The LITESPARK-013 trial's findings indicate that belzutifan, a hypoxia-inducible factor (HIF)-2α inhibitor, demonstrates comparable efficacy in patients with previously treated clear cell renal cell carcinoma (ccRCC) at both the standard 120 mg dose and a higher 200 mg dose. This randomized phase 2 study (NCT04489771) provides evidence supporting the use of the standard dose to maximize therapeutic benefits while minimizing potential exposure-related risks.
The study enrolled 154 patients with measurable disease who had received no more than three prior systemic regimens for locally advanced/metastatic RCC, including no more than one prior anti-PD-1/L1 therapy. Patients were randomized 1:1 to receive either 120 mg or 200 mg of belzutifan once daily. The primary endpoint was objective response rate (ORR) per RECIST v1.1, with secondary endpoints including duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
Efficacy Outcomes
At a median follow-up of 20.1 months (range, 14.8-28.4), the ORR was 23.7% in the 120 mg arm and 23.1% in the 200 mg arm (P = .5312; 95% CI, -14.0% to 12.9%). The median DOR was not reached in the 120 mg arm compared to 16.1 months in the 200 mg arm. No significant differences in PFS or OS were observed between the two groups.
Safety Profile
Treatment-related adverse events (AEs) of grade 3 or 4 were reported in 46.1% of patients in the 120 mg arm and 46.2% in the 200 mg arm. This similar safety profile further supports the use of the 120 mg dose as the optimal choice.
Expert Commentary
Jaime Merchan, MD, professor and director of the phase 1 clinical trials program at the Sylvester Comprehensive Cancer Center at the University of Miami, highlighted that the study aimed to determine efficacy differences between the standard 120 mg dose and the higher 200 mg dose of belzutifan. The results presented at the 2023 European Society of Medical Oncology Annual Meeting indicated similar response rates and no significant differences in median progression-free survival between the two doses, suggesting the 120 mg dose is sufficient for clinical benefit.
Post Hoc Analysis
A post hoc efficacy analysis presented at the 2024 American Society of Clinical Oncology Annual Meeting explored potential correlations between efficacy and various clinical factors, including IMBC scores, differentiation status, number of prior lines of therapy, and type of first-line therapy (tyrosine kinase inhibitors or checkpoint inhibitors). This pooled analysis found no clear correlation between efficacy and any specific subgroup, suggesting belzutifan provides consistent benefits regardless of these factors.
Future Directions
Ongoing and upcoming studies are evaluating belzutifan in combination with tyrosine kinase inhibitors (TKIs) or checkpoint inhibitors in both second-line and first-line settings. Additionally, a phase 3 randomized study is near completion, assessing belzutifan in the adjuvant setting in combination with pembrolizumab.
