A group of researchers analyzed the outcomes of the phase 3 clinical trial COSMIC-313, which compared the use of cabozantinib (C) plus nivolumab (N) and ipilimumab (I) versus a placebo (P) with N plus I in first-line treatment for patients with advanced renal cell carcinoma (aRCC) who have intermediate or poor International Metastatic RCC Database Consortium (IMDC) risk scores.

Data from the COSMIC-313 trial presented at ESMO 2022 showed that C with N plus I improved progression-free survival (PFS) compared with N plus I in first-line aRCC in patients with an intermediate or poor IMDC risk score. In an abstract presented at the 2023 ASCO Genitourinary Cancers Symposium, Thomas Powles, MBBS, MRCP, MD, Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, London, England, and colleagues presented an analysis of outcomes by IMDC risk group.

The COSMIC-313 study consisted of 855 patients who had clear cell aRCC with an intermediate or poor IMDC risk score. Of those patients, 75% were categorized as intermediate and 25% as poor risk. The participants were randomized to receive 40 mg of C or the matched P every day, stratified by region and IMDC risk. Both groups were treated with 4 doses of 3 mg/kg of N plus 1 mg/kg of I every 3 weeks for 4 cycles. Following the 4 cycles, the patients received 480 mg of N every 4 weeks, which continued to be administered for up to 2 years.  

The primary endpoint of the study was PFS, assessed via blinded independent radiology review per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 method guidelines. This assessment was completed for the first 550 randomized patients. Overall survival (OS) served as the secondary endpoint for all the randomized patients, and additional endpoints were objective response rate (ORR) and safety.

The results showed that PFS in intermediate risk patients improved with the treatment of C plus N plus I (HR 0.63, 95% CI 0.47-0.85), and there was a numerical increase in ORR (45, 95% CI 38.1-52.0) and disease control rate (DCR) (88). There was no change in PFS or ORR for poor-risk patients; however, DCR increased numerically with C plus N plus I (81). For both risk groups, progressive disease as best response was lower with C plus N plus I compared to the P plus N plus I. Duration of response was not reached in each treatment group.

For patients with intermediate risk scores, grade 3/4 treatment-related adverse events (TRAEs) occurred in 74% with C plus N plus I vs 42% with P plus N plus I and led to discontinuation of treatment in 14% and 5% of patients, respectively. Grade 3/4 TRAEs occurred in 67% of the IMDC poor risk patients with C plus N plus I vs 38% with P plus N plus I and led to treatment discontinuation in 5% and 4% of patients, respectively.

Overall, the analyses found that the combination of C plus N plus I in first-line treatment improved PFS for patients with aRCC who have intermediate or poor IMDC risk scores. However, the subgroup analysis suggests the benefit was more apparent in patients with intermediate risk scores. Powles and colleagues indicated that their follow-up investigation of OS outcomes for this treatment regimen is currently ongoing.

Reference

Powles T, Motzer RJ, Albiges L, et al. Outcomes by IMDC risk in the COSMIC-313 phase 3 trial evaluating cabozantinib (C) plus nivolumab (N) and ipilimumab (I) in first-line advanced RCC (aRCC) of IMDC intermediate or poor risk. Presented at: the 2023 ASCO GU Cancers Symposium; February 16-18, 2023; San Francisco, CA, and virtual; Abstract 605.