Published Ahead of Print on November 2, 2015 as 10.1200/JCO.2015.61.

4370
The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2015.61.4370

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Postoperative Adjuvant Lapatinib and Concurrent

Chemoradiotherapy Followed by Maintenance Lapatinib
Monotherapy in High-Risk Patients With Resected
Squamous Cell Carcinoma of the Head and Neck: A Phase
III, Randomized, Double-Blind, Placebo-Controlled Study
Kevin Harrington, Stephane Temam, Hisham Mehanna, Anil D’Cruz, Minish Jain, Ida D’Onofrio,
Georgy Manikhas, Zsuzsanna Horvath, Yan Sun, Stefan Dietzsch, Pavol Dubinsky, Petra Holeckova,
Iman El-Hariry, Natalie Franklin, Nigel Biswas-Baldwin, Philippe Legenne, Paul Wissel, Thelma Netherway,
John Farrell, Catherine Ellis, Jing Wang-Silvanto, Mayur Amonkar, Nazma Ahmed, Sergio Santillana,
and Jean Bourhis
Author affiliations appear at the end of
this article. A B S T R A C T

Published online ahead of print at Purpose

www.jco.org on November 2, 2015.
Supported by GlaxoSmithKline. K.H.
acknowledges support from the Royal
Marsden Hospital/Institute of Cancer
Research National Institute for Health
Research Biomedical Research Centre.
GlaxoSmithKline and Novartis funded
editorial support.
K.H. and S.T. contributed equally to this
work.
Presented, in part, at the 50th Annual
Meeting of the American Society of
Clinical Oncology, Chicago, IL, May
30-June 3, 2014.
Authors’ disclosures of potential
conflicts of interest are found in the
article online at www.jco.org. Author
contributions are found at the end of
this article.
Clinical trial information: NCT00424255.
Corresponding author: Jean Bourhis,
MD, PhD, University Hospital Centre,
Bugnon 46, Vaud, Switzerland; e-mail:
jean.bourhis@chuv.ch.
© 2015 by American Society of Clinical
Oncology
0732-183X/15/3399-1/$20.00
DOI: 10.1200/JCO.2015.61.4370
This multicenter phase III study evaluated the efficacy and safety of lapatinib, an epidermal growth
factor receptor/ErbB2 inhibitor, administered concomitantly with chemoradiotherapy and as
maintenance monotherapy in patients with high-risk surgically treated squamous cell carcinoma of
the head and neck (SCCHN).
Patients and Methods
Patients with resected stage II to IVA SCCHN, with a surgical margin ⱕ 5 mm and/or extracapsular
extension, were randomly assigned to chemoradiotherapy (66 Gy total radiation dose and cisplatin
100 mg/m2 per day administered on days 1, 22, and 43) plus placebo or lapatinib (1,500 mg per
day) before and during chemoradiotherapy, followed by 12 months of maintenance monotherapy.
Results
Six hundred eighty-eight patients were enrolled (lapatinib, n ⫽ 346; placebo, n ⫽ 342). With a
median follow-up time of 35.3 months, the study ended early because of the apparent plateauing
of disease-free survival (DFS) events. Median DFS assessed by an independent review committee
was 53.6 months and not reached for lapatinib and placebo, respectively (hazard ratio, 1.10; 95%
CI, 0.85 to 1.43). Investigator-assessed results confirmed the independent review committee
assessment. No significant differences in DFS by human papillomavirus status or overall survival
were observed between treatment arms. Similar numbers of patients in both treatment arms
experienced adverse events (AEs), with more patients in the lapatinib arm than the placebo arm
experiencing serious AEs (48% v 40%, respectively). The most commonly observed treatment-
related AEs were diarrhea and rash, both predominantly in the lapatinib arm.
Conclusion
Addition of lapatinib to chemoradiotherapy and its use as long-term maintenance therapy does not
offer any efficacy benefits and had additional toxicity compared with placebo in patients with
surgically treated high-risk SCCHN.
J Clin Oncol 33. © 2015 by American Society of Clinical Oncology

ity.1 Generally, postoperative radiotherapy is needed

INTRODUCTION
Locally advanced squamous cell carcinoma of the
head and neck (SCCHN) remains a therapeutic
challenge and is frequently treated with surgery
and/or radiotherapy. Long-term remission can be
obtained, but disease recurrence is seen in 15% to
30% of patients at 3 years, depending on factors such
as tumor site and stage, nodal stage, and resectabil-
in patients with locally advanced disease treated with
primary surgery. In addition, in high-risk patients
(with positive resection margins or nodal extracapsular
extension [ECE]), postoperative radiotherapy com-
bined with concomitant chemotherapy is indicated.
The potential benefit of adding chemotherapy
to radiotherapy has been demonstrated in an up-
dated meta-analysis of individual data from more

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132.239.1.230
Copyright 2015 by American Society of Clinical Oncology
 Harrington et al
than 16,000 patients with SCCHN in randomized trials that showed
that concomitant chemotherapy added significant benefits in 5-year
event-free survival and overall survival (OS).2 Addition of chemother-
apy to postoperative radiotherapy has also been tested in two large
phase III randomized studies in high-risk patients with locally ad-
vanced SCCHN. Both studies reported improved disease-free survival
(DFS) or progression-free survival, although only one study reported
improved OS.1,3 Long-term results of one of these trials, Radiation
Therapy Oncology Group 95-01, showed relatively high locoregional
failure rates and poor DFS (⬍ 30% in both arms), suggesting the need
for more effective adjuvant therapy in patients with operable SCCHN
at high risk of relapse.4
Although previous reports suggested that epidermal growth fac-
tor receptor (EGFR, c-ErbB1) is overexpressed in up to 90% of
SCCHN tumors, recent data from the Cancer Genome Atlas Network
suggest that this is a significant overestimate.5 Even so, EGFR-targeted
therapies are potentially beneficial for treating SCCHN,6 and this
approach has been validated in a phase III trial that established a new
standard of care for locally advanced SCCHN using the chimeric
anti-EGFR antibody cetuximab combined with radiotherapy.7 Cetux-
imab, as monotherapy or in combination with cisplatin, has also been
associated with clinical efficacy in patients with platinum-refractory
SCCHN.8,9
Heterodimerization and functional cross-talk between members
of the EGFR/ErbB family suggest that combining chemoradiotherapy
with multitargeted small-molecule tyrosine kinase inhibitors may
be a successful approach for the treatment of SCCHN. To date,
EGFR-targeted agents such as humanized monoclonal antibodies10 or
tyrosine kinase inhibitors,11,12 tested concomitantly with (chemo)ra-
diotherapy, have failed to demonstrate significant benefits in random-
ized trials, emphasizing the need for alternative EGFR-targeting
agents. One such agent is lapatinib, a small-molecule inhibitor of
EGFR and human epidermal growth factor receptor 2 (HER2, ErbB2).
The combination of lapatinib and chemoradiotherapy was well toler-
ated and showed single-agent activity in a small number of patients
with locally advanced SCCHN in phase I and II trials.13,14 Therefore, a
randomized, placebo-controlled, phase III study was designed to eval-
uate the efficacy and safety of lapatinib administered concomitantly
with chemoradiotherapy, followed by maintenance monotherapy for
1 year, in patients with resected SCCHN at high risk of relapse.
PATIENTS AND METHODS
Study Design and Treatment
This was a randomized, double-blind, placebo-controlled, multicenter,
phase III study (ClinicalTrials.gov identifier: NCT00424255; GlaxoSmithKline
protocol number: EGF102988), conducted between December 2006 and
November 2013. Patients with resected high-risk SCCHN (defined as ECE of
nodal disease or positive resection margin [ⱕ 5 mm]) were randomly assigned
in a 1:1 ratio to lapatinib or placebo arms using a GlaxoSmithKline internal
random assignment system, stratifying by nodal stage (N0 or N1 v N2),
primary tumor site, geographical region, and EGFR expression (immunohis-
tochemistry [IHC] EGFR3⫹ v non-EGFR3⫹).
At the start of the treatment phase, randomly assigned treatment (lapa-
tinib or placebo) was administered once daily for 3 to 7 days before commenc-
ing the 6- to 7-week combined therapy phase, where patients received
postoperative adjuvant concurrent chemoradiotherapy (intravenous cisplatin
100 mg/m2 per day on days 1, 22, and 43 plus 2 Gy of radiation per day, 5 days
per week, for a total of 66 Gy to the high-risk planning target volume 2 and
2 © 2015 by American Society of Clinical Oncology
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132.239.1.230
50 Gy to the low-risk planning target volume 1; Appendix, online only) and
lapatinib (1,500 mg taken orally once per day) or placebo. This was followed by
administration of lapatinib monotherapy (1,500 mg orally once per day) or
placebo for 1 year in the maintenance phase or until disease relapse. Carbopla-
tin was allowed if cisplatin could not be given after the first or second cycle
because of nephrotoxicity. Dose reductions or delays in randomly assigned
treatment were permitted in case of grade 3, 4, or unacceptable adverse events
(AEs) or AEs consistently associated with lapatinib. An independent program
of quality assurance and analysis of radiotherapy plans (Radiotherapy Quality
Assurance) was implemented (EqualEstro, Paris, France), with the aim of
ensuring standardized delivery of radiotherapy across treatment arms.
At the time of completion or early discontinuation of study treatment,
patients were observed for recurrence every 4 months for 2 years and then
every 6 months until withdrawal from the study or death. After disease recur-
rence, patients were monitored remotely every 6 months for survival outcome.
All patients gave written informed consent; the study was performed in accor-
dance with good clinical practice guidelines and the Declaration of Helsinki
and approved by local ethics committees.
Patient Population
Eligible patients had a histologically confirmed diagnosis of SCCHN at
the oral cavity, oropharynx, hypopharynx, or larynx; pathologic stage II, III, or
IVA cancer and ECE of nodal disease and/or positive resection margin of ⱕ 5
mm but with no evidence of gross residual disease; primary surgery with a
curative intent completed within 4 to 6 weeks (no later than 8 weeks) before
random assignment; and complete recovery from the surgical procedure.
Details of exclusion criteria are included in the Appendix.
Study End Points and Assessments
The primary end point was DFS (time from random assignment to the
earliest date of disease recurrence or death as a result of any cause) based on
radiologic and/or clinical assessment of electronic case report form data by an
independent review committee. DFS was also assessed by the investigator
(based on scans, endoscopies, or positive biopsy results).
Secondary efficacy end points included OS (time from random assign-
ment until death as a result of any cause); disease-specific survival; time to
locoregional control; time to distant relapse; incidence of second primary
tumor; and clinical outcome with biomarkers including DFS by human pap-
illomavirus (HPV) status15 and EGFR status. Medical resource utilization
(collected via the electronic case report form) and health-related quality of life
(HRQoL) were also evaluated. HRQoL was assessed using the Functional
Assessment of Cancer Therapy–Head and Neck and EQ-5D questionnaires
(further details are provided in the Appendix). Other post hoc analyses
included DFS in patients with or without ECE and with different
surgical margins.
Exposure to chemoradiotherapy was reported descriptively. Compliance
was assessed by tablet count. Safety end points included toxicities (including
late radiation morbidity), measured by recording the incidence and grading of
AEs and serious AEs (SAEs).
Tumor EGFR protein expression levels were evaluated by IHC. HPV
status was determined by evaluating the intratumoral expression levels of
CDKN2A (p16) by IHC and the presence of DNA from high-risk HPV geno-
types (HPV16 and HPV18) by chromogenic in situ hybridization (Appendix
Table A1, online only). Samples that were p16 positive/HPV negative were
re-examined by consensus high-risk HPV polymerase chain reaction for the
detection of HPV DNA. Samples that were p16 positive/HPV positive were
defined as harboring biologically relevant oncogenic HPV infection. Further
details are provided in the Appendix.
Clinical safety and tolerability were assessed in the safety population
(comprising all patients who took at least one dose of study medication). AEs
were graded according to the National Cancer Institute Common Terminol-
ogy Criteria for Adverse Events (version 3) and coded using the Medical
Dictionary for Regulatory Activities (version 15.1).
Statistical Analysis
The planned sample size was 680 patients (340 patients per arm). To
detect a hazard ratio (HR) of 0.7206 with 80% power, approximately 298
JOURNAL OF CLINICAL ONCOLOGY
 Lapatinib and Chemoradiotherapy in SCCHN

