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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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“This approval is based on data from the phase II LITESPARK Study 004, which included 61 patients with VHL-associated RCC [3].”
A Glimpse in the Future of Malignant Mesothelioma Treatment
Pezzicoli, G., Rizzo, M., Perrone, M., Minei, S., Mutti, L., & Porta, C. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.809337 · Cited by 5
Understanding the Impact of Belzutifan on Treatment Strategies for Patients with VHL
Arevalo, A., Patel, N., Muraki, P., Ohtake, S., Bratslavsky, G., Clark, C., Mann, J., Iliopoulos, O., Jonasch, E. W., Srinivasan, R., et al. (2022) · Journal of Kidney Cancer and VHL · doi:10.15586/jkcvhl.v9i3.245 · Cited by 5
“Additionally, efficacy was seen with extra-renal manifestations as 30 and 91% of patients had responses with CNS and pancreatic neuroendocrine tumors, respectively (10).”
BackgroundSelf-citationWang, E., Rupe, E. S., Mukhida, S. S., Johns, A. C., Campbell, M. T., Shah, A. Y., Zurita, A. J., Gao, J., Goswami, S., Jonasch, E., et al. (2025) · European Urology Focus · doi:10.1016/j.euf.2024.09.007 · Cited by 4
Self-citationResende, L. F., Ávila, E. P., & Pliego, J. R. (2025) · ChemPlusChem · doi:10.1002/cplu.202500257 · Cited by 4
Mahdi, W. A., Alhowyan, A., & Obaidullah, A. J. (2025) · Scientific Reports · doi:10.1038/s41598-025-07366-y · Cited by 4
New Treatment Options for Pancreatic Neuroendocrine Tumors: A Narrative Review
Romanowicz, A., Fudalej, M. M., Asendrych, A., Badowska-Kozakiewicz, A. M., Nurzyński, P., & Deptała, A. (2025) · Cancers · doi:10.3390/cancers17233837 · Cited by 6
“Belzutifan, a targeted inhibitor of the HIF signaling pathway that blocks HIF-2alpha [139], was initially studied in patients with renal cell carcinoma (RCC) and non-renal cell neoplasms, including PanNETs, associated with VHL disease [140].”
Chen, D., & Hua, C. (2025) · Frontiers in Medicine · doi:10.3389/fmed.2025.1735808 · Cited by 5
“Results of multiple clinical trials reflect this relationship between metabolic disruption and therapeutic results (11).”
InfluentialTargeting HIF‐2α in renal cell carcinoma: Expanding upon belzutifan
Rodríguez-Alvarado, M., Qin, Q., Tambar, U. K., & Brugarolas, J. (2026) · Cancer · doi:10.1002/cncr.70239 · Cited by 4
Calabrò, C., Ciccimarra, F., Rizzo, A., Cazzato, G., Mura, M. D., Taha, T., Bourlon, M. T., Melichar, B., Študentová, H., Schieber, T. J., et al. (2026) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2026.2627934 · Cited by 4
“Belzutifan acts by blocking the heterodimerization of HIF-2α with HIF-1β, thereby preventing the transcription of hypoxia-target genes and reducing VEGF-mediated tumor growth [16– 18].”
HIF sustain a transcriptional regulatory circuit of EPAS1 expression in renal clear cell carcinoma
Naas, S., Krüger, R., Grampp, S., Lauer, V., Kraus, A., Naas, J., Müller, F., Gsottberger, F., Schiffer, M., Wullich, B., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-68576-0 · Cited by 4
“…HIF-2 inhibitor belzutifan has been licensed for the treatment of VHL-associated tumors in VHL-patients and of advanced sporadic RCC. Belzutifan in combination with established RCC therapeutics met primary endpoints in phase 2 and 3 clinical trials in patients with advanced sporadic RCC 14 – 16 .”
