Belzutifan for Renal Cell Carcinoma in von Hippel–Lindau Disease
Open accessAbstract
BACKGROUND: gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor 2α (HIF-2α). METHODS: In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. We also assessed responses to belzutifan in patients with non-renal cell carcinoma neoplasms and the safety of belzutifan. RESULTS: After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective response was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients [77%]) and central nervous system hemangioblastomas (15 of 50 patients [30%]). Among the 16 eyes that could be evaluated in 12 patients with retinal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treatment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl). CONCLUSIONS: Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.).
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PT2977/belzutifan was approved by the FDA for treatment of RCC in patients with von Hippel-Lindau syndrome.
“PT2977/belzutifan was recently approved by the FDA for the treatment of RCC in patients with von Hippel-Lindau syndrome (47, 48).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [48]
The Abstract Methods identifies PT2977 as the former name of belzutifan and reports its study in patients with VHL-associated renal cell carcinoma. The Discussion reports treatment activity, but our copy does not state that the FDA approved belzutifan for this indication; the approval part of the claim is unsupported. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe most frequent on-target toxicity with HIF-2 inhibitors (PT2385; belzutifan) is anemia from suppression of renal/hepatic erythropoietin.
“The most frequent on-target toxicity with HIF-2 inhibitors (PT2385; belzutifan) is anemia from suppression of renal/hepatic erythropoietin.”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [421]
The Discussion (page unavailable) calls anemia the most common adverse event with belzutifan and an on-target effect of HIF-2α inhibition. Results > Safety (page unavailable) links the hemoglobin decrease to inhibition of the EPO gene and reduced erythropoietin production. The paper does not establish that anemia is the most frequent toxicity with PT2385, nor does it specify renal and hepatic erythropoietin suppression as the mechanism in these patients. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAnemia occurred commonly in early trials and, during prolonged belzutifan therapy, occasionally required transfusion or erythropoiesis-stimulating agents.
“Anemia occurred commonly in early trials and, during prolonged belzutifan therapy, occasionally required transfusion or erythropoiesis-stimulating agents, hence the need for routine hematological monitoring [37,412,421].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [421]
VHL gene mutations lead to stability of HIF subunits and constitutive activation of HIF-mediated transcriptional pathways in patients with VHL, causing progression of renal cell carcinoma.
“VHL gene mutations lead to the stability of HIF subunits and the constitutive activation of HIF‐mediated transcriptional pathways in patients with VHL, causing the progression of renal cell carcinoma.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [24]
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Hypoxia as a Modulator of Inflammation and Immune Response in Cancer
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“Another promising therapy targeting the hypoxia-inducible factor 2α (HIF2α) is currently being evaluated in a phase III trial 17 .”
Targeting hypoxia in solid and haematological malignancies
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“Several clinical studies evaluated the effects of belzutifan in RCCs [66], showing improved bioavailability and efficacy compared to other HIF inhibitors [67].”
BackgroundMetabolic alterations in hereditary and sporadic renal cell carcinoma
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“of patients 27 .”
New drug approvals for 2021: Synthesis and clinical applications
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Mechanisms shared between cancer, heart failure, and targeted anti-cancer therapies
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“Additionally, Belzutifan plus Cabozantinib has shown promising results in advanced ccRCC. 35,36 Prognostic Factors ccRCC is one of the most aggressive subtypes of RCC, with a 5-year survival rate of less than 50% to 70%, compared with 67% to 87% for papillary RCC and 78% to 87% for chromophobe RCC…”
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“14 In the primary analysis, retinal haemangioblastomas were reported in 12 participants, and 16 eyes and all participants showed improvement.”
Self-citationNew Therapeutic Interventions for Kidney Carcinoma: Looking to the Future
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Belzutifan for Advanced Pheochromocytoma or Paraganglioma
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“PAS domains in human transcription factors have become important drug targets for cancer therapy (10-12).”
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“For instance, a study has shown that approximately 70 % of patients with VHL disease develop renal cell carcinomas during their lifetime [57].”
BackgroundStructural Basis for the Allosteric Inhibition of Hypoxia-Inducible Factor 2 by Belzutifan
Ren, X., Diao, X., Zhuang, J., & Wu, D. (2022) · Molecular Pharmacology · doi:10.1124/molpharm.122.000525 · Cited by 43 · see citing works
“disease, the mechanism of possible drug resistance is still unknown (Jonasch et al., 2021).”
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Self-citationThe HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation
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Updates on Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in the Treatment of Renal Anemia
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“Contrary to HIF-1α which is a ccRCC suppressor, HIF-2α is a ccRCC oncoprotein and therefore an interesting therapeutic target already evaluated in several phase 2 that showed anti-tumour activity [25,26].”
BackgroundSelf-citationAdjuvant therapy options in renal cell carcinoma — targeting the metastatic cascade
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Management of Renal Cell Carcinoma: Promising Biomarkers and the Challenges to Reach the Clinic
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“Ongoing drug development has resulted in a second-generation compound (i.e., belzutifan) that was recently FDA-approved for the treatment of tumors in patients with von-Hippel Lindau syndrome [30].”
BackgroundBelzutifan: a novel therapeutic for the management of von Hippel–Lindau disease and beyond
Curry, L. C., & Soleimani, M. (2024) · Future Oncology · doi:10.2217/fon-2023-0679 · Cited by 37 · see citing works
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“Across multiple clinical trials, HIF inhibitors have demonstrated prominent antitumor activity in both patients with ccRCC in VHL disease and those with advanced ccRCC [138–140].”
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Update on the genetics of paragangliomas
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The role of HIF in angiogenesis, lymphangiogenesis, and tumor microenvironment in urological cancers
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“Detailed study design and methods have been previously published (23).”
