ER BC Clin Endpoints FULLDECK
ER BC Clin Endpoints FULLDECK
ER BC Clin Endpoints FULLDECK
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
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
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
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
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
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
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
n = 115 n = 113 n = 99
Trastuzumab +
Chemotherapya Chemotherapya
chemotherapya
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
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
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
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
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
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
• Advanced NSCLC
• Bladder cancer
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
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 irRC2
New, measurable Always represent PD Incorporated into tumor burden
lesions (ie, ≥5 × 5 mm)
New, nonmeasurable Always represent PD Do not define progression (but preclude irRC)
lesions (ie, <5 × 5 mm)
Nonindex lesions Changes contribute to defining BOR of CR, PR, Contribute to defining irRC (complete
SD, and PD disappearance required)
CR Disappearance of all lesions in one observation in Disappearance of all lesions in two
randomized studies. Confirmation is needed for consecutive observations not less than four
nonrandomized studies, according to study weeks apart
protocol
PR At least a 30% decrease in the sum of diameters of A ≥50% decrease in tumor burden
target lesions, taking as reference the baseline compared with baseline in
sum diameters, in the absence of new lesions or two observations at least four weeks apart
unequivocal progression of nonindex lesions
SD Neither sufficient shrinkage to qualify for PR nor A 50% decrease in tumor burden
sufficient increase to qualify for PD, taking as compared with baseline cannot be
reference the smallest sum diameters, in absence established nor 25% increase
of new lesions or unequivocal progression of compared with nadir
nonindex lesions
PD At least a 20% increase in the sum of diameters of At least 25% increase in tumor burden compared
target lesions, taking as reference the smallest with nadir (at any single time point) in two
sum on study. The sum must also demonstrate an consecutive observations at least four
absolute increase of at least 5 mm. The weeks apart
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.
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
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.