Nivolumab Plus Ipilimumab for Metastatic Castration-Resistant Prostate Cancer: Preliminary Analysis of Patients in the CheckMate 650 Trial.

Metastatic castration-resistant prostate cancer (mCRPC) is immunologically "cold" and predominantly resistant to immune checkpoint therapy due to few tumor-infiltrating T cells. Ipilimumab (anti-CTLA-4) or anti-PD-1/PD-L1 monotherapy failed to show a significant benefit. Although the PD-1/PD-L1 pathway is minimally expressed in prostate tumors, we previously demonstrated that PD-1/PD-L1 expression increases as a compensatory inhibitory pathway in parallel with an ipilimumab-induced increase in tumor-infiltrating T cells. Here, we report the largest trial to date in mCRPC with anti-CTLA-4 plus anti-PD-1 (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; CheckMate 650, NCT02985957). With median follow-ups of 11.9 and 13.5 months in cohorts 1 (pre-chemotherapy; n = 45) and 2 (post-chemotherapy; n = 45), objective response rate was 25% and 10%, and median overall survival was 19.0 and 15.2 months, respectively. Four patients, two in each cohort, had complete responses. Exploratory studies identify potential biomarkers of response. Grade 3-4 treatment-related adverse events have occurred in ∼42%-53% of patients, with four treatment-related deaths. Therefore, dose/schedule modifications have been implemented.

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Declaration of Interests P.S. reports stock options and advisory fees from Oncolytics, Jounce, BioAlta, Forty-Seven, Polaris, Marker Therapeutics, Codiak, ImaginAB, Hummingbird, Dragonfly, Lytix, Lava Therapeutics, Achelois, Infinity, and Glympse, and stock options with BioNTx and Constellation, outside the submitted work. R.P. reports personal fees and non-financial support from Bristol Myers Squibb (BMS) and Genentech/Roche; personal fees from Dendreon, EMD Serono/Pfizer, Genomic Health, AstraZeneca, Sanofi, Merck, Bayer, and Jounce Therapeutics; and institutional grants from Janssen, outside the submitted work. V.N. reports research grants paid to the institution from BMS, during the conduct of the study; research grants paid to the institution from Pfizer and Peloton Therapeutics; research grants paid to the institution and personal fees from Janssen; and personal fees from AstraZeneca, outside the submitted work. A.F. reports personal fees from Astellas, Sanofi, Janssen, AAA, and BMS, outside the submitted work. G.G. reports personal fees from Pfizer, BMS, MSD, AstraZeneca, Astellas, Janssen, Bayer, Sanofi, and Ipsen, outside the submitted work. M.D.G. reports personal fees from BioMotiv, Janssen, Astellas, Pfizer, EMD Serono, Seattle Genetics, Incyte, Dracen, Inovio, Dragonfly, and Aileron; research grants from Dendreon and Novartis; and research grants and personal fees from Merck, Genentech, BMS, and AstraZeneca, outside the submitted work. H.M. reports personal fees and travel fees from BMS and Sanofi, travel fees from Bayer, congress fees from Roche, and personal fees from Ipsen, Janssen, and Astellas, outside the submitted work. A.P. reports funding support for this clinical trial from BMS during the conduct of the study; grants from Prostate Cancer Foundation, Phi Beta Psi Charity Trust Research Organization, National Cancer Institute, BMS, and Progenics; grants and personal fees from Clovis; and personal fees from Exelixis, PRIME, Janssen, Jounce Therapeutics, Guidepoint, Merck, and Gerson Lehrman Group, outside of the submitted work. S.K.S reports personal fees from Exelixis, Dava Oncology, Cancer Now, Polaris, and MEDACorp; grants and non-financial support from Parker Institute for Cancer Immunotherapy; grants, personal fees, and non-financial support from Janssen Oncology, AstraZeneca, and BMS; personal fees and non-financial support from Dendreon, Amgen, Bayer, and Society for Immunotherapy of Cancer; and personal fees and ownership interests from Apricity Health, outside the submitted work. M.C. is an employee of and shareholder in BMS. B.S. is an employee of and shareholder in BMS. G.C.H. is an employee of BMS. A.S. is a former employee of and shareholder in BMS. Y.H. is an employee of and shareholder in BMS. K.F. reports personal fees from Amgen, Astellas, AstraZeneca, AAA, Bayer, Clovis, Curevac, ESSA, Genentech, Janssen, MSD, Orion, and Sanofi, outside the submitted work.