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The FDA has the first therapy for cancers associated with von Hippel-Lindau (VHL) disease.

Belzutifan (Welireg), distributed by Merck, targets hypoxia-inducible factor 2α, which drives growth of malignant and benign tumors in VHL. In the absence of approved systemic therapies, most patients with VHL undergo multiple surgeries in their lifetime to remove renal cell carcinoma (RCC) and other VHL-associated tumors. The approval encompasses VHL-associated RCC, central nervous system (CNS) hemangioblastomas, and pancreatic neuroendocrine tumors not requiring immediate surgery.

Supporting data for the approval included results of a phase II trial of single-agent oral belzutifan in 61 patients with VHL-associated RCC, all of whom had non-RCC tumors as well. Eligible patients had at least one measurable RCC tumor, no prior systemic therapy for cancer, and no evidence of metastatic disease.

Patients received belzutifan once daily, continued until disease progression. The primary endpoint was objective response rate (ORR) in VHL-associated RCC. Secondary endpoints included ORR in non-RCC neoplasms, duration of response in RCC and non-RCC tumors, and safety.

As at the 2021 virtual meeting of the American Society of Clinical Oncology (ASCO), all 61 patients had some type of pancreatic neoplasm (pancreatic neuroendocrine tumors in 36% of cases), 50 (82%) had CNS hemangioblastomas, and 16 (26%) had retinal lesions.

The results showed that 30 of 61 (49%) patients achieved partial responses in RCC lesions with belzutifan. An additional 30 patients had stable disease, including four who had unconfirmed partial responses. The remaining patient was not evaluable for response, meaning that no patient in the intention-to-treat analysis had progressive disease during treatment with belzutifan. The median time to treatment response was 8.2 months, and median duration of response had yet to be reached.

In the patients with non-RCC tumors, the ORR was 77% in pancreatic lesions (including six complete responses), 90% (20 of 22) in pancreatic neuroendocrine tumors (three complete responses), and 30% (15 of 50) in CNS hemangioblastomas (three complete responses). Two CNS lesions progressed, but no patient had progression of pancreatic or pancreatic neuroendocrine tumors.

The most common adverse event (AE) associated with belzutifan treatment was anemia (90.2% of patients), which is considered an on-target effect of the drug, explained Ramaprasad Srinivasan, MD, of the National Cancer Institute, during an ASCO poster presentation. Other common AEs included fatigue (65.6%), headache (41.0%), dizziness (39.3%), nausea (34.4%), and dyspnea (23.0%). No patients had a grade 4 AE, and the most frequent grade 3 AEs were anemia (8.2%), hypertension (8.2%), and fatigue (4.9%).

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