Robert J Motzer1, Nizar M Tannir1, David F McDermott1, Osvaldo Arén Frontera1, Bohuslav Melichar1, Toni K Choueiri1, Elizabeth R Plimack1, Philippe Barthélémy1, Camillo Porta1, Saby George1, Thomas Powles1, Frede Donskov1, Victoria Neiman1, Christian K Kollmannsberger1, Pamela Salman1, Howard Gurney1, Robert Hawkins1, Alain Ravaud1, Marc-Oliver Grimm1, Sergio Bracarda1, Carlos H Barrios1, Yoshihiko Tomita1, Daniel Castellano1, Brian I Rini1, Allen C Chen1, Sabeen Mekan1, M Brent McHenry1, Megan Wind-Rotolo1, Justin Doan1, Padmanee Sharma1, Hans J Hammers1, Bernard Escudier1. 1. 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.).
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 .).
RCT Entities:
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 .).
Authors: Robert J Motzer; Thomas E Hutson; Piotr Tomczak; M Dror Michaelson; Ronald M Bukowski; Olivier Rixe; Stéphane Oudard; Sylvie Negrier; Cezary Szczylik; Sindy T Kim; Isan Chen; Paul W Bycott; Charles M Baum; Robert A Figlin Journal: N Engl J Med Date: 2007-01-11 Impact factor: 91.245
Authors: Toni K Choueiri; David J Figueroa; André P Fay; Sabina Signoretti; Yuan Liu; Robert Gagnon; Keith Deen; Christopher Carpenter; Peter Benson; Thai H Ho; Lini Pandite; Paul de Souza; Thomas Powles; Robert J Motzer Journal: Clin Cancer Res Date: 2014-12-23 Impact factor: 12.531
Authors: Suzanne L Topalian; F Stephen Hodi; Julie R Brahmer; Scott N Gettinger; David C Smith; David F McDermott; John D Powderly; Richard D Carvajal; Jeffrey A Sosman; Michael B Atkins; Philip D Leming; David R Spigel; Scott J Antonia; Leora Horn; Charles G Drake; Drew M Pardoll; Lieping Chen; William H Sharfman; Robert A Anders; Janis M Taube; Tracee L McMiller; Haiying Xu; Alan J Korman; Maria Jure-Kunkel; Shruti Agrawal; Daniel McDonald; Georgia D Kollia; Ashok Gupta; Jon M Wigginton; Mario Sznol Journal: N Engl J Med Date: 2012-06-02 Impact factor: 91.245
Authors: Daniel Y C Heng; Wanling Xie; Meredith M Regan; Lauren C Harshman; Georg A Bjarnason; Ulka N Vaishampayan; Mary Mackenzie; Lori Wood; Frede Donskov; Min-Han Tan; Sun-Young Rha; Neeraj Agarwal; Christian Kollmannsberger; Brian I Rini; Toni K Choueiri Journal: Lancet Oncol Date: 2013-01-09 Impact factor: 41.316
Authors: Robert J Motzer; Bernard Escudier; David F McDermott; Saby George; Hans J Hammers; Sandhya Srinivas; Scott S Tykodi; Jeffrey A Sosman; Giuseppe Procopio; Elizabeth R Plimack; Daniel Castellano; Toni K Choueiri; Howard Gurney; Frede Donskov; Petri Bono; John Wagstaff; Thomas C Gauler; Takeshi Ueda; Yoshihiko Tomita; Fabio A Schutz; Christian Kollmannsberger; James Larkin; Alain Ravaud; Jason S Simon; Li-An Xu; Ian M Waxman; Padmanee Sharma Journal: N Engl J Med Date: 2015-09-25 Impact factor: 91.245
Authors: Daniel Y C Heng; Wanling Xie; Meredith M Regan; Mark A Warren; Ali Reza Golshayan; Chakshu Sahi; Bernhard J Eigl; J Dean Ruether; Tina Cheng; Scott North; Peter Venner; Jennifer J Knox; Kim N Chi; Christian Kollmannsberger; David F McDermott; William K Oh; Michael B Atkins; Ronald M Bukowski; Brian I Rini; Toni K Choueiri Journal: J Clin Oncol Date: 2009-10-13 Impact factor: 44.544
Authors: Jedd D Wolchok; Harriet Kluger; Margaret K Callahan; Michael A Postow; Naiyer A Rizvi; Alexander M Lesokhin; Neil H Segal; Charlotte E Ariyan; Ruth-Ann Gordon; Kathleen Reed; Matthew M Burke; Anne Caldwell; Stephanie A Kronenberg; Blessing U Agunwamba; Xiaoling Zhang; Israel Lowy; Hector David Inzunza; William Feely; Christine E Horak; Quan Hong; Alan J Korman; Jon M Wigginton; Ashok Gupta; Mario Sznol Journal: N Engl J Med Date: 2013-06-02 Impact factor: 91.245
Authors: James C Yang; Marybeth Hughes; Udai Kammula; Richard Royal; Richard M Sherry; Suzanne L Topalian; Kimberly B Suri; Catherine Levy; Tamika Allen; Sharon Mavroukakis; Israel Lowy; Donald E White; Steven A Rosenberg Journal: J Immunother Date: 2007 Nov-Dec Impact factor: 4.456
Authors: Nan E Rothrock; Sally E Jensen; Jennifer L Beaumont; Amy P Abernethy; Paul B Jacobsen; Karen Syrjala; David Cella Journal: Value Health Date: 2013-06-19 Impact factor: 5.725
Authors: Sarah Abou Alaiwi; Amin H Nassar; Wanling Xie; Ziad Bakouny; Jacob E Berchuck; David A Braun; Sylvan C Baca; Pier Vitale Nuzzo; Ronan Flippot; Tarek H Mouhieddine; Liam F Spurr; Yvonne Y Li; Taiwen Li; Abdallah Flaifel; John A Steinharter; Claire A Margolis; Natalie I Vokes; Heng Du; Sachet A Shukla; Andrew D Cherniack; Guru Sonpavde; Robert I Haddad; Mark M Awad; Marios Giannakis; F Stephen Hodi; X Shirley Liu; Sabina Signoretti; Cigall Kadoch; Matthew L Freedman; David J Kwiatkowski; Eliezer M Van Allen; Toni K Choueiri Journal: Cancer Immunol Res Date: 2020-04-22 Impact factor: 11.151
Authors: Suguru Shirotake; Yuta Umezawa; Takashi Okabe; G O Kaneko; Kent Kanao; Koshiro Nishimoto; Masafumi Oyama Journal: In Vivo Date: 2020 May-Jun Impact factor: 2.155
Authors: Luciana de M Leite; Paulo G Bergerot; Aldo L A Dettino; José Augusto R; Stenio de C Zequi; Maria Nirvana da C Formiga Journal: Int Braz J Urol Date: 2021 May-Jun Impact factor: 1.541
Authors: Toni K Choueiri; Sabina Signoretti; Abdallah Flaifel; Wanling Xie; David A Braun; Miriam Ficial; Ziad Bakouny; Amin H Nassar; Rebecca B Jennings; Bernard Escudier; Daniel J George; Robert J Motzer; Michael J Morris; Thomas Powles; Evelyn Wang; Ying Huang; Gordon J Freeman Journal: Clin Cancer Res Date: 2019-08-01 Impact factor: 12.531