Expert Review in Breast Cancer

Clinical Trial Endpoints:

An Ongoing Debate
Reference Slides
 Key Principles of Clinical Trial
Endpoints in Drug Development
 Endpoints Need To Match the Stage
of the Clinical Trial

Phase I • Evaluate toxicity

• Determine dose for Phase II
• Study drug disposition (pharmacokinetic, PK)
• Proof of concept that the drug inhibits its target
(pharmacodynamics, PD)
Phase II • Estimate anti-tumor efficacy
• Further define toxicity
• Further PD studies
Phase III • Compare outcomes with usual standard of care
(measure clinical benefit)
Phase IV • Postmarketing safety and efficacy assessment
(after registration) (‘’real world’’ setting)
Endpoints in Phase I and Phase II Trials
• Phase I trials:
– Primary goal: To evaluate toxicity and tolerance (also PK and PD)
– Agents that show no signs of activity rarely succeed in later trials
• Phase II trials:
– Primary goal: To determine anti-tumor activity and if testing in the
expensive phase III studies is warranted
– Appropriate endpoints include:
• Overall response rate (ORR)
– Measured by standardized criteria (eg, RECIST)
• Progression-free survival (PFS)
• Identification of biomarkers is important in early phase trials

RECIST, Response Evaluation Criteria in Solid Tumors

 Endpoints in Phase III Trials
• Goal: To compare outcomes reflecting patient benefit with the usual
standard of care
• The primary endpoints need to show clinically meaningful benefit for
the patient
– The priority for patients is to either live longer or better;
ideally both
• The most relevant endpoints of phase III trials are:
– Overall survival (OS)
– Quality of life (QoL)
• If other endpoints are used, they should be shown to be surrogates
for either OS or QoL
• Appropriate endpoints depend on the disease context; one endpoint
does not fit all indications

Wilson MK, et al. Lancet Oncol. 2015;16(1):e43-e52.

 Overall Survival

• Definition: The time from randomization to death from any cause

• Most straightforward and effective clinical endpoint for assessing
efficacy of a therapy
• Historically, the “gold standard” for demonstration of clinically
meaningful benefit
• But, OS might not be a realistically measurable endpoint

Pazdur R. The Oncologist. 2008;13(suppl 2):19-21. Di Leo A, et al. J Clin Oncol. 2003;21(10):2045-2047.
Wilson MK, et al. Lancet Oncol. 2015;16(1):e43-e52.
 Limitations of OS
As a Clinical Endpoint
• Requires large sample size and long follow-up
– Expensive
– Risk of drug becoming obsolete by the time the trial
is completed

• May be confounded by subsequent therapies

administered after the study drug, including crossover,
and other noncancer causes of mortality
– Increasingly likely if trial in earlier lines of treatment

• Limitations in OS as an endpoint have led to the use of

“surrogate endpoints”

Zhao F. J Clin Oncol. 2016;34(13):1436-1437.

 Only 12% of All MBC Trials Have
Shown an Improvement in OS
Trials, %

MBC, metastatic breast cancer; ND, nondeterminable; NR, not reported; TTP, time to progression
Verma S, et al. Oncologist. 2011;16(1):25-35.
Increasing Use of Time to Event Surrogate
Endpoints for Cancer Drugs Approval
100%

90%
Proportion of Approvals

80%
Time to event
70% Relative risk

60% Symptom

50% Survival

40%

30%

20%

10%

0%
1990-1999 2000-2005 2006-2011

Period

Martell RE, et al. Oncologist. 2013;18(1):104-111.

 Surrogate Endpoints in
Breast Cancer Clinical Trials
• According to regulatory bodies such as the FDA, clinical benefit
can be established through improvements in OS, patient-reported
outcomes, or an established surrogate endpoint that is reasonably
likely to predict clinical benefit
• Examples of surrogate endpoints used in early and metastatic
breast cancer randomized clinical trials:
– Invasive disease-free survival (iDFS)
– Pathological complete response (pCR)
– Progression-free survival
– Time to progression
– Patient reported outcomes (PROs)
– Overall response rate
FDA, United States Food and Drug Administration