InfluentialSelf-citationChoueiri, T. K., Merchan, J. R., Figlin, R. A., McDermott, D. F., Arrowsmith, E. R., Michaelson, M. D., Tykodi, S. S., Heath, E. I., Spigel, D. R., D'souza, A., et al. (2025) · The Lancet Oncology · doi:10.1016/s1470-2045(24)00649-1 · Cited by 38 · see citing works
Self-citationPersonalized drug testing in human pheochromocytoma/paraganglioma primary cultures
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On-Target Side Effects of Targeted Therapeutics of Cancer
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“Belzutifan is efficiently inhibits VHL-mutated tumor growth, but blocking of EPO expression by belzutifan results in treated patients decreased RBC count, HgB levels and consequent systemic hypoxia (9).”
BackgroundEvolution of the HIF targeted therapy in clear cell renal cell carcinoma
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If it’s a target, it’s a pan-cancer target: Tissue is not the issue
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“[41,42].”
The roaring 2020s: a new decade of systemic therapy for renal cell carcinoma
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Self-citationHIF in Gastric Cancer: Regulation and Therapeutic Target
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von-Hippel Lindau and Hypoxia-Inducible Factor at the Center of Renal Cell Carcinoma Biology
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Checkpoint inhibitors and anti-angiogenic agents: a winning combination
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“Promisingly, belzutifan, a HIF2A inhibitor, has demonstrated great potential alone or in combination with cabozantinib in treating von Hippel-Lindau disease and RCC [52, 53].”
BackgroundJonasch, E., Bauer, T. M., Papadopoulos, K. P., Plimack, E. R., Merchan, J. R., McDermott, D. F., Michaelson, M. D., Appleman, L. J., Roy, A., Perini, R. F., et al. (2023) · European Journal of Cancer · doi:10.1016/j.ejca.2023.113434 · Cited by 29 · see citing works
Self-citationManagement of metastatic pheochromocytomas and paragangliomas: when and what
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Hypoxia as a Target for Combination with Transarterial Chemoembolization in Hepatocellular Carcinoma
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“Additionally, in 2021, belzutifan (PT2977) was approved by the U.S. Food and Drug Administration (FDA) for renal cell carcinoma (RCC) and other tumors in patients with von Hippel-Lindau syndrome [83,84], making it the first selective HIF-2 inhibitor to receive approval.”
BackgroundTherapeutic potential of CDK4/6 inhibitors in renal cell carcinoma
Sager, R., Backe, S. J., Ahanin, E. F., Smith, G., Nsouli, I. S., Woodford, M. R., Bratslavsky, G., Bourboulia, D., & Mollapour, M. (2022) · Nature Reviews Urology · doi:10.1038/s41585-022-00571-8 · Cited by 29 · see citing works
Belzutifan (MK-6482): Biology and Clinical Development in Solid Tumors
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Models of renal cell carcinoma used to investigate molecular mechanisms and develop new therapeutics
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“About 2 decades later, belzutifan, a small molecule HIF-2a inhibitor would receive FDA approval for treatment of patients with VHL disease (45).”
BackgroundBelzutifan for the treatment of renal cell carcinoma
Wu, X., Lazris, D., Wong, R. L., & Tykodi, S. S. (2025) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359251317846 · Cited by 31 · see citing works
“21,37 In the LITESPARK-001, -003, and -004 trials, anemia of all grades occurred in 76%–90% of study participants, while 12%–24% of treated patients developed grade 3 anemia.”
- Authors
- Jonasch, E., Donskov, F., Iliopoulos, O., Rathmell, W. K., Narayan, V. K., Maughan, B. L., Oudard, S., Else, T., Maranchie, J. K., Welsh, S. J., Thamake, S., Park, E. K., Perini, R. F., Linehan, W. M., & Srinivasan, R.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- From the University of Texas M.D. Anderson Cancer Center, Houston (E.J.); Aarhus University Hospital, Aarhus, Denmark (F.D.); Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston (O.I.); Vanderbilt University Medical Center, Nashville (W.K.R.); University of Pennsylvania, Philadelphia (V.K.N.); the University of Utah, Salt Lake City (B.L.M.); Hôpital Européen Georges-Pompidou, University of Paris, Paris (S.O.); the University of Michigan, Ann Arbor (T.E.); the University of Pittsburgh, Pittsburgh (J.K.M.); Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom (S.J.W.); Merck, Kenilworth, NJ (S.T., E.K.P., R.F.P.); and the Center for Cancer Research, National Cancer Institute, Bethesda, MD (W.M.L., R.S.).
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2021-11-25
- Volume
- 385
- Issue
- 22
- Pages
- 2036-2046
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC9275515
- OpenAlex
- W3215189579
- Cited by
- 714
- References
- 22
- Citations by year
- 2026: 140 · 2025: 167 · 2024: 135 · 2023: 140 · 2022: 128 · 2021: 4
- FWCI
- 66.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
- 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, HIF-2α inhibition, von Hippel-Lindau disease, renal cell carcinoma, hemangioblastoma, retinal hemangioblastoma, pancreatic lesions, anemia, drug safety, objective response
- MeSH terms
- Adult, Aged, Anemia, Antineoplastic Agents, Carcinoma, Renal Cell, Fatigue, Female, Follow-Up Studies, von Hippel-Lindau Disease, Humans, Indenes, Kidney Neoplasms, Male, Middle Aged, Neoplasms, Multiple Primary, Pancreatic Neoplasms, Age of Onset, Hemangioblastoma, Neuroendocrine Tumors, Disease Progression, Basic Helix-Loop-Helix Proteins
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