Final overall survival for KEYNOTE-002: pembrolizumab (pembro) versus investigator-choice chemotherapy (chemo) for ipilimumab (ipi)-refractory melanoma

Background

In KEYNOTE-002 (NCT01704287), pembro provided superior PFS over investigator-choice chemo in patients (pts) with advanced melanoma and confirmed progression after ≥2 ipi doses (HR 0.57, P 

Methods

540 pts were randomized to pembro 2 mg/kg Q3W (n = 180) or 10 mg/kg Q3W (n = 181) or to 1 of 5 chemo regimens (n = 179). Pembro was given until disease progression or intolerable toxicity. Chemo was given per standard practice. Pts in the chemo arm who progressed could crossover to pembro. Response (RECIST v1.1, central review) was assessed at wk 12, every 6 wk until wk 48, then every 12 wk. Primary end points were OS and PFS. Final analysis was to be done at 370 deaths. OS differences were assessed in the ITT population using the stratified log-rank test with the Hochberg procedure; OS was positive if P was 

Results

As of Nov 16, 2015, median follow-up was 13.5 mo and 368 deaths had occurred. Median OS was 13.4 mo for 2 mg/kg, 14.7 mo for 10 mg/kg, and 11.0 mo for chemo. 18-mo OS rates were 40%, 44%, and 36%; 24-mo rates were 36%, 38%, and 30%. HR (95% CI) for OS was 0.86 (95% CI 0.67-1.10) for 2 mg/kg (P = .1173 ) and 0.74 (0.57-0.96) for 10 mg/kg (P = .0106), with no difference between doses (0.87 [95% CI 0.67-1.12]). When the 98 (55%) pts in the chemo arm who crossed over were censored at crossover, HR (95% CI) was 0.79 (0.58-1.08) for 2 mg/kg (P = .0683) and 0.67 (0.49-0.92) for 10 mg/kg (P = .0068), again with no difference between doses (0.87 [95% CI 0.67-1.12]). 24-mo PFS rates were 16% for 2 mg/kg, 22% for 10 mg/kg, and

Conclusions

Pembro prolonged OS over chemo for ipi-refractory melanoma; with a 55% crossover rate, the difference did not reach statistical significance for either pembro dose. Coupled with the significant PFS benefit, durable responses, and lower rate of high-grade drug-related AEs, these data support pembro as a standard of care for this population.

Clinical trial identification

NCT01704287, originally posted October 8, 2012

Legal entity responsible for the study

Merck & Co., Inc., Kenilworth, NJ, USA

Funding

Merck & Co., Inc., Kenilworth, NJ, USA

Disclosure

O. Hamid: Has served as an advisory board member of Amgen, Novartis, Roche, Bristol-Myers Squibb, and Merck and has been on Speakers' bureau for Bristol-Myers Squibb, Genentech, and Novartis. I. Puzanov: Has received travel expenses, including accommodations, from Merck. R. Dummer: Has received research funding from Novartis, Merck Sharp & Dohme (MSD), Bristol Myers Squibb, Roche, and GlaxoSmithKline. Also, has been a consultant or advisory board member for Novartis, MSD, Bristol Myers Squibb, Roche, GlaxoSmithKline, and Amgen. J. Schachter: Served as advisory board member for MSD and Novartis. Served in Speakers' bureau for Bristol Myers Squibb (BMS), MSD, and Novartis. Received travel expenses from BMS and Roche. A. Daud: Has stock ownership in OncoSec. Has served as advisory board member for Merck and OncoSec. Has received research funding from Merck, OncoSec, Bristol-Myers Squibb, and GlaxoSmithKline. D. Schadendorf: Has served as advisory board member for Amgen, BMS, Roche, Novartis, and Merck. Has received research funding from BMS and Merck. Has received travel expenses, including accommodations, from Amgen, BMS, Roche, Novartis, and Merck. C. Blank: has stock ownership of Verastem and has served as advisory board member of MSD, BMS, Novartis, Roche, Pfizer, and GSK. Has received research funding from Novartis. Received travel expenses from Roche and MSD. Also, provided BMS with expert testimony. C. Robert: Has served as advisory board member of BMS, MSD, Roche, Novartis, Amgen, and Biothera. A.C. Pavlick: Has served as advisory board member of Merck, Bristol Myers Squibb (BMS), and Novartis. Has received research funding from Merck, BMS, and Novartis. F.S. Hodi: Has served as advisory board member for Merck. A. Salama: Has served as advisory board member of Bristol Myers Squibb (BMS). Also, has received research funding for Bristol Myers Squibb, Reata Pharmaceuticals, Genentech, Celldex, and Immunocore. K.A. Margolin: Has served as advisory board member of ImaginAb, BMS, and Genentech. Has received research funding from BMS and Altor. Has received travel expenses, including accommodations, from BMS. Z. Wei, N. Ibrahim: Is a current employee of Merck & Co., Inc. and owns stocks/stock options. S.W. Ebbinghaus: Is a current employee of Merck & Co., Inc. and owns stocks/stock options. Also, has a patent with Merck & Co., Inc. A. Ribas: Has stock ownership of Kite Pharma. Also served as advisory board member for Pfizer, Merck, Amgen, and Roche. All other authors have declared no conflicts of interest.