Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma

Abstract

Background: The efficacy and safety of treatment with cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal-cell carcinoma are unknown.

Methods: In this phase 3, double-blind trial, we enrolled patients with advanced clear-cell renal-cell carcinoma who had not previously received treatment and had intermediate or poor prognostic risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium categories. Patients were randomly assigned to receive 40 mg of cabozantinib daily in addition to nivolumab and ipilimumab (experimental group) or matched placebo in addition to nivolumab and ipilimumab (control group). Nivolumab (3 mg per kilogram of body weight) and ipilimumab (1 mg per kilogram) were administered once every 3 weeks for four cycles. Patients then received nivolumab maintenance therapy (480 mg once every 4 weeks) for up to 2 years. The primary end point was progression-free survival, as determined by blinded independent review according to Response Evaluation Criteria in Solid Tumors, version 1.1, and was assessed in the first 550 patients who had undergone randomization. The secondary end point was overall survival, assessed in all patients who had undergone randomization.

Results: Overall, 855 patients underwent randomization: 428 were assigned to the experimental group and 427 to the control group. Among the first 550 patients who had undergone randomization (276 in the experimental group and 274 in the control group), the probability of progression-free survival at 12 months was 0.57 in the experimental group and 0.49 in the control group (hazard ratio for disease progression or death, 0.73; 95% confidence interval, 0.57 to 0.94; P = 0.01); 43% of the patients in the experimental group and 36% in the control group had a response. Grade 3 or 4 adverse events occurred in 79% of the patients in the experimental group and in 56% in the control group. Follow-up for overall survival is ongoing.

Conclusions: Among patients with previously untreated, advanced renal-cell carcinoma who had intermediate or poor prognostic risk, treatment with cabozantinib plus nivolumab and ipilimumab resulted in significantly longer progression-free survival than treatment with nivolumab and ipilimumab alone. Grade 3 or 4 adverse events were more common in the experimental group than in the control group. (Funded by Exelixis; COSMIC-313 ClinicalTrials.gov number, NCT03937219.).

Figure 1.. Final Analysis of Progression-free Survival (Progression-free Survival Population).

Patients were assigned to receive cabozantinib in addition to nivolumab and ipilimumab (experimental group) or placebo in addition to nivolumab and ipilimumab (control group). The progression-free survival population included the first 550 patients who had undergone randomization. A total of 249 events (disease progression or death) occurred after a median follow-up of 14.9 months. The date of the 249th event was August 23, 2021. Events were adjudicated by an independent radiology committee whose members were unaware of trial-group assignments. NE denotes could not be estimated, and NR not reached.

Figure 2.. Progression-free Survival in Prespecified Subgroups (Progression-free Survival Population).

Patients were assigned to receive cabozantinib in addition to nivolumab and ipilimumab (experimental group) or placebo in addition to nivolumab and ipilimumab (control group). The progression-free survival population included the first 550 patients who had undergone randomization. A total of 249 events (disease progression or death) occurred after a median follow-up of 14.9 months. The date of the 249th event was August 23, 2021. Events were adjudicated by an independent radiology committee whose members were unaware of trial-group assignments. No adjustments were made for multiplicity, and confidence intervals should not be used in place of hypothesis tests. Karnofsky performance-status scores range from 0 to 100, with lower scores reflecting greater disability. The International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) risk category was determined with the use of the IxRS interactive voice- and Web-based response system. The programmed death ligand 1 (PD-L1) tumor proportion score is the percentage of viable tumor cells that show PD-L1 membrane staining of any intensity.