Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial.

In the primary analysis of CheckMate 9ER, nivolumab plus cabozantinib showed superior progression-free survival, overall survival, and objective response over sunitinib in patients with previously untreated advanced renal cell carcinoma (median follow-up of 18·1 months). Here, we report extended follow-up of overall survival and updated efficacy and safety.

This open-label, randomised, phase 3 trial was done in 125 hospitals and cancer centres across 18 countries. We included patients aged 18 years or older with previously untreated advanced or metastatic clear-cell renal cell carcinoma, a Karnofsky performance status of 70% or higher, measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by the investigator, any International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk category, and available tumour tissue for PD-L1 testing. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks plus cabozantinib (40 mg) orally once daily or sunitinib (50 mg orally) once daily (4 weeks per 6-week cycle). Randomisation, stratified by IMDC risk status, tumour PD-L1 expression, and geographical region, was done by permuted block within each stratum using a block size of four, via an interactive response system. The primary endpoint was progression-free survival by blinded independent central review. Overall survival was a secondary endpoint (reported here as the preplanned final analysis according to the protocol). Efficacy was assessed in all randomly assigned patients; safety was assessed in all patients who received at least one dose of any study drug. This ongoing study, closed to recruitment, is registered with ClinicalTrials.gov, NCT03141177.

Between Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to the nivolumab plus cabozantinib group and 328 to the sunitinib group. With an extended follow-up (data cutoff of June 24, 2021; median 32·9 months [IQR 30·4-35·9]), median overall survival was 37·7 months (95% CI 35·5-not estimable) in the nivolumab plus cabozantinib group and 34·3 months (29·0-not estimable) in the sunitinib group (hazard ratio [HR] 0·70 [95% CI 0·55-0·90], p=0·0043) and updated median progression-free survival was 16·6 months (12·8-19·8) versus 8·3 months (7·0-9·7; HR 0·56 [95% CI 0·46-0·68], p<0·0001). Grade 3-4 treatment-related adverse events occurred in 208 (65%) of 320 patients with nivolumab plus cabozantinib versus 172 (54%) of 320 with sunitinib. The most common grade 3-4 treatment-related adverse events were hypertension (40 [13%] of 320 patients in the nivolumab plus cabozantinib group vs 39 [12%] of 320 in the sunitinib group), palmar-plantar erythrodysaesthesia (25 [8%] vs 26 [8%]), and diarrhoea (22 [7%] vs 15 [5%]). Grade 3-4 treatment-related serious adverse events occurred in 70 (22%) of 320 patients in the nivolumab plus cabozantinib group and 31 (10%) of 320 in the cabozantinib group. One additional treatment-related death occurred with sunitinib (sudden death).

With extended follow-up and preplanned final overall survival analysis per protocol, nivolumab plus cabozantinib demonstrated improved efficacy versus sunitinib, further supporting the combination in the first-line treatment of advanced renal cell carcinoma.

Bristol Myers Squibb and Ono Pharmaceutical.

The Lancet. Oncology. 2022 Jun 07 [Epub ahead of print]

Robert J Motzer, Thomas Powles, Mauricio Burotto, Bernard Escudier, Maria T Bourlon, Amishi Y Shah, Cristina Suárez, Alketa Hamzaj, Camillo Porta, Christopher M Hocking, Elizabeth R Kessler, Howard Gurney, Yoshihiko Tomita, Jens Bedke, Joshua Zhang, Burcin Simsek, Christian Scheffold, Andrea B Apolo, Toni K Choueiri

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: ., 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., Bradford Hill Clinical Research Center, Santiago, Chile., Department of Medical Oncology, Gustave Roussy, Villejuif, France., Department of Hemato-Oncology, Urologic Oncology Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico., Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA., Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain., Department of Medical Oncology, Ospedale San Donato, Istituto Toscano Tumori, Arezzo, Italy., Department of Internal Medicine, University of Pavia, Pavia, Italy; Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy., Cancer Clinical Research Unit, Lyell McEwin Hospital, Elizabeth Vale, SA, Australia., Division of Medical Oncology, Department of Internal Medicine, University of Colorado School of Medicine, Aurora, CO, USA., Department of Clinical Medicine, Macquarie University, Sydney, NSW, Australia., Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan., Department of Urology, Eberhard Karls University Tübingen, Tübingen, Germany., Department of Clinical Research, Bristol Myers Squibb, Princeton, NJ, USA., Department of Global Biometrics and Data Science, Bristol Myers Squibb, Princeton, NJ, USA., Department of Clinical Development, Exelixis, Alameda, CA, USA., Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Department of Medical Oncology, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.