Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC).

Abstract

5010 Background: Antiangiogenic agents sunitinib (S) and pazopanib (P) are SOC for mRCC, but new therapies are needed as pts advance through therapy with limited survival benefit. We report preliminary results of a phase I trial of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, in combination with S or P in pts with mRCC. Methods: mRCC patients (≥1 prior systemic therapy) received nivolumab in combination with S (50 mg, 4 wks on, 2 wks off; arm S) or P (800 mg daily; arm P), until progression/unacceptable toxicity. Starting dose of nivolumab was 2 mg/kg IV Q3W (N2), with planned escalation to 5mg/kg IV Q3W (N5). Based on tolerability, arm S N5 cohort was expanded to treatment-naïve pts. Primary objectives were safety/tolerability and determination of maximum tolerated dose (MTD) for the combinations; secondary objective was antitumor activity (objective response rate [ORR] and duration of response [DOR]). Results: 7 pts were assigned to each of arms S N2 and N5. No dose-limiting toxicities (DLTs) were observed and MTD was not reached thus N5 was expanded with 19 additional pts (total n=33). Arm P enrolled 20 pts at N2; 4 DLTs (elevated ALT/AST [n=3], fatigue [n=1]) were observed, leading to closure of this arm. Grade 3–4 related AEs were observed in 24/33 pts (73%) in arm S and 12/20 pts (60%) in arm P. Most common related grade 3–4 AEs included elevated ALT (18%), hypertension and hyponatremia (15% each) in arm S and elevated ALT/ AST (20% each) and fatigue (15%) in arm P. Hepatotoxicities were manageable using treatment algorithms. Grade 3 pneumonitis occurred in 1 pt (arm S, N5). Grade 3–4 related AEs led to therapy discontinuation in 8/33 pts (24%; 1 N2, 7 N5) in arm S and 4/20 pts (20%) in arm P. ORR was 52% (17/33) in arm S and 45% (9/20) in arm P. Responses occurred by first assessment (6 wks) in 41% (arm S) and 56% (arm P) of responding pts and were durable (range: arm S: 12.1+ to 54 wks; arm P: 12.1 to 69.1+ wks). Stable disease rate was 33% (n=11) in arm S and 35% (n=7) in arm P. PFS rate at 24 wks was 78% for arm S and 55% for arm P. Conclusions: Nivolumab plus S or P showed encouraging antitumor activity and a manageable safety profile in pts with mRCC. Additional follow up will be presented. Clinical trial information: NCT01472081.