independently assessed events (disease recurrences or deaths as a result of any
cause) would be required for the final analysis. The expected accrual rate was
15 patients per month for 45 months. Median follow-up time (with 95% CI)
was calculated using the reverse censoring method.16,17 Further details on the
statistical properties of the trial design are provided in the Appendix.
All efficacy analyses were conducted on the intent-to-treat (ITT) popu-
lation, which comprised all patients randomly assigned to study treatment,
regardless of whether they received study medication. DFS and OS were
summarized using Kaplan-Meier curves (all P values are two-sided unless
otherwise stated). Further details are provided in the Appendix.
RESULTS
treatment arms had radiotherapy plans that were approved by the
independent quality assurance group.
Efficacy
According to the study design, approximately 298 independently
assessed DFS events (disease recurrence or death) would be required
for the final analysis. However, because of apparent plateauing of
investigator-reported events (and having reached a median follow-up
time of 35.3 months), it was decided to report the study using data
collected up to a clinical cutoff of March 29, 2013. At this time, there
were 232 independently assessed DFS events.

Study Population Characteristics Primary End Point: Independently Assessed DFS

Patients were enrolled from 84 sites in 21 countries (Appendix).
Overall, 930 patients were screened for study eligibility, and 688
patients were randomly assigned to the ITT population (placebo,
n ⫽ 342; lapatinib, n ⫽ 346; Fig 1). Patient demographics and char-
acteristics were balanced between treatment arms (Table 1). The most
common primary tumor site was the oral cavity (41% of patients). The
hypopharynx was the primary site of disease in 33 patients (10%) in
the placebo arm versus 53 patients (15%) in the lapatinib arm. Disease
characteristics at initial diagnosis were also balanced between treat-
ment arms within subgroups for overall HPV status (HPV positive,
n ⫽ 44; HPV negative, n ⫽ 560). In HPV/p16-positive patients, the
oropharynx was the predominant primary tumor type (86% of pa-
tients), and the proportion of patients with primary TNM stage T2
tumors was higher in this group compared with the overall ITT pop-
ulation (50% v 30%, respectively). Overall, 95% patients in both
DFS events were observed in 110 patients (32%) in the placebo
arm compared with 122 patients (35%) in the lapatinib arm (HR, 1.10;
95% CI, 0.85 to 1.43; P ⫽ .45). The median DFS was 53.6 months in
the lapatinib arm but was not reached in the placebo arm (Fig 2A). On
the basis of Kaplan-Meier estimates from the DFS curves, the percent-
age of patients disease free at 36 months was 62.2% (95% CI, 56.1% to
67.7%) and 61.1% (95% CI, 55.0% to 66.7%) for placebo and lapa-
tinib, respectively; at 60 months, the values were 57.1% (95% CI,
49.5% to 64.0%) and 42.9% (95% CI, 32.3% to 53.1%) for placebo
and lapatinib, respectively (numbers at risk at this time were low).
Secondary End Points
Investigator-assessed DFS events were observed in 39% to 40% of
patients in both arms; no statistically significant difference was ob-
served between the two arms (HR, 1.03; 95% CI, 0.81 to 1.30; P ⫽ .82).

Assessed for eligibility

(N = 930)

Excluded or withdrew from study

(n = 242)

Randomly assigned to ITT population

(n = 688)

Assigned to placebo Assigned to lapatinib

(n = 342) (n = 346)

Analyzed in efficacy population Analyzed in efficacy population

(n = 342) (n = 346)

Analyzed in safety population Analyzed in safety population (n = 349)

(n = 336) Given lapatinib in error (n = 3)

Died (n = 110; 32%) Died (n = 105; 30%)

Ongoing (follow-up) (n = 169; 49%) Ongoing (follow-up) (n = 179; 52%)
Withdrew from study (n = 63; 18%) Withdrew from study (n = 62; 18%)
Patient’s decision (n = 33; 10%) Patient’s decision (n = 36; 10%)
Lost to follow-up (n = 24; 7%) Lost to follow-up (n = 18; 5%)
Investigator decision (n = 3; < 1%) Investigator decision (n = 6; 2%)
Other (n = 3; < 1%) Protocol violation (n = 1; < 1%)
Other (n = 3; < 1%)

Fig 1. Patient flow. ITT, intent to treat.

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132.239.1.230
 Harrington et al

