Abstract Background: Von Hippel-Lindau (VHL) disease is a rare autosomal dominant hereditary syndrome. Patients with VHL disease have a lifelong risk of developing clear-cell renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNET), and hemangioblastomas of the central nervous system (CNS). Belzutifan, a hypoxia-inducible factor-2α inhibitor, received FDA approval in 2021 for adults with VHL-associated RCC, pNET, or CNS hemangioblastomas. Phase 2 data demonstrated objective response rates of 49%, 91%, and 30% by RECIST v1.1, respectively. However, real-world clinical outcomes remain limited. We evaluated the safety and efficacy of belzutifan in a real-world cohort. Methods: We performed a retrospective review of adult patients (≥18 years) at Johns Hopkins Hospital between January 2016 and December 2024 who were genetically or clinically confirmed to have VHL and received belzutifan treatment. Eligible participants had at least one VHL-associated lesion and an available imaging following therapy. Patient demographics and clinical data were collected from EMR. Tumor and cyst characteristics at baseline and during follow-up were evaluated using CT or MRI. The sum of the longest diameters of evaluable lesions—including lesions 1 cm—was used to assess tumor response. Secondary outcomes included duration of therapy, adverse events (AEs), and reasons for treatment discontinuation. Results: Fourteen patients were included (mean ± SD age, 36 ± 14 years; 71% female). Among 10 patients with kidney lesions, 4/10 (40%) had ≥30% decrease over a median treatment duration of 18.5 months (range 12 - 27). All 3 (100%) patients with pNET had a ≥30% decrease, with a median follow-up of 24.7 months (range 12-32). Among 9 patients with CNS hemangioblastomas, 7/9 (78%) had ≥30% decrease over a median treatment duration of 18.1 months (range 7-28). The most common AEs were anemia (35%), dizziness (21%), and headache (21%). One patient discontinued treatment due to anemia, and another due to pregnancy planning. Conclusion: In this real-world cohort of patients with VHL-associated lesions, belzutifan demonstrated clinical activity and a favorable safety profile across various VHL-associated neoplasms. Compared to phase II data, kidney lesions had lower response rates, while pNET and CNS hemangioblastomas showed higher responses. These differences may reflect variations in baseline imaging timing, small patient numbers, or occasional treatment interruptions due to insurance issues or missed doses. These findings support the continued use of belzutifan in VHL disease and highlight the need for larger studies to guide long-term management of VHL-associated tumors. Citation Format: Peixi Ge, Mohamed Atta, Nityasree Srialluri. Safety and efficacy of belzutifan for Von Hippel-Lindau disease-associated tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6650.
Ge et al. (Fri,) studied this question.