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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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Citations
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Self-citationDeficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment
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“Of 50 patients with CNS hemangioblastoma, 30% had a confirmed response, including 6% who had a complete response.(39) Based on these findings, belzutifan has received US Food and Drug Administration approval for VHL‐associated tumors, including hemangioblastoma.”
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“Phase II studies in advanced ccRCC have reported durable disease control with a favorable safety pro fi le (191, 192), FDA in 2021 approved belzutifan for patients with VHL-associated RCC (193).”
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“Belzutifan, approved by the FDA for immunotherapy in renal cell carcinoma associated with VHL syndrome [79], can also be used in combination with the multi-targeted anticancer agent cabozantinib for immunotherapy-resistant clear cell renal carcinoma [80].”
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“Belzutifan is a hypoxia-inducible factor-2 alpha (HIF-2 α ) inhibitor approved in the US for the treatment of renal cancer, pancreatic neuroendocrine tumors, and hemangioblastomas in VHL patients [120].”
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BackgroundGenetics of Pancreatic Neuroendocrine Tumors
Mohindroo, C., McAllister, F. M., & Jesus‐Acosta, A. D. (2022) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2022.07.005 · Cited by 12
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“Belzutifan, an HIF-2alpha inhibitor, has also shown promising results [148].”
BackgroundKhoury, L. Y. E., Pan, X., Hlady, R. A., Wagner, R. T., Shaikh, S., Wang, L., Humphreys, M. R., Castle, E. P., Stanton, M., Ho, T. H., et al. (2023) · Clinical Epigenetics · doi:10.1186/s13148-023-01471-3 · Cited by 11
“In the case of ccRCC, however, VHL is the only consistent truncal mutation, which has only recently become targetable through its downstream HIF effectors, demonstrating the need to delve deeper into other processes contributing to ITH [1, 11, 12].”
BackgroundDiscovery of Cycloalkyl[c]thiophenes as Novel Scaffolds for Hypoxia-Inducible Factor-2α Inhibitors
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“The LITESPARK-004 phase II trial evaluated belzutifan use in 61 VHL disease patients with RCC, the majority of whom had simultaneous central nervous system (CNS) hemangiomas or pancreatic neuroendocrine tumors [8].”
InfluentialZhan, M., Zhao, B., Chen, H., Wu, J., Shi, R., Gao, F., Zhao, L., & Zhu, J. (2026) · Frontiers in Genetics · doi:10.3389/fgene.2025.1752384 · Cited by 10
“The latest clinical data show that belzutifan can effectively improve progression-free survival (PFS) and symptom relief in patients with ccRCC by inhibiting HIF-2 α activity, especially when combined with other targeted drugs (Jonasch et al., 2021; Choueiri et al., 2024; Song et al., 2024).”
Clear cell mesotheliomas with inactivating VHL mutations and near‐haploid genomic features
Michal, M., Kravtsov, O., Ross, J. S., Škanderová, D., Martínek, P., Mosaieby, E., Mata, D. A., Williams, E. A., & Hung, Y. P. (2022) · Genes Chromosomes and Cancer · doi:10.1002/gcc.23119 · Cited by 10
“The identification of VHL alterations in clear cell mesothelioma raises a possibility of targeted therapy, such as belzutifan in tumors associated with von Hippel–Lindau disease.(39) In summary, we described the clinicopathologic and genomic features of a series of clear cell mesotheliomas with inactivating VHL mutati…”
BackgroundImmunological Aspects of Von Hippel-Lindau Disease: A Focus on Neuro-Oncology and Myasthenia Gravis
Norata, D., Peri, M., Giammalva, G., Lupica, A., Paolini, F., Incorvaia, L., Badalamenti, G., Gristina, V., Galvano, A., Russo, A., et al. (2023) · Diagnostics · doi:10.3390/diagnostics13010144 · Cited by 10
“The most promising molecule under investigation is belzutifan (MK-6482, previously called PT2977), an HIF-2α inhibitor that showed activity in patients with RCC and non–RCC neoplasms associated with VHL diseases [20], and a phase 3 trial is planned.”
BackgroundManagement of Pheochromocytomas and Paragangliomas
Passman, J. E., & Wachtel, H. (2024) · Surgical Clinics of North America · doi:10.1016/j.suc.2024.02.014 · Cited by 10
Abu‐Remaileh, M., Persky, N. S., Lee, Y., Root, D. E., & Kaelin, W. G. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2410356121 · Cited by 10
“Moreover, Belzutifan is active against paragan-gliomas caused by gain - of - function HIF2 mutations ( 19 ) and against VHL - associated pancreatic neuroendocrine tumors, which share similarities with paragangliomas ( 18 , 20 ).”