Wilson MK, et al. Lancet Oncol. 2015;16(1):e43-e52. Hudis CA, et al. J Clin Oncol. 2007;25(15):2127-2132. Cortazar P,
et al. Ann Surg Oncol.2015; 22(5):1441-1446. Gourgou-Bourgade S, et al. Ann Oncol.2015;26(5):873-879. Di Maio M,
et al. Nat Rev Clin Oncol. 2016;13(5):319-325.
 Benefits of Surrogate Endpoints

• Quicker completion of trials

• Shorter time to drug approval
• Faster receipt of novel agents by patients
• Greater understanding of clinical pharmacology
and mechanisms of action
• Dose selection guidance
• More efficient screening of promising drugs
• Less cost

Shi Q, et al. Int J Clin Oncol. 2009;14(2):102-111.

 The Role of pCR after
Neoadjuvant Therapy as a
Surrogate Endpoint
in Early Breast Cancer
 pCR After Neoadjuvant Therapy: Definition
 No residual invasive cancer in resected breast and negative axillary lymph
nodes (ypT0 ypN0)
 No residual invasive and in situ cancer in resected breast and negative
axillary lymph nodes (ypT0/Tis ypN0)
Х No residual invasive and in situ cancer in resected breast irrespective of
axillary nodal status (ypT0/is)

Event-Free Survival Overall Survival

100 100
Event-Free Survival, %

Overall Survival, %
80 80

60 60

40 40

20 ypT0ypN0 (n = 1554); HR 0.44 (95% CI 0.39-0.51) 20 ypT0ypN0 (n = 1554); HR 0.36 (95% CI 0.30-0.44)
ypT0/isypN0 (n = 2131); HR 0.48 (95% CI 0.43-0.54) ypT0/isypN0 (n = 2131); HR 0.36 (95% CI 0.31-0.42)
ypT0/is (n = 2598); HR 0.60 (95% CI 0.55-0.66) ypT0/is (n = 2598); HR 0.51 (95% CI 0.45-0.58)
0 0
0 5 10 15 20 0 5 10 15 20
Time Since Randomization, Years Time Since Randomization, Years

CI, confidence interval; HR, hazard ratio; pCR, pathological complete response
Cortazar P, et al. Lancet. 2014;384(9938):164-172.
 pCR and Long-Term Clinical Benefit in Breast
Cancer: CTNeoBC Pooled Analysis
HR-Positive, HER2-Negative
100

Event-Free Survival, %
80
• Individual patients 60
with pCR have 40

superior outcomes 20
HR 0.49 (95% CI 0.33-0.71)
• HER2+ and triple negative 0
0 1 2 3 4 5 6 7 8 9

breast cancer (TNBC) 100

HER2-Positive

Event-Free Survival, %
have highest pCR rates 80

• Eradication of invasive 60

40
cancer from breast +
20
nodes predicts 0
HR 0.39 (95% CI 0.31-0.50)

best outcome 0 1 2 3 4 5 6 7 8 9

100 Triple Negative

– Residual DCIS not Event-Free Survival, %
80
prognostically important
60

40

20
HR 0.24 (95% CI 0.18-0.33)
0
0 1 2 3 4 5 6 7 8 9
DCIS, ductal carcinoma in situ, HR, hormone receptor
Time Since Randomization, Years
Cortazar P, et al. Lancet. 2014;384(9938):164-172.
pCR After Neoadjuvant Chemotherapy is a
Meaningful Endpoint in TNBC

1
98% P = .24
Probability of Being Alive

94%
.9
88%
.8
P = .0001

.7
68%
.6
pCR/nonTNBC
pCR/TNBC
.5 RD/nonTNBC
RD/TNBC
.4
1 2 3 4 5 6 7
Time After Surgery, Years

Liedtke C, et al. J Clin Oncol. 2008;26(8):1275-1281.

 pCR As a Surrogate for Outcome:
Biology Matters
A 1.0 B 1.0 C 1.0

Proportion Disease Free

Proportion Disease Free
Proportion Disease Free

0.8 0.8 0.8

0.6 0.6 0.6

0.4 Luminal A 0.4 Luminal B HER2-Neg 0.4 Luminal B HER2-Pos

pCR (n = 105) pCR (n = 40) pCR (n = 126)
0.2 no pCR (n = 1532) 0.2 no pCR (n = 317) 0.2 no pCR (n = 625)
Log-rank Log-rank Log-rank
P = .388 P = .005 P = .445
0 25 50 75 100 123 0 25 50 75 100 123 0 25 50 75 100 123
Disease-Free Survival, Months Disease-Free Survival, Months Disease-Free Survival, Months

