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

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.

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.

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.

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. identifier: NCT01472081 . Registered 16 November 2011.

Journal for immunotherapy of cancer. 2018 Oct 22*** epublish ***

Asim Amin, Elizabeth R Plimack, Marc S Ernstoff, Lionel D Lewis, Todd M Bauer, David F McDermott, Michael Carducci, Christian Kollmannsberger, Brian I Rini, Daniel Y C Heng, Jennifer Knox, Martin H Voss, Jennifer Spratlin, Elmer Berghorn, Lingfeng Yang, Hans J Hammers

Immunotherapy program, Levine Cancer Institute, Carolinas HealthCare System, 1024 Morehead Medical Drive, Charlotte, NC, 28204, USA. ., Division of Genitourinary Medical Oncology, Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA., Division of Oncology, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14203, USA., Department of Medicine at The Geisel School of Medicine and The Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center, Lebanon, NH, 03756, USA., Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, 37203, USA., Department of Medicine, Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA, 02215, USA., Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA., Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, V5Z 4E6, Canada., Lerner College of Medicine, Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, 44195, USA., Department of Oncology, Tom Baker Cancer Center, University of Calgary, Calgary, AB, T2N 4N2, Canada., Cancer Clinical Research Unit (CCRU), Princess Margaret Cancer Centre, Toronto, ON, M5G 1Z5, Canada., Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T6G 1Z2, Canada., Oncology - Global Clinical Research, Bristol-Myers Squibb, Princeton, NJ, 08541, USA., Department of Internal Medicine, UT Southwestern - Kidney Cancer Program, Dallas, TX, 75390, USA.