Tu, R., Ma, J., Chen, Y., Kang, Y., Ren, D., Cai, Z., Zhang, R., Pan, Y., Liu, Y., Da, Y., et al. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-07136-0 · Cited by 11
“Although HIF2 α inhibition would be a powerful approach for the treatment of ccRCC, the current strategies were only designed to inhibit its transcriptional activity, which has a signi fi cant limitation [15 – 17].”
Delgado‐Bellido, D., Chacón-Barrado, A., Olmedo-Pelayo, J., Perez, C. J., Gilabert-Prieto, P., Díaz‐Martín, J., García-Díaz, Á., Oliver, F. J., & de Álava, E. (2025) · Cell Death and Differentiation · doi:10.1038/s41418-025-01469-9 · Cited by 10
“5H. Belzutifan in combination with FAKi: promising candidates for the treatment of metastatic uveal melanoma patients It has been reported that Belzutifan is a promising drug for patients with ccRCC harboring VHL mutations [26].”
Recent Developments in the Management of Renal Cell Cancer
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“Of the two main targets, HIF-1 and HIF-2, only a direct HIF-2 inhibitor, belzutifan, has been approved for clinical use.(158) Belzutifan is currently undergoing clinical assessment in combination with the anti-PD-1 antibody pembrolizumab and other compounds on ccRCC (NCT04736706).”
BackgroundDiagnosis in Neuroendocrine Neoplasms: From Molecular Biology to Molecular Imaging
Kopp, R. M., Espinosa-Olarte, P., & Alonso‐Gordoa, T. (2022) · Cancers · doi:10.3390/cancers14102514 · Cited by 9
“matostatin receptors; VHL, Von Hippel-Lindau [98].”
Jonasch, E. W., Song, Y., Freimark, J., Berman, R., Nguyen, H. H., Signorovitch, J., & Sundaram, M. (2022) · Clinical Genitourinary Cancer · doi:10.1016/j.clgc.2022.12.008 · Cited by 10
Self-citationDiseases of Hereditary Renal Cell Cancers
Iliopoulos, O. (2023) · Urologic Clinics of North America · doi:10.1016/j.ucl.2023.01.010 · Cited by 10
Self-citationPredictive and prognostic biomarkers in urological tumours
Cimadamore, A., Franzese, C., Loreto, C. D., Blanca, A., Antonio Lopez-beltran, B., Crestani, A., Giannarini, G., Tan, P. H., Carneiro, B. A., El‐Deiry, W. S., et al. (2023) · Pathology · doi:10.1016/j.pathol.2023.10.016 · Cited by 12
Celada, L., Cubiella, T., San‐Juan‐Guardado, J., Martínez, A. S. J., Valdés, N., Jiménez‐Fonseca, P., Díaz, I., Enguita, J. M., Astudillo, A., Álvarez-González, E., et al. (2022) · Cancers · doi:10.3390/cancers14122986 · Cited by 11
“Belzutifan, a potent and selective small-molecule inhibitor of HIF2α analog of PT2385, has proven to be of remarkable therapeutic benefit for patients with ccRCC and the Pacak-Zhuang syndrome caused by loss-of-function mutations in VHL or gain-of-function mutations in EPAS1, respectively [25,26].”
BackgroundSakellakis, M., Spathas, N., Tsaousis, K. T., Nikitiadis, E. N., Linardou, H., & Diakonis, V. F. (2022) · Cureus · doi:10.7759/cureus.27266 · Cited by 10
“Belzutifan is a novel HIF-2alpha inhibitor, currently used against von Hippel-Lindau diseaseassociated RCC [119].”
BackgroundMethodTherapeutic Management of Metastatic Clear Cell Renal Cell Carcinoma: A Revolution in Every Decade
Larroquette, M., Lefort, F., Héraudet, L., Bernhard, J., Ravaud, A., Domblides, C., & Gross‐Goupil, M. (2022) · Cancers · doi:10.3390/cancers14246230 · Cited by 10
“Belzutifan was also evaluated in a phase II trial for patients with RCC due to von Hippel–Lindau hereditary disease, resulting in an ORR of 49% (median duration of response not reached), leading to FDA approval of belzutifan for this population in August 2021 [53].”
