In CheckMate 9ER study among patients with previously untreated advanced renal-cell carcinoma (RCC), nivolumab plus cabozantinib had significant benefits over sunitinib in terms of progression-free survival (PFS), overall survival (OS), and the likelihood of objective response. Efficacy benefits of combination treatment were consistent across prespecified subgroups. The combination treatment was associated with substantial side effects with 19.7% of the patients who discontinued at least one of the study drugs prematurely and 5.6% discontinued both. However, quality of life (QoL) was maintained according to Dr. Toni K. Choueiri of the Dana–Farber Cancer Institute in Boston, MA, Dr. Robert J. Motzer of the Memorial Sloan Kettering Cancer Center in New York, NY, US and CheckMate 9ER investigators who published the study findings in 4th March 2021 issue of The New England Journal of Medicine.

The authors wrote in the study background that both cabozantinib and nivolumab are approved for the treatment of advanced RCC and improved OS as single agents in phase III studies. In a phase I dose-finding study of nivolumab plus cabozantinib that involved patients with advanced genitourinary cancers, a cabozantinib dose of 40 mg per day had similar efficacy to that of 60 mg per day, but had fewer side effects.

The CheckMate 9ER investigators performed this phase III randomised, open-label study to compare the efficacy and safety of the combination of nivolumab plus cabozantinib with sunitinib in the first-line treatment of patients with advanced RCC with clear-cell histological features.

The study team randomly assigned adult patients with previously untreated clear-cell, advanced RCC to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The study primary endpoint was PFS determined by blinded independent central review. Secondary endpoints included OS, objective response determined by independent review, and safety. Health-related QoL was an exploratory endpoint.

In total, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months, the median PFS was 16.6 months (95% confidence interval [CI] 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI 7.0 to 9.7) with sunitinib (hazard ratio [HR] for disease progression or death, 0.51; 95% CI 0.41 to 0.64; p < 0.001).

The probability of OS at 12 months was 85.7% (95% CI 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI 70.5 to 80.0) with sunitinib (HR for death, 0.60; 98.89% CI 0.40 to 0.89; p = 0.001).

An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (p < 0.001).

Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups.

Side events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the study drugs due to side events, and 5.6% discontinued both.

Patients reported better health-related QoL with nivolumab plus cabozantinib than with sunitinib.

The authors concluded that nivolumab plus cabozantinib had significant benefits over sunitinib in terms of PFS, OS, and likelihood of response in patients with previously untreated advanced RCC.

The study results were previously presented in part at the ESMO 2020 Virtual Congress.

The study was supported by Bristol Myers Squibb in collaboration with Ono Pharmaceutical and with Exelixis, Ipsen Pharma, and Takeda Pharmaceutical. The authors thanked the staff of Dako, an Agilent Technologies company, for collaborative development of the PD-L1 IHC 28-8 pharmDx assay.


Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2021;384:829-841.