At the American Society of Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2025, held on 13-15 February, final results from the randomised, multicentre, double-blind, Phase III COSMIC-313 clinical trial were presented. The trial evaluated the effect of triplet therapy with Exelixis’s Cabometyx and Bristol Myers Squibb’s Opdivo and Yervoy versus standard-of-care Opdivo and Yervoy combination as a front-line therapy for intermediate or poor-risk advanced or metastatic renal cell carcinoma (RCC).
RCC is the most common kidney cancer, with one-third of patients diagnosed in advanced stages. According to leading data and analysis company GlobalData’s Renal Cell Carcinoma (RCC): Epidemiology Forecast to 2033 report, the number of diagnosed incident cases of RCC in the eight major markets (the US, France, Germany, Italy, Spain, the UK, Japan, and China) will grow to 227,737 cases by 2033. Cabometyx is a multitargeted tyrosine kinase inhibitor (TKI) that received US Food and Drug Administration (FDA) approval in 2017 based on Phase II CABOSUN clinical trial data as a monotherapy for previously untreated patients with advanced RCC.
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In the COSMIC-313 trial, 855 patients with advanced or metastatic RCC were randomised 1:1 into the experimental arm (Cabometyx plus Opdivo plus Yervoy; n=428) and the comparator arm (placebo plus Opdivo plus Yervoy; n=427). The primary endpoint, median progression-free survival was 16.6 months for the Cabometyx arm (hazard ratio [HR] 0.82, 95% confidence interval [CI]: 0.69, p=0.98) compared to 11.2 months for the comparator arm. At the median follow-up of 45.0 months, the secondary endpoint of overall survival (OS) for intermediate and poor-risk advanced RCC patients was not significantly different between the Cabometyx and placebo arms, at 41.9 months and 42.0 months, respectively, (HR: 1.02, 95% CI: 0.85–1.23, p=0.84). However, in a biomarker analysis, patients with high M2 macrophage abundance showed better OS in the Cabometyx arm. Treatment-emergent adverse events (TEAEs) were comparable between the arms, with grade 3 and 4 TEAEs being higher in the Cabometyx arm (81% versus 62%), and 1% of patients having a TEAE grade 5 in both arms.
If successful, the COSMIC-313 clinical trial could lead to the triplet regimen becoming the new standard of care for intermediate and poor-risk advanced RCC patients. In August 2024, Exelixis first disclosed that the Cabometyx triplet combination missed the OS endpoint and cancelled its possible label expansion. The final result of the COSMIC-313 trial is not the only disappointment for Exelixis. In September 2024, Exelixis announced a numerical but not statistically significant improvement in OS data for Cabometyx and Roche’s Tecentriq combination treatment for metastatic castration-resistant prostate cancer from the Phase III CONTACT-02 clinical trial. Exelixis is awaiting an FDA decision on a new drug application for previously treated advanced pancreatic neuroendocrine tumours (pNET) by April 2025. If Cabometyx gains approval for pNET patients, it may provide the company with an incremental revenue opportunity for Exelixis given the niche market size.
Amid the recent setbacks for Cabometyx, Exelixis is focusing on its new next-generation TKI. Zanzalitinib, in combination with Opdivo is compared to Pfizer’s Sutent in unresectable, locally advanced, or metastatic untreated RCC in the Phase III STELLAR-304 trial. Additionally, two planned Phase III pivotal trials for RCC will evaluate zanzalintinib in combination with Merck’s Welireg. According to GlobalData’s analyst consensus forecast, Cabometyx and zanzalintinib will reach global sales of $2.6bn and $818m, respectively, by 2030.
