Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma
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, F Salvador Palazzo, J J Zarba, D M Gomez Bradley, M E Richardet, M S Varela, G Recondo, H Gurney, D Pook, J Goh, A G Hill, I D Davis, M A Khattak, P De Souza, R Joshi, M Schmidinger, W Loidl, P Wolter, S Rottey, B Beuselinck, C H Barrios, A Murad, F A Barros Schutz, S J Azevedo, A Malzyner, D A Rodrigues Rosa, J A Rinck, C K Kollmannsberger, W Miller, D Y C Heng, G A Bjarnason, N S Basappa, S Sridhar, S Ghedira, O A Frontera, P Salman, P F Gonzalez Mella, S Mondaca, A Quiroga, L R Gomez Wolff, B Melichar, E Kubala, R Lakomy, M Sochor, F Donskov, P Geertsen, N V Jensen, P Bono, P-L Kellokumpu-Lehtinen, B Escudier, P Barthelemy, A Ravaud, G Gravis, S Oudard, F Priou, C Chevreau, G Mouillet, F Rolland, M O Grimm, S A Pahernik, B Hadaschik, F Zengerling, V Gruenwald, E Herrmann, M Retz, P J Goebell, L Bergmann, G Von Amsberg, C Ohlmann, M Schostak, T Schnoeller, J van Essen, J Kocsis, B Piko, L Mangel, L Geczi, R McDermott, J A McCaffrey, V Neiman, R Leibowitz-Amit, D Keizman, A Peer, A Sella, C Porta, S Bracarda, G Procopio, U Basso, G Carteni, U De Giorgi, Y Tomita, T Kondo, G Kimura, T Inoue, Y Wakumoto, M Yao, Y Fujii, W Obara, M Oya, K Tsuchiya, T Kojima, K Harada, T Kato, T Sugiyama, M Takahashi, M Uemura, S Ebara, S Fukasawa, Y Kawano, K Kobayashi, C Ohyama, K Tatsugami, H Uemura, H Kume, F Hongo, S Takahashi, A Takamoto, N Tohru, J L Lee, S Y Rha, Y A Lopez Chuken, J Rodriguez Cid, A Dominguez Andrade, C A Hernandez, S J Oosting, J Haanen, C Van Herpen, M Ziobro, R Zdrojowy, P Tomczak, D Castellano, E Grande, P Maroto, I Duran, C Suarez, E Esteban, J Puente, U Harmenberg, J H Liu, W C Chang, M Erman, H Senol Coskun, F Dane, T Powles, R Hawkins, P Nathan, M Gore, J Wagstaff, B Venugopal, R J Motzer, H J Hammers, N M Tannir, P Sharma, D F McDermott, E R Plimack, S George, T K Choueiri, B Rini, S Tykodi, A Amin, M R Harrison, S Srinivas, B S Redman, B Carthon, J Gao, M Carducci, H M Kluger, T E Hutson, D Vaena, Y Zakharia, T Olencki, S Pal, N Dawson, M N Fishman, J R Infante, S G Nair, H Drabkin, T Logan, L Appleman, R A Figlin, J Brugarolas, C W Ryan, H D Mannuel, D Quinn, J M Randall, S K Williamson, U N Vaishampayan, R M Graham, 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, F Salvador Palazzo, J J Zarba, D M Gomez Bradley, M E Richardet, M S Varela, G Recondo, H Gurney, D Pook, J Goh, A G Hill, I D Davis, M A Khattak, P De Souza, R Joshi, M Schmidinger, W Loidl, P Wolter, S Rottey, B Beuselinck, C H Barrios, A Murad, F A Barros Schutz, S J Azevedo, A Malzyner, D A Rodrigues Rosa, J A Rinck, C K Kollmannsberger, W Miller, D Y C Heng, G A Bjarnason, N S Basappa, S Sridhar, S Ghedira, O A Frontera, P Salman, P F Gonzalez Mella, S Mondaca, A Quiroga, L R Gomez Wolff, B Melichar, E Kubala, R Lakomy, M Sochor, F Donskov, P Geertsen, N V Jensen, P Bono, P-L Kellokumpu-Lehtinen, B Escudier, P Barthelemy, A Ravaud, G Gravis, S Oudard, F Priou, C Chevreau, G Mouillet, F Rolland, M O Grimm, S A Pahernik, B Hadaschik, F Zengerling, V Gruenwald, E Herrmann, M Retz, P J Goebell, L Bergmann, G Von Amsberg, C Ohlmann, M Schostak, T Schnoeller, J van Essen, J Kocsis, B Piko, L Mangel, L Geczi, R McDermott, J A McCaffrey, V Neiman, R Leibowitz-Amit, D Keizman, A Peer, A Sella, C Porta, S Bracarda, G Procopio, U Basso, G Carteni, U De Giorgi, Y Tomita, T Kondo, G Kimura, T Inoue, Y Wakumoto, M Yao, Y Fujii, W Obara, M Oya, K Tsuchiya, T Kojima, K Harada, T Kato, T Sugiyama, M Takahashi, M Uemura, S Ebara, S Fukasawa, Y Kawano, K Kobayashi, C Ohyama, K Tatsugami, H Uemura, H Kume, F Hongo, S Takahashi, A Takamoto, N Tohru, J L Lee, S Y Rha, Y A Lopez Chuken, J Rodriguez Cid, A Dominguez Andrade, C A Hernandez, S J Oosting, J Haanen, C Van Herpen, M Ziobro, R Zdrojowy, P Tomczak, D Castellano, E Grande, P Maroto, I Duran, C Suarez, E Esteban, J Puente, U Harmenberg, J H Liu, W C Chang, M Erman, H Senol Coskun, F Dane, T Powles, R Hawkins, P Nathan, M Gore, J Wagstaff, B Venugopal, R J Motzer, H J Hammers, N M Tannir, P Sharma, D F McDermott, E R Plimack, S George, T K Choueiri, B Rini, S Tykodi, A Amin, M R Harrison, S Srinivas, B S Redman, B Carthon, J Gao, M Carducci, H M Kluger, T E Hutson, D Vaena, Y Zakharia, T Olencki, S Pal, N Dawson, M N Fishman, J R Infante, S G Nair, H Drabkin, T Logan, L Appleman, R A Figlin, J Brugarolas, C W Ryan, H D Mannuel, D Quinn, J M Randall, S K Williamson, U N Vaishampayan, R M Graham
Abstract
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 .).
Conflict of interest statement
No other potential conflict of interest relevant to this article was reported.
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Source: PubMed