D 1.0 E 1.0 F 1.0

Proportion Disease Free

Proportion Disease Free
Proportion Disease Free

0.8 0.8 0.8

0.6 0.6 0.6

Luminal A (n = 105)
0.4
HER2-Pos (non-lum) 0.4
TNBC 0.4 Luminal B HER2 negative (n = 40)
Luminal B HER2 positive (n = 126)
pCR (n = 164) pCR (n = 282) HER2 positive (nonluminal; n = 164)
0.2 no pCR (n = 373) 0.2 no pCR (n = 629) 0.2 Triple negative (n = 282)
Log-rank Log-rank Log-rank
P<.001 P<.001 P<.001

0 25 50 75 100 123 0 25 50 75 100 123 0 25 50 75 100 123

Disease-Free Survival, Months Disease-Free Survival, Months Disease-Free Survival, Months

Neg, negative; Pos, positive

von Minckwitz G, et al. J Clin Oncol. 2012;30(15):1796-1804.
 NOAH Trial: Neoadjuvant Trastuzumab in
HER2-Positive LABC
• Open label, randomized phase III trial
HER2-Positive LABC HER2-Negative LABC
(IHC 3+ or FISH+) (IHC 0/1+)

n = 115 n = 113 n = 99

Trastuzumab +
Chemotherapya Chemotherapya
chemotherapya

Surgery followed by radiotherapyb

Trastuzumab 19 patients crossed

continued to week 52 over to trastuzumab

aChemotherapy: Doxorubicin, paclitaxel x 3 paclitaxel x 4 cyclophosphamide, methotrexate, 5-fluorouracil x 3

bHR-positive patients received adjuvant tamoxifen

FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; LABC, locally advanced breast cancer
Gianni L, et al. Lancet. 2010;375(9712):377-384.
 NOAH Trial: Trastuzumab Improves
pCR Rates in HER2-Positive LABC
50 P = .0007

40 43%
Patients With pCR, %

30 P = .37

20 22%
17%
10

0
With Without HER2-Negative
Trastuzumab Trastuzumab
HER2-Positive
Gianni L, et al. Lancet. 2010;375(9712):377-384.
 NOAH Trial: Improved pCR Rate
Translates Into Improved Outcome

5-Year Event-Free Survival 5-Year Overall Survival

100 HR 0.66 (95% CI 0.43-1.01)

100 Chemotherapy plus trastuzumab
Log-rank P value = .055
Chemotherapy 90
90
Event-Free Survival, %

HR 0.64 (95% CI 0.44-0.93)

Overall Survival, %
80 80
Log-rank P value = .016
70 70

60 60

50 50

40 40

30 30
Chemotherapy Plus Chemotherapy Chemotherapy Plus Chemotherapy
20 Trastuzumab (n = 117) (n = 118) 20 Trastuzumab (n = 117) (n = 118)
Events 49 (42%) 62 (53%) Events 36 (31%) 47 (40%)
10 10
5-year event-free survival (95% CI) 58% (48-66) 43% (34-52) 5-year Overall survival (95% CI) 74% (64-81) 63% (53-71)
0 0
0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84
Number at risk Number at risk
Chemotherapy plus 117 Chemotherapy plus 117 113 107 92 78 70 53 28
110 88 77 66 56 43 24 trastuzumab
trastuzumab
Chemotherapy 118 Chemotherapy 118 112 95 81 69 56 37 21
98 69 55 49 39 28 14

Gianni L, et al. Lancet Oncol. 2014;15(6):640-647.

