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Feature: von Hippel-Lindau (VHL) Disease and the Newly FDA Approved Agent Belzutifan

Karin Abernathy, PharmD
PGY2 Oncology Pharmacy Resident
Vanderbilt University Medical Center
Nashville, TN

Von Hippel-Lindau (VHL) disease is a multisystem neoplastic predisposition disorder due to autosomal dominant mutations in the VHL tumor suppressor gene. Tumors may affect the central nervous system (CNS), kidneys, adrenal glands, pancreas, and reproductive organs.1 The most common manifestations associated with VHL disease include CNS hemangioblastomas, clear cell renal carcinoma (RCC), and pancreatic neuroendocrine tumors (pNETs). Benign, visceral cysts also occur frequently in the kidneys, pancreas, or epididymis (in males) and may be detected in combination with malignant VHL-associated tumors.

VHL disease is present in about 1 in 36,000 individuals and may present in childhood, adolescence, or adulthood, with a mean age at initial presentation of 26 years. Life expectancy for patients with VHL disease is low, between 40-52 years, and VHL-related mortality is most commonly due to complications of RCC and CNS tumors. The majority of affected individuals will have a positive family history through a germline mutation, but up to 20% of cases arise from de novo mutations. The development of VHL disease is most often related to Knudson’s two-hit hypothesis of hereditary tumorigenesis, in that patients inherit a germline mutation of the VHL gene from an affected parent and a wildtype gene from the unaffected parent. The germline mutation of the gene represents the first hit, and if a somatic mutation occurs and results and inactivates the normal allele (second hit), the individual is then prone to tumor formation.2

The Pathogenesis of VHL Disease
The VHL gene is located on chromosome 3p25 and encodes the VHL protein that functions as a tumor suppressor. Additionally, this VHL protein forms a multiprotein complex with elongin B, elongin C, and cullin 2, which collectively targets several proteins for proteasomal degradation, subsequently regulating their levels within the cell. The VHL component in the complex functions as an E3 ubiquitin ligase for target molecules that once covalently bound, undergo degradation by the proteasome. Other functions of the VHL protein include regulation of cytokinesis, control of microtubule function, and regulation of the cell cycle.1

Involved in the pathogenesis of VHL disease are hypoxia-inducible factor (HIF) 1 and 2, which are two of the major proteins regulated by VHL. In general, these transcription factors regulate glucose transport, lipid metabolism, pH homeostasis, and angiogenesis. The protein complex including VHL is additionally responsible for ubiquitin-mediated degradation of HIF. Therefore, in instances of loss of function of the VHL gene, there is sustained expression of pro-tumorigenic molecules that include vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), erythropoietin, and transforming growth factor alpha (TGF-α). Collectively, these upregulated target molecules lead to cell proliferation, angiogenesis, and tumorigenesis.2

The diagnosis of VHL disease is generally made by a positive family history, detection of a germline pathogenic VHL gene variant, and presence of at least one VHL-associated tumor. Specific pathogenic variants or deletions of the VHL gene can influence the phenotype or clinical manifestations of disease. Variable presentations of VHL disease have led to classification of VHL subtypes, type I and type II, based on the presence of pheochromocytoma (a type of neuroendocrine tumor found on the adrenal glands). Type I disease has a very low risk of pheochromocytomas (generally absent), with higher risk for retinal and CNS hemangioblastoma, RCC, pancreatic cysts, and other neuroendocrine tumors. Type II VHL is associated with high risk for pheochromocytomas and is further subcategorized by additional risk of RCC, with type 2A conferring low risk of RCC and type 2B conferring high risk of RCC. Type 2C VHL is a disease consisting only of pheochromocytoma. Deletions in VHL, as well as nonsense and truncating variants appear more commonly in type I disease, while missense variants are more common in type II disease.2

Risks, Diagnosis, and Complications of VHL
In order to prevent severe VHL-associated complications, the VHL Alliance has published suggested active surveillance guidelines in patients at risk for VHL disease, or those known to have VHL but do not yet have symptoms. At any age, patients with a family history may choose to undergo genetic testing and counseling to determine their risk for developing VHL disease and need for surveillance. This includes annual eye and neurologic examinations started at the age of 1 in pediatric patients known to carry the VHL mutation. By the time patients are ages 5 and older, biannual quality ultrasounds or MRI (preferred) should be completed to assess the areas of the kidneys, pancreas, adrenals, brain, and spine to assess for any abnormalities.3

CNS hemangioblastomas are the most common tumors in patients with VHL disease and tend to present with multiple lesions. Annual retinal examinations are crucial in vision preservation and early MRI screening is indicated in patients at risk for VHL disease to establish an earlier diagnosis and minimize disease related complication. The most common complication in patients who survive to older than age 60 is clear cell renal cell carcinoma, in approximately 70% of VHL patients.2,3

Effects of belzutifan for Adult Patients with VHL
In August of 2021, the FDA approved belzutifan (MK-6482) via priority review for adult patients with VHL requiring therapy for associated RCC, CNS hemangioblastomas, or pNETs, not requiring immediate surgery. Belzutifan is a small molecule inhibitor of hypoxia-inducible factor 2 alpha (HIF-2α), a transcription factor that regulates genes that promote adaptation to hypoxia. Under normal oxygenation conditions, HIF-2α is targeted for ubiquitin-proteasomal degradation by the VHL protein. In patients with VHL disease, the dysfunctional VHL protein results in the stabilization and accumulation of HIF-2α. When belzutifan binds to HIF-2α, this prevents the interaction between the HIF-2α and hypoxia-inducible factor 1 beta, resulting in reduced transcription and expression of target genes that are associated with cellular proliferation, angiogenesis, and tumor growth.4,5

