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

Abstract 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. 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. 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. 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.