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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 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]
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“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]
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“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]
In the citing paper
“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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“Several drugs that inhibit HIF activity (54, 55) could be considered for such trials.”
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“These observations have 79 justified the development of pharmacological HIF2α inhibitors (8, 9), one of which is now 80 FDA approved for the treatment of ccRCC in VHL syndrome patients who harbor 81 germline mutations in pVHL (10).”
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“…hypoxic response 15,16,68,69 , including with respect to the clinical relevance of HIF-2α upregulation in renal cell carcinoma/von Hippel–Lindau disease 76 , as well as the therapeutic upregulation of HIF-α for the treatment of anaemia and, potentially, acute myeloid leukaemia 77,78 (Fig.”
Hypoxia‐Inducible Factors as Guardians of Cancer Stem Cell Fate: Implications for Novel Therapies
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“Therapeutically, the selective inhibition of HIFs, notably exemplified by the clinical efficacy of the HIF-2α antagonist belzuti-fan (MK-6482) in both VHL-associated and sporadic clear-cell renal cell carcinoma, has established direct HIF targeting as a feasible treatment approach [196].”
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“Notably, efficacy in patients with germline VHL mutations 107 is superior to that seen in the sporadic setting.”
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“In contrast, redifferentiation approaches such as selumetinib plus radioiodine remain clinically relevant to thyroid cancer because of their close relationship to dedifferentiation and radioiodine-refractory disease [115,116].”
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“The signalling cascade of HIF-1 alpha/STAT3/NF-B is blocked by drugs such as Belzutifan, a HIF-2 alpha inhibitor that decreases the expression level of PD-L1 and decreases immunosuppression (Choueiri et al., 2021; Jonasch et al., 2021; Choueiri et al., 2023).”
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“Although drugs targeting the key molecules or genes of the metabolic pathway, such as glutaminase and HIF-2α, have been developed and applied in clinical trials for RCC, their objective response rate and safety are unsatisfactory [25, 26], highlighting the necessity of our study.”
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“При БГЛ для РП длительный контроль заболевания был достигнут при применении белзутифана в 97% случаев, а объективный ответ наблюдался в 49% случаев; длительный ответ также наблюдался в 30% случаев гемангиобластом центральной нервной системы [10].”
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“Belzutifan is a first-in-class selective HIF-2α inhibitor FDA-approved for adult patients with VHL disease who require treatment for renal cell carcinoma, central nervous system hemangioblastoma, and pancreatic neuroendocrine tumors not requiring immediate surgery [48, 49].”
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RESPONSE OF A VON HIPPEL–LINDAU–ASSOCIATED OPTIC NERVE HEMANGIOBLASTOMA TO BELZUTIFAN
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The selection of targeted therapies for relapsed or refractory advanced renal cell carcinoma
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“There was also activity seen against other VHL-associated neoplasms present in these patients [76].”
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“This theory would explain the observed 30% partial response rate of Belzutifan in VHL-associated hemangioblastomas [42], while this drug and PT2385, a first-generation HIF-2 α inhibitor [57], demonstrated clinical efficacy in VHL patients with renal cell carcinoma (RCC) [40,41,62].”
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Fabbro, S. D., Cicinelli, M. V., Lattanzio, R., Bousyf, S., Bruno, L., Antropoli, A., Bianco, L., Bruschi, E., Arrigo, A., Pipitone, G. B., et al. (2025) · Ophthalmology Science · doi:10.1016/j.xops.2025.100846 · Cited by 2
Implementation and outcome of personalized treatment strategies in advanced genitourinary cancers
Klostermann, A., Debertshäuser, T., Benary, M., Biernath, N., Erber, B., Tahbaz, R., Möbs, M., Joosten, M., Schmitt, W., Kim, T., et al. (2025) · ESMO Open · doi:10.1016/j.esmoop.2025.105497 · Cited by 2
Meiman, D., Skaar, T. C., Shugg, T., & Quinney, S. K. (2025) · JCO Precision Oncology · doi:10.1200/po-25-00153 · Cited by 2
Metabolic Reprogramming in Kidney Cancer: Implications for Therapy
Edo, E. T. (2025) · annals of urologic oncology · doi:10.32948/auo.2025.06.02 · Cited by 2
“Emerging technologies such as metabolomic profiling, hyperpolarized MRI, and single-cell analysis are providing unprecedented insights into kidney cancer metabolism, enabling more precise targeting of metabolic vulnerabilities [22].”
Khan, A., Alsakran, W. A., Barry, A., Badawi, A. H., & Magliyah, M. (2025) · International Journal of Retina and Vitreous · doi:10.1186/s40942-025-00721-1 · Cited by 2
“Recently, belzutifan, a hypoxia-inducible factor 2a (HIF-2a), was approved for the management of extraocular manifestations of VHL disease [19].”
Future treatment options in metastatic clear cell renal cell carcinoma
Simonaggio, A., Auvray, M., Rochand, A., Thibault, C., Gervais, C., Oudard, S. M., & Vano, Y. A. (2022) · Bulletin du Cancer · doi:10.1016/s0007-4551(22)00238-7 · Cited by 2
Self-citationHepcidin as a prognostic biomarker in clear cell renal cell carcinoma.