MethodMolecular Basis of Pancreatic Neuroendocrine Tumors
Maluchenko, A., Maksimov, D. O., Antysheva, Z., Krupinova, J. A., Avsievich, E. S., Glazova, O., Бодунова, Н. А., Karnaukhov, N., Feidorov, I. Y., Salimgereeva, D. A., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252011017 · Cited by 11
“It is noteworthy that the HIF-2 α inhibitor belzutifan represents a novel promising non-interventional option for inherited VHL-related pancreatic NETs, and has already been FDA-approved for renal cell carcinoma [40].”
BackgroundGating residues govern ligand unbinding kinetics from the buried cavity in HIF ‐2α PAS ‐B
Silvestrini, M., Solazzo, R., Boral, S., Cocco, M. J., Closson, J. D., Masetti, M., Gardner, K. H., & Chong, L. T. (2024) · Protein Science · doi:10.1002/pro.5198 · Cited by 7
“…of HIF pathways is found in several cancers (Bos et al. 2003; Zagzag et al. 2000), targeted disruption of the HIF-2 α /ARNT interaction by ligand binding to the buried HIF-2 α cavity has become a clinically useful therapeutic strategy for certain cancers (Chen et al. 2016; Jonasch et al. 2021).”
BackgroundRequirement for Cyclin D1 Underlies Cell-Autonomous HIF2 Dependence in Kidney Cancer
Shirole, N. H., Kesar, D., Lee, Y., Goodale, A. B., Syamala, S., Kukreja, S., Li, R., Qiu, X., Yu, W., Goldman, S. R., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-1378 · Cited by 11
Zhao, M., Zhang, D., Jiang, H., Kuganesan, N., Natarajan, S., Pu, L., Thakkar, K. N., Zhao, H., Le, Q., Giaccia, A. J., et al. (2025) · Science Advances · doi:10.1126/sciadv.adv2417 · Cited by 10
Development of small molecule inhibitors of hypoxia-inducible factors for cancer therapy
Semenza, G. L. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2025.100075 · Cited by 10
Extracellular Vesicles—A New Potential Player in the Immunology of Renal Cell Carcinoma
Kleibert, M., Majka, M., Łakomska, K., & Czystowska, M. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12050772 · Cited by 9
“Indeed, FDA approved the use of belzutifan (a small molecule inhibitor of HIF-2α) in patients with RCC harboring the VHL mutation [17].”
BackgroundNarayan, V., & Jonasch, E. W. (2022) · Cancers · doi:10.3390/cancers14215313 · Cited by 9
“The clinical activity of belzutifan in VHL disease was specifically tested in a phase 2, non-randomized, open-label clinical trial of 61 patients with germline VHL alteration and at least one measurable, non-metastatic primary RCC [51].”
MethodSelf-citationTakagi, T. (2022) · International Journal of Urology · doi:10.1111/iju.15103 · Cited by 9
Shao, I., Peng, P., Wu, H., Chen, J., Lai, J. C., Chang, J., Wu, H., Wu, K., Pang, S., & Hsu, K. (2023) · Cancer Medicine · doi:10.1002/cam4.5723 · Cited by 9
Mustafi, D., Huang, J., Ting, M. A., Waligorski, N., Stacey, A. W., & Huang, L. C. (2023) · Retina · doi:10.1097/iae.0000000000003973 · Cited by 9
Govindarajan, A., Castro, D. V., Zengin, Z. B., Salgia, S. K., Patel, J., & Pal, S. K. (2022) · Cancers · doi:10.3390/cancers14092049 · Cited by 9
Kim, M., Shim, H. S., Kim, S., Lee, I. H., Kim, J., Yoon, S., Kim, H., Park, I., Jeong, J. H., Yoo, C., et al. (2023) · Cancer Research and Treatment · doi:10.4143/crt.2023.1043 · Cited by 8
Spinal cord hemangioblastomas in von Hippel–Lindau disease
Kreatsoulas, D. C., & Lonser, R. R. (2023) · Neuro-Oncology Advances · doi:10.1093/noajnl/vdad153 · Cited by 8
“46,47 Belzutifan is a small-molecule inhibitor of the HIF 2 α subunit.”