The effects of belzutifan were investigated in the ongoing Study 004 ( identifier NCT034401788), a phase 2, open-label study comprised of 61 patients with VHL-associated RCC. This was diagnosed based on a VHL germline alteration and with at least one measurable solid tumor localized to the kidneys. The diagnosis of RCC could be radiologic evidence only (no histologic diagnosis required). Other patients enrolled in the trial had other VHL-associated tumors including CNS hemangioblastomas and pNETs. Participants in the study could not have received any prior treatment with HIF-2α inhibitors or other systemic anti-cancer therapies. Any patients with immediate need for surgical intervention or with evidence of metastatic disease were excluded from the trial.4

In this single arm study, patients received belzutifan 120 mg orally once daily until either disease progression or unacceptable toxicity. The primary endpoint was overall response rate by radiology assessment with additional endpoints including duration of response and time to response. In the study population, the median age was 41 years [range 19-66 years], 53% were male, 90% were white, and 82% had an ECOG performance status of 0. VHL Type 1 disease represented 84% of the patients and median time from diagnosis of VHL to enrollment was 17.9 months [range 2.8-96.7]. Prior surgical procedures for RCC had been performed in 77% of patients.4

Follow-up for the trial patients was a minimum of 12 months. The overall response rate (ORR) was 49% (95% CI: 36, 62) in the patients with VHL-RCC. The median duration of response in the VHL-RCC patients was not reached; 56% of responders had a duration of response of at least 12 months, and a median time to response of 8 months. In patients with other VHL-associated non- RCC tumors, there were 24 patients with measurable CNS hemangioblastomas that showed an ORR of 63%. The median duration of response in the CNS hemangioblastoma patients was not reached and 73% exhibited a response duration of at least 12 months. In the patients with measurable pNET, the ORR was 83%, the median duration of response was not reached, and 50% of patients had a response duration of at least 12 months.4

Regarding safety of belzutifan, the most common adverse reactions reported in at least 25% of patients included laboratory findings such as decreased hemoglobin, anemia, increased creatinine, and increased glucose. Common clinical symptoms in the patients who received belzutifan were fatigue, headache, dizziness, and nausea. The most common serious adverse events occurring in Study 004 were anemia in 90% of patients (grade 3 anemia in 7%) and hypoxia in 1.6% of patients. Transfusions may be required and are recommended as clinically indicated, while erythropoiesis stimulating agents are not recommended in the setting of belzutifan-induced anemia at this time. Patient’s oxygen saturation should be monitored prior to initiation of, and periodically throughout, treatment with belzutifan. There are no dose modifications for renal or hepatic impairment, but specific dose modification recommendations are provided in the belzutifan prescribing information in patients who experience anemia, hypoxia, or other adverse reactions of grade 3 or 4 severity.4,5

Hepatic metabolism of belzutifan is primarily via UGT2B17 and CYP2C19, as well as CYP3A4 (to a lesser extent). Pharmacogenomic testing may be considered in patients with severe toxicity, as individuals who are UGT2B17, CYP2C19, or dual UGT2B17 and CYP2C19 poor metabolizers have higher drug steady state area under the curve (AUC) exposure compared with patients who are UGT2B17 normal (extensive) metabolizers and CYP2C19 nonpoor (ultrarapid, rapid, normal, and intermediate) metabolizers. As a weak CYP3A4 inducer, belzutifan may decrease serum concentrations of CYP3A4 substrates and require therapy monitoring.5

Belzutifan carries a United States (US) Boxed Warning for embryo-fetal toxicity, as exposure to the drug during pregnancy may cause embryo-fetal harm. Pregnancy status should be assessed prior to initiation. Additionally, belzutifan may render some hormonal contraceptive products ineffective and patients should be counseled on these risks and the need for effective nonhormonal contraception.5

In conclusion, understanding the genetic basis and pathogenesis of VHL disease has led to improvements in preemptive surveillance screening to help facilitate earlier diagnoses of VHL disease. Although high morbidity and mortality are associated with VHL disease, specifically in the case of multiple malignant lesions, early diagnosis and intervention may clinically impact the preservation of organ function or further disease progression. Belzutifan, a first-in-class targeted HIF-2α inhibitor, is the first FDA-approved medication for the treatment of VHL-related tumors and in the future, there is hope that other targeted agents may be found safe and effective in the treatment of patients with VHL disease.


  1. Maher ER, Sandford RN. Von hippel-lindau disease: an update. Curr Genet Med Rep. 2019;7(4):227-235.
  2. Varshney N, Kebede AA, Owusu-Dapaah H, Lather J, Kaushik M, Bhullar JS. A review of von hippel-lindau syndrome. J Kidney Cancer VHL. 2017;4(3):20-29.
  3. Active Surveillance Guidelines. VHL Alliance. 2020. Available at: Guidelines-2020.pdf
  4. Srinivasan R, Donskov F, Iliopoulos O, et al. Phase 2 study of belzutifan (MK-6482), an oral hypoxia-inducible factor 2α (HIF-2α) inhibitor, for Von Hippel-Lindau (Vhl) disease-associated clear cell renal cell carcinoma (Ccrcc). JCO. 2021;39(15_suppl):4555-4555.
  5. Welireg (belzutifan). Package insert. Merck & Co. Inc; 2021.