Zhou, Z., Wu, J., Yang, Y., Gao, P., Wang, L., & Wu, Z. (2022) · PubMed Central · Cited by 2
Use of genomic markers to improve epidemiologic and clinical research in urology
Cancel‐Tassin, G., & Koutros, S. (2023) · Current Opinion in Urology · doi:10.1097/mou.0000000000001126 · Cited by 2
“Belzutifan, a highly specificHIF2a inhibitor, was developed based on the role of VHL in the regulation of the expression of the a-subunit of the transcription factor hypoxia-inducible factor (HIF) and received FDA approval for the treatment of nonmetastatic renal cell carcinomas tumors from patients who carry VHL germ…”
Neurofibromatosis type1, type 2, tuberous sclerosis and Von Hippel-Lindau disease
Elbeltagy, M., & Abbassy, M. A. (2023) · Child s Nervous System · doi:10.1007/s00381-023-06160-3 · Cited by 2
“In one study, hemangioblastomas showed partial response in 24% of the cases and complete response in 6%, and more than 75% showed at least stationary disease for 1 year [159].”
Backgroundvon Hippel-Lindau syndrome-related congenital polycythemia and response to belzutifan
Amaral, P. S., Mohan, S. R., & Beckermann, K. E. (2024) · Haematologica · doi:10.3324/haematol.2024.285724 · Cited by 3
“8 Consequently, it exhibits antitumor activity and concurrently reduces plasma erythropoietin”
BackgroundBacigalupa, Z. A., Brown, W. A., Krystofiak, E., Wolf, M. M., Hongo, R. A., Landis, M. D., Amason, E. K., Beckermann, K. E., Rathmell, J. C., & Rathmell, W. K. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.04.21.489116 · Cited by 2
“Belzutifan (MK-6482, previously PT19 2399) is the first of such molecules to have received FDA approval for the treatment of adult 20 patients with VHL disease who need therapy for ccRCC and other hemangioblastomas [22].”
BackgroundSelf-citationBelzutifan in Europe: A New Targeted Therapy for Clear Cell Renal Cancer
Graham, C., Albiges, L. K., Grimm, M., & Powles, T. B. (2025) · European Urology · doi:10.1016/j.eururo.2025.04.009 · Cited by 2
Sugiyama, Y., Kuramitsu, S., Eguchi, K., Ito, M., Ando, R., Matsuno, H., Suzaki, N., & Maesawa, S. (2024) · Journal of Neurosurgery Case Lessons · doi:10.3171/case23757 · Cited by 1
“20,21 Although Neth et al. 22 demonstrated the safety and tolerance of belzutifan for CNS HBs, with favorable responses in patients with VHL disease, fatal intracranial hemorrhage has also been reported as an adverse effect of belzutifan.”
Backgroundvon Hippel-Lindau Syndrome and Secondary Hypertension: A Case Report
Bose, S., Rajalakshmi, K. V., Kumaresan, A. P., & Simon, J. (2024) · Cureus · doi:10.7759/cureus.61702 · Cited by 1
“Belzutifan, an HIF2a inhibitor, has recently been approved by the United States Food and Drug Administration [8] for use in VHL, especially renal cell carcinoma [9], CNS hemangioblastomas, or pancreatic neuroendocrine tumors, not requiring immediate surgery.”
BackgroundGenetik in der Nephrologie – was ist neu?
Bartram, M. P., Beck, B. B., & Müller, R. (2024) · DMW - Deutsche Medizinische Wochenschrift · doi:10.1055/a-2198-0363 · Cited by 1
“Hierzu gehört u.a. der große Erfolg der HIF2-Inhibi-tion mittels Belzutifan bei Von-Hippel-Lindau-Syndrom, der erstmalig eine medikamentöse Therapie dieser Er-krankung möglich macht [18].”
Greene, J., Wang, Z., Harris, B. H. L., Dodwell, D. J., & Lord, S. (2025) · Cancer Control · doi:10.1177/10732748251317681 · Cited by 1
“39,40”
Jonasch, E. W., Song, Y., Freimark, J., Mohan, M., Signorovitch, J., & Sundaram, M. (2025) · Clinical Genitourinary Cancer · doi:10.1016/j.clgc.2025.102349 · Cited by 1
Self-citationMcKay, R. R., Eapen, R. S., Wulff-Burchfield, E. M., & Hofman, M. S. (2025) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk-25-473862 · Cited by 1
Belzutifan in von Hippel-Lindau disease
Ciccarese, C., Iacovelli, R., & Tortora, G. (2025) · The Lancet Oncology · doi:10.1016/s1470-2045(25)00153-6 · Cited by 1
de Oliveira, A. C. F., Noronha, F. B., de Oliveira, F. L. Q., de Oliveira, F. N. G., & Boente, L. D. A. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-15609-0.00029-5 · Cited by 1
Ngwa, V. M., Hwang, Y., Song, W., Edwards, D. N., & Chen, J. (2025) · Cancer Gene Therapy · doi:10.1038/s41417-025-00934-4 · Cited by 1
Wu, C. W., Huang, Y.-R. M., Ziadeh, H., Jong, B.-E., Dalal, P., Lin, H.-T. C., Majmundar, A. J., Tsai, Y., Hijaz, A., Stoller, M. L., et al. (2025) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2025.151655 · Cited by 1
Loebach, L., Millan, B., Antony, M. B., Solomon, J., Ricketts, C., Koller, C. R., Patel, M. H., Blachman-Braun, R., Gurram, S., Vocke, C. D., et al. (2025) · Urology · doi:10.1016/j.urology.2025.07.031 · Cited by 1
Self-citationBelzutifan for Ocular Tumors in Patients with von Hippel-Lindau Disease
Jamshidi, F., Tadros, S., Lozano, L. P., Boldt, H. C., & Binkley, E. M. (2025) · Ocular Oncology and Pathology · doi:10.1159/000548701 · Cited by 1
“In the subgroup analysis of 12 patients (16 eyes) with RH, with a median 37.3-month follow-up, all tumors responded, and no new tumors developed while on treatment [8, 10].”