(33% to 37% across treatments; Appendix Fig A1, online only). No

Table 1. Patient Demographic and Clinical Characteristics (including
stratification factors)
treatment effect was observed for DFS by HPV and EGFR status (Fig
3). No significant differences were observed between treatment arms
No. of Patients (%)
in DFS assessed in other subgroups (Fig 3).
Placebo Arm Lapatinib Arm Median OS was not reached in either treatment arm. Overall, 110
Characteristic (n ⫽ 342) (n ⫽ 346)
patients (32%) died in the placebo arm, compared with 105 patients
Age, years
(30%) in the lapatinib arm (Fig 4). On the basis of Kaplan-Meier
Median 55.0 54.0
Range 24-74 27-74
estimates from the OS curves, the percentage of patients alive at 36
Male sex 287 (84) 286 (83) months was 66.2% (95% CI, 60.4% to 71.4%) and 67.9% (95% CI,
Race category 62.1% to 73.0%) for placebo and lapatinib, respectively; at 60 months,
White 220 (64) 222 (64) the values were 57.3% (95% CI, 50.0% to 63.9%) and 56.6% (95% CI,
Black 1 (⬍ 1) 0 47.3% to 64.8%) for placebo and lapatinib, respectively.
Asian 121 (35) 123 (36) Results from analyses of additional secondary efficacy vari-
Other 0 1 (⬍ 1)
ables (disease-specific survival, time to locoregional recurrence,
Clinical stage
I 4 (1) 4 (1)
time to distant relapse, and incidence of second primary tumor)
II 31 (9) 34 (10) were consistent with the primary efficacy analyses; no difference
III 77 (23) 90 (26) between the two treatment arms was observed (Appendix Table 2,
IVa 230 (67) 216 (62) online only).
Missing 0 2 (⬍ 1) In HRQoL assessments using Functional Assessment of Cancer
p16 status Therapy–Head and Neck and EQ-5D questionnaires, similar trends
Positive 42 (12) 48 (14)
were observed in both treatment arms. Clinically meaningful de-
Negative 282 (82) 271 (78)
Unknown 18 (5) 7 (8)
creases from baseline were observed in all HRQoL scores at the end of
Overall HPV statusⴱ chemotherapy, indicating worsening of HRQoL (Appendix; Appen-
Positive 21 (6) 23 (7) dix Figs A2 and A3, online only). The decrease was significantly greater
Negative 284 (83) 276 (80) for patients on lapatinib than placebo. During the maintenance phase,
Unknown 37 (11) 47 (14) average scores returned to baseline values on most scales by mainte-
Stratification factors
nance week 8 and remained unchanged throughout this phase. How-
N stage
N0, N1 135 (39) 135 (39)
ever, patients receiving lapatinib had lower mean scores than those
N2 207 (61) 211 (61) receiving placebo. Both groups displayed clinically meaningful de-
Primary site of disease creases in HRQoL at the point of early withdrawal of treatment.
Oral cavity 145 (42) 140 (40) Overall, the amount of reported unscheduled medical resource utili-
Larynx 80 (23) 77 (22) zation was low and similar across treatment arms and corresponded to
Oropharynx 68 (20) 65 (19) the time points at which the greatest declines in HRQoL were observed
Hypopharynx 33 (10) 53 (15)
(Appendix Table A3, online only).
Multiple sites 16 (5) 11 (3)
Region†
Western 217 (63) 219 (63) Safety
Non-Western 125 (37) 127 (37) There were no significant differences between treatment arms in
EGFR expression exposure to placebo/lapatinib (Table 2), chemotherapy (Appendix
Non-3⫹ 99 (29) 104 (30) Table A4, online only), or radiotherapy (Appendix Table A5, online
3⫹ 243 (71) 242 (70) only). Overall, compliance was high in both treatment arms; 83% and
Abbreviation: EGFR, epidermal growth factor receptor. 76% of patients in the placebo and lapatinib arms, respectively, were
ⴱ
Defined by results of p16 expression (immunohistochemistry) and human
papillomavirus (HPV) DNA detection (chromogenic in situ hybridization);
ⱖ 80% compliant.
polymerase chain reaction was performed in certain cases to adjudicate A similar number of patients in both treatment arms experienced
discordant p16 and HPV results. AEs (Table 3). The most commonly observed AEs in both treatment
†Western region contains Canada, the United States, Austria, Croatia, Czech
Republic, Estonia, France, Germany, Greece, Hungary, Italy, Russia, Slovak arms were mucosal inflammation and nausea. In total, 224 patients
Republic, Spain, and the United Kingdom. Non-Western region contains (67%) in the placebo arm experienced grade 3 or 4 AEs compared with
Argentina, China, Hong Kong, India, Philippines, and Thailand.
263 patients (75%) in the lapatinib arm. The most common grade 3 or
4 AEs were lymphopenia and mucosal inflammation.
Overall, 204 patients (61%) and 228 patients (65%) in the pla-
Median DFS was 59.0 months in the placebo arm compared with 51.5 cebo and lapatinib arms, respectively, experienced AEs considered
months in the lapatinib arm (Fig 2B). On the basis of Kaplan-Meier related to study treatment. The most commonly observed treatment-
estimates from the DFS curves, the percentage of patients disease free related AEs were diarrhea (placebo [n ⫽ 25; 7%] v lapatinib [n ⫽ 96;
at 36 months was 57.7% (95% CI, 51.8% to 63.2%) and 56.9% (95% 28%], P ⬍ .001) and rash (placebo [n ⫽ 27; 8%] v lapatinib [n ⫽ 84;
CI, 50.8% to 62.5%) for placebo and lapatinib, respectively; at 60 24%], P ⬍ .001). Nausea was experienced by 75 patients (22%) and 82
months, the values were 49.3% (95% CI, 39.8% to 58.1%) and 41.8% patients (23%) in the placebo and lapatinib arms, respectively (P ⫽
(95% CI, 32.0% to 51.4%) for placebo and lapatinib, respectively. .75); vomiting was experienced by 58 patients (17%) and 76 patients
Fewer HPV/p16-positive patients (14% to 22% across treat- (22%) in the placebo and lapatinib arms, respectively (P ⫽ .19). SAEs
ments) had a DFS event compared with HPV/p16-negative patients were experienced by 133 patients (40%) and 166 patients (48%) in the

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 Lapatinib and Chemoradiotherapy in SCCHN

A 1.0
B 1.0
CRT + lapatinib CRT + lapatinib
CRT + placebo CRT + placebo
Disease-Free Survival

Disease-Free Survival
0.8 0.8
(probability)

(probability)
0.6 0.6

Placebo arm Lapatinib arm Placebo arm Lapatinib arm

0.4 0.4
n 342 346 n 342 346
Events: progression 110 (32) 122 (35) Events: disease recurrence 132 (39) 139 (40)
or death, n (%) or death, n (%)
0.2 Median DFS (95% CI) NR (54.6 to NR) 53.6 (45.8 to NR) 0.2 Median DFS (95% CI) 59.0 (38.0 to NR) 51.5 (38.9 to 61.2)
Hazard ratio (95% CI) 1.10 (0.85 to 1.43) Hazard ratio (95% CI) 1.03 (0.81 to 1.30)
Two-sided P .45 Two-sided P .82

0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70

Time Since Random Assignment (months) Time Since Random Assignment (months)
No. at risk No. at risk
Lapatinib 346 215 177 130 88 42 11 1 Lapatinib 346 237 188 135 90 44 11 1
Placebo 342 209 172 127 89 45 8 Placebo 342 224 183 131 91 47 11

Fig 2. Kaplan-Meier estimates of disease-free survival (DFS) in intent-to-treat population: (A) independently assessed and (B) investigator assessed. CRT,
chemoradiotherapy; NR, not reached.

placebo and lapatinib arms, respectively. Lymphopenia (5% of pa-
tients in both arms) and mucosal inflammation (nine patients [3%]
and 17 patients [5%] in the placebo and lapatinib arms, respectively),
were the most commonly experienced SAEs.
Sixteen patients (5%) and 25 patients (7%) experienced fatal AEs
in the placebo and lapatinib arm, respectively. Sepsis and pneumonia
were the most common known reasons for fatal SAEs (ⱕ 1% of
patients in each arm). Two patients (⬍ 1%) in the placebo arm and
three patients (⬍ 1%) in the lapatinib arm had fatal AEs that were
considered related to study medication by the investigator. The
occurrence of late radiation morbidity events was similar between
the placebo and lapatinib arms (20% and 16% of patients,
respectively), and grade ⱖ 3 events occurred in 4% of patients in
both arms.
DISCUSSION
Despite a strong scientific rationale and supportive data from earlier
phase I and II studies, this phase III trial of lapatinib in combination

Subgroup n Hazard ratio (95% CI) P

All 688 .45
HPV status (HPV/p16)
Positive 44 .70
Negative 560 .29
Unknown 84 .56
ECE
Status 1: positive 320 .30
Status 1: negative 363 .81
Status 2: positive and surgical 471 .91
margins > 5 mm or negative
Status 2: positive and surgical 110 .91
margins ≤ 5 mm
Status 3: negative and surgical 527 .26
margins ≥ 1 mm or positive
Status 3: negative and surgical 42 .71
margins < 1 mm
Any involved surgical margin < 1 mm 209 .58
ECE positive and any involved 91 .91
surgical margins < 1 mm
Baseline EGFR IHC status
Non 3+ 203 .24
3+ 485 .92

0 1 2 3 4 5

Favors Lapatinib Favors Placebo

Fig 3. Forest plot summarizing disease-free survival (DFS) subgroup analyses (intent-to-treat population). DFS was independently assessed; all P values were
two-sided. ECE, extracapsular extension; EGFR, epidermal growth factor receptor; HPV, human papillomavirus; IHC, immunohistochemistry.

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132.239.1.230
 Harrington et al

1.0 CRT + lapatinib Table 3. Summary of On-Therapy and Follow-Up Overall Incidence of
CRT + placebo Adverse Events Occurring in ⱖ 15% of Patients in Either Treatment Arm
(overall and by grade [safety population])
0.8
No. of Patients (%)
Overall Survival
(probability)

