Adding cabozantinib to treatment with nivolumab and ipilimumab prolongs progression-free survival (PFS) in patients with intermediate- to poor-risk renal cell carcinoma (RCC), according to results from the phase 3 COSMIC-313 trial.
“This is the first study to use an immuno-oncology doublet standard of care as the control group,” said study presenter Toni K. Choueiri, MD, of the Dana-Farber Cancer Institute in Boston.
He added that follow-up for overall survival is ongoing. Dr Choueiri presented the PFS results and other findings from the trial at ESMO Congress 2022.
The COSMIC-313 trial (ClinicalTrials.gov Identifier: NCT03937219) enrolled patients with clear cell, intermediate- to poor-risk RCC. Patients were either previously untreated or they had received 1 prior systemic adjuvant therapy if they had completely resected RCC and if recurrence occurred 6 months or more after the last dose of adjuvant therapy.
A total of 855 patients were randomly assigned to receive cabozantinib plus nivolumab and ipilimumab (n=428) or placebo plus nivolumab and ipilimumab (n=427). The initial triplet or doublet therapy was given for 4 cycles. After that, patients continued treatment with nivolumab — in combination with cabozantinib or placebo — until loss of clinical benefit, intolerable toxicity, or the 2-year mark.
The median age at baseline was 61 (range, 19-85) years in the cabozantinib arm and 60 (range, 28-87) years in the placebo arm. Most patients were men (76% and 73%, respectively), had PD-L1 expression below 1% (64% vs 62%), had intermediate-risk disease (75% both arms), and had prior nephrectomy (65% in both arms).
PFS, Response, and Safety
The primary endpoint was PFS by blinded independent review committee, analyzed after 249 events in the PFS intent-to-treat population. This population is the first 550 patients randomized. The median follow-up in this group was 20.2 months.
The primary endpoint was met. The median PFS was not reached in the cabozantinib arm and was 11.3 months in the placebo arm (hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P =.013).
The PFS benefit was driven primarily by patients with intermediate-risk RCC. In this group, the median PFS was not reached in the cabozantinib arm and was 11.4 months in the placebo arm (HR, 0.63; 95% CI, 0.47-0.85). In the poor-risk cohort, the median PFS was 9.5 months and 11.2 months, respectively (HR, 1.04; 95% CI, 0.65-1.69).
The objective response rate was 43% in the cabozantinib arm and 36% in the placebo arm. The disease control rate was 86% and 72%, respectively. In both arms, 3% of patients achieved a complete response. The median duration of response was not reached in either arm.
Treatment-related adverse events (TRAEs) that led to discontinuation of any treatment occurred in 45% of patients in the cabozantinib arm and 24% of those in the placebo arm. Discontinuation of all treatment components occurred in 12% and 5%, respectively.
The most common grade 3-4 TRAEs that occurred more frequently in the cabozantinib arm than the placebo arm were ALT increase (26% vs 6%), AST increase (20% vs 5%), lipase increase (9% vs 6%), and hypertension (8% vs 2%).
There were 3 patients in each arm who experienced a grade 5 TRAE. Causes of death in the cabozantinib arm were gastrointestinal hemorrhage, hepatic failure, and respiratory failure. Causes of death in the placebo arm were renal failure, myocarditis, and sudden death.
Disclosures: This study was supported by Exelixis, Inc. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Choueiri TK, Powles TB, Albiges L, et al. Phase III study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313). Presented at ESMO 2022; September 9-13, 2022. Abstract LBA8.