Dr McKay on the Role of Casdatifan Plus Cabozantinib in Clear Cell RCC

“These findings underscore the value of rational combination therapy in RCC. [Although] we don’t have direct head-to-head comparisons in this study, historic data suggest that single-agent cabozantinib…typically has a response rate of 25% to 30%, depending on the context, and the 46% [overall] response rate seen here with this combination is a numeric improvement.”

Rana R. McKay, MD, FASCO, a professor in the Department of Medicine and Department of Urology at the University of California, San Diego Health, detailed the significance of casdatifan plus cabozantinib (Cabometyx) demonstrating better outcomes compared with casdatifan or cabozantinib alone for the second-line treatment of patients with clear cell renal cell carcinoma (RCC).

The expansion cohort of the phase 1 ARC-20 study (NCT05536141) evaluated the safety and preliminary efficacy of casdatifan plus cabozantinib for the treatment of patients with clear cell RCC who previously received anti–PD-1/PD-L1 therapy. Results from the trial were presented at the 2025 ASCO Annual Meeting. The data emphasized the value of the combination in this patient population, McKay began. Although the study did not have a head-to-head comparison, historical data have demonstrated response rates of approximately 25% to 30% with single-agent cabozantinib, she explained. Nevertheless, in the post immuno-oncology population of ARC-20 (n = 24), the confirmed overall response rate (ORR) was 46% (95% CI, 25.6%-67.2%), displaying a numeric improvement in ORR vs historical data, she added. Casdatifan targets the HIF-2α pathway, which is fundamental in clear cell RCC, according to McKay. Therefore, as cabozantinib provides multikinase inhibition, the improved ORR is derived from the complementary mechanism of action of casdatifan, according to McKay.

At a median follow-up of 5.3 months (range, 2.8-9.1), the best overall response included 1 complete response and 10 partial responses. Twelve patients had stable disease, and 1 patient experienced disease progression. At a median follow-up of 3.7 months (range, 1.1-9.1), the most common any-grade treatment-related adverse effects in the safety population (n = 42) related to any of the study drugs included anemia (69%), fatigue (55%), increased alanine aminotransferase levels (38%), and diarrhea (36%).

Based on these data, the dual approach could be synergistic and will be tested in a phase 3 trial, McKay concluded.