Glover, M. J., Waguespack, S. G., Campbell, M. T., Varghese, J. M., Ng, C. S., Lu, Y., & Jiménez, C. (2026) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgag182 · Cited by 4
Emerging therapies of hemangioblastomas
Sanghadia, C., Martinez, M. E., McNulty, M., Russ, E., Woolridge, M. G., Cao, D. T., Micunovic, M., Roberts, J., Pérez, J. C., & Lucke-Wold, B. P. (2023) · Exploration of neuroscience · doi:10.37349/en.2023.00031 · Cited by 4
Toxicity Management of Systemic Kidney Cancer Therapies
Qin, Q., Nein, E., Flaten, A., & Zhang, T. (2023) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2023.05.006 · Cited by 4
Yang, D., Li, Q., Lu, P., Wu, D., Li, W., Meng, X., Xing, M., Shangguan, W., Chen, B., Yang, J., et al. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105535 · Cited by 4
“…to promote renal cell carcinoma progression and is regulated by VHL. Previously, many studies have focused on the development of HIF2 α -targeted therapies for patients, and the FDA approved a HIF2 α inhibitor, belzutifan (Welireg, Merck), for adult patients with VHL-associated tumors in 2021 (30).”
BackgroundKim, M., Shim, H. S., Kim, S., Lee, I. H., Kim, J., Yoon, S., Kim, H., Park, I., Jeong, J. H., Yoo, C., et al. (2024) · Journal of Pathology and Translational Medicine · doi:10.4132/jptm.2023.11.01 · Cited by 5
Ali, M., Eid, M., Saliby, R. M., Choi, S. S., McKay, R. R., Siva, S., Braun, D. A., & Chen, Y. (2024) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_438658 · Cited by 4
Beauchamp, L., Indulkar, S. T., Erak, E., Salimian, M., & Matoso, A. (2024) · Surgical pathology clinics · doi:10.1016/j.path.2024.10.002 · Cited by 4
Kandemir, E. A. (2022) · Journal of Oncology Pharmacy Practice · doi:10.1177/10781552221112015 · Cited by 5
“No complete responses were observed; however, almost all patients had disease control among 61 patients with VHL-associated RCC.(8) The most common adverse events were anemia (90%) and fatigue (66%), and grade 3 to 5 adverse events were observed in 33% of the patients.”
BackgroundInfluentialChen, P.-W., Huang, S., Chou, W., Chang, F., Cheng, Y., & Wang, H. (2022) · Phytomedicine · doi:10.1016/j.phymed.2022.154570 · Cited by 4
Rosellini, M., Marchetti, A., Tassinari, E., Nuvola, G., Rizzo, A., Santoni, M., Mollica, V., & Massari, F. (2022) · Expert Review of Precision Medicine and Drug Development · doi:10.1080/23808993.2022.2156786 · Cited by 4
“neuroendocrine tumors and hemangioblastomas associated with VHL disease [51].”
BackgroundÖrökletes vesetumor-szindrómák.
Sánta, F., Semjén, D., & Kuthi, L. (2023) · Orvosi Hetilap · doi:10.1556/650.2023.32729 · Cited by 4
Perrier, M., Scoazec, J., & Walter, T. (2023) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359231171041 · Cited by 4
HIF inhibition: Current strategies and clinical challenges
Więch-Walów, A., Bartoszewska, S., Barton, A., Czechowicz, P., Dudzik, J., Wielockx, B., Collawn, J. F., & Bartoszewski, R. (2026) · Redox biology · doi:10.1016/j.redox.2026.104220 · Cited by 3
“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].”