0.6 All Gradesⴱ Grades 3 and 4†

Placebo Lapatinib Placebo Lapatinib

Arm Arm Arm Arm
0.4
Adverse Event (n ⫽ 336) (n ⫽ 349) (n ⫽ 336) (n ⫽ 349)
Placebo arm Lapatinib arm
n 342 346 Any event 328 (98) 344 (99) 224 (67)‡ 263 (75)
0.2 Events: deaths, n (%) 110 (32) 105 (30) Mucosal inflammation 214 (64) 229 (66) 57 (17)§ 84 (24)
Median OS (95% CI) NR (NR to NR) NR (58.8 to NR)
Hazard ratio (95% CI) 0.96 (0.73 to 1.25) Nausea 152 (45) 184 (53) 4 (1) 14 (4)
Rash 101 (30) 170 (49) 14 (4) 20 (6)
0 10 20 30 40 50 60 70 Vomiting 118 (35) 160 (46) 13 (4) 23 (7)
Dry mouth 130 (39) 148 (42) 10 (3) 16 (5)
Time Since Random Assignment (months)
Diarrhea 41 (12) 148 (42) 4 (1)㛳 20 (6)
No. at risk
Lapatinib 346 266 226 178 115 67 20 3 Dysphagia 115 (34) 128 (37) 39 (12) 56 (16)
Placebo 342 274 221 164 114 75 24 Lymphopenia 88 (26) 99 (28) 70 (21) 80 (23)
Weight decreased 65 (19) 92 (26) 9 (3) 12 (3)
Fig 4. Kaplan-Meier estimate of overall survival (OS; intent-to-treat population). Leukopenia 102 (30) 85 (24) 43 (13) 40 (11)
CRT, chemoradiotherapy; NR, not reached.
Anemia 60 (18) 77 (22) 7 (2) 16 (5)
Neutropenia 82 (24) 73 (21) 36 (11) 49 (14)
Pyrexia 64 (19) 66 (19) 0 4 (1)
with platinum-based chemoradiotherapy in patients with surgically Decreased appetite 71 (21) 65 (19) 9 (3) 11 (3)
treated high-risk SCCHN failed to meet its primary end point of DFS Constipation 73 (22) 58 (17) 2 (⬍ 1) 0
by independent review committee. In addition, no statistically signif- Asthenia 47 (14) 58 (17) 5 (1) 7 (2)
icant differences were seen in secondary end points, such as Radiation skin injury 78 (23) 54 (15) 7 (2) 5 (1)
Stomatitis 55 (16) 52 (15) 16 (5) 25 (7)
investigator-assessed DFS or OS. Exploratory analyses of the DFS data
Oropharyngeal pain 67 (20) 45 (13) 2 (⬍ 1) 2 (⬍ 1)
did not identify any patient subgroup that derived benefit (or experi-
enced detriment) from the addition of lapatinib to chemoradiother- NOTE. Only P values indicating statistically significant differences between
placebo and lapatinib are indicated.
apy. These results should be interpreted in light of the fact that ⴱ
Any event row contains patients with at least one adverse event regardless
lapatinib had a 0% response rate in a phase II study of EGFR inhibitor– of relationship to study treatment.
†Any event row contains patients with at least one adverse event with
naive or –refractory relapsed/metastatic SCCHN.18 Certainly, these maximum overall toxicity of grade 3 or 4 regardless of relationship to study
findings should serve as a note of caution on the risks of initiating large treatment.
‡P ⫽ .019.
phase III studies (of this and other drugs) with insufficient evidence of §P ⫽ .04.
single-agent activity. Although the results of this study are consistent 㛳P ⫽ .022.
with recently published trials that have combined EGFR-targeted
antibody therapies (cetuximab or panitumumab) with chemora-
diotherapy,10,19 the findings do not preclude the possibility that
small molecules with greater activity than lapatinib against EGFR
Table 2. Study Drug Exposure and Dose Delays (safety population) (eg, gefitinib, afatinib) may have a role in this context. Lapatinib
No. of Patients (%) has established efficacy in HER2-positive metastatic breast can-
Drug Exposure and Placebo Lapatinib
cer20; however, results of randomized studies in other EGFR-
Dose Delays (n ⫽ 336) (n ⫽ 349) driven cancers have been disappointing,21,22 suggesting that
Daily dose, mgⴱ lapatinib is more effective as an HER2 inhibitor than as an EGFR
Median 1,500 1,500 inhibitor in the clinic.
Range 782-1,500 750-1,500 When planning this study, projections of likely DFS and OS
Time on study treatment, weeks rates were based on data from practice-changing historical studies,
Mean 45.5 45.1 notably Radiation Therapy Oncology Group 95-01.1 However, the
SD 23.04 23.94
rates of reported DFS and OS events in the current study were
Median 62.9 62.9
Range 0-69 0-72
much lower than the projected rates, such that the required num-
Patients in maintenance phase ber of DFS events was not reached. In retrospect, it may have been
ⱖ 9 months 196 (58) 209 (60) more appropriate to base DFS and OS projections on the chemo-
No. of dose delays per patient radiotherapy arm of the European Organisation for Research and
0 219 (65) 192 (55) Treatment of Cancer 22931 study, given that most patients in this
1 55 (16) 76 (22)
study were recruited in non-US sites and the inclusion criteria
ⱖ2 62 (18) 81 (23)
Patients with dose reductions 27 (8) 47 (13)
included patients with close (⬍ 5 mm) margins.3 Although there
are caveats to cross-trial comparison of outcome data, the chemo-
Abbreviation: SD, standard deviation.
ⴱ
Daily dose was the cumulative dose divided by the duration of exposure.
radiotherapy arms of the current study and the European Organi-
sation for Research and Treatment of Cancer 22931 study seem to

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132.239.1.230
 Lapatinib and Chemoradiotherapy in SCCHN

be similar, suggesting that the control arm in our study performed

as would have been expected. This observation lends further
strength to the conclusion that the addition of lapatinib to chemo-
radiotherapy adds no benefit in managing patients with high-risk
postoperative SCCHN.
Exposure to the study medication was balanced, and compliance
was high in both treatment arms. Although similar rates of tolerability
were observed, diarrhea and rash were observed more frequently in
the lapatinib arm, consistent with the known toxicities of this drug. In
addition, there were more grade 3 or 4 AEs and deaths in the lapatinib
arm. Despite the additional toxicity, there was no evidence that
lapatinib had a significant effect on HRQoL over and above che-
moradiotherapy, in part likely as a result of the high symptom
burden these patients already experience. Because the HRQoL
values returned to baseline during the adjuvant phase, this study
adds to the existing literature that lapatinib is well tolerated as
maintenance monotherapy. In conclusion, in patients with surgi-
cally treated high-risk SCCHN, the addition of lapatinib to chemo-
radiotherapy and its use as long-term maintenance therapy offered
no benefit in efficacy and had additional toxicity compared with
chemotherapy alone.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at
www.jco.org.
AUTHOR CONTRIBUTIONS
Conception and design: Kevin Harrington, Stephane Temam, Hisham
Mehanna, Iman El-Hariry, Nigel Biswas-Baldwin, Philippe Legenne, Paul
Wissel, Mayur Amonkar, Jean Bourhis
Provision of study materials or patients: Kevin Harrington, Stephane
Temam, Pavol Dubinsky, Jean Bourhis
Collection and assembly of data: Kevin Harrington, Stephane Temam,
Hisham Mehanna, Anil D’Cruz, Minish Jain, Ida D’Onofrio, Georgy
Manikhas, Zsuzsanna Horvath, Yan Sun, Stefan Dietzsch, Pavol
Dubinsky, Petra Holeckova, Natalie Franklin, Nigel Biswas-Baldwin,
Paul Wissel, John Farrell, Catherine Ellis, Nazma Ahmed, Sergio
Santillana, Jean Bourhis
Data analysis and interpretation: Kevin Harrington, Stephane Temam,
Hisham Mehanna, Natalie Franklin, Nigel Biswas-Baldwin, Philippe
Legenne, Paul Wissel, Thelma Netherway, Catherine Ellis, Jing
Wang-Silvanto, Mayur Amonkar, Sergio Santillana, Jean Bourhis
Manuscript writing: All authors
Final approval of manuscript: All authors