 NeoSphere: Neoadjuvant Pertuzumab and
Trastuzumab
• Open-label, phase II randomized trial

TD (n = 107) FEC q 3 w x 3
trastuzumab + Trastuzumab q 3 w
Patients with
operable or docetaxel cycles 5-17
locally advanced/
inflammatory
PTD (n = 107) FEC q 3 x 3
HER2-positive pertuzumab + Trastuzumab q 3 w
breast cancer trastuzumab + cycles 5-17
docetaxel
Chemo-naïve Docetaxel q 3 w x
and primary PT (n = 107) 4→FEC q 3 w x 3
tumors >2 cm pertuzumab + Trastuzumab q 3 w
(N = 417) trastuzumab cycles 5-17
PD (n = 96) FEC q 3 w x 3
pertuzumab + Trastuzumab q 3 w
docetaxel cycles 5-21
D, docetaxel; FEC, 5-fluorouracil, epirubicin, and cyclophosphamide; P, pertuzumab; T, trastuzumab; q 3 w, every 3 weeks
Gianni L, et al. Lancet Oncol. 2012;13(1):25-32.
 NeoSphere: pCR Rates
Intent-to-Treat Population
50 TD vs PTD: P = .0141
45 PTD vs PD: P = .003
40 TD vs PT: P = .0198
pCR, % ± 95% CI

35
30
25
20
15
10
5
29.0 45.8 16.8 24.0
0
TH
TD THP
PTD HP
PT TP
PD
Pertuzumab in combination with trastuzumab and chemotherapy was the
first neoadjuvant regimen approved in the US (2013) and EU (2015) based
on improvement of pCR rates in the NeoSphere trial
Gianni L, et al. Lancet Oncol. 2012;13(1):25-32.
 NeoSphere: PFS and DFS at 5 Years
Support the Primary Endpoint of pCR

DFS, disease-free survival; PFS, progression-

free survival
Gianni L, et al. Lancet Oncol. 2016;17(6):791-800.
 TRYPHAENA: pCR Improvement Further
Supports the Results from the NeoSphere Trial

100 ypT0/is ypT0 ypN0

Pathologic Complete Response, %

90
80
70 66.2
61.6
60 57.3
50.7 51.9
50 45.3
40
30
20
10
0
FEC+H+P x3 FEC x3 TCH+P x6
→ T+H+P x3 → T+H+P x3 (n = 77)
Schneeweiss A, et al. Ann Oncol. 2013;24(9):2278-2284. (n = 73) (n = 75)
 Results of the Phase III Adjuvant APHINITY Trial
Awaited to Confirm Neoadjuvant Pertuzumab Results
Completion of a total of 52
Adjuvant chemotherapy
weeks anti-HER2 therapy

Taxane +
AC
Trastuzumab +
± 5-FU 3-4 Trastuzumab + Pertuzumab
Pertuzumab
cycles
3-4 cycles
A
Taxane +
AC
Trastuzumab +
± 5-FU 3-4 Trastuzumab + Placebo
Pertuzumab
cycles
3-4 cycles
N = 4800
Physician’s
choice Docetaxel + Carboplatin +
Trastuzumab + Pertuzumab Trastuzumab + Pertuzumab
6 cycles

B
Docetaxel + Carboplatin +
Trastuzumab + Placebo Trastuzumab + Placebo
6 cycles

Accrual completed
National Institutes of Health. Available at: https://clinicaltrials.gov/ct2/show/NCT01358877. Accessed October 27, 2016.
 WSG-ADAPT HER2+/HR+ Phase II Trial:
Neoadjuvant T-DM1 ± Endocrine Therapy

A B C

pCR rates substantially higher in T-DM1

containing arms (P<.001) A or B vs C

HER2+/HR+; HER2-positive/hormone receptor-positive; T-DM1,

trastuzumab-emtansine
Harbeck N, et al. J Clin Oncol. 2015;33(suppl); Abstract 506.
 Surrogate Endpoints in
Metastatic Breast Cancer
 Time to Event Surrogate Endpoints in
Metastatic Breast Cancer (MBC)
• Progression-free survival (PFS) – The time from
randomization until objective tumor progression
or death
• Time to progression (TTP) – The time from
randomization until objective tumor progression
(does not include deaths)
• PFS and TTP are currently the most frequently used
endpoints for drug approvals in the metastatic setting
– PFS is preferred over TTP

Verma S, et al. Oncologist. 2011;16(1):25-35. Wilson M, et al. Lancet Oncol. 2015;16:e32-e42.