Emerging Therapeutic Targets in Rheumatoid Arthritis: Focusing on HIF-1α, Nrf2, STATs, and RORγt
Prajapati, P. S., Singh, P. K., & Doshi, G. (2025) · Current Drug Targets · doi:10.2174/0113894501372670250408074908 · Cited by 3
Beckermann, K. E., Shah, N. J., Campbell, M. T., Haas, N. B., Nelson, A. A., Ornstein, M. C., Mao, S. S., Keshava-Prasad, H., Hammers, H. J., Gao, X., et al. (2025) · The Oncologist · doi:10.1093/oncolo/oyaf138 · Cited by 3
Self-citationÁvila, E. P., Lopes, K. L., de Almeida, M. V., & Pliego, J. R. (2025) · Asian Journal of Organic Chemistry · doi:10.1002/ajoc.202500481 · Cited by 3
Oxymatrine inhibited the progression of renal cell carcinoma by increasing TOR1AIP1 expression
Yan, X., Zhao, K., Zhang, Z., Yin, X., Han, Y., Jiang, Z., He, T., & Wang, K. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1611069 · Cited by 3
Zhao, W., Demczyszyn, S. M., Coffey, N. J., Jiang, Y., Kim, B., Bowers, S., Bowman, C. E., Noji, M., Jang, C., Simon, M. C., et al. (2025) · JCI Insight · doi:10.1172/jci.insight.182711 · Cited by 3
Germline Mutations as Cancer Drug Targets
Tang, T., Maresso, K. C., Ngeow, J. Y. Y., Vilar, E., & Yap, T. A. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-1241 · Cited by 3
Strowd, R. E., III, de la Fuente, M. I., Bauer, T. M., Papadopoulos, K. P., Chen, K., Perini, R. F., Liu, Y., & McDermott, D. F. (2025) · Neuro-Oncology Advances · doi:10.1093/noajnl/vdaf242 · Cited by 3
Self-citationThe Hippo pathway in clear cell renal cell carcinoma (ccRCC): a nexus with the VHL disruption?
Waeckel, T., Lefranc, R., Waeckel, M., Riffet, M., Tillou, X., Levallet, G., & Bazille, C. (2026) · Translational Oncology · doi:10.1016/j.tranon.2026.102721 · Cited by 4
“However, such drugs exert systemic effects that can lead to adverse events, including cytopenias, colitis and cutaneous xerosis [26].”
The hypoxic tumor microenvironment: Functional and metabolic reprogramming of key immune populations
Ojaroodi, A. F., Shokravi, S., Eskandarzadeh, S., Ghahremanzadeh, A., Alizadeh, F., Amirikar, F., Mobayen, G., Mahrooghi, D., Lahouty, M., Shamsasenjan, K., et al. (2026) · Pathology - Research and Practice · doi:10.1016/j.prp.2026.156443 · Cited by 5
Gene mutation profiling and clinical significances in patients with renal cell carcinoma
Wang, Y., He, P., Zhou, X., Wang, C., Fu, J., Zhang, D., Liao, D., Zhou, Z., Wu, C., & Gong, W. (2023) · Clinics · doi:10.1016/j.clinsp.2023.100259 · Cited by 3
“It was also shown that this drug can treat Central Nervous System (CNS) hemangioblastoma, retinal hemangioblastoma, and pNET disease.(14,18) Although these great accomplishments have been achieved, the other gene mutations and the prognosis significances of gene mutations in mRCC patients remain defined.”
BackgroundLuo, W., Sun, C., & Yu, S. (2023) · Case Reports in Oncology · doi:10.1159/000531876 · Cited by 3
“In 2021, belzutifan was approved by the US Food and Drug Administration (FDA) for the adult patients with VHL-associated RCC, CNS hemangioblastoma, or pancreatic neuroendocrine tumors without immediate surgery, thus providing a medical option [7, 8].”
Zhao, S., Li, H., Luo, W., Hu, Z., Wang, Y., Liu, T., Zhang, Y., & Dai, R. (2024) · Shock · doi:10.1097/shk.0000000000002479 · Cited by 3
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“(Jonasch et al., 2021).”
Ohe, C., Yoshida, T., Amin, M. B., Smith, S. C., Shiohara, M., Tsujio, N., Kato, M., Uno, R., Tsuzuki, T., & Kohashi, K. (2025) · Pathology International · doi:10.1111/pin.70012 · Cited by 3
“The HIF ‐ 2 α inhibitor has recently been approved by the Food and Drug Administration for treating VHL ‐ mutated cancers [38], with potential future applications in advanced ccRCC [39].”
Zhang, S., Li, Y., & Wen, W. (2025) · BMC Nephrology · doi:10.1186/s12882-025-04303-z · Cited by 3
Sri, K. H., Ravisankar, P., Konidala, S. K., & Puttagunta, S. B. (2025) · Biomedical Chromatography · doi:10.1002/bmc.70168 · Cited by 3
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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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