Background Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma.
Methods We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level,0.04), objective response rate (alpha level,0.001), and progression-free survival (alpha level,0.009) among patients with intermediate or poor prognostic risk. Results A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. Conclusions Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749 .).
The New England journal of medicine. 2018 Mar 21 [Epub ahead of print]
Robert J Motzer, Nizar M Tannir, David F McDermott, Osvaldo Arén Frontera, Bohuslav Melichar, Toni K Choueiri, Elizabeth R Plimack, Philippe Barthélémy, Camillo Porta, Saby George, Thomas Powles, Frede Donskov, Victoria Neiman, Christian K Kollmannsberger, Pamela Salman, Howard Gurney, Robert Hawkins, Alain Ravaud, Marc-Oliver Grimm, Sergio Bracarda, Carlos H Barrios, Yoshihiko Tomita, Daniel Castellano, Brian I Rini, Allen C Chen, Sabeen Mekan, M Brent McHenry, Megan Wind-Rotolo, Justin Doan, Padmanee Sharma, Hans J Hammers, Bernard Escudier, CheckMate 214 Investigators
From Memorial Sloan Kettering Cancer Center, New York (R.J.M.), and Roswell Park Cancer Institute, Buffalo (S.G.) - both in New York; University of Texas M.D. Anderson Cancer Center, Houston (N.M.T., P. Sharma); Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center (D.F.M.), and Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School (T.K.C.), Boston; Centro Internacional de Estudios Clínicos (O.A.F.) and Fundación Arturo López Pérez (P. Salman), Santiago, Chile; Palacký University and University Hospital Olomouc, Olomouc, Czech Republic (B.M.); Fox Chase Cancer Center, Philadelphia (E.R.P.); Hôpitaux Universitaires de Strasbourg, Strasbourg (P.B.), Bordeaux University Hospital, Hôpital Saint-André, Bordeaux (A.R.), and Institut Gustave Roussy, Villejuif (B.E.) - all in France; Istituto di Ricovero e Cura a Carattere Scientifico San Matteo University Hospital Foundation, Pavia (C.P.), and Ospedale San Donato, Azienda Unità Sanitaria Locale Toscana Sud-Est, Istituto Toscano Tumori, Arezzo (S.B.) - both in Italy; Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free NHS Trust (T.P.), and Cancer Research UK (R.H.), London; Aarhus University Hospital, Aarhus, Denmark (F.D.); Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, and Tel Aviv University, Tel Aviv - both in Israel (V.N.); British Columbia Cancer Agency, Vancouver, Canada (C.K.K.); Westmead Hospital and Macquarie University, Sydney (H.G.); Jena University Hospital, Jena, Germany (M.-O.G.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Porto Alegre, Brazil (C.H.B.); Niigata University, Niigata, Japan (Y.T.); Hospital Universitario 12 de Octubre, Madrid (D.C.); Cleveland Clinic Taussig Cancer Institute, Cleveland (B.I.R.); Bristol-Myers Squibb, Princeton, NJ (A.C.C., S.M., M.B.M., M.W.-R., J.D.); and Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore (H.J.H.).