This randomized, open-label, phase 3 trial compared the efficacy and safety of cabozantinib (60 mg daily) versus everolimus (10 mg daily) in patients with advanced renal-cell carcinoma (RCC) that had progressed after VEGFR-targeted therapy. The primary endpoint was progression-free survival, with overall survival and objective response rate as secondary endpoints. The median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus, representing a 42% reduction in the rate of disease progression or death (hazard ratio, 0.58; 95% CI, 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). An interim analysis showed a trend toward longer overall survival with cabozantinib (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005), but it did not reach statistical significance. Adverse events were managed with dose reductions, and the most common grade 3 or 4 adverse events were hypertension, diarrhea, and fatigue with cabozantinib, and anemia, fatigue, and hyperglycemia with everolimus. The study concluded that cabozantinib provided longer progression-free survival compared to everolimus in patients with RCC that had progressed after VEGFR-targeted therapy.This randomized, open-label, phase 3 trial compared the efficacy and safety of cabozantinib (60 mg daily) versus everolimus (10 mg daily) in patients with advanced renal-cell carcinoma (RCC) that had progressed after VEGFR-targeted therapy. The primary endpoint was progression-free survival, with overall survival and objective response rate as secondary endpoints. The median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus, representing a 42% reduction in the rate of disease progression or death (hazard ratio, 0.58; 95% CI, 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). An interim analysis showed a trend toward longer overall survival with cabozantinib (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005), but it did not reach statistical significance. Adverse events were managed with dose reductions, and the most common grade 3 or 4 adverse events were hypertension, diarrhea, and fatigue with cabozantinib, and anemia, fatigue, and hyperglycemia with everolimus. The study concluded that cabozantinib provided longer progression-free survival compared to everolimus in patients with RCC that had progressed after VEGFR-targeted therapy.