Abstract
To report the efficacy of oral HIF-2α inhibitor belzutifan in participants with von Hippel-Lindau disease-associated retinal hemangioblastomas in LITESPARK-004. Subgroup analysis of the phase 2, single-arm, open-label LITESPARK-004 study. Adults with ≥1 von Hippel-Lindau disease-associated measurable renal cell carcinoma tumor not requiring immediate surgical intervention were eligible. Participants received oral belzutifan 120 mg once daily until disease progression or unacceptable treatment-related toxicity. Efficacy of belzutifan in retinal hemangioblastomas was a secondary end point, measured as response (improved, stable, or progressed) by independent reading center certified graders based on color fundus imaging performed every 12 weeks using the investigator's preferred imaging standards. Additional assessments, where available, included optical coherence tomography and ultra-widefield fluorescein angiography. Among 61 participants in LITESPARK-004, 12 had ≥1 evaluable active retinal hemangioblastoma in 16 eyes at baseline per independent reading center. As of April 1, 2022, the median follow-up for participants with ocular von Hippel-Lindau disease at baseline was 37.3 months. All 16 eyes were graded as improved, with a response rate of 100.0% (95% confidence intervals, 79.4-100.0). No new retinal hemangioblastomas or ocular disease progression were reported as of data cutoff date. Eight participants had additional multimodal eye assessments performed at the National Institutes of Health study site. Among this subgroup, 10 of 24 hemangioblastomas in 8 eyes of 6 participants measured ≥500 μm in greatest linear dimension at baseline and were further analyzed. All 10 hemangioblastomas had a mean area reduction of ≥15% by month 12 and ≥30% by month 24. Belzutifan showed promising activity against ocular von Hippel-Lindau disease, including capacity to control retinal hemangioblastomas, with effects sustained for >2 years while on treatment.
Overview
- The study aims to evaluate the efficacy of oral HIF-2α inhibitor belzutifan in participants with von Hippel-Lindau disease-associated retinal hemangioblastomas in LITESPARK-004. The study is a phase 2, single-arm, open-label study that enrolled adults with ≥1 von Hippel-Lindau disease-associated measurable renal cell carcinoma tumor not requiring immediate surgical intervention. Participants received oral belzutifan 120 mg once daily until disease progression or unacceptable treatment-related toxicity. The primary objective of the study is to assess the efficacy of belzutifan in retinal hemangioblastomas, measured as response (improved, stable, or progressed) by independent reading center certified graders based on color fundus imaging performed every 12 weeks using the investigator's preferred imaging standards. Additional assessments, where available, include optical coherence tomography and ultra-widefield fluorescein angiography. The study aims to answer the question of whether belzutifan is effective in controlling retinal hemangioblastomas in patients with von Hippel-Lindau disease.
Comparative Analysis & Findings
- The study found that all 16 eyes were graded as improved, with a response rate of 100.0% (95% confidence intervals, 79.4-100.0). No new retinal hemangioblastomas or ocular disease progression were reported as of data cutoff date. Eight participants had additional multimodal eye assessments performed at the National Institutes of Health study site. Among this subgroup, 10 of 24 hemangioblastomas in 8 eyes of 6 participants measured ≥500 μm in greatest linear dimension at baseline and were further analyzed. All 10 hemangioblastomas had a mean area reduction of ≥15% by month 12 and ≥30% by month 24. The study found that belzutifan showed promising activity against ocular von Hippel-Lindau disease, including capacity to control retinal hemangioblastomas, with effects sustained for >2 years while on treatment.
Implications and Future Directions
- The study's findings suggest that belzutifan is effective in controlling retinal hemangioblastomas in patients with von Hippel-Lindau disease. The study's results support the use of belzutifan as a potential treatment option for patients with ocular von Hippel-Lindau disease. The study's limitations include the small sample size and the lack of a control group. Future studies should include a larger sample size and a control group to further evaluate the efficacy and safety of belzutifan in patients with ocular von Hippel-Lindau disease. The study's findings also suggest that additional multimodal eye assessments may be useful in monitoring the response to belzutifan treatment. Future studies should explore the use of additional imaging modalities, such as optical coherence tomography and ultra-widefield fluorescein angiography, to monitor the response to belzutifan treatment in patients with ocular von Hippel-Lindau disease.