Randomized comparison of two doses of the anti-programmed death-1 monoclonal antibody MK-3475 for ipilimumab (IPI)-refractory and IPI-naive melanoma

R. Kefford, O. Hamid, C. Robert, A. Ribas, J. D. Wolchock, F. S. Hodi, A. M. Joshua, W. J. Hwu, T. C. Gangadhar, A. Patnaik, P. Hersey, J. Weber, R. Joseph, K. Gergich, X. Li, P. Chun, S. Ebbinghaus, S. P. Kang, A. Daud

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MK-3475 has shown durable antitumor activity in melanoma across multiple doses and schedules. We compared the efficacy and safety of two MK-3475 doses in patients with melanoma (study sponsored by Merck Sharp & Dohme Corp.). In sepa- rate cohorts, ipilimumab-naive (IPI-N) and ipilimumab-refrac- tory (IPI-R) patients were randomized 1: 1 to MK-3475 2 or 10 mg kg¯¹ every 3 weeks (2 Q3W or 10 Q3W). IPI-N patients received ≤ 2 prior systemic therapies. IPI-R patients had any number of prior therapies and unequivocal or con- firmed progressive disease per immune-related response crite- ria (irRC) after ≥ 2 IPI doses; all BRAF-mutant patients were previously treated with BRAF inhibitors. The primary endpoint was overall response rate (ORR) assessed by RECIST 1.1 every 12 weeks by independent central review. Investigator-assessed response by irRC was also obtained. A total of 103 IPI-N (2 Q3W, n = 51; 10 Q3W, n = 52) and 173 IPI-R (2 Q3W, n = 89; 10 Q3W, n = 84) patients were randomized. In both cohorts, treatment arms were well balanced for known prog- nostic factors. As of the 18 October 2013 cut-off, all IPI-N and 47% of IPI-R patients had ≥ 9 months of follow-up. Among evaluable IPI-N patients, no significant between-dose differences were observed for ORR by RECIST (33% with 2 Q3W vs. 40% with 10 Q3W; P = 0.4835) or irRC (39% vs. 40%; P = 0.9040). There were also no between-dose differ- ences in IPI-R patients (RECIST 26% vs. 26%; P = 0.9558; irRC 27% vs. 32%; P = 0.4568). Response duration ranged from 6+ to 39+ weeks by RECIST (4+ to 42+ weeks by irRC) in both cohorts (median not reached), with ~90% of responses ongoing. Median progression-free survival (PFS) was similar between doses in IPI-N (27 vs. 23 weeks by RE- CIST; 36 vs. 26 weeks by irRC) and IPI-R (22 vs. 14 weeks by RECIST; 31 vs. 25 weeks by irRC) patients. In IPI-N patients, 24-week PFS rates were 51% vs. 48% by RECIST and 60% vs. 50% by irRC. In IPI-R patients, 24-week PFS rates were 45% vs. 37% by RECIST and 57% vs. 57% by irRC. The safety profile was generally similar between patients treated with 2 Q3W and 10 Q3W. There were no drug-related deaths. In summary, MK-3475 2 mg kg¯¹ Q3W and 10 mg kg¯¹ Q3W provided similar efficacy and safety in both IPI-N and IPI-R patients. Treatment was well tolerated with an acceptable toxicity profile. The high ORR provided by MK-3475 comes with long durability in both IPI-N and IPI-R melanoma.
Original languageEnglish
Article number097
Pages (from-to)e56
Number of pages1
JournalBritish Journal of Dermatology
Issue number3
Publication statusPublished - 19 Sept 2014
Externally publishedYes
Event15th World Congress on Cancers of the Skin - Edinburgh, United Kingdom
Duration: 3 Sept 20146 Sept 2014


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