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Motzer RJ , Tannir NM , McDermott DF , Aren Frontera O , Melichar B , Choueiri TK , Plimack ER , Barthelemy P , Porta C , George S , Powles T , Donskov F , Neiman V , Kollmannsberger CK , Salman P , Gurney H , Hawkins R , Ravaud A , Grimm MO , Bracarda S , Barrios CH , Tomita Y , Castellano D , Rini BI , Chen AC , Mekan S , McHenry MB , Wind-Rotolo M , Doan J , Sharma P , Hammers HJ , Escudier B
Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma
N Engl J Med. 2018 Apr 5;378(14) :1277-1290
PMID: 29562145    PMCID: PMC5972549    URL: https://www.ncbi.nlm.nih.gov/pubmed/29562145
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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 .).
1533-4406 Motzer, Robert J Tannir, Nizar M McDermott, David F Aren Frontera, Osvaldo Melichar, Bohuslav Choueiri, Toni K Plimack, Elizabeth R Barthelemy, Philippe Porta, Camillo George, Saby Powles, Thomas Donskov, Frede Neiman, Victoria Kollmannsberger, Christian K Salman, Pamela Gurney, Howard Hawkins, Robert Ravaud, Alain Grimm, Marc-Oliver Bracarda, Sergio Barrios, Carlos H Tomita, Yoshihiko Castellano, Daniel Rini, Brian I Chen, Allen C Mekan, Sabeen McHenry, M Brent Wind-Rotolo, Megan Doan, Justin Sharma, Padmanee Hammers, Hans J Escudier, Bernard CheckMate 214 Investigators Journal Article United States N Engl J Med. 2018 Mar 21. doi: 10.1056/NEJMoa1712126.