Pivotal RCC trial of cabozantinib plus nivolumab and ipilimumab hits enrollment goal

Enrollment has been completed in the pivotal phase 3 COSMIC-313 trial exploring the triplet of cabozantinib (Cabometyx) plus nivolumab (Opdivo) and ipilimumab (Yervoy) as a frontline treatment for patients with advanced intermediate- or poor-risk renal cell carcinoma (RCC).1

The multicenter, double-blinded COSMIC-313 trial (NCT03937219) is randomizing patients to nivolumab/ipilimumab plus either cabozantinib or matching placebo. The enrollment goal was approximately 840 patients. The primary end point of the trial is progression-free survival, with secondary outcome measures including overall survival (OS) and objective response rate (ORR).

“Following the promising final results of a phase 1b trial evaluating this triplet combination in advanced genitourinary tumors, this milestone in the phase 3 pivotal trial brings us a step closer to understanding whether cabozantinib in combination with nivolumab and ipilimumab may improve outcomes for patients with previously untreated advanced kidney cancer,” Gisela Schwab, MD, president, Product Development and Medical Affairs and chief medical officer, Exelixis, the developer of cabozantinib, stated in a press release.

“We look forward to sharing initial results from the event-driven analysis of COSMIC-313 when available and to learning more about the potential of cabozantinib in combination with immunotherapies,” added Schwab.

Phase 1b trial

The activity of the triplet regimen was previously demonstrated in a phase 1b trial, the final results of which were presented at the 2021 Genitourinary Cancers Symposium.2 The study explored both the doublet of cabozantinib plus nivolumab and the triplet of cabozantinib plus nivolumab and ipilimumab in patients with multiple tumor types.

Among the 16 patients in the trial with previously treated metastatic RCC, the ORR was 62.5%. Regarding safety, the most common grade 3/4 treatment-related adverse events (AEs) observed across all patients receiving the triplet were fatigue (16%), hypertension (11%), dehydration (5.3%), and thromboembolic event (5.3%). The most frequent immune-related grade 3/4 AEs in patients receiving the triplet were hepatitis (7%) and colitis (7%).

CheckMate-214 Trial

According to Exelixis, results from the pivotal CheckMate-214 trial informed the design of the COSMIC-313 study. That study supported the April 2018 approval of the combination of nivolumab and ipilimumab for the frontline treatment of patients with intermediate- or poor-risk advanced RCC.

The randomized, open-label phase 3 CheckMate-214 trial evaluated the combination of nivolumab and ipilimumab versus sunitinib (Sutent) in patients with previously untreated advanced or metastatic RCC. Four-year follow-up data were presented at the 2020 European Society for Medical Oncology virtual congress.3

In intermediate- to poor-risk patients treated with nivolumab/ipilimumab, the median OS was 48.1 months, compared with 26.6 months in patients who received sunitinib (HR, 0.65). The 4-year OS rate for the combination treatment and sunitinib groups was 50.0% and 35.8%, respectively.

Regarding response, ORR was also higher in patients receiving combination treatment versus sunitinib, with more ongoing responses in intermediate- to poor-risk patients (65% vs 50%, respectively). Median duration of response was not reached in the combination treatment arm and was 19.7 months for sunitinib.


1. Exelixis Announces Enrollment Completion in Phase 3 COSMIC-313 Pivotal Trial of Cabozantinib in Combination with Nivolumab and Ipilimumab Versus Nivolumab and Ipilimumab in Previously Untreated Advanced Renal Cell Carcinoma. Published online March 30, 2021. Accessed March 31, 2021. https://bit.ly/31yKeCD.

2. Exelixis Announces Final Phase 1 Results from Clinical Trial Sponsored by the National Cancer Institute at ASCO GU for Cabozantinib in Combination with Nivolumab with or without Ipilimumab in Patients with Refractory Metastatic Genitourinary Tumors. Published online February 12, 2021. Accessed March 31, 2021. https://bit.ly/2POEIJ9

3. Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma 711P in CheckMate 214: 4-year follow-up and subgroup analysis of patients without nephrectomy. Presented at: European Society of Medical Oncology virtual congress; September 19-21, 2020. Abstract 711P.

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