Combination immune checkpoint inhibitor regimens have demonstrated enhanced antitumor activity compared with monotherapy in multiple tumor types. Two combination regimens with low or high doses of nivolumab and ipilimumab (nivolumab 3 mg/kg + ipilimumab 1 mg/kg [N3I1 arm], nivolumab 1 mg/kg + ipilimumab 3 mg/kg [N1I3 arm]) recently demonstrated efficacy and safety in the open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study in patients with metastatic renal cell carcinoma (mRCC) (Hammers et al. JCO 2017). Here we present updated safety and efficacy results in these two arms with extended follow-up.

Patients with mRCC received intravenous N3I1, N1I3, every 3 weeks for four doses, followed by nivolumab monotherapy 3 mg/kg every 2 weeks until progression or toxicity. Updates to key endpoints included safety/tolerability (primary) and preliminary efficacy (secondary/exploratory).

Forty-seven patients were each assigned to the N3I1 and N1I3 arms. Median follow-up was 37.7 (N3I1) and 36.0 (N1I3) months, respectively. Patients in the N3I1 and N1I3 arms received a median of 10.0 and 7.0 doses of nivolumab, respectively. Grade 3-4 treatment-related adverse events (AEs) were reported in 43% (N3I1) and 64% (N1I3) of patients; The most common grade 3-4 treatment-related AEs with possible immune-mediated etiology in the N3I1 and N1I3 arms were gastrointestinal (4% and 23%) and hepatic (6% and 21%). Any-grade treatment-related AEs leading to discontinuation occurred in 11% (N3I1) and 26% (N1I3) of patients. Antitumor efficacy is summarized in the table. The median duration of response (DOR) was 105.0 weeks and 79.4 weeks in the N3I1 and N1I3 arms, respectively. Median overall survival (OS) was not reached in either arm.

This study was the first to investigate the combination of two checkpoint inhibitors for the treatment of mRCC. Long-term follow-up continues to support the safety and promising efficacy of nivolumab plus ipilimumab combination therapy in mRCC. While both the N3I1 and N1I3 arms had high objective response rate (ORR) and durable responses with promising OS, the better safety profile observed with the lower ipilimumab dose regimen support the phase III clinical development of N3I1in CheckMate 214 (NCT02231749).