BACKGROUND: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting. METHODS: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment. FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4-36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6-not estimable] vs 26·6 months [22·1-33·4]; hazard ratio [HR] 0·66 [95% CI 0·54-0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9-10·0] vs 8·3 months [7·0-8·8]; HR 0·77 [95% CI 0·65-0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2-not estimable]; HR 0·71 [95% CI 0·59-0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1-11·1] vs 9·7 months [8·3-11·1]; HR 0·85 [95% CI 0·73-0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related. INTERPRETATION: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.

Bristol Myers Squibb Princeton NJ USA

Department of Cancer Services Oncology Mount Vernon Cancer Centre Northwood Middlesex UK

Department of Genitourinary Medical Oncology University of Texas MD Anderson Cancer Center Houston TX USA

Department of Genitourinary Oncology Barts Cancer Institute Cancer Research UK Experimental Cancer Medicine Centre Queen Mary University of London Royal Free National Health Service Trust London UK

Department of Genitourinary Oncology Dana Farber Cancer Institute Brigham and Women's Hospital Boston MA USA; Harvard Medical School Boston MA USA

Department of Hematology and Medical Oncology Beth Israel Deaconess Medical Center Dana Farber Harvard Cancer Center Boston MA USA

Department of Hematology and Medical Oncology Cleveland Clinic Taussig Cancer Institute Cleveland OH USA

Department of Hematology and Oncology Fox Chase Cancer Center Philadelphia PA USA

Department of Internal Medicine Division of Hematology and Oncology University of Michigan Comprehensive Cancer Center Ann Arbor MI USA

Department of Medical Oncology Centro de Invetigación Clínica Bradford Hill Santiago Chile

Department of Medical Oncology Fundación Arturo López Pérez Santiago Chile

Department of Medical Oncology Gustave Roussy Villejuif France

Department of Medical Oncology Hôpitaux Universitaires de Strasbourg Strasbourg France

Department of Medical Oncology Hospital Universitario Marques de Valdecilla IDIVAL Santander Spain

Department of Medical Oncology IRCCS San Matteo University Hospital Foundation Pavia Italy

Department of Medical Oncology Service de Cancérologie Médicale Hôpital Européen Georges Pompidou Paris France

Department of Medical Oncology University Medical Center Groningen University of Groningen Groningen Netherlands

Department of Medical Oncology Westmead Hospital and Macquarie University Sydney NSW Australia

Department of Medicine British Columbia Cancer Agency Vancouver BC Canada

Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA

Department of Medicine Roswell Park Cancer Institute Buffalo NY USA

Department of Medicine University of Washington and Fred Hutchinson Cancer Research Center Seattle WA USA

Department of Oncology Aarhus University Hospital Aarhus Denmark

Department of Oncology and Urology The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD USA

Department of Oncology Davidoff Cancer Center Rabin Medical Center Petah Tikva Israel; Tel Aviv University Tel Aviv Israel

Department of Oncology Monash Health Melbourne VIC Australia

Department of Oncology Ospedale San Donato Azienda USL Toscana Sud Est IstitutoToscanoTumori Arezzo Italy

Department of Oncology Palacky University and University Hospital Olomouc Olomouc Czech Republic

Department of Oncology Tom Baker Cancer Center University of Calgary Calgary AB Canada

Department of Oncology University Hospitals Leuven Leuven Belgium

Department of Urology Jena University Hospital Jena Germany

Department of Urology Niigata University Niigata Japan

Division of Medical Oncology Duke Cancer Institute Durham NC USA

Interdisciplinary Genitourinary Oncology at the West German Cancer Center Clinic for Internal Medicine and Clinic for Urology University Hospital Essen Essen Germany

Levine Cancer Institute Atrium Healthcare Charlotte NC USA

Oncology Department Sheba Medical Center Ramat Gan Israel

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ClinicalTrials.gov
NCT02231749