Pediatric patients with von Hippel–Lindau and hemangioblastomas treated successfully with belzutifan
Duan, E., Robinson, M., Davis, C., Pruthi, S., Shin, C. S., Lewis, M. A., Martínez-Agosto, J. A., Gorin, M. B., Shuch, B. M., Friedman, D. L., et al. (2024) · Pediatric Blood & Cancer · doi:10.1002/pbc.31371 · Cited by 8
Fang, Y., Shen, F., Huang, R., Lin, Y., Wu, Y., Li, Q., Xie, Z., Yang, X., Zhang, Z., Jin, X., et al. (2025) · ACS Nano · doi:10.1021/acsnano.4c14277 · Cited by 9
Belzutifan's role in the treatment landscape of clear cell renal cell carcinoma
Chen, A. H., & Grana, A. K. (2025) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.70023 · Cited by 8
“29,31 Thus, while there were some similar reported toxicities among the trial participants in LITESPARK-004 and - 005, the differences in incidence for certain adverse effects may be attributed to the differences in disease presentation/course, patient demographics, and the setting (earlier vs.…”
Ma, K., Li, Q., Zhang, Y., Wang, J., Jia, W., Liu, J., Liu, B., Li, Q., Wang, Q., & Zeng, K. (2025) · Neoplasia · doi:10.1016/j.neo.2025.101186 · Cited by 10
Cardiometabolic disease and cardio-oncology: Insights from iPSC models and tissue engineering
Kojic, A., Moslehi, J. J., Ky, B., & Wu, J. C. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102261 · Cited by 10
“78,79 Together, these findings underscore the genotype-phenotype link between VHL mutation, cancer predisposition, and cardiac-metabolic remodeling.”
Rhein, K., Kotsis, F., Ganner, A., Astheimer, S., Steiert, C., Laich, Y., Jilg, C. A., Klingler, J., & Neumann‐Haefelin, E. (2025) · BMC Cancer · doi:10.1186/s12885-025-15192-8 · Cited by 8
“No signal emerged that ESAs compromised tumor response rates or progression-free survival [13, 21].”
InfluentialGenetic Testing and Counselling for Hereditary Renal Carcinoma: What Do Clinicians Need to Know?
Re, C., Pecoraro, A., Stewart, G. D., Caliò, A., Erdem, S., Kalaycı, T., Uyguner, Z. O., Larcher, A., Campi, R., Amparore, D., et al. (2025) · European Urology Open Science · doi:10.1016/j.euros.2025.10.009 · Cited by 8
“Care for patients with VHL disease has been transformed by belzutifan, an HIF2 a inhibitor, for which an objective response rate of 49% was observed in a phase 2 trial in VHL-associated RCC without tumours >3 cm requiring immediate surgery and no metastatic disease [66].”
Neoadjuvant Systemic Therapy in Localized and Locally Advanced Renal Cell Carcinoma
Khaleel, S. S., Jiang, S., Kotecha, R. R., & Hakimi, A. A. (2022) · Frontiers in Urology · doi:10.3389/fruro.2022.864778 · Cited by 8
“In this regard, Belzutifan (MK6482) is a potent small molecule inhibitor of HIF-2a that has shown impressive activity in neoplasms associated with VHL disease, with a recent phase 2 trial of this agent in patients with renal cell carcinoma associated with VHL disease, noting an ORR of 49% in patients with RCC kidney t…”
BackgroundSomaticIDH1Hotspot Variants in Chinese Patients With Pheochromocytomas and Paragangliomas
Li, M., He, Y., Pang, Y., Zhang, J., Feng, Y. Y., He, Y., Xu, X., Wei, Y., Zhong, D., Deng, W., et al. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac653 · Cited by 8
Giraudet, A., Vinceneux, A., Pretet, V., Paquet, E., Lajusticia, A. S., Khayi, F., Badel, J., Boyle, H. J., Fléchon, A., & Kryza, D. (2023) · Pharmaceuticals · doi:10.3390/ph16070995 · Cited by 8
“The treatment of metastatic ccRCC is based on targeted agents such as antiangiogenic tyrosine kinase inhibitors (VEGF receptor tyrosine kinase inhibitors, VEGFR TKI) as metastases are highly vascularized due to the overproduction of platelet-derived and vascular endothelial growth factors (PDGFs and VEGFs).”
BackgroundInfluentialAykut, A., Else, T., & Demirci, H. (2024) · Canadian Journal of Ophthalmology · doi:10.1016/j.jcjo.2024.05.025 · Cited by 8
Self-citationNeuroendocrine Tumors: Germline Genetics and Hereditary Syndromes
Lauricella, E., Chaoul, N., D’Angelo, G., Giglio, A., Cafiero, C., Porta, C., & Palmirotta, R. (2025) · Current Treatment Options in Oncology · doi:10.1007/s11864-024-01288-z · Cited by 8
“These results culminated in regulatory approval by FDA and UK regulators for the treatment of VHL disease-associated renal cell carcinoma, central nervous system hemangio-blastoma and panNETs [83, 84].”
