Clinical Pearls & Morning Reports
Published May 10, 2023
Choueiri et al. conducted a phase 3 trial that evaluated cabozantinib in addition to nivolumab and ipilimumab (experimental group) as compared with placebo in addition to nivolumab and ipilimumab (control group) in patients with previously untreated advanced renal-cell carcinoma who had intermediate or poor risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) categories. Read the NEJM Original Article here.
Q: How effective are currently available therapies for clear-cell, advanced renal-cell carcinoma?
A: Tyrosine kinase inhibitors and immune checkpoint inhibitors are standard treatments for clear-cell, advanced renal-cell carcinoma as single agents or in combination. In the phase 3 CheckMate 214 trial, which included patients with advanced renal-cell carcinoma who had intermediate or poor prognostic risk according to the IMDC categories, first-line therapy with nivolumab and ipilimumab resulted in higher overall survival and objective response rates than with sunitinib. However, 20% of the patients who received nivolumab and ipilimumab had progressive disease as the best response.
Q: What are some of the targets of cabozantinib?
A: Cabozantinib is a tyrosine kinase inhibitor that targets multiple receptor tyrosine kinases involved in tumor growth, angiogenesis, metastasis, and immune regulation, including vascular endothelial growth factor receptor, MET, and the TAM family of kinases (TYRO3, AXL, MER). Cabozantinib improved outcomes as compared with sunitinib in previously untreated patients with advanced renal-cell carcinoma when administered as a single agent in the CABOSUN trial and in combination with nivolumab in the phase 3 CheckMate 9ER trial.
A: The primary end point of the trial was progression-free survival. The probability of progression-free survival at 12 months was 0.57 (95% confidence interval [CI], 0.50 to 0.63) in the experimental group and 0.49 (95% CI, 0.42 to 0.55) in the control group (hazard ratio for disease progression or death, 0.73; 95% CI, 0.57 to 0.94; P = 0.01). In prespecified subgroup analyses, the progression-free survival benefit associated with the addition of cabozantinib to nivolumab and ipilimumab was maintained, except in the subgroup of patients who had poor IMDC risk. In the progression-free survival population, 43% (95% CI, 37 to 49) of the patients in the experimental group and 36% (95% CI, 30 to 42) in the control group had a response, according to blinded independent review; 3% of the patients in both groups had a complete response. Follow-up for overall survival is ongoing.
A: Elevated liver transaminase levels were the most common grade 3 or 4 adverse events in the experimental group and the most common events related to the trial regimen that led to discontinuation of any component. Adverse events were more frequent and were of higher grade in the experimental group than in the control group. Adverse events associated with both cabozantinib and immune checkpoint inhibitors (e.g., hepatic-enzyme elevation, diarrhea, and skin effects) and discontinuations owing to adverse events were more common in the experimental group than in the control group.