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Cabozantinib Plus Nivolumab and Ipilimumab for Renal Cell Carcinoma
TAKE-HOME MESSAGE
- This phase III trial showed that treatment with cabozantinib plus nivolumab and ipilimumab was associated with significantly longer progression-free survival and higher response rates than immunotherapy alone in patients with untreated, intermediate to poor prognostic risk, advanced clear cell renal cell carcinoma. Adverse events were more frequent and of higher grade in the cabozantinib plus immunotherapy group, with a higher discontinuation rate, especially in patients with grade 3 to 4 transaminitis.
- Cabozantinib plus nivolumab and ipilimumab as a first-line treatment in patients with intermediate to poor prognostic risk advanced clear cell renal cell carcinoma led to better progression-free survival outcomes. The evaluation of overall survival outcomes is ongoing.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
The efficacy and safety of treatment with cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal-cell carcinoma are unknown.
METHODS
In this phase 3, double-blind trial, we enrolled patients with advanced clear-cell renal-cell carcinoma who had not previously received treatment and had intermediate or poor prognostic risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium categories. Patients were randomly assigned to receive 40 mg of cabozantinib daily in addition to nivolumab and ipilimumab (experimental group) or matched placebo in addition to nivolumab and ipilimumab (control group). Nivolumab (3 mg per kilogram of body weight) and ipilimumab (1 mg per kilogram) were administered once every 3 weeks for four cycles. Patients then received nivolumab maintenance therapy (480 mg once every 4 weeks) for up to 2 years. The primary end point was progression-free survival, as determined by blinded independent review according to Response Evaluation Criteria in Solid Tumors, version 1.1, and was assessed in the first 550 patients who had undergone randomization. The secondary end point was overall survival, assessed in all patients who had undergone randomization.
RESULTS
Overall, 855 patients underwent randomization: 428 were assigned to the experimental group and 427 to the control group. Among the first 550 patients who had undergone randomization (276 in the experimental group and 274 in the control group), the probability of progression-free survival at 12 months was 0.57 in the experimental group and 0.49 in the control group (hazard ratio for disease progression or death, 0.73; 95% confidence interval, 0.57 to 0.94; P = 0.01); 43% of the patients in the experimental group and 36% in the control group had a response. Grade 3 or 4 adverse events occurred in 79% of the patients in the experimental group and in 56% in the control group. Follow-up for overall survival is ongoing.
CONCLUSIONS
Among patients with previously untreated, advanced renal-cell carcinoma who had intermediate or poor prognostic risk, treatment with cabozantinib plus nivolumab and ipilimumab resulted in significantly longer progression-free survival than treatment with nivolumab and ipilimumab alone. Grade 3 or 4 adverse events were more common in the experimental group than in the control group. (Funded by Exelixis; COSMIC-313 ClinicalTrials.gov number, NCT03937219.).
Additional Info
Disclosure statements are available on the authors' profiles:
Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma
N. Engl. J. Med 2023 May 11;388(19)1767-1778, TK Choueiri, T Powles, L Albiges, M Burotto, C Szczylik, B Zurawski, E Yanez Ruiz, M Maruzzo, A Suarez Zaizar, LE Fein, FA Schutz, DYC Heng, F Wang, F Mataveli, YL Chang, M van Kooten Losio, C Suarez, RJ MotzerFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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Although doublet regimens are established for patients with clear cell renal cell carcinoma (ccRCC), the safety and efficacy of triplet combinations remain poorly defined. COSMIC-313 was a phase III trial that randomized 855 patients with treatment-naïve IMDC intermediate/poor-risk ccRCC to cabozantinib plus nivolumab and ipilimumab (triplet) or placebo plus nivolumab and ipilimumab (doublet).
The study demonstrated a significant improvement in progression-free survival (PFS) favoring the triplet over the doublet regimen. In subgroup analyses, patients with intermediate-risk disease appeared to have a greater PFS benefit from the triplet than from the doublet regimen, whereas patients with poor-risk disease appeared to have similar PFS between the regimens. Although the rates of complete and partial responses were similar between the treatment arms, the triplet regimen was associated with a higher rate of disease control and a lower rate of progressive disease. The triplet regimen was associated with higher rates of grade 3 to 4 adverse events leading to dose reductions, drug discontinuation, and corticosteroid use.
The key takeaway of the COSMIC-313 trial is that the addition of cabozantinib to nivolumab and ipilimumab demonstrated a PFS benefit relative to nivolumab plus ipilimumab. As the overall survival results continue to mature, the selection of patients who may benefit from the triplet regimen will need to be carefully weighed against the significant risk of adverse events. Further studies investigating combination regimens are ongoing.