Syst-18 belzutifan treatment for patients with von hippel-lindau disease–associated central nervous system hemangioblastomas enrolled in the phase 2 litespark-004 study

Abstract Previous results of the ongoing single-arm, phase 2 LITESPARK-004 (NCT03401788) study showed clinically meaningful antitumor activity with the HIF-2α inhibitor belzutifan for von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), CNS hemangioblastomas, and other neoplasms. Adults with VHL disease diagnosis based on germline VHL alteration, ≥1 measurable RCC tumor, and no prior systemic anticancer treatment received belzutifan 120 mg orally once daily. End points included ORR, DOR, and PFS per RECIST v1.1; linear growth rate (LGR); and safety. CNS hemangioblastomas were assessed with measurable (≥1 cm) and/or nonmeasurable disease at baseline, which included associated cysts if present, or with measurable disease at baseline excluding associated cysts. Of enrolled patients, 50/61 (82%) had ≥1 CNS hemangioblastoma evaluable at baseline; 22/50 patients (44%) underwent ≥1 CNS-related surgery within 4 years before starting belzutifan treatment. Median follow-up for patients with CNS hemangioblastomas was 38.0 months (range, 36.1-46.1). ORR was 44% and DCR was 90%. Median DOR was not reached (NR; range, 3.7+ to 38.7+ months). Median PFS was NR (95% CI, 38 months-NR). After initiating belzutifan, median LGR for all evaluable patients was –1.6 mm/year (range, –7.0 to 3.1). A total of 25/50 patients (50%) had ≥1 measurable CNS hemangioblastomas, excluding any associated cysts. For these patients, ORR was 76% and DCR was 96%. Median DOR was NR (range, 3.7+ to 38.7+ months). Median PFS was NR (95% CI, 36 months-NR). After initiating belzutifan, median LGR was –1.1 mm/year (range, –3.9 to –0.1). Of all patients, 1/50 (2%) underwent a CNS-related surgery after starting belzutifan. Two patients (3%) discontinued treatment due to treatment-related adverse events. In summary, consistent and durable antitumor activity was observed in patients with CNS hemangioblastomas. Our data demonstrated that belzutifan induced the shrinkage of VHL disease-related CNS hemangioblastomas with or without the presence of associated cysts.