Volumetric analysis of central nervous system hemangioblastomas during belzutifan treatment holiday in von Hippel–Lindau (VHL) disease patients.

Abstract

e22659 Background: Belzutifan produces durable volumetric responses in von Hippel–Lindau (VHL)–associated central nervous system (CNS) hemangioblastomas. However, data describing tumor behavior during treatment holidays are limited. Methods: We conducted a retrospective lesion-level volumetric analysis of VHL patients with CNS hemangioblastomas treated with belzutifan at Massachusetts General Brigham Cancer Institute between September 2018 and January 2026 who experienced a treatment interruption (holiday) ≥3 months. Longitudinal MRI data were retrospectively reviewed. Lesions were classified at holiday baseline as measurable (≥10 mm), submeasurable (5–9 mm), or non-measurable ( < 5 mm). The primary endpoint was lesion-level volumetric change during treatment holiday; secondary endpoints included ORR, best overall response, and time to response per RECIST 1.1. Lesion-level volumetric analyses were performed for measurable and submeasurable lesions. Treatment holiday was offered after ≥9 months of sustained maximal response. The study was conducted under an institutional review board–approved protocol. Results: Nine patients were included. At treatment initiation baseline imaging, 16 measurable, 11 submeasurable, and 34 non-measurable lesions were identified. At treatment holiday baseline, 7 measurable, 5 submeasurable, and 9 non-measurable lesions were evaluable. Median duration of belzutifan therapy prior to treatment interruption was 34.4 months (range, 2.9–57.7). Median duration of treatment interruption was 12.7 months (IQR, 9.3–15.3). Seven patients had RECIST-evaluable measurable disease. The ORR was 85.7% (6/7 partial responses; 95% CI, 42.1–99.6), with stable disease observed in 14.3% (1/7). No RECIST-defined progression occurred prior to treatment withholding. Median TTR was 5.9 months (range, 1.8–7.9), and responses were ongoing at the time of treatment interruption in all responding patients. From treatment holiday baseline to last eligible MRI, 10/12 evaluable lesions (83.3%) demonstrated volumetric increase ≥10%, while 2/12 lesions (16.7%) decreased in size by ≥10%. Among lesions that grew during treatment holiday, the median volumetric increase was +116.1% (IQR, 187.1), over a median duration of 8.7 months (IQR, 6.0). Conclusions: During belzutifan treatment holiday, most evaluable CNS lesions demonstrated mild volumetric increase over time, although lesion behavior was heterogeneous and occurred over several months rather than immediately after treatment withholding. These findings provide early, lesion-level insight into CNS hemangioblastoma dynamics during belzutifan holidays and support cautious clinical monitoring during treatment interruption. Ongoing follow-up and expanded analyses will further characterize lesion dynamics during belzutifan treatment holidays.