 PFS as a Primary Endpoint:
Advantages and Disadvantages
Advantages
• Available earlier than overall survival (OS)
− Progression events occur earlier than
death events
• Smaller sample size
Disadvantages
• Not statistically validated as a surrogate
for survival in all settings
• Frequent radiological or other
assessment

• Shorter follow-up • Subject to measurement error bias

particularly in open-label trials
• Not influenced by crossover or
subsequent therapies − Uncertainty of time of relapse
or progression
• Generally based on objective and
quantitative assessment • Censoring bias

− Measurement of stable − Imbalanced withdrawal of patients

disease included who are censored prior to progression

• Less influenced by competing causes

of death
• Leads to faster availability of effective
new treatments
• Less expensive

Villaruz LC, et al. Clin Cancer Res. 2013;19(10):2629-2636. Korn RL, et al. Clin Cancer Res. 2013;19(10):2607-2612. Broglio KR,
et al. J Natl Cancer Inst. 2009;101(23):1642-1649. Templeton AJ, et al. Eur J Cancer. 2015;51(6):721-724. Michiels S, et al. Ann
Oncol. 2016;27(6);1029-1034. Fallowfield LJ, et al. Nat Rev Clin Oncol. 2011;9(1):41-47.
 CLEOPATRA Trial: PFS Improvement
Predicted Subsequent Improvement in OS

PFS (Independent Review) Final OS Analysis

PD, progressive disease

Baselga J, et al. N Engl J Med. 2012;366(2):109-119. Swain SM, et al. N Engl J Med. 2015;372(8):724-734.
 E2100 (Paclitaxel + Bevacizumab): PFS
Benefit Did Not Translate Into OS Benefit

Miller K, et al. N Engl J Med. 2007;357(26):2666-2676.

 BOLERO-2 Trial: PFS Benefit Did Not
Translate Into OS Benefit

PFS (local assessment) OS

ORR, overall response rate; PK, pharmacokinetics

Baselga J, et al. N Engl J Med. 2012;366(6):520-529. Piccart M, et al. Ann Oncol. 2014;25(12):2357-2362.
 Is PFS a Meaningful Endpoint?
There should be a substantial incremental
improvement to be clinically meaningful:
• PFS improvement at least 3 to 4 months in first-line
and 2 to 3 months in second- and later lines
• No deterioration in quality of life
• New therapy does not add substantial toxicity

The ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS)

ESMO-MCBS, European Society for Medical Oncology Magnitude of Clinical Benefit Scale; HR, hazard ratio; QoL, quality of life
Cherny NI, et al. Ann Oncol. 2015;26(8):1547-1573.
 Objective Response Rate as a
Surrogate Endpoint in MBC
• Objective Response Rate (ORR): Proportion of patients with tumor size
reduction of a predefined amount (partial [PR] and complete response
[CR]) and for a minimum time period
– Evaluation of tumor response is defined by “Response Evaluation Criteria
in Solid Tumors’’ (RECIST); is a subject to measurement error
• ORR can be assessed in single-arm studies; assessed earlier and in
smaller studies than OS
• Effect attributable to drug, not natural history of disease
• Not a direct measure of clinical benefit; only a subset of patients benefit
• Not a comprehensive measure of drug activity
• Duration of response: Time from initial response until documented
progression. Might be more clinically relevant endpoint, particularly in
the era of targeted therapy
• Stable disease (SD) is not generally used as a criterion of response but
is a guide for treatment continuation
Wilson M, et al. Lancet Oncol. 2015;16:e32-e42.
 Patient Reported Outcomes (PRO):
Definition and Relevance
• Measurement of the patient’s condition reported directly by
the patient, without interpretation by a clinician or anyone else
• Uses tools such as:
– QoL instruments
– Symptom scales
– Patient reported outcomes version of the Common Terminology
Criteria for Adverse Events (CTCAE)
• Regulatory authorities have provided guidance for the use
of PRO in trials, emphasizing the importance of the
patient’s perspective
• These assessments are increasingly important in the era of
oral chemotherapy or targeted therapy, where patient compliance
is important

Di Maio M, et al. Nat Rev Clin Oncol. 2016;13(5):319-325. Wilson M, et al. Lancet Oncol 2015;16:e32-e42.
 Underreporting of Treatment-Related
Toxicities By Physicians, Relative to Patients

Di Maio M, et al. J Clin Oncol. 2015;33(8):910-915.