REFERENCES
1. Cooper JS, Pajak TF, Forastiere AA, et al:
Postoperative concurrent radiotherapy and chemo-
therapy for high-risk squamous-cell carcinoma of the
head and neck. N Engl J Med 350:1937-1944, 2004
2. Pignon JP, le Maître A, Maillard E, et al:
Meta-analysis of chemotherapy in head and neck
cancer (MACH-NC): An update on 93 randomised
trials and 17,346 patients. Radiother Oncol 92:4-14,
2009
3. Bernier J, Domenge C, Ozsahin M, et al:
Postoperative irradiation with or without concomi-
tant chemotherapy for locally advanced head and
neck cancer. N Engl J Med 350:1945-1952, 2004
4. Cooper JS, Zhang Q, Pajak TF, et al: Long-
term follow-up of the RTOG 9501/intergroup phase
III trial: Postoperative concurrent radiation therapy
and chemotherapy in high-risk squamous cell carci-
noma of the head and neck. Int J Radiat Oncol Biol
Phys 84:1198-1205, 2012
5. Cancer Genome Atlas Network: Comprehen-
sive genomic characterization of head and neck
squamous cell carcinomas. Nature 517:576-582,
2015
6. Kalyankrishna S, Grandis JR: Epidermal
growth factor receptor biology in head and neck
cancer. J Clin Oncol 24:2666-2672, 2006
7. Bonner JA, Harari PM, Giralt J, et al: Radio-
therapy plus cetuximab for squamous-cell carci-
noma of the head and neck. N Engl J Med 354:
567-578, 2006
8. Vermorken JB, Trigo J, Hitt R, et al: Open-
label, uncontrolled, multicenter phase II study to
evaluate the efficacy and toxicity of cetuximab as a
single agent in patients with recurrent and/or meta-
static squamous cell carcinoma of the head and
neck who failed to respond to platinum-based ther-
apy. J Clin Oncol 25:2171-2177, 2007
9. Baselga J, Trigo JM, Bourhis J, et al: Phase II
multicenter study of the antiepidermal growth factor
receptor monoclonal antibody cetuximab in combi-
nation with platinum-based chemotherapy in pa-
tients with platinum-refractory metastatic and/or
recurrent squamous cell carcinoma of the head and
neck. J Clin Oncol 23:5568-5577, 2005
10. Mesía R, Henke M, Fortin A, et al: Chemora-
diotherapy with or without panitumumab in patients
with unresected, locally advanced squamous-cell
carcinoma of the head and neck (CONCERT-1): A
randomised, controlled, open-label phase 2 trial.
Lancet Oncol 16:208-220, 2015
11. Gregoire V, Hamoir M, Chen C, et al: Gefitinib
plus cisplatin and radiotherapy in previously un-
treated head and neck squamous cell carcinoma:
A phase II, randomized, double-blind, placebo-
controlled study. Radiother Oncol 100:62-69, 2011
12. Martins RG, Parvathaneni U, Bauman JE, et
al: Cisplatin and radiotherapy with or without erlo-
tinib in locally advanced squamous cell carcinoma of
the head and neck: A randomized phase II trial. J Clin
Oncol 31:1415-1421, 2013.
13. Harrington KJ, El-Hariry IA, Holford CS, et al:
Phase I study of lapatinib in combination with
chemoradiation in patients with locally advanced
squamous cell carcinoma of the head and neck. J
Clin Oncol 27:1100-1107, 2009
14. Harrington K, Berrier A, Robinson M, et al:
Randomised phase II study of oral lapatinib com-
bined with chemoradiotherapy in patients with ad-
vanced squamous cell carcinoma of the head and
neck: Rationale for future randomised trials in hu-
man papilloma virus-negative disease. Eur J Cancer
49:1609-1618, 2013
15. Ritchie JM, Smith EM, Summersgill KF, et al:
Human papillomavirus infection as a prognostic fac-
tor in carcinomas of the oral cavity and oropharynx.
Int J Cancer 104:336-344, 2003
16. Shuster JJ: Median follow-up in clinical trials.
J Clin Oncol 9:191-192, 1991
17. Schemper M, Smith TL: A note on quantifying
follow-up in studies of failure time. Control Clin
Trials 17:343-346, 1996
18. de Souza JA, Davis DW, Zhang Y, et al: A
phase II study of lapatinib in recurrent/metastatic
squamous cell carcinoma of the head and neck. Clin
Cancer Res 18:2336-2343, 2012
19. Ang KK, Zhang Q, Rosenthal DI, et al: Ran-
domized phase III trial of concurrent accelerated
radiation plus cisplatin with or without cetuximab for
stage III to IV head and neck carcinoma: RTOG
0522. J Clin Oncol 32:2940-2950, 2014
20. Cameron D, Casey M, Oliva C, et al: Lapatinib
plus capecitabine in women with HER-2-positive
advanced breast cancer: Final survival analysis of a
phase III randomized trial. Oncologist 15:924-934,
2010
21. Ravaud A, Hawkins R, Gardner JP, et al:
Lapatinib versus hormone therapy in patients with
advanced renal cell carcinoma: A randomized phase
III clinical trial. J Clin Oncol 26:2285-2291, 2008
22. Wülfing C, Machiels JP, Richel DJ, et al: A
single-arm, multicenter, open-label phase 2 study of
lapatinib as the second-line treatment of patients
with locally advanced or metastatic transitional cell
carcinoma. Cancer 115:2881-2890, 2009

Affiliations
Kevin Harrington, Institute of Cancer Research and Royal Marsden Hospital, London; Hisham Mehanna, Institute of Head and Neck
Studies and Education, University of Birmingham, Birmingham; Natalie Franklin and John Farrell, GlaxoSmithKline, Uxbridge, United
Kingdom; Stephane Temam and Jean Bourhis, Institut Gustave- Roussy, Villejuif; Ida D’Onofrio, Hôpital Forcilles, Paris, France; Anil
D’Cruz, Tata Memorial Hospital, Mumbai; Minish Jain, Ruby Hall Clinic–Cancer Centre, Pune, India; Georgy Manikhas, St Petersburg City
Oncology Dispensary, St Petersburg, Russia; Zsuzsanna Horvath, Szent Imre University Teaching Hospital Budapest, Budapest, Hungary; Yan

www.jco.org © 2015 by American Society of Clinical Oncology 7

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Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
132.239.1.230
 Harrington et al

Sun, Beijing Cancer Hospital, Beijing, China; Stefan Dietzsch, Hospital and Policlinic for Radiation Therapy and Radio-oncology, Leipzig,
Germany; Pavol Dubinsky, East Slovakia Cancer Institute, Kosice, Slovakia; Petra Holeckova, Institute of Radiation Oncology, Hospital Na
Bulovce, and 1st Medical Faculty of Charles University, Prague, Czech Republic; Iman El-Hariry, Synta Pharmaceutical, Lexington, MA; Paul
Wissel and Mayur Amonkar, Novartis Pharmaceuticals, East Hanover, NJ; Catherine Ellis and Sergio Santillana, GlaxoSmithKline,
Philadelphia, PA; and Nigel Biswas-Baldwin, Philippe Legenne, Thelma Netherway, Jing Wang-Silvanto, and Nazma Ahmed, Novartis
Pharma AG, Basel, Switzerland.
■ ■ ■

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 Lapatinib and Chemoradiotherapy in SCCHN

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Postoperative Adjuvant Lapatinib and Concurrent Chemoradiotherapy Followed by Maintenance Lapatinib Monotherapy in High-Risk Patients
With Resected Squamous Cell Carcinoma of the Head and Neck: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Kevin Harrington No relationship to disclose
Honoraria: Merck Sharp & Dohme, Amgen, Oncos Therapeutics,
Cellgene Iman El-Hariry
Consulting or Advisory Role: Merck Sharp & Dohme, Amgen (Inst), No relationship to disclose
Viralytics Inc (Inst), Lytix Natalie Franklin
Speakers’ Bureau: Merck Sharp & Dohme, Amgen Employment: GlaxoSmithKline, Roche
Research Funding: Oncolytics Biotech (Inst), Genelux (Inst), Viralytics Stock or Other Ownership: GlaxoSmithKline
(Inst), AstraZeneca (Inst)
Nigel Biswas-Baldwin
Stephane Temam Employment: GlaxoSmithKline
No relationship to disclose Stock or Other Ownership: GlaxoSmithKline
Hisham Mehanna Philippe Legenne
Employment: Warwickshire Head Neck Clinic Employment: GlaxoSmithKline
Leadership: Warwickshire Head neck Clinic, Warwickshire Head Neck
Stock or Other Ownership: GlaxoSmithKline
Clinic (I)
Stock or Other Ownership: Warwickshire Head Neck Clinic Paul Wissel
Honoraria: AstraZeneca Employment: GlaxoSmithKline
Speakers’ Bureau: Merck Sharp & Dohme, Sanofi Pasteur, Merck Stock or Other Ownership: GlaxoSmithKline
Research Funding: GlaxoSmithKline (Inst), Merck Sharp & Dohme
(Inst), Sanofi Pasteur (Inst), Silence Therapeutics (Inst), Thelma Netherway
GlaxoSmithKline Biologicals (Inst) Employment: GlaxoSmithKline, Novartis
Travel, Accommodations, Expenses: Sanofi Pasteur, Merck Sharp & Stock or Other Ownership: GlaxoSmithKline, Novartis
Dohme, Merck Travel, Accommodations, Expenses: GlaxoSmithKline, Novartis

Anil D’Cruz John Farrell

Honoraria: Merck Serono Employment: GlaxoSmithKline
Travel, Accommodations, Expenses: Merck Serono Stock or Other Ownership: GlaxoSmithKline

Minish Jain Catherine Ellis

No relationship to disclose Employment: GlaxoSmithKline
Stock or Other Ownership: GlaxoSmithKline
Ida D’Onofrio
No relationship to disclose Jing Wang-Silvanto
Employment: GlaxoSmithKline
Georgy Manikhas Stock or Other Ownership: GlaxoSmithKline
No relationship to disclose
Mayur Amonkar
Zsuzsanna Horvath Employment: Novartis Pharmaceuticals
No relationship to disclose
Stock or Other Ownership: GlaxoSmithKline, Novartis Pharmaceuticals
Yan Sun
Nazma Ahmed
No relationship to disclose
No relationship to disclose
Stefan Dietzsch
Sergio Santillana
No relationship to disclose
Employment: GlaxoSmithKline Oncology, Takeda Pharmaceuticals
Pavol Dubinsky Stock or Other Ownership: GlaxoSmithKline Oncology, Takeda
Honoraria: Merck, Merck Sharp & Dohme, Amgen Pharmaceuticals
Research Funding: Quintiles, Merck
Jean Bourhis
Petra Holeckova Consulting or Advisory Role: Merck Serono

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 Harrington et al

Acknowledgment
We thank all patients and their families, investigators, and study staff; the independent data monitoring committee; and the BioClinica
(independent review committee), EqualEstro (Radiotherapy Quality Assurance), and PAREXEL (independent statistics) teams. The authors also
thank Jen Carver, Jhangir Irani, Sejal Patel, Zuheb Ali, and all members of the GlaxoSmithKline central and monitoring team. Lapatinib is an asset
of Novartis AG as of March 2, 2015. Editorial support was provided by Karen Yee, PhD, of Fishawack Indicia, funded by GlaxoSmithKline and
Novartis Pharmaceuticals Corporation.

