Phase 2 LITESPARK-013 Demonstrates Efficacy of Higher Belzutifan Doses for ccRCC

The phase 1 LITESPARK-001 study examined belzutifan, a hypoxia-inducible factor 2α inhibitor, for the treatment of clear cell renal cell carcinoma (ccRCC), yet the maximal tolerated dose was not reached for dosages up to 240 mg per day.

The recommended phase 2 dose (RP2D) was 120 mg once per day based on pharmacodynamics, pharmacokinetics (PK), and safety. As a result, the phase 2 LITESPARK-013 study was developed to determine if a higher dose of belzutifan could improve efficacy while maintaining an acceptable safety profile. Dr. Neeraj Agarwal, of the Huntsman Cancer Institute, presented the study’s results at the European Society for Medical Oncology Congress 2023.

Patients included in the study had advanced ccRCC; 3 or more prior systemic regimens for advanced ccRCC, including an anti-PD-1/L1 agent; and disease progression during or after an anti-PD-1/L1 agent. Each patient was randomized 1:1 to receive belzutifan 120 mg or 200 mg once a day. Patients were grouped based on International Metastatic Renal Cell Carcinoma Database Consortium risk score (0 vs 1-2 vs 3-6) and number of prior tyrosine kinase inhibitor therapies for advanced ccRCC (0 vs 1 vs 2-3).

The primary end point was objective response rate (ORR), and secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and PK. The data cutoff was February 2023.

A total of 154 patients were enrolled (76 in the 120-mg arm, 78 in the 200-mg arm), and the median follow-up was 20.1 months (range, 14.8-28.4 months). The ORR was 23.7% in the 120-mg arm and 23.1% in the 200-mg arm (95% CI, −14.0 to 12.9; P=.5312). PFS (median, 7.3 vs 9.1 months; hazard ratio [HR], 0.94; 95% CI, 0.63-1.40) and OS (medians not reached; HR, 1.11; 95% CI, 0.65-1.90) did not differ between arms.

In the 120-mg arm, median DOR was not met (range, 2.6+ to 16.1+), and it was 16.1 months (2.1+ to 23.5+) in the 200-mg arm. A total of 64.7% and 51.3% of patients had ongoing responses ≥15 months, respectively. Treatment-related adverse events (TRAEs) occurred in 142 patients (70 [92.1%] with 120 mg; 72 [92.3%] with 200 mg). Treatment was discontinued due to a TRAE in 2 patients (2.6%) in the 120-mg arm and 7 patients (9.0%) in the 200-mg arm. Treatment-related anemia (81.6% with 120 mg; 83.3% with 200 mg) and hypoxia (23.7% with 120 mg; 26.9% with 200 mg) was similar between arms.

The efficacy of belzutifan was similar between the RP2D of the 120-mg and 200-mg treatment arms and was consistent with prior reports of antitumor activity in patients with ccRCC. Safety was consistent with the known safety profile of belzutifan, and this study supports the use of 120 mg administered once daily as the preferred belzutifan dose.