Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study

Abstract

Background: Combination treatment with immune checkpoint inhibitors and antiangiogenic drugs has shown encouraging preliminary antitumor activity across various tumor types including advanced or metastatic renal cell carcinoma (aRCC). The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of nivolumab in combination with antiangiogenic tyrosine kinase inhibitors or ipilimumab. Long-term outcomes from this study for the combination of nivolumab plus sunitinib or pazopanib in aRCC are presented.

Methods: Patients with aRCC received nivolumab plus either sunitinib (50 mg/day, 4 weeks on/2 weeks off; N + S) or pazopanib (800 mg/day; 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. Primary endpoints were safety and tolerability; antitumor activity was a secondary endpoint.

Results: Arm N + S enrolled 33 patients, 19 of whom were treatment-naïve; this arm advanced to the expansion phase. Median follow-up was 50.0 months. Patients experienced high frequencies of adverse events (AEs) including treatment-related AEs (100%), grade 3/4 treatment-related AEs (82%), and treatment-related AEs leading to discontinuation (39%). Investigator-assessed objective response rate (ORR) was 55% (18/33) and median progression-free survival (PFS) was 12.7 months. Median overall survival (OS) was not reached. Arm N + P enrolled 20 patients, all had ≥1 prior systemic therapy; this arm was closed due to dose-limiting toxicities and did not proceed to expansion. Median follow-up was 27.1 months. Patients treated with N + P experienced high frequencies of AEs including treatment-related AEs (100%), grade 3/4 treatment-related AEs (70%), and treatment-related AEs leading to discontinuation (25%). Investigator-assessed ORR was 45% (9/20) and median PFS was 7.2 months. Median OS was 27.9 months.

Conclusions: The addition of standard doses of sunitinib or pazopanib to nivolumab resulted in a high incidence of high-grade toxicities limiting future development of either combination regimen. While there was no adverse impact on response and the OS outcome was notable, the findings suggest that the success of combination regimens based on immune checkpoint inhibitors and antiangiogenic drugs may be dependent on careful selection of the antiangiogenic component and dose.

Trial registration: Clinicaltrials.gov identifier: NCT01472081 . Registered 16 November 2011.

Keywords: Antiangiogenic; Immune checkpoint inhibitor; Metastatic renal cell carcinoma; Nivolumab; Pazopanib; Sunitinib; Tyrosine kinase inhibitor.

Conflict of interest statement

Ethics approval and consent to participate

The CheckMate 016 study was approved by the local site-specific institutional review boards or an independent ethics committee and conducted in accordance with International Conference on Harmonisation Good Clinical Practice guidelines. Written informed consent was obtained from all patients based on Declaration of Helsinki principles before initiation of any study procedures. The trail was registered on Consent for publication

Not applicable.

Competing interests

The following represents disclosure information provided by authors of this manuscript.

AA. Honoraria: Bristol-Myers Squibb, Pfizer, Merck, Exelixis. Consulting or Advisory Role: Bristol-Myers Squibb, Merck. Research Funding: Bristol-Myers Squibb, Merck, Dynavax. Travel, Accommodations, Expenses: Bristol-Myers Squibb, Pfizer, Merck, Exelixis. ERP. Consulting or Advisory Role: Bristol-Myers Squibb, Acceleron, Astellas, AstraZeneca, Dendreon, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Pfizer, Eli Lilly Inc., SynerGene Therapeutics, Inovio, Clovis, Horizon Pharma, Exelixis, Aveo Pharmaceuticals (Inst), Bristol-Myers Squibb (Inst), Dendreon (Inst), GlaxoSmithKline (Inst), Eli Lilly Inc. (Inst), Merck (Inst), Peloton (Inst), Pfizer (Inst). Research Funding: Bristol-Myers Squibb, Acceleron (Inst), AstraZeneca (Inst). Patents, Royalties, Other Intellectual Property: U.S. Patent Application No. 14/588,503, pending, filed 1/2/2015; US Patent Application No. 15/226,474, pending, filed 7/1/2015. Travel, Accommodations, Expenses: Bristol-Myers Squibb. Other Relationship: Bristol-Myers Squibb (fees for participating in review activities; for writing or reviewing the manuscript; for providing writing assistance, medicines, equipment, or admin support; development of educational presentations); Merck (fees for development of educational presentations); Roche (fees for development of educational presentations); Novartis (fees for development of educational presentations). MSE. Stock ownership (managed account): Bristol-Myers Squibb. LDL. No relationship to disclose. TMB. Employment: Tennessee Oncology, Sarah Cannon Research Institute. Consulting or Advisory Role: Ignyta (Inst), Guardant Health, Loxo, Pfizer, Moderna Therapeutics (Inst). Research Funding: (Inst) Daiichi Sankyo, Medpacto, Inc., Incyte, Mirati Therapeutics, MedImmune, AbbVie, AstraZeneca, Leap Therapeutics, MabVax, Stemline Therapeutics, Merck, Lilly, GlaxoSmithKline, Novartis, Pfizer, Principa Biopharma, Genentech/Roche, Deciphera, Merrimack, Immunogen, Millennium, Ignyta, Calithera Biosciences, Kolltan Pharmaceuticals, Peleton, Immunocore, Roche, Aileron Therapeutics, Bristol-Myers Squibb, Amgen, Moderna Therapeutics, Sanofi, Boehringer Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio. DFM. Consulting or Advisory Role: Array BioPharma, Bristol-Myers Squibb, Eisai, Exelixis, Genentech, Merck, Novartis, Pfizer. Research Funding: Prometheus (Inst). MC. Consulting or Advisory Role: AstraZeneca, Merck, Astellas, Medivation. CK. Honoraria: Bristol-Myers Squibb, Pfizer. Consulting or Advisory Role: Bristol-Myers Squibb, Pfizer. BIR. Consulting or Advisory Role: Bristol-Myers Squibb. DYCH. Consulting or Advisory Role: Bristol-Myers Squibb, Pfizer, Novartis. JK. No relationship to disclose. MHV. Honoraria: Novartis. Consulting or Advisory Role: GlaxoSmithKline, Exelixis, Natera, Calithera, Pfizer. Research Funding: Bristol-Myers Squibb, Roche/Genentech. Travel, Accommodations, Expenses: Takeda, Novartis. JS. Honoraria: Celgene, Lilly. Consulting or Advisory Role: Celgene, Lilly. Research Funding: Celgene, Sanofi, Roche. EB. Employment: Bristol-Myers Squibb. Stock or Other Ownership: Bristol-Myers Squibb. LY. Employment: Bristol-Myers Squibb, at the time the study was performed. Stock or Other Ownership: Bristol-Myers Squibb, at the time the study was performed. HJH. Consulting or Advisory Role: Bristol-Myers Squibb, Pfizer, Exelixis. Research Funding: Bristol-Myers Squibb. Travel, Accommodations, Expenses: Bristol-Myers Squibb, Pfizer, Exelixis.

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Figures

Fig. 1

Time to response, duration of response, and time on therapy (weeks) in arm N + S. Patients with confirmed response are presented (n = 18)

Fig. 2

Kaplan–Meier plots of progression-free survival (a) and overall survival (b) in arm N + S

Fig. 3

Time to response, duration of response, and time on therapy (weeks) in arm N + P. Patients with confirmed response are presented (n = 9, no ongoing responses were observed)

Fig. 4

Kaplan–Meier plots of progression-free survival (a) and overall survival (b) in arm N + P