Belzutifan earned FDA approval for VHL-associated renal cell carcinoma, pancreatic neuroendocrine tumors, and CNS hemangioblastomas on the strength of the clinical trial NCT03401788, but its efficacy in sporadic tumors was never clearly defined. For sporadic patients, the only established options remain surgical resection and radiation therapy, and neither works when a tumor recurs in a location that cannot be safely resected or re-irradiated. Because the pathophysiology of sporadic CNS hemangioblastomas closely mirrors that of VHL-related tumors, the Wisconsin team theorized that the HIF-2α approach validated in VHL disease could translate to the sporadic setting.

VHL disease results from mutation of the VHL gene on chromosome 3, which causes constitutive activation of hypoxia-inducible factors even under normal oxygen conditions, driving dysregulated cell growth across multiple tissues. Experiments have shown that HIF-2α specifically promotes aggressive growth and a vascular proliferative phenotype that may drive malignancy in VHL disease — precisely the biology that makes hemangioblastomas so vascular and so dangerous near the brainstem. Belzutifan was developed to shut down that signal.

In VHL-associated CNS hemangioblastomas, the clinical evidence is now substantial: of 61 patients with at least one solid kidney lesion in the pivotal trial, 39 percent also had CNS hemangioblastomas, and 63 percent of those patients showed a radiographic response. Stevens and colleagues were the first to report two VHL patients with strong early clinical and radiographic responses, including reduction in tumor diameter and perilesional edema of intracranial and spinal hemangioblastomas. Zhang and colleagues demonstrated a 30 percent response rate with 30 to 50 percent size reduction over the duration of treatment, and a retrospective study by Zamarud and colleagues found that CNS hemangioblastomas decreased 30 percent in size at approximately the four-month mark even when belzutifan had been started for renal cell carcinoma.

The critical molecular bridge between the VHL and sporadic worlds came from Taieb and colleagues, who screened 28 sporadic hemangioblastomas for somatic HIF2A mutations by direct sequencing. The patients had no family history of VHL and no personal history of VHL clinical manifestations, yet two of the 28 — a 7.1 percent incidence rate — carried HIF2A mutations. One patient had HIF2A missense mutations, and the other had a coexistence of somatic HIF2A and VHL mutations.

The team identified the Q557* variant of HIF-2A, which loses its hypoxia sensing function but maintains its transcriptional activity, producing a pseudohypoxic state even under normoxic conditions. This finding established for the first time that HIF2A participates in the tumorigenesis of some sporadic hemangioblastomas and should be considered a susceptibility gene candidate — and a target — in this population. The first Wisconsin case shows how desperate the clinical situation can become.

A 23-year-old woman presented with new-onset headache, neck stiffness, and imbalance. MRI revealed a 4-centimeter cyst with an enhancing nodule in the posterior fossa and resultant hydrocephalus. She underwent resection, and pathology confirmed a WHO Grade 1 hemangioblastoma.

Germline genetic testing for VHL was negative, with no pathogenic mutations, variants of unknown significance, or gross deletions or duplications identified in any of the genes analyzed. Systemic imaging at diagnosis was negative, and there were no clinical stigmata or family history to support a VHL diagnosis. Molecular testing of the tumor itself could not be completed because there was not enough tissue.

Nine years later, she re-presented with headache, nausea, and vomiting, and MRI demonstrated a 3-centimeter local recurrence with hydrocephalus. A ventriculoperitoneal shunt was placed, and neuroaxis imaging and cerebrospinal fluid studies were negative for drop metastases. Because of the tumor's proximity to the brainstem and its size, she completed fractionated radiation therapy — 54 Gy in 30 fractions — with a positive radiographic response.

Six years after that, an asymptomatic radiographic recurrence prompted a second resection confirming recurrent disease, though postoperative imaging showed residual disease along the posterior margin of the brainstem. Four months later, a second lesion appeared in the right basal frontal region and was completely resected. Updated spinal MRI then showed faint superficial leptomeningeal enhancement and intradural, extramedullary enhancement most pronounced in the thoracic cord, concerning for drop metastases, although CSF analysis including cytology remained negative.

After multiple surgeries over the past year, residual disease was not amenable to surgery, and given her prior radiation, focused radiation was not ideal because of significantly increased toxicity to the brainstem. With conventional options exhausted, the team started belzutifan at 120 mg daily. Two months after initiation, MRI demonstrated improvement: the fourth ventricle lesion, which measured 1.6 x 1.6 x 0.8 cm before treatment, measured 1.3 x 1.1 x 0.7 cm afterward, and the leptomeningeal enhancement of the thoracic spinal cord resolved entirely.

