The efficacy and safety of treatment with cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal-cell carcinoma are unknown.
In this phase 3, double-blind trial, we enrolled patients with advanced clear-cell renal-cell carcinoma who had not previously received treatment and had intermediate or poor prognostic risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium categories. Patients were randomly assigned to receive 40 mg of cabozantinib daily in addition to nivolumab and ipilimumab (experimental group) or matched placebo in addition to nivolumab and ipilimumab (control group). Nivolumab (3 mg per kilogram of body weight) and ipilimumab (1 mg per kilogram) were administered once every 3 weeks for four cycles. Patients then received nivolumab maintenance therapy (480 mg once every 4 weeks) for up to 2 years. The primary end point was progression-free survival, as determined by blinded independent review according to Response Evaluation Criteria in Solid Tumors, version 1.1, and was assessed in the first 550 patients who had undergone randomization. The secondary end point was overall survival, assessed in all patients who had undergone randomization.
Overall, 855 patients underwent randomization: 428 were assigned to the experimental group and 427 to the control group. Among the first 550 patients who had undergone randomization (276 in the experimental group and 274 in the control group), the probability of progression-free survival at 12 months was 0.57 in the experimental group and 0.49 in the control group (hazard ratio for disease progression or death, 0.73; 95% confidence interval, 0.57 to 0.94; P = 0.01); 43% of the patients in the experimental group and 36% in the control group had a response. Grade 3 or 4 adverse events occurred in 79% of the patients in the experimental group and in 56% in the control group. Follow-up for overall survival is ongoing.
Among patients with previously untreated, advanced renal-cell carcinoma who had intermediate or poor prognostic risk, treatment with cabozantinib plus nivolumab and ipilimumab resulted in significantly longer progression-free survival than treatment with nivolumab and ipilimumab alone. Grade 3 or 4 adverse events were more common in the experimental group than in the control group. (Funded by Exelixis; COSMIC-313 ClinicalTrials.gov number, NCT03937219.).
The New England journal of medicine. 2023 May 11 [Epub]
Toni K Choueiri, Thomas Powles, Laurence Albiges, Mauricio Burotto, Cezary Szczylik, Bogdan Zurawski, Eduardo Yanez Ruiz, Marco Maruzzo, Alberto Suarez Zaizar, Luis E Fein, Fabio A Schutz, Daniel Y C Heng, Fong Wang, Fabio Mataveli, Yu-Lin Chang, Maximiliano van Kooten Losio, Cristina Suarez, Robert J Motzer, COSMIC-313 Investigators
From the Department of Medical Oncology, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School - both in Boston (T.K.C.); the Department of Genitourinary Oncology, Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free NHS Trust, London (T.P.); the Department of Cancer Medicine, Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France (L.A.); Bradford Hill Clinical Research Center, Santiago (M.B.), and James Lind Centro de Investigación del Cáncer, Temuco (E.Y.R.) - both in Chile; the Postgraduate Medical Center, Department of Oncology, European Health Center, Otwock, Warsaw (C. Szczylik), and the Department of Outpatient Chemotherapy, Professor Franciszek Łukaszczyk Oncology Center, Bydgoszcz (B.Z.) - both in Poland; Oncology Unit 1, Department of Oncology, Istituto Oncologico Veneto IRCCS, Padua, Italy (M.M.); Consultorio de Medicina Especializada, Benito Juárez, Mexico City (A.S.Z.); Instituto de Oncología de Rosario, Rosario, Argentina (L.E.F.); Latin American Cooperative Oncology Group, Porto Alegre, and Beneficência Portuguesa de São Paulo, São Paulo - both in Brazil (F.A.S.); the Department of Medical Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada (D.Y.C.H.); Exelixis, Alameda, CA (F.W., F.M., Y.-L.C.); Bristol Myers Squibb, Boudry, Switzerland (M.K.L.); the Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Barcelona (C. Suarez); and the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (R.J.M.).