Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma.
Motzer, Robert J. M.D.; Tannir, Nizar M. M.D.; McDermott, David F. M.D.; Frontera, Osvaldo Aren M.D.; Melichar, Bohuslav M.D., Ph.D.; Choueiri, Toni K. M.D.; Plimack, Elizabeth R. M.D.; Barthelemy, Philippe M.D., Ph.D.; Porta, Camillo M.D.; George, Saby M.D.; Powles, Thomas M.D.; Donskov, Frede M.D., Ph.D.; Neiman, Victoria M.D.; Kollmannsberger, Christian K. M.D.; Salman, Pamela M.D.; Gurney, Howard M.D.; Hawkins, Robert M.D.; Ravaud, Alain M.D., Ph.D.; Grimm, Marc-Oliver M.D.; Bracarda, Sergio M.D.; Barrios, Carlos H. M.D.; Tomita, Yoshihiko M.D., Ph.D.; Castellano, Daniel M.D.; Rini, Brian I. M.D.; Chen, Allen C. M.D.; Mekan, Sabeen M.D.; McHenry, Brent M. Ph.D.; Wind-Rotolo, Megan Ph.D.; Doan, Justin M.Sc., M.P.H.; Sharma, Padmanee M.D., Ph.D.; Hammers, Hans J. M.D., Ph.D.; Escudier, Bernard M.D.; the CheckMate 214 Investigators
[Article]
New England Journal of Medicine.
378(14):1277-1290, April 5, 2018.
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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.)
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