Belzutifan is active in VHL-related cancers
Romero, D. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00587-w · Cited by 8
Adashek, J. J., Breunig, J. J., Posadas, E. M., Bhowmick, N. A., Ellis, L., Freedland, S. J., Kim, H. L., Figlin, R. A., & Gong, J. (2022) · Drugs · doi:10.1007/s40265-022-01683-6 · Cited by 8
“In this Phase II, single-arm trial, belzutifan administered orally at 120 mg daily in patients with VHL-associated RCC demonstrated an encouraging 49 % (95 % CI 36–62 %) in patients who had previously been treated with surgical therapies [93].”
BackgroundDetermining Front-Line Therapeutic Strategy for Metastatic Clear Cell Renal Cell Carcinoma
Zarrabi, K. K., Lanade, O., & Geynisman, D. M. (2022) · Cancers · doi:10.3390/cancers14194607 · Cited by 8
“Belzutifan (MK-6482) is a second-generation HIF-2α inhibitor with remarkable efficacy in von Hippel–Lindau disease-associated RCC [83].”
BackgroundProteomics Characterization of Clear Cell Renal Cell Carcinoma
Miranda, J., Trilla‐Fuertes, L., López‐Vacas, R., López‐Camacho, E., García‐Fernández, E., Pertejo, A., Lumbreras-Herrera, M. I., Zapater‐Moros, A., Díaz‐Almirón, M., Dittmann, A., et al. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12010384 · Cited by 8
“In line with the importance of this pathway, we have to mention that Belzutifan [32], an HIF-2α antagonist, has been recently approved by the US Food and Drug Administration (FDA) for the treatment of ccRCC.”
BackgroundFDA Approval Summary: Belzutifan for VHL Disease Tumors—Letter
Trinh, J. Q., Ellithi, M., Shonka, N., & Bergan, R. C. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-2968 · Cited by 8
Molecular Characterization of TFE3-Rearranged Renal Cell Carcinoma in Children and Adolescents
Liu, H., Liu, H., Chen, J., Yin, X., Zhu, S., Hu, X. W., Tang, Y., He, S., Zhao, J., Zhang, X., et al. (2025) · Modern Pathology · doi:10.1016/j.modpat.2025.100748 · Cited by 7
Jung, N. Y., & Park, J. B. (2025) · Journal of Korean Neurosurgical Society · doi:10.3340/jkns.2025.0018 · Cited by 7
“Additionally, the HIF-2α inhibitor belzutifan has shown promising anti-tumor activity, including stabilizing disease and reducing progression rates 18,47,88) .”
Yang, Y., Fan, B., & Hu, X. (2025) · International Journal of Clinical Pharmacy · doi:10.1007/s11096-025-01953-9 · Cited by 6
“This finding aligns with previous clinical data from LITESPARK-004 and -005, where anemia occurred in 90% and 88% of patients, respectively [12, 13].”
Targeting conserved domains of hypoxia-inducible factors for cancer therapy
Salman, S., Huang, T. Y., Hwang, Y., Kumar, A., Datan, E., Wicks, E. E., Cho, E., Lee, S. N., Chen, C. O., Peng, Y., et al. (2026) · The Journal of Experimental Medicine · doi:10.1084/jem.20251009 · Cited by 8
“…initial approval by the FDA for VHL disease-associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors, and subsequent approvals have included patients with advanced or metastatic RCC (Fallah et al., 2022, 2024; Jonasch et al., 2021).”
Motzer, R. J., McDermott, R., Park, S. H., Burotto, M., Iacovelli, R., Verzoni, E., Suárez, C., Eto, M., Cutuli, H. J., Porta, C., et al. (2026) · The Lancet · doi:10.1016/s0140-6736(26)01089-5 · Cited by 7
Self-citationChou, Y., Pan, S., & Lin, S. (2022) · Kidney Research and Clinical Practice · doi:10.23876/j.krcp.22.118 · Cited by 9
“HIF-2α has been implicated tumorigenesis in VHL-reconstituted ccRCC [72], and HIF-2α inhibitor has been tested in phase 2 clinical trials for ccRCC in VHL disease [73].”
