4:
C = min(C1,C2) and with probability 0.25 from the other treatment arm.
• Otherwise, if V12 ≥ 4:
V = min(V1,V2) and with probability 0.25 from the other treatment arm.
• Otherwise, randomly assign treatment among the two treatment arms using
probabilities (0.5, 0.5).

1/TDM4370g/BO21977–A2

EMILIA Trial TDM1 Protocolo

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EMILIA Trial TDM1 Protocolo

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Protocol

This supplement contains the following items:

Section 1: Original protocol, final protocol, summary of changes

Section 3: Statistical analysis plan amendment

PROTOCOL AMENDMENT APPROVAL

Name Reason for Signing Date and Time

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

PROTOCOL AMENDMENT APPROVAL

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

• All instances of T-DM1 and trastuzumab MCC-DM1 have been revised to

LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMSThe list of

SECTION 1.2.4: Study TDM4450g

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

Patient-reported outcomes (PROs) as assessed by the FACT-B (female patients only)

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

An independent Data Monitoring Committee (DMC) will monitor monitored accumulating

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

SECTION 3.4: SAFETY PLAN

SECTION 3.4.1.1: Risks associated with Trastuzumab Emtansine

Reversible thrombocytopenia has been commonly observed in completed and ongoing

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

Infusion-related reactions are known to occur with the administration of monoclonal

Importantly, preliminary evaluations of safety in the randomized study TDM4450g

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

SECTION 3.4.1.2: Risks associated with Capecitabine

SECTION 3.4.1.3: Risks associated with Lapatinib

SECTION 3.4.2: Trastuzumab Emtansine Safety Plan

SECTION 4.1.4.1: Inclusion Criteria for Cross-Over Patients

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

SECTION 4.1.4.2: Exclusion Criteria for Cross-Over Patients

1. History of treatment with trastuzumab emtansine

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

5. History of symptomatic CHF or serious cardiac arrhythmia requiring treatment

8. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular,

SECTION 4.2: Method of Treatment Assignment and Blinding

Randomization will be stratified by the following criteria:

• World region (United States, Western Europe, Other)

SECTION 4.3.1.2: Trastuzumab Emtansine Dosage and Administration

SECTION 4.3.1.3.2: Dose Modification for Hepatotoxicity

Patients receiving trastuzumab emtansine at 3.6 mg/kg who experience a Grade 3 or 4

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

SECTION 4.5.2.1: Screening Assessments for Control Patients Who Cross

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

SECTION 4.5.4.2: Cycle 1, Day 8 ( ± 3 Days)

SECTION 4.5.4.3: Cycle 1, Day 15 ( ± 3 Days)

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

SECTION 4.5.4.4: Cycle 2-34 + , Day 1 ( ± 3 Days)

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

SECTION 4.5.4.5: Cycle 2-34 + , Day 8 ( ± 3 Days)

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

SECTION 4.5.6: Follow-Up Assessments after Study Drug Completion

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

Patient-reported outcomes (PROs) as assessed by the FACT-B (female patients only)

SECTION 4.8.6: HER2 Confirmatory Testing

SECTION 4.9.10: Interim Analysis

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd

SECTION 5.1.4: Protocol-Defined Events of Special Interest/Non-Serious

o Symptomatic CHF (left ventricular systolic dysfunction Grade ≥ 3)

• Potential drug-induced liver injury

SECTION 5.1.5: Pregnancy and Contraception

Trastuzumab emtansine —F. Hoffmann-La Roche Ltd