Appendix

Methods
Radiation treatment. A detailed description of radiation target volumes and dose prescription is provided in the Radiation Therapy
Protocol Guidelines (Data Supplement). Patients in both arms of this study received a conventionally fractionated course of radiotherapy.
Irradiation was planned using either a standard two-dimensional technique or a three-dimensional conformal technique. The use of
intensity-modulated radiation therapy was not allowed. The selection of technique was left to the discretion of each center. Only linear
accelerator– based treatments (photon energy ⱖ 4 MV or electrons) were allowed.
Exclusion criteria. Patients were excluded if they had tumors of the nasopharynx, paranasal sinuses, or nasal cavity or tumors with
histology other than squamous cell carcinomas; evidence of distant metastases, gross postoperative residual disease, or second primary
tumor; any prior or concurrent anticancer treatment or concurrent treatment with an investigational agent; or history of another
malignancy within the last 5 years (excluding resected basal or squamous skin cancers).
Health-related quality of life (HRQoL) assessment. Functional Assessment of Cancer Therapy–Head and Neck (FACT-H&N,
comprising Functional Assessment of Cancer Therapy–General [FACT-G] and a head and neck subscale) and EQ-5D questionnaires
were completed at day 1 (before dose), at the end of chemotherapy, every 8 weeks during the first year of follow-up, and at discontinuation
of randomly assigned therapy. During the next 2 years of follow-up, patients were asked to complete the questionnaire every 4 months.
A minimal clinically important difference (ie, a clinically meaningful change) is defined as ⫹6 (improvement) and ⫺12 (worsening)
for the FACT-H&N total score, ⫹4 (improvement) and ⫺8 (worsening) for the FACT-G score, and ⫹3 (improvement) and ⫺3
(worsening) for the head and neck subscale score and Trial Outcome Index (TOI; Ringash J, et al: Qual Life Res 13:725-733, 2004); 0.08
for the EQ-5D utility score; and 7 for the EQ-5D thermometer score (Pickard AS, et al: Health Qual Life Outcomes 5:70, 2007).
Tissue samples. Tissue sections (4 ␮m) and/or tissue blocks of the formalin-fixed and paraffin-embedded (FFPE) diagnostic biopsies
or resection specimens were collected. For the analysis, where only tissue sections were available, these were used. Where tissue blocks were
available, tissue microarrays (TMAs) were constructed. Briefly, hematoxylin and eosin–stained sections were prepared from the blocks to
confirm the presence of tumor, and the slides were annotated by a pathologist to guide TMA core selection. Up to four 0.6-mm diameter
tumor cores per block were transferred from the donor block to the recipient TMA block. A hematoxylin and eosin–stained section of the
prepared TMA was examined to assess adequate tumor sampling. Thick tissue curls (10 ␮m) were taken from available blocks for DNA
extraction and downstream polymerase chain reaction (PCR) analysis.
HPV analysis protocol. All samples were analyzed for p16 expression by immunohistochemistry (IHC). Samples were assessed for
high-risk (HR) HPV DNA using a protocol based on that described and validated by Smeets et al (Int J Cancer 121:2465-2472, 2007).
Samples were assessed by HPV in situ hybridization (ISH). For samples that were found to be p16 positive/HPV negative by ISH using
TMAs, whole tissue sections were tested to reduce misclassification as a consequence of possible sampling limitations inherent to TMA
analysis. If the sample remained p16 positive/HPV negative by ISH on the whole tissue section, the sample was then examined by
consensus HR-HPV PCR to control for the suboptimal sensitivity of HPV ISH compared with target amplification techniques (Smeets SJ,
et al: Int J Cancer 121:2465-2472, 2007). This latter protocol has been previously validated and proven to have the same accuracy as using
p16 and HPV-PCR (Thavaraj S, et al: J Clin Pathol 64:308-312, 2011). For all samples in this study, samples that showed evidence of HPV
DNA (either by ISH or consensus PCR) and showed high p16 expression (HPV positive/p16 positive) were defined as harboring
biologically relevant oncogenic HPV infection (Smeets SJ, et al: Int J Cancer 121:2465-2472, 2007).
HPV and p16 testing methods. p16 IHC was carried out using a proprietary kit (CINtec Histology; MTM Laboratories AG,
Heidelberg, Germany) on a Benchmark Autostainer (Ventana Medical Systems, Tucson, AZ). Tissue from an oropharyngeal squamous
cell carcinoma with high p16 expression was used as a positive control. The primary antibody was omitted from negative controls. A binary
(positive and negative) scoring system was adopted, and p16 IHC was scored as positive if there was strong and diffuse nuclear and
cytoplasmic staining present in more than 70% of the malignant cells (Singhi AD, et al: Cancer 116:2166-2173, 2010). All other staining
patterns were scored as negative.
HR-HPV ISH was carried out using proprietary reagents (Inform HPV III Family 16 Probe [B]; Ventana) on a Benchmark
Autostainer (Ventana). The Inform HPV III Family 16 Probe (B) detects HR genotypes 16, 18, 31, 33, 35, 39, 51, 52, 56, 58, and 66. The
following three control samples were used: FFPE CaSki cells (HPV-16 positive; 600 copies per cell), HeLa cells (HPV-18 positive; 10 to 50
copies per cell), and C-33A (HPV-negative cell line; Ventana). A binary scoring system was used. The HR-HPV ISH test was scored as
positive if there was a blue reaction product that colocalized with the nuclei of malignant cells. Diffuse staining of tumor and stromal

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132.239.1.230
 Lapatinib and Chemoradiotherapy in SCCHN

tissues, considered to represent nonspecific chromogen precipitate, was scored as negative. Pale staining limited to the nucleoli of cells and
staining of occasional leukocytes and stromal cells were also disregarded, in line with the manufacturer’s instructions (Ventana).
For consensus PCR for oncogenic HPV, DNA was extracted from tissue curls using the Qiagen (Hilden, Germany) FFPE kit (without
xylene washes). The yield of DNA was quantified using nanodrop spectrophotometry. DNA adequacy was assessed by amplification of the
human ␤-globin gene. HPV typing was performed using the GP5⫹/6⫹ primer set (Jacobs MV, et al: Clin Microbiol 35:791-795, 1997).
Samples were tested by PCR enzyme immunoassay using a cocktail of probes for 14 HR-HPV types and separately with a cocktail of probes
for six low-risk types. Samples testing positive for ab HR-HPV type were subject to second PCR and assayed with each of the 14 HR probes
independently of each other. A sample was defined as HR-HPV DNA positive if it tested positive in the HR-HPV cocktail reaction and an
HR-HPV genotype was identified in the second PCR reaction.
Scoring methods. The criteria used to score the p16 expression and HR-HPV ISH were defined before commencing the study. Two
pathologists analyzed the test results independently. Before commencing the study, a training set of 45 tonsil squamous cell carcinomas
was used to calibrate the two scorers, obtaining greater than 95% concordance (data not shown). The p16 IHC and HR-HPV ISH tests
were assessed separately alongside corresponding hematoxylin and eosin–stained sections, and the scores were collated by the study
coordinator. Any discordant scores (5%) between the pathologists were resolved at a meeting between the pathologists to establish a
consensus. In addition, all samples scored as p16 negative/HPV positive and p16 positive/HPV negative were reviewed by the two
pathologists together to ensure correct categorization.
Hypotheses. The study was designed to provide evidence to either support the null hypothesis (H0: ␭ ⱖ 1) or reject it in favor of the
alternative hypothesis (HA: ␭ ⬍ 1), where ␭ is the hazard ratio (HR) for disease-free survival (DFS; lapatinib/placebo). Assuming the DFS
curves are consistent with proportional hazards, then the null hypothesis represents equality of the median DFS in the two treatment arms,
or a lower median DFS in the lapatinib arm, and the alternative hypothesis represents a higher median DFS in the lapatinib arm.
Sample size assumptions. The following assumptions were made in the estimation of the required sample size: exponential distribu-
tions of DFS; an HR of 0.7206, which originates from estimated DFS rates at 2 years after random assignment of 65% in the lapatinib arm
and 55% in the placebo arm (an absolute increase of 10%), resulting in an approximate median DFS of 39 and 28 months in the lapatinib
arm and placebo arm, respectively; a 1:1 random assignment scheme, with a total of approximately 680 patients, 340 patients per arm (on
the basis of observed cure rates in the studies reported by Bernier et al3 and Cooper et al,4 it was anticipated that a portion of patients
entered onto the study may never reach an end point of recurrence of disease; therefore, more patients were recruited to allow for this); a
2.5% risk of erroneously claiming superiority of lapatinib in the presence of no true underlying difference (one-sided type I error); an 80%
chance of successfully detecting am HR of 0.7206, which equates to detecting a 39% increase in median DFS in patients who receive
lapatinib (39 months; HR, 0.0179) relative to placebo (28 months; HR, 0.0249); and an average constant accrual rate of 15 patients per
month for 45 months.
Efficacy end points. Greenwood’s formula was used to calculate the SE of the Kaplan-Meier curve estimates. The Pike estimator of the
HR and associated 95% CIs were also presented. DFS was compared between treatment arms using a nonstratified log-rank test. Cox
regression models were used to explore the effect of prognostic factors, including stratification factors and HPV status. The adjusted HR,
95% CI, and two-sided Wald ␹2 P values were presented.
HRQoL. For HRQoL analyses, data collected from FACT-H&N and EQ-5D questionnaires were summarized descriptively and
listed to show FACT-H&N responses for subscale, total, FACT-G, and TOI scores, and EQ-5D domain scores, thermometer values, and
derived utility scores. Changes from baseline were also summarized for each treatment arm with an analysis of covariance performed to
compare differences between study arms in FACT-G scores, TOI scores, EQ-5D utility scores, and thermometer scores.
Quality-of-life responder analyses were also performed to indicate scores that were clinically meaningful. Patients with missing
baseline assessments for FACT-H&N were excluded from analysis.
Results
Secondary end point: HRQoL. For HRQoL, at the end of chemoradiotherapy, clinically meaningful decreases from baseline were
observed in both arms in all HRQoL measures, as follows: FACT-H&N total (lapatinib, ⫺17.9; placebo, ⫺13.5), FACT-G (lapatinib,
⫺11.1; placebo, ⫺7.8), TOI (lapatinib, ⫺16.0; placebo, ⫺12.2), head and neck subscale (lapatinib, ⫺7.0; placebo, ⫺5.6), EQ-5D utility
(lapatinib, ⫺0.14; placebo, ⫺0.12), and EQ-5D thermometer (lapatinib, ⫺8.4; placebo, ⫺7.7) scores. All of these declines (except both
scores of EQ-5D) were found to be significantly worse (P ⬍ .05) for the patients on lapatinib than those on placebo. Results for FACT-G
and EQ-5D utility are illustrated in Appendix Figures A1 and A2 (showing changes in scores from baseline across all the treatment phases
in the study).
During the maintenance period, no clinically meaningful decreases from baseline were observed in both arms of all HRQoL measures
except TOI scores at maintenance week 8 (lapatinib, ⫺8.5; placebo, ⫺5.0). However, patients receiving lapatinib had significantly less
favorable changes (P ⬍ .05) than patients given placebo in FACT-H&N total score, FACT-G score (Fig A2), and TOI at multiple time
points throughout the maintenance period.
On treatment withdrawal, both groups displayed clinically meaningful declines in FACT-H&N total (lapatinib, ⫺14.9; placebo,
⫺16.2), FACT-G (lapatinib, ⫺10.1; placebo, ⫺12.2; Fig A1), TOI (lapatinib, ⫺11.9; placebo, ⫺12.5), head and neck subscale (lapatinib,
⫺4.9; placebo, ⫺4.1), EQ-5D utility (lapatinib, ⫺0.11; placebo, ⫺0.23), and EQ-5D thermometer scores (lapatinib, ⫺3.3; placebo,

