A First-Line Triplet for Kidney Cancer: A Targeted Drug Plus Dual Immunotherapy

One notable presentation at ESMO Congress 2022 concerned the international COSMIC-313 trial in advanced kidney cancer. Its results showed that adding cabozantinib to nivolumab plus ipilimumab in first-line advanced renal cell cancer prolonged progression-free survival . However, the increased frequency of adverse events must also be considered.

Cabozantinib plus Nivolumab plus Ipilimumab (C+N+I) led, among 550 previously untreated patients with intermediate- or poor-risk advanced renal cell carcinoma (RCC), to a significant 27% reduction in progression risk compared with N+I (hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.57-0.94; p=0.013). Median progression-free survival was not reached in the C+N+I arm because treatment kept cancer controlled in more than half of patients (95% CI, 14.0 to not estimable), versus 11.3 months with N+I (95% CI, 7.7-18.2).

With the triplet and doublet, objective response rates were 43% and 36%, respectively , and median response duration was not reached in either arm.

In this global, double-blind randomized study, patients with advanced clear-cell RCC received N+I every 3 weeks for 4 cycles, followed by N every 4 weeks for up to 2 years. Randomization to cabozantinib or placebo was stratified by region and disease risk, and progression-free survival was assessed by blinded independent review.

Meeting its primary endpoint, COSMIC-313 is the first trial to show that adding a TKI to dual checkpoint inhibition can improve PFS in this setting. But do these results change current practice?

The findings are certainly exciting and important. What is still missing is treatment that delivers complete, durable responses with better long-term outcomes. The triplet appears to prevent early progression, a major advantage over the FDA-approved nivolumab/ipilimumab doublet. However, we must wait to see whether the progression-free survival results translate into overall survival benefits. Efficacy must also be balanced against the triplet’s additional adverse effects.

In COSMIC-313, serious grade 3-4 treatment-related adverse events occurred in 73% receiving the triplet and 41% receiving the doublet. The triplet also caused discontinuation of all treatment components more than twice as often (12% versus 5%). More triplet recipients developed elevated liver enzymes. Three patients in each arm experienced grade 5 treatment-related adverse events: gastrointestinal hemorrhage, liver failure and respiratory failure in the triplet arm, and kidney failure, myocarditis and sudden death in the doublet arm.

COSMIC-313 safety data seem to reflect an exploratory analysis presented earlier this year from the discontinued C+N+I arm of CheckMate 9ER, involving 50 advanced kidney cancer patients. More information about COSMIC-313’s safety profile is therefore needed to define the triplet’s future role. Dose modifications for adverse events were common in CheckMate 9ER, and 40% had at least one serious grade 3-4 immune-mediated liver adverse event. The full scientific article is needed to understand how dose reduction and discontinuation affected outcomes in COSMIC 313.

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Below are FDA-approved advanced kidney cancer treatments and indirect comparisons based on survival data:

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