Preliminary results from the phase I, open-label, parallel-cohort, dose-escalation CheckMate 016 study combining nivolumab, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, with the tyrosine kinase inhibitors (TKIs) sunitinib or pazopanib for patients with metastatic renal cell carcinoma (mRCC), have shown encouraging clinical activity, albeit with substantial toxicity (Amin et al. ESMO 2014). Here we present updated safety and efficacy results with extended follow-up.

Patients with mRCC received nivolumab plus sunitinib (50 mg, 4 weeks on/2 weeks off; arm N+S) or pazopanib (800 mg/day; arm N+P) until progression/unacceptable toxicity. The nivolumab starting dose was 2 mg/kg every 3 weeks, with planned escalation to 5 mg/kg every 3 weeks. Arm N+S advanced to expansion; arm N+P was closed due to dose-limiting toxicities. Primary endpoints were safety/tolerability; the secondary endpoint was preliminary antitumor activity.

Arm N+S enrolled 33 patients, 19 of whom were treatment-naïve, and arm N+P enrolled 20 patients, all of whom had ≥1 prior systemic therapy. Median follow-up was 50.0 (arm N+S) and 27.1 (arm N+P) months. Median duration of therapy (N+S) was 45.1 weeks for nivolumab and 28 weeks for sunitinib. Median duration of therapy (N+P) was 15.1 weeks for nivolumab and 13.9 weeks for pazopanib. The most common any-grade drug-related adverse events (AEs) were fatigue, diarrhea, and nausea. Generally, treatment with N+S or N+P resulted in greater frequencies of AEs, serious AEs, AEs leading to discontinuation, and select AEs than previously observed with either agent alone (see Table). Immune-modulating medication was used in 18/33 (55%) patients in arm N+S and 12/20 (60%) of patients in arm N+P. Investigator-assessed objective response rates were 55% (18/33) in arm N+S, with two complete responses (6.1%), and 45% (9/20) in arm N+P, with no complete responses. Median (95% confidence interval [CI]) duration of response was 60.2 (37.1-not reached) weeks in arm N+S and 30.1 (12.1-174.1) weeks in arm N+P. Median (95% CI) progression-free survival was 12.7 (11.0-16.7) months in arm N+S and 7.2 (2.8-11.1) months in arm N+P. Overall survival will be reported.

The addition of sunitinib or pazopanib to nivolumab showed encouraging antitumor activity and progression-free survival in pretreated and frontline patients with mRCC, however, a higher incidence of high-grade toxicities was observed with the combinations compared with nivolumab, sunitinib, or pazopanib monotherapy. Combination strategies of nivolumab with ipilimumab and other TKIs are currently under investigation.