In a randomised, double-blind, phase III COSMIC-313 study that involved patients with previously untreated advanced renal cell carcinoma (RCC) who had intermediate or poor prognostic risk according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) categories, treatment with cabozantinib plus nivolumab and ipilimumab resulted in significantly longer progression-free survival (PFS) than treatment with nivolumab and ipilimumab.
Grade 3 or 4 adverse events and discontinuations were more frequent in the cabozantinib plus nivolumab and ipilimumab group. Follow-up for overall survival (OS) is ongoing. The results are published by Dr. Toni K. Choueiri of the Dana–Farber Cancer Institute in Boston, MA, US, Dr. Robert J. Motzer of the Memorial Sloan Kettering Cancer Center in New York, NY, US, and colleagues on 11 May 2023 in The New England Journal of Medicine.
The authors wrote that tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) are standard treatments for clear-cell, advanced RCC as single agents or in combination. In the phase III CheckMate 214 study, which included patients with advanced RCC who had intermediate or poor prognostic risk according to the IMDC categories, first-line treatment with nivolumab and ipilimumab resulted in higher OS and objective response rate than with sunitinib. However, 20% of the patients who received nivolumab and ipilimumab had progressive disease as the best response.
Cabozantinib is a TKI that targets multiple receptor tyrosine kinases involved in tumour growth, angiogenesis, metastasis, and immune regulation, including VEGFR, MET, and the TAM family of kinases. Cabozantinib improved outcomes as compared with sunitinib in previously untreated patients with advanced RCC in the CABOSUN study and in combination with nivolumab in the phase III CheckMate 9ER study. An exploratory analysis in the CheckMate 9ER study that included a small cohort of patients who received cabozantinib with nivolumab and ipilimumab showed that this triplet regimen had clinical activity and an acceptable safety profile.
In the COSMIC-313 study, patients were randomly assigned to receive 40 mg of cabozantinib daily in addition to nivolumab and ipilimumab or matched placebo in addition to nivolumab and ipilimumab. Nivolumab 3 mg per kilogram of body weight and ipilimumab 1 mg per kilogram were administered once every 3 weeks for 4 cycles. Patients then received nivolumab maintenance treatment 480 mg once every 4 weeks for up to 2 years.
The primary endpoint was PFS, as determined by blinded independent review according to RECIST v1.1 and was assessed in the first 550 patients who had undergone randomisation. The secondary endpoint was OS, assessed in all patients who had undergone randomisation.
Overall, 855 patients underwent randomisation, 428 were assigned to the cabozantinib plus nivolumab and ipilimumab group and 427 to the nivolumab and ipilimumab group. Among the first 550 patients who had undergone randomisation, 276 in the cabozantinib plus nivolumab and ipilimumab group and 274 in the nivolumab and ipilimumab group, the probability of PFS at 12 months was 0.57 in the cabozantinib plus nivolumab and ipilimumab group and 0.49 in the nivolumab and ipilimumab group (hazard ratio for disease progression or death 0.73; 95% confidence interval [CI] 0.57 to 0.94; p = 0.01). The median PFS was not reached (95% CI 14.0 months to could not be estimated) in the cabozantinib plus nivolumab and ipilimumab group and was 11.3 months (95% CI 7.7 to 18.2) in the nivolumab and ipilimumab group.
In the PFS population, 43% of the patients in the cabozantinib plus nivolumab and ipilimumab group and 36% in the nivolumab and ipilimumab group had a response, according to blinded independent review; 3% of the patients in both groups had a complete response. Response outcomes as assessed by the investigators were consistent with those as determined by blinded independent review.
Grade 3 or 4 adverse events occurred in 79% of the patients in the cabozantinib plus nivolumab and ipilimumab group and in 56% in the nivolumab and ipilimumab group. Adverse events related to the study regimen that led to discontinuation of any component occurred in 45% of the patients in the cabozantinib plus nivolumab and ipilimumab group and in 24% in the nivolumab and ipilimumab group. A total of 12% of the patients in the cabozantinib plus nivolumab and ipilimumab group and 5% in the nivolumab and ipilimumab group discontinued all components owing to a single adverse event.
The most common adverse events related to the study regimen that led to discontinuation of any component were increased alanine aminotransferase level (19% in the cabozantinib plus nivolumab and ipilimumab group and 4% in the nivolumab and ipilimumab group), increased aspartate aminotransferase level (15% and 3%, respectively), and immune-mediated hepatitis (5% and 1%, respectively).
Deaths that were related to the study regimen and occurred within 100 days before the last dose of the study regimen were observed in 5 patients (1%) in the cabozantinib plus nivolumab and ipilimumab group (1 event each of acute hepatic failure, gastrointestinal haemorrhage, hepatic failure, immune-mediated hepatitis, and respiratory failure) and in 4 patients (1%) in the nivolumab and ipilimumab group (1 event each of myocarditis, perforated ulcer, renal failure, and sudden death).
The authors commented that the results of subgroup analyses in previous studies that evaluated TKIs in combination with anti-PD1 agents for the first-line treatment of advanced RCC have suggested that the benefit of ICI combinations as compared with sunitinib is greater for patients with poor risk than for patients with intermediate risk. However, in this study, the addition of a TKI to nivolumab and ipilimumab did not appear to provide a benefit over nivolumab and ipilimumab in the subgroup of patients with poor risk, although interpretability is limited by the small subgroup size, and differences in populations confound comparisons across studies. Exploratory analyses according to individual IMDC risk factors may provide further insight into patient characteristics associated with outcomes.
Other ongoing phase III studies are evaluating combinations of TKIs and ICIs either as a triplet regimen or administered sequentially and their results may further inform the use of combination treatments.
The findings were previously presented in part at ESMO 2022 Congress (Paris, France, 9-13 September).
The study was supported by Exelixis. Bristol-Myers Squibb provided nivolumab and ipilimumab.
Choueiri TK, Powles T, Albiges L, et al. for the COSMIC-313 Investigators. Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. N Engl J Med 2023; 388:1767-1778.