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J Neurol Surg B Skull Base
DOI: 10.1055/a-2724-4297
Original Article

Belzutifan in Von Hippel-Lindau–associated Hemangioblastomas: A Systematic Review and Meta-analysis

Authors

  • Kiana J. Yeganeh 

    1   Ponce Health Sciences University School of Medicine, Ponce, Puerto Rico, United States
    2   Department of Neurosurgery, Brain, and Spine, University of South Florida, Tampa, Florida, United States

  • Emma Sargent

    2   Department of Neurosurgery, Brain, and Spine, University of South Florida, Tampa, Florida, United States
    3   Forida Atlantic University Charles E. Schmidt College of Medicine, Boca Raton, Florida, United States

  • Gaddiel Ahmed

    1   Ponce Health Sciences University School of Medicine, Ponce, Puerto Rico, United States

  • Farina Klocksieben

    4   Research Methodology and Biostatistics Core, University of South Florida, Tampa, Florida, United States

  • Elliot Pressman

    2   Department of Neurosurgery, Brain, and Spine, University of South Florida, Tampa, Florida, United States

  • Kunal Vakharia

    2   Department of Neurosurgery, Brain, and Spine, University of South Florida, Tampa, Florida, United States

Funding Information This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Abstract

Introduction

Belzutifan, a selective hypoxia-inducible factor 2 α inhibitor, was recently approved for treating renal cell carcinoma in patients with Von Hippel-Lindau (VHL) disease. Given the lack of effective systemic therapies for VHL-associated hemangioblastomas (HBs), we conducted a systematic review and meta-analysis to evaluate its efficacy in this patient population.

Methods

Scientific databases and clinical trial registries were systematically reviewed for studies evaluating belzutifan in VHL-associated HBs. Outcomes included objective response rate, rate of dose reduction and treatment interruption due to adverse events, time to response (TTR), duration of response (DOR), tumor progression, and incidence of anemia. Analyses were performed using STATA 17.

Results

Seven studies comprising 106 patients were included. Overall, 67% of patients achieved a therapeutic response (95% CI: 48–84; I2 = 65.4%). Dose reductions occurred in 19% (95% CI: 4–38; I2 = 70.6%) and treatment interruptions in 6% (95% CI: 0–25; I2 = 78.7%). The median TTR was 4 months, median DOR was 13 months, and tumor progression occurred in 2.8% of patients. Anemia occurred in 73.6%, with only 7.7% progressing to grade 3.

Conclusion

Belzutifan demonstrates promising efficacy in VHL-associated HBs, achieving therapeutic responses and reducing tumor progression with minimal need for treatment interruption. Anemia is the most frequent AE but rarely progresses to grade 3; monitoring for transfusions and dose adjustment is recommended. Caution is warranted in interpreting pooled results given the high inter-study heterogeneity (I2 > 60%), particularly for ORR, rate of dosage decrease, treatment interruption, and anemia. Future studies with larger cohorts are needed to improve reliability and generalizability.

Keywords

HIF-2a - meta-analysis - belzutifan - systematic review - Von Hippel-Lindau - hemangioblastomas

Data Availability Statement

All data relevant to the study are included in the article or uploaded as supplementary material. Further inquiries can be directed to the corresponding author.


Contributors' Statement

K.Y.: conceptualization, data curation, investigation, visualization, writing—original draft, review and editing; E.S.: conceptualization, writing—original draft, review and editing; G.A.: data curation, investigation, visualization, writing—original draft, review and editing; F.K.: statistical analysis, writing—original draft; E.P.: supervision, writing—review and editing; K.V.: supervision, writing—review and editing.


Clinical Trial Registration

This study was prospectively registered with PROSPERO at the protocol stage of the review (ID# CRD42024569955).


Supplementary Material



Publication History

Received: 13 August 2025

Accepted: 13 October 2025

Accepted Manuscript online:
17 October 2025

Article published online:
04 November 2025

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