Adding cabozantinib to nivolumab and ipilimumab as first-line therapy, compared with placebo, results in prolonged progression-free survival (PFS) among untreated patients with advanced renal cell carcinoma (RCC), with no new safety signals seen, as shown by the results of the phase III COSMIC-313 study.
Overall survival (OS) outcomes did not improve, but investigators noted in exploratory biomarker analyses that adding cabozantinib to nivolumab and ipilimumab improves survival in patients with high levels of M2-like macrophages.
A total of 855 patients were randomly assigned to receive either cabozantinib 40 mg (n=428) or placebo (n=427) once daily plus nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks (four cycles) at 152 study sites across 25 countries. Treatment was followed by maintenance therapy with cabozantinib or placebo plus nivolumab 480 mg every 4 weeks for a maximum of 2 years.
Of the participants, 426 in the cabozantinib (triplet) arm and 423 in the placebo (doublet) arm were included in the safety analyses. Crossover between treatment groups was not allowed.
The updated median PFS over a median follow-up of 45.0 months was longer in the triplet arm than the double arm (16.6 vs 11.2 months; hazard ratio [HR], 0.82, 95 percent confidence interval [CI], 0.69‒0.98). [Ann Oncol 2026;37:861-871]
Median OS did not significantly differ between arms (HR, 1.02, 95 percent CI, 0.85‒1.23; p=0.84). The safety profile was similar with the previous analysis, with grade 3/4 treatment-related adverse events occurring in 75 percent and 43 percent of patients in the triplet and doublet arms, respectively.
Notably, the addition of cabozantinib to nivolumab and ipilimumab correlated with significant improved PFS and OS in RCC patients with higher levels of M2-like macrophages when compared with placebo. Moreover, responders in the triplet arm showed increased angiogenic signatures and reduced immune-related pathways, while those in the doublet arm demonstrated robust immune activation.
“Results from exploratory biomarker analyses suggest that M2-like macrophage levels are associated with baseline prognostic factors and may be predictive of clinical benefit,” the investigators said. “Preclinical and clinical validation of these results is ongoing.”
Treatment response
In the intention-to-treat analysis, 46 percent and 37 percent of patients in the triplet and doublet arms, respectively, showed a response. The proportion of patients with progressive disease as their best response was significantly lesser in the cabozantinib arm (8 percent vs 20 percent).
“These data are similar to those reported in the primary analysis, suggesting that the percentage of patients with an objective response did not increase with longer follow-up,” the investigators said. [N Engl J Med 2023;388:1767-1778]
“Despite a lower objective response rate in the doublet arm, landmark estimates of duration of response at later time points were numerically higher than in the triplet arm,” they added.
These differences must be interpreted with caution given the small number of patients remaining at risk and the influence of censoring at longer follow-up, according to the investigators.
“Further research is needed to confirm these observations and elucidate the contribution of each component to sustaining antitumor responses,” they said.
An oral tyrosine kinase inhibitor, cabozantinib targets several kinases involved in tumour pathogenesis and immune regulation, including vascular endothelial growth factor receptor, MET, and the TAM kinases. [Mol Cancer Ther 2011;10:2298-2308; Cancer Treat Rev 2021;98:102221]