Belzutifan Demonstrates Promise in Von Hippel-Lindau Disease

A recent retrospective analysis determined that belzutifan (Welireg) achieved notable disease control, partial responses (PRs), and a manageable safety profile in patients with advanced Von Hippel-Lindau (VHL) disease.¹

A specialized German VHL center examined 8 patients for whom standard surgical or ablative treatments were high-risk or contraindicated.

Disease stabilization in at least 1 affected organ was achieved in all 8 patients, with a partial tumor response observed in 3. The therapy demonstrated effective tumor control across multiple organ systems, including renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas (HBLs), and neuroendocrine tumors (NETs).

Over a median treatment duration of 16.4 months (range, 3.6-26 months), belzutifan effectively controlled tumor growth and stabilized disease. In at least 1 affected organ, all 8 patients achieved disease stabilization. PR was observed in 3 patients. Tumor regression was observed in all affected organ types, and the most significant decrease in tumor size was observed in the first 12 months. Notably, 5 patients were selected for treatment but were denied insurance coverage or stopped therapy early. Among the 5 patients, 4 experienced higher rates of tumor progression and required tumor-reduction procedures. This suggests accelerated disease progression without belzutifan.

During the study, disease progression was observed in 2 patients but resulted in the emergence of new lesions. One patient developed a new small retinal hemangioblastoma after 23.6 months, and another patient experienced a recurrence of RCC at a nephrectomy site after 11 months.

The authors of the study noted that while belzutifan can effectively contain existing disease, it does not eliminate the risk of new tumor formation.

Of the total patients, 1 had a significant improvement in tumor differentiation. This patient had a grade 3 gastric NET and liver metastases and previously failed to respond to platinum-based therapy. After 21 months of treatment, a follow-up biopsy showed that the gastric NET had been downgraded from a grade 3 to a grade 1.

Anemia was the most significant and universal adverse event (AE), affecting 100% of patients. However, it was manageable through close monitoring, dose reductions, and the use of erythropoiesis-stimulating agents (ESAs). Other AEs, such as mild liver enzyme elevations and leukocytopenia, were transient and did not require treatment modifications.

Of the total patients, 2 patients reported anemia-related fatigue. In these cases, hemoglobin levels declined by approximately 28% from baseline. Permanent dose reduction from 120 mg to 80 mg occurred in 3 patients. Likely due to the small patient population, the incidence was slightly higher than rates reported in larger clinical trials (83%-90%).

“While the effectiveness of belzutifan in this cohort is promising, the treatment does present some challenges due to its [adverse] effect profile,” stated Rhein et al, authors of the study. “Anemia, a known consequence of HIF-2α inhibition, was observed in all patients, with varying degrees of severity but particularly pronounced in female patients. Moderate anemia required the use of [ESAs] in [3] patients, and dose reductions were necessary in [3] cases. It is important to reassess dose reductions considering the noted adaptations following initial declines in hemoglobin levels, which showed slight improvement throughout the treatment course.”

Other AEs included liver enzyme elevation (n = 4), leukocytopenia (n = 5), infections (n = 2), and new-onset diabetes mellitus (n = 2).

The median age of patients was 45 years (range, 29-59). Of the patients, 5 were male and 3 were female. All patients had CNS HBL, 88% (n = 7) had retinal HBL, 75% had RCC (n = 6), and 50% (n = 4) had NETs.

Belzutifan received FDA approval in 2021 for patients with VHL with tumors not requiring immediate surgery. This followed the results of the phase 2 LITESPARK-004 (NCT03401788) trial. Before its marketing authorization in Germany in February 2025, belzutifan was used on an off-label basis.

Rhein et al determined that future research should focus on larger, multicenter studies and collaborative patient registries to validate these preliminary observations.

REFERENCE

1. Rhein K, Kotsis F, Ganner A, et al. Belzutifan for patients with Von Hippel-Lindau (VHL) disease-associated heterogeneous tumors – a retrospective single center analysis. BMC Cancer. 2025;25(1):1686. doi:10.1186/s12885-025-15192-8