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.

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, number NCT02231749, and is ongoing but now closed to recruitment.

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.

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.

Bristol-Myers Squibb and ONO Pharmaceutical.

The Lancet. Oncology. 2019 Aug 16 [Epub ahead of print]

Robert J Motzer, Brian I Rini, David F McDermott, Osvaldo Arén Frontera, Hans J Hammers, Michael A Carducci, Pamela Salman, Bernard Escudier, Benoit Beuselinck, Asim Amin, Camillo Porta, Saby George, Victoria Neiman, Sergio Bracarda, Scott S Tykodi, Philippe Barthélémy, Raya Leibowitz-Amit, Elizabeth R Plimack, Sjoukje F Oosting, Bruce Redman, Bohuslav Melichar, Thomas Powles, Paul Nathan, Stéphane Oudard, David Pook, Toni K Choueiri, Frede Donskov, Marc-Oliver Grimm, Howard Gurney, Daniel Y C Heng, Christian K Kollmannsberger, Michael R Harrison, Yoshihiko Tomita, Ignacio Duran, Viktor Grünwald, M Brent McHenry, Sabeen Mekan, Nizar M Tannir, CheckMate 214 investigators

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: ., Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA., Department of Hematology and Medical Oncology, Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA, USA., Department of Medical Oncology, Centro de Invetigación Clínica Bradford Hill, Santiago, Chile., Department of Oncology and Urology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA., Department of Medical Oncology, Fundación Arturo López Pérez, Santiago, Chile., Department of Medical Oncology, Gustave Roussy, Villejuif, France., Department of Oncology, University Hospitals Leuven, Leuven, Belgium., Levine Cancer Institute, Atrium Healthcare, Charlotte, NC, USA., Department of Medical Oncology, IRCCS San Matteo University Hospital Foundation, Pavia, Italy., Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA., Department of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel; Tel Aviv University, Tel Aviv, Israel., Department of Oncology, Ospedale San Donato, Azienda USL Toscana Sud-Est, IstitutoToscanoTumori, Arezzo, Italy., Department of Medicine, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Department of Medical Oncology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France., Oncology Department, Sheba Medical Center, Ramat Gan, Israel., Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA., Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands., Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA., Department of Oncology, Palacky University, and University Hospital Olomouc, Olomouc, Czech Republic., 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 Cancer Services: Oncology, Mount Vernon Cancer Centre, Northwood, Middlesex, UK., Department of Medical Oncology, Service de Cancérologie Médicale Hôpital Européen Georges Pompidou, Paris, France., Department of Oncology, Monash Health, Melbourne, VIC, Australia., Department of Genitourinary Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA., Department of Oncology, Aarhus University Hospital, Aarhus, Denmark., Department of Urology, Jena University Hospital, Jena, Germany., Department of Medical Oncology, Westmead Hospital and Macquarie University, Sydney, NSW, Australia., Department of Oncology, Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada., Department of Medicine, British Columbia Cancer Agency, Vancouver, BC, Canada., Division of Medical Oncology, Duke Cancer Institute, Durham, NC, USA., Department of Urology, Niigata University, Niigata, Japan., Department of Medical Oncology, Hospital Universitario Marques de Valdecilla, IDIVAL, Santander, Spain., Interdisciplinary Genitourinary Oncology at the West-German Cancer Center, Clinic for Internal Medicine (Tumor Research) and Clinic for Urology, University Hospital Essen, Essen, Germany., Bristol-Myers Squibb, Princeton, NJ, USA., Department of Genitourinary Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.