Halperin, R., & Tirosh, A. (2023) · Cancers · doi:10.3390/cancers15061739 · Cited by 7
“Belzutifan [25] HIF 2 inhibitor 61 (22) RCC 30/61 SD, 30/61 PR PNEN 20/22 (91%) confirmed response, 3 CR CNS HB—15/50 confirmed response, 3 CR Retinal HB—12/12 confirmed response Dose reduction— 15%, Dose interruption— 43%, Stopped treatment— 11%”
BackgroundMethodInfluentialHIF2α, Hepcidin and their crosstalk as tumour-promoting signalling
Formica, V., Riondino, S., Morelli, C., Guerriero, S., D’Amore, F., Grazia, A. D., Blanco, G. D. V., Sica, G. S., Arkenau, H., Monteleone, G., et al. (2023) · British Journal of Cancer · doi:10.1038/s41416-023-02266-2 · Cited by 8
“Encouraging results have also been obtained with the use of belzutifan in ccRCC patients with inherited VHL disease [61].”
BackgroundResultvon Hippel–Lindau disease-related neoplasia with an emphasis on renal manifestations
Tekin, B., Erickson, L. A., & Gupta, S. (2023) · Seminars in Diagnostic Pathology · doi:10.1053/j.semdp.2023.11.003 · Cited by 7
Nguyen, C. B., Knaus, C., Li, J., Accardo, M.-L., Koeppe, E. S., Vaishampayan, U. N., Alva, A. S., & Else, T. (2023) · JCO Precision Oncology · doi:10.1200/po.23.00168 · Cited by 7
Self-citationGulati, S., & Lara, P. N. (2024) · Kidney Cancer · doi:10.3233/kca-230024 · Cited by 7
Pancreatic Neuroendocrine Tumors in French VHL Mutation Carriers
Müller, M., Hammel, P. R., Couvelard, A., Védié, A., Cros, J. F., Burnichon, N., Hercent, A., Sauvanet, A., Richard, S., & de Mestier, L. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae310 · Cited by 7
Ishiyama, Y., Yagisawa, T., Ichioka, M., Hagiwara, A., Shimizu, T., Omoto, K., Nozaki, T., Inui, M., Ino, J., Takeda, K., et al. (2024) · Transplantation Proceedings · doi:10.1016/j.transproceed.2024.05.029 · Cited by 7
Jiménez, C., Baudrand, R. F., Uslar, T., & Bulzico, D. (2024) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359241301359 · Cited by 7
“62,63 The MTD of belzutifan has not been determined.”
The Role of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Tumors
Yellapragada, S. V., Forsythe, S. D., Madigan, J. P., & Sadowski, S. M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26125635 · Cited by 7
Tamukong, P. K., Kuhlmann, P., You, S., Su, S., Wang, Y., Yoon, S., Gong, J., Figlin, R. A., Janes, J. L., Freedland, S. J., et al. (2022) · Urologic Oncology Seminars and Original Investigations · doi:10.1016/j.urolonc.2022.07.010 · Cited by 7
Ged, Y. M. A., & Lee, C. (2022) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2022.2128336 · Cited by 7
Saeed, Z., Tasleem, A., Asthagiri, A. R., Schiff, D., & Jo, J. (2023) · JCO Precision Oncology · doi:10.1200/po.23.00066 · Cited by 7
de Joode, K., van de Geer, W. S., van Leenders, G. J. L. H., Hamberg, P., Westgeest, H. M., Beeker, A., Oosting, S. F., van Rooijen, J. M., Beerepoot, L. V., Labots, M., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-37764-z · Cited by 6
“More recently, Hypoxia Inducible Factor (HIF) inhibition has also shown proven efficacy in patients with VHL alterations 82 .”
Chan, K. H., Li, N., Lador, R., Amsbaugh, M. J., Gonzalez, A. O., & Cen, P. (2024) · Journal of Investigative Medicine High Impact Case Reports · doi:10.1177/23247096241231641 · Cited by 7
Greco, F., D’Andrea, V., Zobel, B. B., & Mallio, C. A. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46040203 · Cited by 8
“It has been demonstrated that HIF-1 α hinders the tumor growth of RCC by suppressing cell-cycle progression regulated by c-Myc [47].”
BackgroundTommasi, C., Scartabellati, G., Giannarelli, D., Giorgi, U. D., Brighi, N., Fornarini, G., Rebuzzi, S. E., Puglisi, S., Caffo, O., Kinspergher, S., et al. (2023) · Therapeutic Advances in Urology · doi:10.1177/17562872231187216 · Cited by 7
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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