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

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.