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Cited by 180Renal cell carcinoma treatmentCancer, Hypoxia, and MetabolismEar and Head Tumors

FDA Approval Summary: Belzutifan for von Hippel-Lindau Disease-Associated Tumors

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Fallah, Jaleh, Brave, Michael H., Weinstock, Chana, Mehta, Gautam U., Bradford, Diana, Gittleman, Haley, Bloomquist, Erik W., Charlab, Rosane +14 more·2022·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-22-1054PMC PMC9669093
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Abstract

On August 13, 2021, the FDA approved belzutifan (WELIREG, Merck), a first-in-class hypoxia-inducible factor (HIF) inhibitor for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. The FDA granted approval based on the clinically meaningful effects on overall response rate (ORR) observed in patients enrolled in Study MK-6482-004. All 61 patients had VHL-associated RCC; some also had CNS hemangioblastomas and/or pNET. For VHL disease–associated RCC, ORR was 49% [95% confidence interval (CI), 36–62], median duration of response (DoR) was not reached, 56% of responders had DoR ≥12 months, and median time to response was 8 months. Twenty-four patients had measurable CNS hemangioblastomas with an ORR of 63% (95% CI, 41–81), and 12 patients had measurable pNET with an ORR of 83% (95% CI, 52–98). For these tumors, median DoR was not reached, with 73% and 50% of patients having response durations ≥12 months for CNS hemangioblastomas and pNET, respectively. The most common adverse reactions, including laboratory abnormalities, reported in ≥20% were anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Belzutifan can render some hormonal contraceptives ineffective and can cause embryo-fetal harm during pregnancy. This article summarizes the data and the FDA thought process supporting traditional approval of belzutifan for this indication.

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  • Since HIF-1α was discovered in 1991 and HIF-2α in 1997, the importance of the HIF pathway in oxygen sensing was affirmed by the 2019 Nobel Prize and by FDA approval of belzutifan in 2021.

    “Since the discovery of HIF-1α in 1991, and of HIF-2α in 1997, the significance of the HIF pathway in oxygen sensing has been affirmed by the awarding of the 2019 Nobel Prize in Physiology and Medicine for the discovery of HIF, followed by the FDA approval of belzutifan in 2021 [111, 112].”

    From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [112]

    The Abstract and Introduction (page not provided) state that the FDA approved belzutifan, a HIF inhibitor, in August 2021. The passages do not give the 1991 and 1997 discovery dates or discuss the 2019 Nobel Prize; those parts of the sentence are not supported by this source. (LLM, conf=0.86)

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  • The clinical success of HIF-2α-specific allosteric inhibitors underscores the importance of exploiting unique structural vulnerabilities, whereas the lack of analogous pockets in HIF-1α necessitates alternative approaches.

    “The clinical success of HIF-2α–specific allosteric inhibitors underscores the importance of exploiting unique structural vulnerabilities, whereas the lack of analogous pockets in HIF-1α necessitates alternative approaches”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [40]

    The Introduction and Conclusion report FDA approval and a favorable benefit–risk profile for belzutifan, a HIF-2α inhibitor, in specified VHL-associated tumors. The Nonclinical pharmacology and toxicology section says belzutifan binds HIF-2α, but the paper does not describe an allosteric pocket or say that HIF-1α lacks an analogous pocket and therefore requires alternative approaches. Page numbers were not provided in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Only one selective HIF inhibitor targeting HIF-2α (belzutifan) has reached clinical approval to date, first in the United States in 2021 and subsequently in the European Union in 2025.

    “only one selective HIF inhibitor - targeting HIF-2α (PT2977/pt2799, belzutifan; WELIREG™) - has reached clinical approval to date, first in the United States in 2021 and subsequently in the European Union in 2025 [40]”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [40]

    The Introduction identifies belzutifan as a first-in-class HIF-2α inhibitor and states that the FDA approved it on August 13, 2021. The 2022 paper does not support the claim that it remained the only approved selective HIF inhibitor to date or that the European Union approved it in 2025. Page numbers were not provided in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Belzutifan became the first direct HIF inhibitor approved for clinical use (FDA 2021; EU conditional approval 2025) in VHL disease-associated renal cell carcinoma, CNS hemangioblastomas, and pancreatic neuroendocrine tumors without an immediate surgical indication.

    “Belzutifan became the first direct HIF inhibitor approved for clinical use (FDA 2021; EU conditional approval 2025) in von Hippel–Lindau disease–associated renal cell carcinoma, central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors without an immediate surgical indication [40].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [40]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • Belzutifan received FDA approval in 2021 for VHL disease-associated renal cell carcinoma, CNS hemangioblastomas, and pancreatic neuroendocrine tumors that do not require immediate surgical intervention.

    “This approach culminated in the approval of the HIF-2α antagonist PT2977 (belzutifan; WELIREG™), which received FDA approval in 2021 for the treatment of von Hippel–Lindau (VHL) disease–associated renal cell carcinoma, central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors that do not require immediate surgical intervention, followed by conditional approval in the European”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [40]

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Authors
Fallah, J., Brave, M. H., Weinstock, C., Mehta, G. U., Bradford, D., Gittleman, H., Bloomquist, E. W., Charlab, R., Hamed, S. S., Miller, C. P., Dorff, S. E., Chambers, W. A., Mixter, B. D., Dinin, J., Pierce, W. F., Ricks, T. K., Tang, S., Donoghue, M., Pazdur, R., Amiri-Kordestani, L., Ibrahim, A., & Beaver, J. A.
Affiliations
  • United States Food and Drug Administration (US)
  • 1Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.
Corresponding author
Fallah, Jaleh
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2022-06-21
Volume
28
Issue
22
Pages
4843-4848
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-22-1054
PMC
PMC9669093
OpenAlex
W4283259206
Cited by
180
References
9
Citations by year
2026: 47 · 2025: 51 · 2024: 45 · 2023: 28 · 2022: 9
FWCI
21.76
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
U.S. Food and Drug Administration
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Oncology › Ear and Head Tumors
Keywords
belzutifan, von Hippel-Lindau disease, renal cell carcinoma, pancreatic neuroendocrine tumors, FDA approval, overall response rate, adverse effects, embryo-fetal toxicity
MeSH terms
Adult, Antineoplastic Agents, Carcinoma, Renal Cell, Female, von Hippel-Lindau Disease, Humans, Kidney Neoplasms, Pregnancy, Central Nervous System Neoplasms, Neuroectodermal Tumors, Primitive, Hemangioblastoma

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