Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma

Abstract

Background: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known.

Methods: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma 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 primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point.

Results: Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival 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 for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival 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 (hazard ratio 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. Adverse 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 trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib.

Conclusions: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).

Figure 1.. Progression-free and Overall Survival in the Intention-to-Treat Population.

The intention-to-treat population included all the patients who underwent randomization. Shown are Kaplan–Meier estimates of progression-free survival (Panel A) and overall survival (Panel B). Progression-free survival was assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1, by blinded independent central review of radiologic imaging. NE denotes could not be estimated, and NR not reached.

Figure 2.. Progression-free and Overall Survival According to Subgroup.

Shown is the analysis of progression-free survival (Panel A) and overall survival (Panel B), according to subgroup. The International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) prognostic risk, programmed death ligand 1 (PD-L1) status, and geographic region (stratification factors) were recorded at screening by means of interactive response technology among all the patients who underwent randomization. Karnofsky performance-status scores range from 0 to 100, with lower scores indicating greater disability. Median progression-free survival and 95% confidence intervals according to subgroup are provided in Table S2 in the Supplementary Appendix.