Standard-dose pembrolizumab plus alternate-dose ipilimumab in advanced melanoma: KEYNOTE-029 cohort 1C, a phase 2 randomized study of two dosing schedules

Purpose: Standard-dose pembrolizumab plus alternative-dose ipilimumab (1 mg/kg Q3W for 4 doses) were tolerable and had robust antitumor activity in advanced melanoma in cohort B of the phase 1 KEYNOTE-029 study. Cohort C evaluated standard-dose pembrolizumab with two other alternative ipilimumab regimens. Patients and Methods: Patients with treatment-naive unresectable stage III/IV melanoma were randomly assigned 1:1 to pembrolizumab 200 mg Q3W for ≤24 months plus ipilimumab 50 mg Q6W for 4 doses (PEM200þIPI50), or the same pembrolizumab regimen plus ipilimumab 100 mg Q12W for 4 doses (PEM200þIPI100). Primary end points were incidence of grade 3–5 treatment-related adverse events (TRAE) and objective response rate (ORR) per RECIST v1.1 by independent central review. Per protocol-defined thresholds, grade 3–5 TRAE incidence ≤26% indicated meaningful toxicity reduction and ORR ≥48% indicated no decrease in efficacy versus data reported for other PD-1 inhibitor/ipilimumab combinations. Results: Median follow-up on February 18, 2019, was 16.3 months in PEM200þIPI50 (N ¼ 51) and 16.4 months in PEM200þIPI100 (N ¼ 51). Grade 3–5 TRAEs occurred in 12 (24%) patients in PEM200þIPI50 and 20 (39%) in PEM200þIPI100. One patient in PEM200þIPI50 died from treatment-related autoimmune myocarditis. Immune-mediated AEs or infusion reactions occurred in 21 (42%) patients in PEM200þIPI50 and 28 (55%) in PEM200þIPI100. ORR was 55% in PEM200þIPI50; 61% in PEM200þIPI100. Conclusions: Pembrolizumab 200 mg Q3W plus ipilimumab 50 mg Q6W or 100 mg Q12W demonstrated antitumor activity above the predefined threshold; pembrolizumab plus ipilimumab 50 mg Q6W had lower incidence of grade 3–5 TRAEs than the predefined threshold, suggesting a reduction in toxicity.