The response has been maintained after 24 months of treatment. The drug was well tolerated — anemia, hypoxia, and fatigue were all Grade 1 by the Common Terminology Criteria for Adverse Events, pulse oximetry remained in the normal range, and the only interruption was a single month for a respiratory infection, with no dose reduction. Her functional scores were unchanged before and after treatment, at a Karnofsky Performance Status of 80 and an ECOG score of 1.

She has been able to work full time throughout more than two years on the medication and remains on treatment. The second case involved a 33-year-old man whose left toe numbness progressed to left leg numbness, inability to move his right foot, and numbness and weakness of both hands, with right pupil enlargement on examination. Spinal MRI revealed a C7-T1 mass measuring 1.1 by 2.9 centimeters, and angiography showed a small feeding branch from the right vertebral artery and a larger branch from the left costocervical trunk, most consistent with a hemangioblastoma.

He underwent embolization followed by C6 to T2 laminectomy and resection, emerging with an incomplete C6 injury and spastic quadriplegia. Pathology confirmed a WHO Grade 1 spinal cord hemangioblastoma, postoperative MRI showed persistent tumor, and germline testing was again negative for VHL. Seventeen years after initial presentation, he declined clinically with bilateral leg numbness and left hand weakness alongside radiographic recurrence, and completed fractionated cervical spine radiation of 46 Gy in 23 fractions.

An intrathecal baclofen pump was placed for spasticity, and a later T5 laminectomy with syringo-subarachnoid shunt was complicated by an epidural hematoma requiring emergent evacuation. Nine years after that recurrence and radiation, MRI demonstrated slow progression of tumor over several years, but the location made redo surgery or re-irradiation inadvisable. Bevacizumab was initiated first, yet produced no significant radiographic response or clinical benefit and was discontinued.

Belzutifan was then started and was tolerated well, with regular monitoring by complete blood count and pulse oximetry. Eight months after initiation, he reported subjective improvement, and there was radiographic improvement as well: the spinal lesion shrank from 1.1 x 2.9 cm to 0.6 x 1.6 cm on his most recent MRI. He experienced mild fatigue and a mild dip in hemoglobin, both Grade 1 by CTCAE grading, and never required a dose reduction or interruption.

His post-treatment scores are a Karnofsky Performance Status of 70 and an ECOG score of 2. Most strikingly, he has begun feeling both legs and hands again, moving his right foot for the first time in five years, with more strength in his hands and more energy — a functional recovery that formal response criteria, which were not applied in this report, cannot fully capture. The authors are careful about what two cases can and cannot prove.

VHL itself is thought to be underdiagnosed, and some apparently sporadic hemangioblastomas may occur in the setting of undiagnosed VHL or mosaicism, particularly since information on assay sensitivity for low-level VHL mosaicism was not available. Next-generation sequencing of the tumors was not performed, so it cannot be definitively determined whether the responses stemmed from an acquired HIF2A mutation or, less likely, from somatic VHL inactivation within the tumor itself. With only two patients, the safety of belzutifan in this population cannot be established, and formal response criteria were not applied in the second case.

The most common adverse effects of belzutifan across studies remain anemia, headache, renal function impairment, dizziness, and fatigue. Still, the implications are considerable: a systemic medication option for the roughly 75 percent of hemangioblastoma patients without VHL could fundamentally alter clinical management, especially for those with recurrent or unresectable disease. For now, two shrinking tumors on MRI stand as the first preliminary evidence that a pseudohypoxic pathway druggable in VHL disease may be druggable in sporadic disease too.

Subject of Research: Belzutifan as a possible novel treatment for sporadic central nervous system hemangioblastoma: a report of two cases and focused review of the literature

Article Title: Belzutifan as a possible novel treatment for sporadic central nervous system hemangioblastoma: a report of two cases and focused review of the literature

Article References: Bureau, B. L., Shahbandi, A., Shabani, S., & Connelly, J. M. (2026). Belzutifan as a possible novel treatment for sporadic central nervous system hemangioblastoma: a report of two cases and focused review of the literature. Frontiers in Oncology, 16, Article 1935078. https://doi.org/10.3389/fonc.2026.1935078

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1935078

Keywords: belzutifan, hemangioblastoma, HIF-2α inhibitor, von Hippel-Lindau, sporadic CNS tumors, neuro-oncology, case report, targeted therapy, pseudohypoxia, brainstem tumor, possible, novel