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 Harrington et al

⫺11.4). However, the differences between treatment arms was not statistically significant (P ⬎ .05) except for EQ-5D, with both scores
significantly in favor of lapatinib compared with placebo (P ⬍ .05; Appendix Fig 3A).
Overall responder analyses showed that HRQoL worsened in more lapatinib-treated patients than patients taking placebo (P ⬍ .05)
according to FACT-H&N total scores and FACT-G scores, but the differences were not significant in TOI and head and neck subscale
scores (P ⬎ .05; Appendix Table A6).
EGF102988 Study Sites and Investigators
Sites in order of patient recruitment numbers were as follows: India (n ⫽ 119), France (n ⫽ 116), China (n ⫽ 80), Germany (n ⫽ 51),
Hungary (n ⫽ 41), the Russian Federation (n ⫽ 40), Spain (n ⫽ 36), the Czech Republic (n ⫽ 29), Slovakia (n ⫽ 24), Thailand (n ⫽ 22),
United Kingdom (n ⫽ 21), Greece (n ⫽ 21), Croatia (n ⫽ 18), Italy (n ⫽ 17), Austria (n ⫽ 15), the Philippines (n ⫽ 14), Argentina (n ⫽
9), Hong Kong (n ⫽ 8), United States of America (n ⫽ 3), Canada (n ⫽ 3), and Estonia (n ⫽ 1).
Argentina (n ⫽ 3): Blajman, Cesar R., MD; Campos, Claudio A., MD; Fein, Luis E., MD.
Austria (n ⫽ 3): Greil, Richard, MD; Kornek, Gabriela, MD; Scholtz, Arne-Wulf, MD.
Canada (n ⫽ 2): Jha, Naresh, MD, FRCPC, MBBS; Nabid, Abdenour, MD.
China (n ⫽ 7): Gao, Li, MD; Hu, Chaosu, MD; Hu, Guoqing, MD; Pan, Jianji, PhD; Sun, Yan, MD; Wu, Shao Xiong, MD; Yuan,
Zhiyong, MD.
Croatia (n ⫽ 2): Prgomet, Drago, MD; Virag, Mîso Mihajlo, MD.
Czech Republic (n ⫽ 4): Cervena, Renata, MD; Cincibuch, Jan, MD; Feltl, David, MD, PhD; Holeckova, Petra, MD.
Estonia (n ⫽ 1): Kuddu, Maire, MD.
France (n ⫽ 15): Babin, Emmanuel, MD; Banal, Alain, MD; Borel, Christian, MD; Cupissol, Didier, MD, PhD; Degardin, Marian,
MD; Delalande, Cecile, MD; Delord, Jean-Pierre, MD; D’Onofrio, Ida, MD; Duparc, Angelique, MD; Jadaud, Eric, MD; Lacau Saint
Guily, Jean, MD; Prevost, Alain, MD; Racadot, Séverine, MD; Temam, Stephane, MD; Zawadi, Ayman, MD.
Germany (n ⫽ 6): Classen, Johannes, Dr Med; Debus, Juergen P, Dr Med; Kortmann, Rolf-Dieter, Dr Med; Lang, Stephan, MD, PhD;
Schreiber, Andreas, Dr Med, MRCP; Vordermark, Dirk, Dr Med, PhD.
Greece (n ⫽ 4): Antonadou, Theodosia, MD; Maroudias, Nikolaos, MD; Psyrri, Amanda, MD; Skarlos, Dimosthenis, MD, PhD.
Hong Kong (n ⫽ 2): Au, Kwok Hung, MBBS; Chan, Yu Wai, Jimmy, MBBS.
Hungary (n ⫽ 3): Csejtei, András, MD; Horvai, Géza, MD; Remenár, Éva, MD.
India (n ⫽ 5): Almel, Sachin, MD; D’Cruz, Anil K., MBBS, MS; Iyer, Subramania, MS, MCh, FRCS; Jain, Minish M, MD; Kumar, R.
Rejnish, MD.
Italy (n ⫽ 5): Bacigalupo, Almalina, MD; Bianco, Roberto, MD; Caponigro, Francesco, MD; Nolè, Franco, MD; Villa, Eugenio, MD.
Philippines (n ⫽ 1): Pontejos, Alfredo Q., Jr, MD.
Russia (n ⫽ 3): Biakhov, Mikhail, MD, DSc; Manikhas, Georgy M., MD, PhD; Romanov, Ilya S., MD, PhD.
Slovakia (n ⫽ 1): Dubinsky, Pavol, MD.
Spain (n ⫽ 11): Ales, Jose E., MD; Ballester Navarro, Inmaculada, MD; Del Campo, Jose Maria, MD; Espinosa Arranz, Enrique, MD;
García Sáenz, Jose Angel, MD; Iglesias Docampo, Lara; Lavernia, Javier, MD; López, Rafael, MD; Martínez Galán, Joaquina, MD; Morales
Murillo, Serafin, MD; Rubio, Jordi, MD.
Thailand (n ⫽ 2): Chitapanarux, Imjai, MD; Eursritanakorn, Sirima.
United Kingdom (n ⫽ 7): Goodchild, Kathleen, BSc (Hons), MBBS, MRCP, FRCR; Guerrero Urbano, Maria Teresa, PhD, FRCR;
Harrington, Kevin J., BSc, MBBS, MRCP (United Kingdom); Junor, Elizabeth, MRCP, MD, FRCR; Kelly, Charles G., MB ChB, MSc,
FRCP; Robinson, Martin H., MD, MRCP; Simcock, Richard, MBBS, MRCP, FRCR.
United States (n ⫽ 2): Cordero, Joehassin, MD; Reimers, Hans J. Joachim, MD, PhD.

Table A1. Derivation of Overall HPV Status Based on Separate HPV/p16 Results

p16
Result HPV ISH Result HPV PCR Result Overall Status for Analysis
Positive Positive Not tested Positive
Positive Negative Positive Positive
Positive Negative Negative Negative
Positive Negative Not tested/unknown Unknown
Positive Unknown Not tested Unknown
Negative Negative Not tested Negative
Negative Positive Not tested Negative
Negative Unknown Not tested Negative
Unknown Any Not tested Unknown

Abbreviations: HPV, human papillomavirus; ISH, in situ hybridization; PCR, polymerase chain reaction.

