Evaluation of Off-Label Belzutifan in Advanced VHL-Associated Tumors

Overview

This retrospective analysis from the Freiburg VHL Center evaluates off-label use of belzutifan in patients with advanced tumors associated with Von Hippel-Lindau (VHL) disease. The study highlights belzutifan’s role as a last-line, organ-preserving therapy in cases where conventional treatments risked significant organ dysfunction or were ineffective.

Background

Von Hippel-Lindau disease is a hereditary tumor syndrome characterized by multiple benign and malignant tumors including renal cell carcinoma, CNS and retinal hemangioblastomas, pheochromocytomas, and neuroendocrine tumors. Standard management involves surveillance and surgical or ablative interventions, but repeated treatments often compromise organ function. Belzutifan, a HIF-2α inhibitor, was FDA-approved in 2021 for VHL-associated tumors based on clinical trial data, but real-world experience outside trials remains limited. This study reports on off-label belzutifan use in advanced VHL cases at a major German center.

Data Highlights

Patients treated with belzutifan received doses of 80–120 mg for at least two months between 2022 and 2024. Surveillance included imaging and laboratory monitoring every three months. The cohort consisted of adults with genetically or clinically confirmed VHL disease and advanced tumor manifestations where surgery or ablative therapies posed high risks to organ function. Treatment decisions were multidisciplinary and individualized, focusing on preserving renal and visual function among others.

Key Findings

• Belzutifan was used off-label in patients with advanced VHL tumors where conventional therapies risked organ failure or were ineffective.
• Multidisciplinary assessment guided patient selection, emphasizing preservation of renal function and vision.
• Patients had extensive prior interventions and limited functional reserve, particularly in renal and CNS involvement.
• Belzutifan was administered at an initial dose of 120 mg with close monitoring every three months.
• Insurance approval was required for off-label use, reflecting the therapy’s high cost and limited prior real-world data.

Clinical Implications

Belzutifan offers a promising organ-preserving medical therapy for patients with advanced VHL-associated tumors who face high risks from surgery or ablative treatments. Careful multidisciplinary evaluation is essential to identify candidates who may benefit most, particularly those with compromised renal or visual function. Regular monitoring is critical to assess efficacy and safety during treatment.

Conclusion

This single-center retrospective analysis supports the feasibility and rationale of off-label belzutifan use in advanced VHL disease, highlighting its potential to preserve organ function when conventional options are limited or risky. Further studies are warranted to confirm long-term outcomes and safety.

References

1. LITESPARK-004 Study Group 2021 -- Belzutifan in VHL-Associated RCC
2. Freiburg VHL Center Experience 2024 -- Off-Label Belzutifan Use
3. US FDA 2021 -- Approval of Belzutifan for VHL Disease