 Quality of Life Outcomes Are Not Frequently
Assessed in Phase III Breast Cancer Trials
122 phase III MBC clinical trials
• Progression-based endpoints and OS were included as endpoints
in 98.4 and 95.9% of studies
• Quality of life was assessed only in 46 (37.7%) studies
− As a primary endpoint in three studies and as a secondary endpoint
in 43 trials
• About half of these trials showed no statistically significant
differences in the QoL endpoint

Most Commonly Used Instruments to Evaluate QoL

Frequency Instrument Brief Description
16 (34.8%) EORTC QLQ-C30 • 5 functional scales (physical, role, cognitive, emotional,
(European Organization for Research and social)
Treatment of Cancer Quality of Life • 3 symptom scales (fatigue, pain, nausea & vomiting)
Questionnaire – Core) • Global health status
13 (28.3%) FACT-B (Functional Assessment of Cancer • 4 dimensions (physical, social/family, emotional, functional)
Therapy – Breast Cancer) • 9 questions specific to breast cancer patients

6 (13.0%) EORTC QLQ-BR23 (EORTC Quality of Life • EORTC QLQ-C30

Questionnaire – Breast Cancer) • 23 questions specific to breast cancer patients
4 (8.7%) RSCL (Rotterdam Symptom Checklist) • Questions related to physical and psychological symptoms

Tatla R, et al. J Clin Oncol. 2012;30(suppl 27): Abstract 129.

Clinical Endpoints for Breast
Cancer Immunotherapy Trials
 Immunotherapy Is Taking the Center Stage in
the Management of Several Solid Tumors

• Immunotherapy can target several steps in the immune cycle

Immunotherapy is the new standard

of care in the management of:
• Melanoma (adjuvant and advanced)

• Advanced NSCLC

• Renal cell carcinoma

• Bladder cancer

• Head and neck cancer

NSCLC, non-small cell lung cancer

Chen DS, et al. Immunity. 2013;39(1):1-10.
 Is Breast Cancer Immunogenic?
TNBC is particularly attractive for cancer immunotherapy:

• No current targeted therapy options–high unmet medical need

• Higher density of TILs than tumors with lower proliferative rate
• Relatively high mutational burden that can produce neoantigens
leading to an immune response
• Higher rates of PD-L1 expression, which can inhibit T-cell
anti-tumor responses

PD-L1, programmed death-ligand 1; TIL, tumor-infiltrating lymphocytes; TNBC, triple negative breast cancer

Loi S, et al. Ann Onc. 2014;25(8):1544-1550. Mittendorf EA, et al. Cancer Immunol Res. 2014;2(4):361-370.
Lehman BD, et al. J Clin Invest. 2011;121(7):2750–2767. Cimino-Mathews A, et al. Hum Pathol. 2016;47(1):52-63.
 PD-1/PD-L1 Checkpoint Inhibitors May
Restore Tumor-Specific T-Cell Immunity

Tumor cell

PD-1, programmed cell death protein 1

Schmid P. Presented at: European Society for Medical Oncology 2016 Congress; October 7-11, 2016: Copenhagen, Denmark.
 Early Trials With PD-1 and PD-L1
Inhibition in TNBC Are Encouraging

Pembrolizumab Atezolizumab Avelumab

(n=32) (n=21) (n=58/9)
Target PD-1 PD-L1 PD-L1
Tumor PD-L1 ≥1% (58%+) ≥5% All / ≥1%
ORR 18.5% 19%* 8.6% / 44.4%
SD 25.9% 27% (≥24 weeks) 22.4%
*3 patients that were recorded as progression of disease had pseudo-progression

• Studies investigating checkpoint inhibitors in combinations are ongoing

ORR, overall response rate; SD, stable disease

Nanda R, et al. Cancer Res. 2014;74(24 Suppl): Abstract S1-09. Emens LA, et al. Presented at: AACR Annual Meeting 2015;
April 18-22; Philadelphia, PA. Dirix L, et al. Cancer Res. 2015;75(9 Suppl): Abstract S1-S9. Schmid P. Presented at: European
Society for Medical Oncology 2016 Congress; October 7-11, 2016: Copenhagen, Denmark.
 Challenges and Recommendations for
Assessment of Cancer Immunotherapy

Hoos A, et al. J Natl Cancer Inst. 2010;102(18):1388-1397.

