Belzutifan Received FDA Approval for Treating Cancers Associated with Von Hippel-Lindau Disease

On August 13, 2021, the FDA (US Food and Drug Administration) approved treatment for von Hippel-Lindau (VHL) disease -associated renal cell carcinoma, central nervous system hemangioblastomas or pancreatic neuroendocrine tumors (pNET) in adults not requiring immediate surgery: the oral hypoxia-inducible factor inhibitor called belzutifan (Welireg, Merck).

What Is Von Hippel-Lindau Disease?

Von Hippel-Lindau (VHL) disease, associated with tumors arising in multiple organs, is a hereditary syndrome. The most common VHL-related tumors include hemangioblastomas, which are blood vessel tumors of the brain, spinal cord and retina, and kidney tumors. Retinal tumors are also called retinal angiomas and can cause blindness if not treated promptly. People with VHL have a high risk of the most common kidney cancer type, clear cell renal cell carcinoma and pancreatic neuroendocrine tumor, a type of tumor developing in the pancreas. These people may also develop an adrenal gland or pheochromocytoma.

What Causes VHL?

VHL is an inherited genetic condition. This means the risk of developing certain tumor types and other features of VHL can be passed from generation to generation. The gene associated with the VHL molecule is also called VHL. VHL gene deletions or mutations (changes), when inherited, increase a person's risk of developing any of the different VHL manifestations described above. Almost everyone with VHL syndrome has an identifiable VHL genetic mutation.

How Is VHL Inherited?

Normally, each cell has 2 copies of every gene: 1 inherited from the mother and 1 from the father. VHL follows an autosomal dominant inheritance pattern in which inheriting 1 copy of the altered gene will probably result in mutation of the second, normal copy. This puts the individual at risk of developing cancer.

A parent with a gene mutation may pass a copy of their normal gene or their mutated gene to a child. A child with a parent who has the mutation therefore has a 50% chance of inheriting it. A brother, sister or parent of a person with the mutation also has a 50% chance of carrying the same mutation. Up to 10% of people with VHL have no family history. This means they have a de novo mutation and are the first people in their family to have this genetic change.

The First Hypoxia-Inducible Factor Inhibitor to Receive FDA Approval

Hypoxia-inducible factor 2 alpha (HIF-2α) inhibitor belzutifan is an antiangiogenic agent that inhibits the growth of new blood vessels feeding tumors.

Reflections of the 2019 Nobel Prize in Medicine

The 2019 Nobel Prize in Medicine was awarded for studies of how cells sense the presence of oxygen and hypoxia (low oxygen) adaptation. Tumors also need to use cellular mechanisms of hypoxia adaptation effectively in order to grow rapidly. This led to the idea that drugs targeting tumor cells' mechanisms of adapting to hypoxia might be effective in cancer treatment, and drug development in this area began.

FDA Approval Through Study 004

The new, first-in-class small molecule, HIF-2 alpha inhibitor called belzutifan (code name MK-6482), was studied in patients diagnosed with VHL-associated kidney cancer and a VHL germline alteration (inherited mutation), in Study 004, an open-label clinical trial of 61 patients with at least one measurable kidney tumor.

Enrolled patients also had other VHL-associated tumors, including central nervous system hemangioblastomas and pancreatic neuroendocrine tumors. Patients received belzutifan 120 mg once daily until disease progression or unacceptable adverse effects.

Results

The primary efficacy endpoint, assessed by an independent review committee using RECIST v1.1, was the radiologically measured overall response rate. Additional efficacy endpoints included duration of response and time to response.

• In patients with VHL-associated kidney cancer, an overall response rate of 49% (95% CI:36, 62) was reported.
• All responding patients with VHL-associated kidney cancer were followed for at least 18 months from treatment initiation. Median duration of response was not reached; 56% of responders had a response duration of ≥ 12 months and median time to response was 8 months.
• In patients with other non-kidney-cancer VHL-associated tumors, the overall response rate was 63% in 24 patients with measurable central nervous system hemangioblastomas and 83% in 12 patients with measurable pancreatic neuroendocrine tumors. Median duration of response was not reached for these patients.

Side Effects

The most common adverse effects, including laboratory abnormalities reported in ≥ 20% of patients receiving belzutifan, were decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose and nausea. Anemia and hypoxia due to belzutifan can be severe. In Study 004, anemia occurred in 90%, including grade 3 anemia in 7%. Patients should receive blood transfusions if clinically necessary. Erythropoiesis-stimulating agents are not recommended for treating anemia in patients receiving belzutifan. In Study 004, hypoxia occurred in 1.6%. Belzutifan can make some contraceptive drugs ineffective, and exposure during pregnancy can cause embryo-fetal harm.

Dose

The recommended belzutifan dose is 120 mg orally once daily, with or without food.