Long-term safety of belzutifan in von Hippel-Lindausyndrome: A single-center experience.

10605 Background: Belzutifan has improved control in Von Hippel-Lindau (VHL) syndrome, reducing the need for interventions. However, its long-term safety and side effect burden remain incompletely understood. This study evaluates long-term safety, tolerability and the impact of dose modifications in VHL patients (pts) treated with belzutifan. Methods: A single-center retrospective study of VHL pts ≥ 18 years treated with belzutifan at Vanderbilt (Nov 2018 - Dec 2024). Demographic and clinical data were collected. The primary endpoint was treatment discontinuation. Secondary endpoints included incidence of adverse events (AEs) (any-grade and grade ≥ 3 per CTCAE 5.0), dose reductions, time to dose reduction, treatment interruptions, subsequent procedures, and treatment failure (defined as radiological progression per RECIST 1.1 or physician assessment) while on treatment. Follow-up duration was defined as the time from the belzutifan initiation to last follow-up or discontinuation. Results: Twenty-five pts were identified, with a median age of 42 years, 64% female and 88% white, with a baseline hemoglobin of 13.7 (range: 11.0 – 19.0). As of January 2025, the median follow-up was 32.5 months (mo) (range: 2.5 – 75). Most common VHL-associated neoplasms included CNS hemangioblastomas (88%), renal cell carcinoma (72%), and pNET (32%). All pts started belzutifan at 120 mg. AEs occurred in 92% of pts (detailed in Table 1). Anemia was observed in 64% of pts (no grade ≥ 3), with a median onset of 3.4 mo (range: 1.1 – 17.7). Treatment interruptions were required by 68% of pts. At the last follow-up, 32% remained on 120 mg, 52% were on 80 mg, and 16% discontinued. The median time to discontinuation was 33 mo (range: 24.5 – 34); due to symptomatic anemia (1 pt), grade 3 hypoxia (1pt), disease progression (1pt) and a non-related death (1pt). Dose reductions were needed by 60% of pts, primarily due to anemia, with a median time to dose reduction of 6.8 mo (range: 1 – 17). Among the 15 pts with dose reductions, none experienced treatment failure during a median follow-up of 21.3 mo (range: 1 – 31), although one pt had persistent grade 3 hypoxia. No pts required transfusions and 8% received erythropoietin stimulating agents. Before belzutifan, 92% of pts had undergone procedures related to VHL manifestations. Following treatment initiation, 8% required additional procedures. Conclusions: These findings provide long-term safety data on belzutifan in VHL. While AE were common, dose reductions were effective in maintaining tolerability without compromising disease control. Adverse events in at least 5% of the safety population (25 pts). Any-grade Grade ≥ 3 Leading to dose reduction Leading to discontinuation Fatigue 20 (80) 1 (4) 4 (16) 0 Anemia 16 (64) 0 9 (36) 1 (4) Nausea 8 (32) 0 2 (8) 0 Dizziness 8 (32) 0 0 0 Headache 7 (28) 0 1 (4) 0 Hypoxia 2 (8) 1 (4) 1 (4) 1 (4) AST or ALT elevation 2 (8) 0 1 (4) 0 Cognitive impairment 2 (8) 0 0 0 Pericardial Effusion 2 (8) 1 (4) 2 (8) 0