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 Lapatinib and Chemoradiotherapy in SCCHN

Table A2. Additional Secondary End Points (intent-to-treat population)

Parameter (95% CI)

End Point Placebo Arm (n ⫽ 342) Lapatinib Arm (n ⫽ 346)

Disease-specific survival
Died as a result of head and neck cancer (events)
No. 89 79
% 26 23
Median cumulative incidence estimate of time to death as a result of head and neck cancer,
months NR (NR to NR) NR (NR to NR)
Nonstratified HR 0.89 (0.66 to 1.21)
Patients who died as a result of head and neck cancer at 36 months, % 27.3 (22.3 to 32.6) 24.6 (19.7 to 29.7)
Patients who died as a result of head and neck cancer at 60 months, % 35.0 (28.4 to 41.8) 33.1 (25.2 to 41.1)
Time to locoregional control
Patients with independently assessed locoregional recurrence
No. 49 40
% 14 12
Median cumulative incidence estimate of time to locoregional control, months NR (NR to NR) NR (NR to NR)
Nonstratified HR 0.81 (0.54 to 1.23)
Patients with independently assessed locoregional recurrence at 36 months, % 17.0 (12.9 to 21.7) 13.0 (9.3 to 17.2)
Patients with independently assessed locoregional recurrence at 60 months, % 17.7 (13.4 to 22.5) 17.5 (12.0 to 23.8)
Time to distant relapse
Patients with independently assessed distant recurrence
No. 51 63
% 15 18
Cumulative incidence estimate of time to distant recurrence (months), median (95% CI) NR (NR to NR) NR (NR to NR)
Nonstratified HR 1.23 (0.85 to 1.78)
Patients with independently assessed distant recurrence at 36 months, % 18.0 (13.7, 22.8) 21.5 (16.9 to 26.6)
Patients with independently assessed distant recurrence at 36 months, % 18.9 (14.3 to 23.9) 25.7 (19.3 to 32.4)
Incidence of second primary tumor
Independently assessed second primary malignancy incidence rate
No. 5 9
% 1.5 2.6
95% CI, % 0.5 to 3.4 1.2 to 4.9
Difference in incidence rate 1.1 (⫺1.2 to 3.6)
OR for incidence rate 1.80 (0.53 to 6.91)

Abbreviations: HR, hazard ratio; NR, not reached; OR, odds ratio.

Table A3. Unscheduled Medical Resource Use: Time Points at Which the Highest Proportion of Patients Reported Use, by Item, Through the Maintenance
Period and the Withdrawal From Treatment Visit
Lapatinib (n ⫽ 346) Placebo (n ⫽ 342)

Category and Type of Resource No. (%) Reported at No. (%) Reported at
Medical office visits
Primary care physician visits 22 (6) MW8 22 (6) MW8
Medical specialist visit 38 (11) MW16 39 (11) MW8
Nurse practitioner, physician’s assistant, or nurse visits 3 (1) End of CRT, MW8 4 (1) End of CRT, MW8, MW16
Telephone calls 3 (1) MW8 4 (1) End of CRT, MW8
Laboratory tests/radiology procedures
Nonstudy laboratory visits 11 (3) End of CRT, MW8 13 (4) MW8
Nonstudy radiology visits 10 (3) End of CRT 11 (3) MW16
Other nonstudy visits 6 (2) MW8 11 (3) WD
Home health care: home health care visits 2 (1) MW8 2 (1) WD
Hospital extended care
Days in general ward 19 (5) End of CRT 12 (4) End of CRT
Days in intensive care 2 (1) WD 2 (1) MW16, WD
Days in extended care facility 1 (⬍ 1) MW56, WD 1 (⬍ 1) WD
Urgent care: emergency room visits 5 (1) End of CRT 7 (2) End of CRT, MW8

Abbreviations: CRT, chemoradiotherapy; MW, maintenance week; WD, withdrawal.

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 Harrington et al

Table A4. Summary of Exposure to Chemotherapy (safety population)

Variable Placebo (n ⫽ 336) Lapatinib (n ⫽ 349)

ⴱ
No. of cycles of cisplatin received, No. (%)
0 11 (3) 9 (3)
1 19 (6) 28 (8)
2 92 (27) 106 (30)
3 214 (64) 205 (59)
4 0 0
5 0 1 (⬍ 1)†
Total actual dose of cisplatin, mg/m2
No. of patients 325 340
Mean (SD) 251.46 (60.143) 243.25 (63.324)
Median (range) 280.00 (37.6-300.0) 266.52 (56.7-300.0)
Total actual dose of cisplatin, mg
No. of patients 325 340
Mean (SD) 436.75 (115.786) 420.13 (118.187)
Median (range) 458.00 (50.0-655.8) 437.50 (80.0-692.0)
Total duration of cisplatin, days
No. of patients 325 340
Mean (SD) 36.30 (12.766) 34.84 (13.636)
Median (range) 43.00 (1.0-59.0) 43.00 (1.0-59.0)
Switch from cisplatin to carboplatin, No. (%) 328 344
Cisplatin only 316 (96) 334 (97)
Carboplatin only 3 (⬍ 1) 4 (1)
Switched 10 (3) 6 (2)
No. of chemotherapy cycles received,‡, No. (%)
0 8 (2) 5 (1)
1 11 (3) 25 (7)
2 96 (29) 104 (30)
3 218 (65) 208 (60)
4 1 (⬍ 1) 2 (⬍ 1)
5 1 (⬍ 1) 3 (⬍ 1)
6 0 0
7 1 (⬍ 1) 2 (⬍ 1)

Abbreviation: SD, standard deviation.

ⴱ
Any dose in the electronic case report form was considered a cycle, regardless of regimen (13 patients had ⱕ14 days between doses).
†After the second cisplatin dose of an every-3-week regimen, one patient switched to a weekly regimen and received three additional doses, resulting in a total
of five cisplatin cycles.
‡Includes both cisplatin and carboplatin. Some patients were on a weekly cisplatin/carboplatin regimen.

Table A5. Summary of Exposure to Radiotherapy (safety population)

Radiotherapy Variable Placebo (n ⫽ 336) Lapatinib (n ⫽ 349)
Actual cumulative dose, Gy
No. of patients 328 345
Mean (SD) 64.65 (7.331) 63.47 (11.238)
Median (range) 66.00 (4.0-76.0) 66.00 (8.0-86.0)
Actual cumulative dose, fractions
No. of patients 328 345
Mean (SD) 32.32 (3.666) 31.72 (5.620)
Median (range) 33.00 (2.0-38.0) 33.00 (4.0-43.0)
Duration of treatment phase (days)
No. of patients 328 345
Mean (SD) 47.41 (6.905) 46.43 (9.261)
Median (range) 47.00 (2.0-76.0) 47.00 (4.0-70.0)

Abbreviation: SD, standard deviation.

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 Lapatinib and Chemoradiotherapy in SCCHN

Table A6. Overall Quality-of-Life Responder Status Based on FACT Scores

% Change
Scale and Type
of Change Lapatinib (n ⫽ 307) Placebo (n ⫽ 306) P
FACT H&N subscale .082
Improvement 19 25
Stable 4 5
Worsening 78 70
FACT TOI .098
Improvement 18 22
Stable ⬍1 2
Worsening 82 76
FACT-G .038
Improvement 30 39
Stable 3 4
Worsening 66 57
FACT-H&N total .007
Improvement 24 33
Stable 4 7
Worsening 72 60

NOTE. Overall responder status determined at the first visit that showed a clinically relevant improvement or worsening. Percentages may not add to 100% as a
result of rounding.
Abbreviations: FACT, Functional Assessment of Cancer Therapy; FACT-G, Functional Assessment of Cancer Therapy–General; FACT-H&N, Functional Assessment
of Cancer Therapy–Head and Neck; TOI, Trial Outcome Index.

1.0 HPV−/placebo
HPV−/lapatinib
Disease-Free Survival

HPV+/placebo
0.8 HPV+/lapatinib
(probability)

0.6

0.4
HPV/p16− HPV/p16+
0.2 Placebo arm Lapatinib arm Placebo arm Lapatinib arm
n 284 276 21 23
Events: disease recurrence 93 (33) 102 (37) 3 (14) 5 (22)
or death, n (%)
0 Median DFS (95% CI) NR (54.6 to NR) 51.5 (42.6 to 61.2) NR (NR to NR) NR (NR to NR)
Hazard ratio (95% CI) 1.16 (0.88 to 1.54) 1.32 (0.33 to 5.33)
Two-sided P .29 .70

0 10 20 30 40 50 60 70

Time Since Random Assignment (months)

No. at risk
HPV−/placebo 284 173 142 107 74 36 6
HPV−/lapatinib 276 164 134 102 71 34 10 1
HPV+/placebo 21 15 12 8 6 4 1
HPV+/lapatinib 23 18 18 13 7 2 1

Fig A1. Kaplan-Meier estimates of disease-free survival (DFS; intent-to-treat population) independently assessed by human papillomavirus (HPV) status (HPV and
p16). NR, not reached.

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 Harrington et al

Adjusted Mean Change

From Baseline (95% CI)
4
2
0
−2
−4
−6
−8
−10
−12 Lapatinib
−14 Placebo
−16
8* 16* 24* 32* 40* 48 56*
e

py -

en al
ra mo
lin

tm w
Maintenance Weeks
*

t
ea ra
se

he e
ot ch

tr hd
Ba

di f

it
ra d o

om W
En

fr
Scheduled Assessments

Fig A2. Adjusted mean change from baseline in the Functional Assessment of Cancer Therapy–General score. (*) Denotes a statistically significant (P ⬍ .05)
difference versus placebo. Estimates that fall outside of the shaded region can be interpreted as a clinically meaningful change based on Ringash et al (Qual Life Res
13:725-733, 2004).

0.08
Adjusted Mean Change
From Baseline (95% CI)

−0.08

−0.16

−0.24 Lapatinib
Placebo
−0.32
8 16* 24 32 40 48 56
e

py -

en al
ra mo
lin

tm w
Maintenance Weeks
*

t
ea ra
se

he e
ot ch

tr hd
Ba

di f

it
ra o

om W
d
En

fr

Scheduled Assessments

Fig A3. Adjusted mean change from baseline in the EQ-5D utility index score. (*) Denotes a statistically significant (P ⬍ .05) difference versus placebo. Estimates
that fall outside of the shaded region can be interpreted as a clinically meaningful change based on Pickard et al (Health Qual Life Outcomes 5:70, 2007).

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