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

BJU Int. 2014 Oct;114(Suppl 4):2


Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has clinical activity in mRCC. VEGF TKIs suppress regulatory T cells and myeloid-derived suppressor cells, making the immune environment more conducive for T-cell–mediated antitumor activity. Combining VEGF TKIs with positive immune modulation may result in greater/more durable therapeutic benefit. We report preliminary results of a phase I trial of nivolumab combined with sunitinib or pazopanib in mRCC.

Methods: mRCC patients received IV nivolumab plus sunitinib (50 mg, 4 weeks on/2 weeks off; arm S) or pazopanib (800 mg daily; arm P) until progression/unacceptable toxicity. Starting nivolumab dose was 2 mg/kg every 3 weeks (N2), with planned escalation to 5 mg/kg every 3 weeks (N5). Based on tolerability, arm S + N5 was expanded to treatment-naïve patients. Primary objectives were safety/tolerability and determination of maximum tolerated dose (MTD); secondary objective was antitumor activity.

Results: Seven patients each were treated in arms S + N2 and S + N5. No dose-limiting toxicities (DLTs) were observed and MTD was not reached; S + N5 was thus expanded by 19 patients. Four DLTs (elevated KCA 2014 CA209-016 sut/paz abstract_Final Submitted ALT/AST [n = 3], fatigue [n = 1]) were observed in P + N2 (n = 20 treated patients); this arm was therefore closed. Grade 3/4–related adverse events (AEs) were observed in 27/33 patients (82%) in arm S and 14/20 patients (70%) in arm P. Most common related grade 3/4 AEs were elevated ALT and hypertension (18% each) in arm S; and elevated ALT and AST, and diarrhea (20% each) in arm P. Grade 3 pneumonitis occurred in one patient (S + N5). Grade 3/4-related AEs led to discontinuation in 10/33 patients (30%) in arm S and 4/20 patients (20%) in arm P. Objective response rate (ORR) was 52% (17/33) and 45% (9/20), respectively. At 5% PD-L1 cutoff, ORR was 20% and 58.3% in PD-L1+ and PD-L1– patients, respectively, in arm S; and 50.0% and 46.7% in arm P. Responses occurred by first assessment (6 weeks) in 41% and 56% of patients, respectively. Duration of response range was 18.1–80 + and 12.1–90.1 + weeks, respectively. Progression-free survival rate at 24 weeks was 79% and 55%, respectively.

Conclusions: Nivolumab plus sunitinib showed encouraging antitumor activity and a manageable safety profile in mRCC patients. The pazopanib arm also showed encouraging antitumor activity but was closed due to DLTs. PD-L1 status did not appear to enrich for response.

Copyright © 1999-2015 John Wiley & Sons, Inc.

Comment from Henk van der Poel: Phase I study data: Nivolumab and sunitinib most attractive combination. Nivolumab and pazopanib resulted in dose-limiting toxicity in 20% of patients and seems less attractive.  Both combinations showed interesting response rates.