Treatment with checkpoint inhibitors can result in durable responses and deepening of responses over time with conversion of SD to PR or CR, and PR to CR. In the randomized KEYNOTE-002 study (NCT01704287), pembro 2 mg/kg or 10 mg/kg improved PFS (HR 0.57 and 0.50; P
Pts were treated until disease progression (PD), unacceptable toxicity or investigator/pt decision. Response (RECIST v1.1; investigator review) was assessed at wk 12, every 6 wk until wk 48, then every 12 wk, and confirmed by subsequent scan. Survival was assessed every 12 wk during follow-up. Pembro arms were combined given no difference in efficacy of doses.
As of 3 Feb 2017, median follow-up duration was 42.7 mo. In pembro-treated pts, median PFS was 4.2 mo (95% CI 3.3-5.6), and 36-mo PFS rate was 16%. Median OS was 14.0 mo (11.8-16.2), and 36-mo OS rate was 30%. 99 of 361 pts had CR (n = 29) or PR (n = 70) for ORR of 27.4% (95% CI 22.9-32.3); 88 pts had SD. Median time to response was 2.9 mo. Of 29 pts with CR, 5 converted from SD, 21 from PR. Of 70 pts with PR, 28 converted from SD. Median time from SD to PR was 2.7 mo (range 0.9-25.2), from SD to CR was 6.9 mo (3.9-21.9), and from PR to CR was 8.0 mo (1.4-25.2). Median DOR was not reached in pts with CR or PR (Table). Median duration of SD was 6.9 mo (range 0.8+ to 38.8+). 9 (31%) pts with CR, 28 (40%) with PR and 63 (72%) with SD had subsequent PD; in these pts, median duration of CR was 17.1 mo (5.5-36.1), PR 7.7 mo (2.0-31.8), and SD 5.8 mo (2.7-25.3). Median PFS and OS were longer in pts with CR or PR (Table).
Responses to pembro are durable and associated with prolonged OS in ipi-refractory melanoma. Even in these heavily pretreated pts best response can evolve over time, with late conversions from SD to PR/CR and PR to CR observed.Table:
|Outcomes||CR (n = 29)||PR (n = 70)||SD (n = 88)||All-treated (N = 361)|
|Median time to response*, mo (range)||2.9 (2.4-24.9)||2.9 (1.9-27.9)||−||2.9 (1.9-27.9)|
|Median DOR, mo (range)||NR (5.5-41.6+)||NR (1.9+ to 43.5+)||6.9 (0.8+ to 38.8+)†||NR (1.9+ to 43.5+)|
|Median PFS, mo (95% CI)||41.0 (38.9-NR)||35.8 (27.9-NR)||7.0 (5.8-9.7)||4.2 (3.3-5.6)|
|12/24/36-mo PFS rate‡||97%/75%/72%||76%/66%/49%||24%/6%/1%||29%/21%/16%|
|Median OS, mo (95% CI)||NR (NR-NR)||NR (NR-NR)||16.5 (13.8-20.5)||14.0 (11.8-16.2)|
|12/24/36-mo OS rate‡||100%/93%/89%||96%/86%/71%||71%/31%/24%||55%/37%/30%|
Best overall response with confirmation;†
Duration of SD;‡
Kaplan-Meier method for censored data; CI, confidence interval; NR, not reached
Clinical trial identification
mk-3475-002 ClinicalTrials.gov NCT01704287 First received: October 8, 2012 Last updated: March 28, 2017 Last verified: March 2017
Legal entity responsible for the study
Merck & Co., Inc.
Merck & Co., Inc.
A. Daud: Received research funding from and is an advisory board member of Merck & Co., Inc. R. Dummer: Received honoraria from MSD, Merck & Co., Inc.\'s international counterpart. D. Schadendorf: Received research, honoraria and travel funding from Merck & Co., Inc. Serves as an advisory board member and on speaker\'s bureau for Merck & Co., Inc. O. Hamid: Serves on an advisory board for and has received research funding from Merck & Co., Inc. C. Robert: Received honoraria from Merck & Co., Inc. F.S. Hodi: Advisory board member for Merck & Co., Inc. J. Schachter: Received honoraria from MSD, an international division of Merck & Co., Inc. A.C. Pavlick: Been a consultant for Merck & Co., Inc. R. Gonzalez: Received travel funding, research grants and honoraria from Merck & Co., Inc. Served as an advisory board member for Merck & Co., Inc. C.U. Blank: Served on advisory board and on speaker\'s bureau for Merck & Co., Inc. Received honoraria from Merck & Co., Inc. S.J. O’day: Received research funding for and served as an advisory board member of Merck & Co., Inc. A.K. Salama: Received research funding for and has been an advisory board member of Merck & Co., Inc. K. Margolin: Received researched funding from Merck & Co., Inc. J. Yang: Employee of Merck & Co., Inc. and may own stock options in the company. B. Homet Moreno: Employee of Merck & Co., Inc. and may own stock options in the company. N. Ibrahim: Employee of Merck & Co., Inc. and may own stock options in the company. A. Ribas: Received honoraria from Merck & Co., Inc. All other authors have declared no conflicts of interest.