 Immunotherapy: Atypical
Patterns of Response
Four patterns of tumor response
to immunotherapy have
Initial response Stable disease
been described:
• Regression of the initial lesions
without appearance of new lesions
• Unchanged tumor burden, but
followed by a slow, continuous
regression of the overall tumor Initial of T volume then response New lesions then response
burden in some patients
• Regression of initial lesions
associated with the appearance
of new lesions
• Regression of lesions after an initial
increase of the overall tumor
burden (flare)

Wolchok JD, et al. Clin Cancer Res. 2009;15(23):7412-7420.

 Pseudo-Progression

on atezolizumab in TNBC

West HJ. JAMA Oncol. 2015;1(1):115. Emens LA, et al. Presented at: AACR Annual Meeting 2015; April 18-22;
Philadelphia, Pennsylvania.
Evaluation of Response to Immunotherapy: Immune
Related Response Criteria Differ from RECIST
RECIST1
New, measurable Always represent PD
lesions (ie, ≥5 × 5 mm)
New, nonmeasurable Always represent PD
lesions (ie, <5 × 5 mm)
Nonindex lesions Changes contribute to defining BOR of CR, PR,
SD, and PD
CR Disappearance of all lesions in one observation in
randomized studies. Confirmation is needed for
nonrandomized studies, according to study
protocol
PR At least a 30% decrease in the sum of diameters of
target lesions, taking as reference the baseline
sum diameters, in the absence of new lesions or
unequivocal progression of nonindex lesions
SD Neither sufficient shrinkage to qualify for PR nor
sufficient increase to qualify for PD, taking as
reference the smallest sum diameters, in absence
of new lesions or unequivocal progression of
nonindex lesions
PD At least a 20% increase in the sum of diameters of
target lesions, taking as reference the smallest
sum on study. The sum must also demonstrate an
absolute increase of at least 5 mm. The
appearance of one or more new lesions is also
considered progression
BOR, best overall response; CR, complete response; PD, progressive disease; PR, partial response; RECIST, Response Evaluation In Criteria
in Solid Tumors
1. Eisenhauer EA, et al. Eur J Cancer. 2009;45(2):228-247. 2. Wolchok JD, et al. Clin Cancer Res. 2009;15(23):7412-7420.
irRC2
Incorporated into tumor burden
Do not define progression (but preclude irRC)
Contribute to defining irRC (complete
disappearance required)
Disappearance of all lesions in two
consecutive observations not less than four
weeks apart
A ≥50% decrease in tumor burden
compared with baseline in
two observations at least four weeks apart
A 50% decrease in tumor burden
compared with baseline cannot be
established nor 25% increase
compared with nadir
At least 25% increase in tumor burden compared
with nadir (at any single time point) in two
consecutive observations at least four
weeks apart
 Lessons Learned From Immunotherapy Trials
in Melanoma and Lung Cancer
Immunotherapy induces highly durable tumor response,
resulting in a plateau in the tail of survival curve

• The benefit of the immunotherapy drug

in comparison with the standard is
detected later in the study
• Medians do not capture the effect of the
drug (x), while the landmark analysis
may be the best tool to magnify the (y)
– In immunotherapy trials the effect
shown with a landmark analysis is
replicated at months 18 and 24 in
both lung and melanoma
• HR may be used, although the
reduction in the risk of the event
in the first part of the curve is
not proportional

Pilotto S, et al. Transl Lung Cancer Res 2015;4(6):704-712.

 Perspectives for Trial Design With Immune
Checkpoint Inhibitors: Emerging Issues
and Proposed Solutions

Efforts to develop appropriate endpoints for immunotherapy

in breast cancer are ongoing!

OS, overall survival; PFS, progression-free survival; irPFS, immune-related progression-free survival
Pilotto S, et al. Transl Lung Cancer Res 2015;4(6):704-712.