Dr Tykodi on the Current Limitations of Cabozantinib-Based Triplets in Advanced RCC

"The narrative [with triplet regimens] is that there are too many [adverse] effects. Patients can’t tolerate the therapy, and too many patients are stopping treatment. So you really aren’t delivering the triplet therapy as intended to enough patients to see benefit. This is the fear going forward [with] other attempts to build on top of the doublets that we have."

Scott Tykodi, MD, PhD, an associate professor in the Clinical Research Division and an affiliate investigator in the Translational Science and Therapeutics Division at Fred Hutchinson Cancer Center; as well as an associate professor in the Division of Hematology and Oncology at the University of Washington School of Medicine, discussed the clinical efficacy and potential role for cabozantinib (Cabometyx) plus checkpoint inhibition for patients with favorable-risk advanced renal cell carcinoma (RCC), as well as the challenges posed by the increased toxicities associated with such triplet regimens.

Enthusiasm for triplet regimens including cabozantinib, such as the combination studied in the phase 3 COSMIC-313 trial (NCT03937219), has been tempered by tolerability concerns, Tykodi began. The prevailing interpretation of results from COSMIC-313 has been that, despite the biologic rationale, the addition of cabozantinib to nivolumab (Opdivo) plus ipilimumab (Yervoy) did not confer substantial benefit over nivolumab plus ipilimumab alone, he stated. Many patients in the trial experienced significant toxicities, leading to early discontinuation or inability to maintain full-dose treatment, which limited the regimen’s effectiveness in practice, Tykodi said.

This challenge of achieving the intended therapeutic intensity and maintaining tolerability with existing triplet regimens raises broader concerns about the feasibility of future triplet regimens incorporating TKIs, he explained. As such, the field’s attention has turned to ongoing trials evaluating alternative combinations that may be more tolerable. Tykodi highlighted the pending results of the 3-arm, phase 3 LITESPARK-012 study (NCT04736706) evaluating belzutifan (Welireg) in combination with lenvatinib (Lenvima) and pembrolizumab (Keytruda), which may offer a more favorable safety profile compared with TKIs, given belzutifan’s relatively mild toxicity spectrum. He also referenced another study arm that includes a low-dose CTLA-4 inhibitor with lenvatinib and pembrolizumab, designed to test whether modified dosing can improve tolerability without sacrificing efficacy.

Although COSMIC-313 represented a scientifically sound effort to enhance outcomes in favorable-risk RCC, the results underscore the challenges of balancing efficacy and toxicity in multi-agent regimens, Tykodi concluded. He expressed interest in seeing whether emerging strategies can improve on this balance in subsequent triplet trials.