Final results of the phase 3 COSMIC-313 study comparing first-line cabozantinib plus nivolumab and ipilimumab with nivolumab plus ipilimumab in patients with advanced renal-cell carcinoma
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Authors
Albiges L.
Motzer R.
Aguirre S.A.T.
Kanesvaran R.
Centkowski P.
Reimers M.A.
Pablo Sade J.
Pouessel D.
Biscaldi E.
Esteban E.
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2025
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Background: The randomized, double-blind, phase 3 COSMIC-313 study (ClinicalTrials.gov: NCT03937219) met its primary endpoint, demonstrating significantly improved progression-free survival (PFS) with the combination of cabozantinib plus nivolumab and ipilimumab versus placebo plus nivolumab and ipilimumab in patients with previously untreated advanced renal-cell carcinoma (aRCC) who had intermediate or poor prognostic risk according to International Metastatic RCC Database Consortium (IMDC) categories (Choueiri et al. N Engl J Med. 2023). Here, the secondary endpoint of overall survival (OS) is presented, as well as updated efficacy and safety data and the results of exploratory biomarker analyses. Method(s): In COSMIC-313, patients with previously untreated IMDC intermediate- or poor-risk aRCC were randomized to receive oral cabozantinib 40 mg once daily or placebo. Both groups received nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) intravenously every 3 weeks for four cycles, followed by nivolumab therapy (480 mg every 4 weeks) for up to 2 years. The primary endpoint (previously reported) was PFS by blinded independent central review per Response Evaluation Criteria in Solid Tumors version 1.1 in the first 550 randomized patients. The secondary endpoint was OS in all randomized patients. Immune subsets (deconvoluted from RNA-sequencing data) associated with improved OS with cabozantinib plus nivolumab and ipilimumab versus placebo plus nivolumab and ipilimumab were identified using a random forest model. Result(s): Overall, 855 patients were randomized to cabozantinib plus nivolumab and ipilimumab (n = 428) or placebo plus nivolumab and ipilimumab (n = 427); of these, 75% had intermediate-risk and 25% had poor-risk disease per IMDC. With a median follow-up of 45.0 months, the improvement in PFS with cabozantinib plus nivolumab and ipilimumab was maintained; median PFS was 16.6 months (95% confidence interval [CI], 14.0-22.6) with cabozantinib plus nivolumab and ipilimumab and 11.2 months (95% CI, 9.3-14.0) with placebo plus nivolumab and ipilimumab (hazard ratio [HR], 0.82 [95% CI, 0.69-0.98]). There was no significant difference in median OS between cabozantinib plus nivolumab and ipilimumab and placebo plus nivolumab and ipilimumab in the intention- to-treat population (Table) or by IMDC risk group. The objective response rate (ORR) was higher with cabozantinib plus nivolumab and ipilimumab, and fewer patients had progressive disease as a best response (Table). Grade 3/4 treatment-emergent adverse events (TEAEs) were reported in 81% of patients treated with cabozantinib plus nivolumab and ipilimumab and 62% of those treated with placebo plus nivolumab and ipilimumab. The most common grade 3/4 TEAEs were increased alanine aminotransferase (27% and 6%, respectively) and increased aspartate aminotransferase (20% and 5%, respectively). Grade 5 treatment-related adverse events occurred in 1% of patients in each group. Exploratory biomarker analyses showed no significant differences in OS according to baseline c-Met or programmed death-ligand 1 levels. A higher abundance of M2 macrophages was observed in patients with poor-risk disease per IMDC, a high baseline sum of target lesions, or visceral metastasis. In patients with higher levels of M2 macrophages, treatment with cabozantinib plus nivolumab and ipilimumab was associated with improved OS versus placebo plus nivolumab and ipilimumab (HR, 0.51 [95% CI, 0.31-0.86]). Further analyses of angiogenic and immune signatures are ongoing. Conclusion(s): For patients with intermediate- or poor-risk aRCC, first-line treatment with cabozantinib plus nivolumab and ipilimumab continued to demonstrate PFS and ORR benefits over placebo plus nivolumab and ipilimumab. OS was comparable between the two arms, and there were no new safety signals. Patients with tumors that had high levels of M2 macrophages had improved OS with cabozantinib plus nivolumab and ipilimumab versus placebo plus nivolumab and ipilimumab..
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The oncologist