InfluentialThe Role of Intra-tumor Hypoxia in Cancer Cells Immune Escape Mechanism
Farhangnia, P., Delbandi, A., Aghamohamadi, N., Safdarian, A. R., & Akbarpour, M. (2025) · Springer eBooks · doi:10.1007/978-3-032-00759-9_61 · Cited by 1
Case report: Von Hippel-Lindau syndrome with multisystem involvement: a therapeutic dilemma
He, S., Wang, C., Yang, J., Shen, J., Zeng, X., Zheng, J., & Wang, Y. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1633911 · Cited by 1
“Multiple phase II/III trials have demonstrated their ability to suppress tumor progression in VHL patients (14, 15).”
EndoCompass project: research roadmap for endocrine causes and consequences of cancer
Carroll, J. S., Castinetti, F., Follin, C., Luque, R. M., Stuart, A. A. V., Giwercman, A., Grozinsky‐Glasberg, S., Krausz, C. G., Paschou, S. Α., Peeters, R. P., et al. (2025) · European Journal of Endocrinology · doi:10.1093/ejendo/lvaf066 · Cited by 1
Babu, B. S., Dutta, K., & Mondal, S. (2025) · Journal of Pharmacy And Bioallied Sciences · doi:10.4103/jpbs.jpbs_92_25 · Cited by 1
“[4,5] The chemical structure of Belzutifan is 3‑{[(1S,2S,3R)‑ 2,3‑difluoro‑1‑hydroxy‑7‑methanesulfonyl‑2,3‑dihydro‑1 H‑inden‑4‑yl]oxy}‑5‑fluoro benzonitrile [F igure 1].”
Glienke, M., Himmelsbach, R., Zirngibl, M., Metzger, P., Kühn, J., Miething, C., Sigle, A., Gratzke, C., Nientiedt, C., Rassner, M. P., et al. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1688779 · Cited by 1
“The identi fi cation of VHL mutations in approximately one-third of RCC patients reaf fi rms the therapeutic relevance of targeting the hypoxia-inducible factor (HIF) axis.”
InfluentialSimhachalam, P., & Sabithakala, T. (2025) · Biomedical Chromatography · doi:10.1002/bmc.70333 · Cited by 1
Exploiting tumor lineage features for precision cancer therapy
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“HIF-2 α inhibitor has shown ef fi cacy in VHL syndrome – associated renal cell carcinoma, including in cases with prior resistance to anti-PD-1 therapy [5, 6].”
Auernhammer, C. J., Wang, K., Macciò, U., Knösel, T., Hungbauer, M., Schilbach, K., Maurer, J., Peischer, L., Reul, A., Kuzmenko, E., et al. (2026) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaf705 · Cited by 1
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“…& Co., Inc.) is an FDA approved HIF2 α inhibitor for patients with advanced renal cell carcinoma (RCC) following treatment with a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) 16,40 .”
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Rare solid tumours as indicators of hereditary cancer syndromes
Rivera, B., Torrezan, G. T., Roca, C., Goudie, C., & Foulkes, W. D. (2026) · European Journal of Human Genetics · doi:10.1038/s41431-026-02091-0 · Cited by 1
“In VHL patients, belzutifan (a HIF-2 α inhibitor) leads to objective responses in roughly half of renal lesions and shows activity in other VHL-linked tumours, shifting care away from repetitive surgery toward biology-based control [66].”
Huang, W., Chaudhary, A., Sun, Z., Reuben, C. S., Balaji, S., Catey, A. R., Luo, S., Cai, W., Hsu, J. C., & Xu, J. (2026) · Journal of Nanobiotechnology · doi:10.1186/s12951-026-04338-w · Cited by 2
“The clinical approval of belzutifan, a selective HIF-2α inhibitor, offers a compelling pharmacological approach to disrupt hypoxia-driven signaling, facilitating its incorporation into multifunctional nanotherapeutic designs [116].”
Belzutifan Attenuates Choroidal Neovascularization by Suppressing the HIF ‐2α/ PAI ‐1 Axis
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Self-citation
Metadata
- 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 › Oncology › 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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