Dr Qin on Ongoing Investigations of Belzutifan Combinations in Advanced ccRCC

Qian (Janie) Qin, MD, assistant professor, Division of Hematology and Oncology, Department of Internal Medicine, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, discusses several belzutifan (Welireg) combination strategies under investigation in advanced clear cell renal cell carcinoma (ccRCC).

Current research has demonstrated that HIF2α inhibition appears to be well tolerated when given as a monotherapy in RCC, Qin begins. Accordingly, there is substantial interest in exploring the agents efficacy in combination with other standard agents in this space, Qin states. For example, the first-in-class, small molecule HIF2α inhibitor belzutifan is currently being investigated in several clinical trials alongside VEGF TKIs.

In the phase 2 LITESPARK-003 trial (NCT03634540), belzutifan was evaluated in combination with cabozantinib (Cabometyx) for patients with advanced ccRCC who had been previously exposed to immunotherapy. Patients received a daily 120 mg dose of belzutifan and 60 mg dose of cabozantinib (Cabometyx) in 2 cohorts of patients. Cohort 1 consisted of treatment-naïve patients, and cohort 2 was comprised of patients who had received up to 2 prior lines of systemic therapy and immune checkpoint inhibitors.

Preliminary efficacy results showed that the combination generated promising antitumor activity and manageable safety in both populations, producing a confirmed overall response rate (ORR) of 57% in cohort 1. An updated analysis of cohort 2 revealed that the combination elicited an ORR of 30.8% and a disease control rate of 92% after approximately 2 years of follow up.

These results support further study of VEGF TKI and HIF-2 inhibitor combinations in RCC. One such study is the phase 3 LITESPARK-011 trial (NCT04586231), which will investigate the combination of belzutifan and lenvatinib (Lenvima) vs cabozantinib alone in patients with advanced RCC who experienced disease progression after prior anti-PD-1/PD-L1 therapy in the first- or second-line setting or as adjuvant therapy.