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.

Background: 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.
Methods: 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.
Findings: 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).
Interpretation: 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.
Funding: Bristol Myers Squibb and Ono Pharmaceutical.
Competing Interests: Declaration of interests RJM reports advisory board fees from AstraZeneca, AVEO Pharmaceuticals, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer; and institutional funding from Bristol Myers Squibb (BMS), Eisai, Exelixis, Genentech/Roche, Merck, and Pfizer. TP reports grants from AstraZeneca, Roche, BMS, Exelixis, Ipsen, Merck, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas Pharma, Johnson & Johnson, and Eisai; consulting fees from BMS, Merck, AstraZeneca, Ipsen, Pfizer, Novartis, Incyte, Seattle Genetics, Roche, Exelixis, MSD, Merck Serono, Astellas Pharma, Johnson & Johnson, and Eisai; and travel support from Pfizer, MSD, AstraZeneca, Roche, and Ipsen. MB reports consulting fees from Roche/Genentech, BMS, MSD Oncology, Novartis, AstraZeneca; and speakers' bureau fees from Roche/Genentech, MSD Oncology, BMS, and AstraZeneca. BE reports an institutional research grant from BMS; consulting fees from Pfizer, BMS, Ipsen, AVEO, Oncorena, and Eisai; honoraria from Pfizer, BMS, Ipsen, Oncorena, and Eisai; and travel support from BMS, Ipsen, and MSD. MTB reports consulting fees from BMS, Asofarma, Eisai, MSD Oncology, Janssen Oncology, Novartis, Bayer, and Ferring; speakers' bureau fees from Asofarma, MSD Oncology, BMS, Bayer, Eisai, Janssen Oncology, Ipsen, Pfizer, Merck, Ferring, Tecnofarma, Medicamenta, AstraZeneca, and Astellas Pharma; honoraria from BMS and Tecnofarma; payment for expert testimony from Asofarma; travel support from Asofarma, Janssen-Cilag, MSD Oncology, BMS Mexico, Pfizer, Ipsen, and Sanofi; and steering committee honoraria from BMS. AYS reports research grants from BMS, Eisai, 4D Pharma, and EMD Serono; consulting fees from Exelixis, BMS, Pfizer, and EMD Serono; and honoraria from Eisai and Oncology Information Group. CSu reports research grants from AB Science, Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim España, BMS, Clovis Oncology, Exelixis, Genentech, GlaxoSmithKline, Hoffman-La Roche, Novartis Farmaceutica, Pfizer, and Sanofi-Aventis; speakers' bureau fees from Astellas Pharma, Bayer, BMS, EUSA Pharma, Hoffmann-La Roche, Ipsen, and Pfizer; and advisory board fees from Astellas Pharma, Bayer, BMS, EUSA Pharma, Hoffman-La Roche, Ipsen, MSD, Novartis, Pfizer, and Sanofi-Aventis. AH reports advisory board fees from MSD and Janssen. CP reports consulting fees from Angelini Pharma, AstraZeneca, BMS, Eisai, EUSA Pharma, Ipsen, Merck Serono, and MSD; speakers' bureau fees from BMS, EUSA Pharma, General Electric, Ipsen, and MSD; payment for expert testimony from EUSA Pharma and Pfizer; and travel support from Roche. CMH reports institutional research grant from BMS, and stock options from Telix Pharmaceuticals, Volpara Health Technologies, Alcidon, and Nanosonics. ERK reports a personal research grant from Medivation/Astellas; institutional research grant from BMS, Genentech/Roche, Pfizer, and Merck Serono; and stock options from Johnson & Johnson. HG reports advisory board fees from BMS, Ipsen, MSD, AstraZeneca, Janssen-Cilag, Pfizer, Roche, and Merck Serono; speakers' bureau fees from Merck Serono; and travel support from AstraZeneca. YT reports institutional research grants from Ono Pharmaceutical, Takeda, and Astellas; and honoraria from BMS, Pfizer, Ono Pharmaceutical, and Astellas. JB reports institutional research grants from BMS, Astellas Pharma, Ipsen, MSD Oncology, Novartis, Roche, Exelixis, Pfizer, and Seagen; consulting fees from BMS, Eisai, EUSA Pharma, Ipsen, MSD Oncology, AstraZeneca, Roche, Pfizer, and Merck; and speakers' bureau fees from MSD Oncology, BMS, Merck, Pfizer, Ipsen, and Roche. JZ and BS are employed by and have stock ownership in BMS. CSc is employed by and has stock ownership in Exelixis. TKC reports research grants, consulting fees, honoraria, and advisory board fees from AstraZeneca, Aravive, AVEO, Bayer, BMS, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVIA, Infinity, Ipsen, Janssen, Kanaph, Lilly, Merck, NiKang, Nuscan, Novartis, Pfizer, Roche, Sanofi-Aventis, Surface Oncology, Takeda, Tempest, UpToDate, and continuing medical education events (Peerview, OncLive, MJH, and others), outside the submitted work; institutional patents filed on molecular mutations and immunotherapy response, and circulating tumour DNA; leadership fees from the National Comprehensive Cancer Network, US NCI Genitourinary Steering Committee, American Society of Clinical Oncology, and European Society for Medical Oncology; stock ownership in Pionyr, Tempest, Osel, and NuscanDx; other financial or non-financial interests include medical writing and editorial assistance support that might in part have been funded by communications companies; potential funding (in part) from non-US sources or foreign institutions for mentoring of several non-US citizens on research projects; independent funding by drug companies or royalties potentially involved in research around the subject matter (institutional); and support in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at the Dana-Farber Cancer Institute. ABA declares no competing interests.
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