In the phase 1 LITESPARK-001 study of the HIF-2α inhibitor belzutifan for ccRCC, the MTD was not reached for dosages up to 240 mg per day, and the RP2D was 120 mg QD based on PD, PK, and safety. The phase 2 LITESPARK-013 study (NCT04489771) examined if a higher belzutifan dose could improve efficacy while maintaining an acceptable safety profile.
Pts with advanced ccRCC, measurable disease per RECIST v1.1, ≤3 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 were randomly assigned 1:1 to belzutifan 120 mg or 200 mg QD. Pts were stratified by IMDC risk score (0 vs 1-2 vs 3-6) and number of prior TKI therapies for advanced ccRCC (0 vs 1 vs 2-3). Primary end point was ORR per RECIST v1.1 by blinded independent central review. Secondary end points included DOR, PFS, OS, safety, and PK. Database cutoff was February 10, 2023.
154 pts were enrolled (120 mg: n=76; 200 mg: n=78). Baseline characteristics were well balanced between arms. Median follow-up was 20.1 months (range 14.8-28.4). ORR was 23.7% (18 PR) vs 23.1% (4 CR; 14 PR) for the 120 mg and 200 mg arms, respectively (P=0.5312; −0.5% [95% CI, −14.0 to 12.9] using the Miettinen-Nurminen method stratified by IMDC risk). PFS (median 7.3 vs 9.1 months; 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. Median DOR was not reached for the 120 mg arm (range 2.6+ to 16.1+) and was 16.1 mo (2.1+ to 23.5+) for the 200 mg arm; 64.7% and 51.3% of pts had ongoing responses ≥15 mo, respectively. 142 pts had a treatment-related AE (TRAE; 70 [92.1%] with 120 mg; 72 [92.3%] with 200 mg]. 2 pts (2.6%) in the 120 mg arm and 7 (9.0%) in the 200 mg arm discontinued treatment due to a TRAE. Treatment-related anemia (81.6% with 120 mg and 83.3% with 200 mg) and hypoxia (23.7% with 120 mg and 26.9% with 200 mg) was similar between arms.
The efficacy of belzutifan was similar between the RP2D of 120-mg dose and the 200-mg dose and was consistent with prior reports of antitumor activity in ccRCC. Safety at both doses was consistent with the known safety profile of belzutifan. These results further support 120 mg QD as the preferred dose for belzutifan.
NCT04489771.