{"entity":{"id":"belzutifan","kind":"drug","name":"Belzutifan","aka":[],"tldr":"Belzutifan is the first HIF-2α inhibitor, born from Nobel-winning biology, and is now approved after kidney cancer surgery with pembrolizumab.","summary":"Belzutifan is a small-molecule HIF-2-alpha inhibitor that blocks HIF-2-alpha from dimerising with ARNT, silencing the hypoxia programme that drives clear-cell kidney cancer when VHL is lost; it is taken as 120 mg once daily. It was approved in 2021 for VHL disease-associated renal cell carcinoma, CNS haemangioblastoma and pancreatic neuroendocrine tumours, in 2023 for advanced RCC after PD-1/PD-L1 and VEGF-TKI therapy (LITESPARK-005), in 2025 for pheochromocytoma and paraganglioma, and in Q2 2026 as adjuvant therapy for clear-cell RCC with pembrolizumab (LITESPARK-022). Merck markets it. Anaemia and hypoxia are on-mechanism effects because HIF-2-alpha regulates erythropoietin. Whether the adjuvant benefit translates into survival, and which patients respond, remain open. For a newcomer: the first drug from the Nobel-winning biology of how cells sense oxygen.","status":"approved","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Belzutifan","links":[{"label":"FDA label (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=Belzutifan"}],"tags":[],"related":[],"cancers":["rcc","clear-cell-rcc","spinal-cord-tumours","pancreatic-net","hereditary-ppgl","metastatic-ppgl"],"sections":[],"technologies":["kinase-inhibitors"],"targets":["hif2a"],"drugs":[],"companies":["merck"],"institutions":[],"pathways":[],"terms":[],"trials":["nct07049926","nct03634540","nct04924075","nct05468697","nct04626479","nct04586231","nct05899049","nct04976634","nct04626518","nct06428396","nct07405164","nct04489771"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"brand":"Welireg","modality":"Small-molecule HIF-2α inhibitor","mechanism":"Blocks HIF-2α/ARNT dimerisation.","approvals":[{"region":"US","year":2021,"indication":"VHL-associated RCC, CNS haemangioblastoma, pNET"},{"region":"US","year":2023,"indication":"Advanced RCC after PD-1/PD-L1 and VEGF-TKI"},{"region":"US","year":2026,"indication":"Adjuvant clear-cell RCC with pembrolizumab"},{"region":"EU","year":2025,"indication":"ccRCC after ≥2 lines; VHL-associated tumours; 12 Feb 2025 (conditional)","note":"Conditional marketing authorisation"}],"mechanismSteps":["Belzutifan binds the PAS-B pocket of HIF-2α","HIF-2α cannot dimerise with HIF-1β (ARNT)","Transcription of VEGF, GLUT1, cyclin D1 and other hypoxia genes stops","VHL-deficient tumour cells lose their growth programme; erythropoietin falls (anaemia)"],"dosing":{"route":"Oral","schedule":"120 mg once daily","modifications":"Hold for haemoglobin <8 g/dL or hypoxia; permanently discontinue for life-threatening hypoxia","monitoring":"Haemoglobin and oxygen saturation before and during treatment; embryo-fetal toxicity","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications"},"toxicity":[{"event":"Anaemia","note":"LITESPARK-005: ~83% any grade, ~33% grade 3"},{"event":"Hypoxia"},{"event":"Fatigue"},{"event":"Nausea"},{"event":"Oedema"},{"event":"Dyspnoea"}],"access":[{"country":"US","reimbursement":"Medicare Part D (oral); commercial plans per formulary, often with prior authorisation","assistance":"https://www.merckaccessprogram-welireg.com","source":"https://www.cms.gov/medicare/payment/part-b-drugs/asp-pricing-files","asOf":"2026-09-06"},{"country":"UK","reimbursement":"NICE: appraisal for RCC after IO and VEGF-TKI (2025-26)","source":"https://www.nice.org.uk/guidance/published?ngt=Technology%20appraisal%20guidance","asOf":"2026-09-06"}],"regulatoryEvents":[{"date":"2021-08-13","type":"approval","region":"US","note":"VHL disease-associated RCC, CNS haemangioblastoma, pNET: first HIF-2α inhibitor","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications"},{"date":"2023-12-14","type":"approval","region":"US","note":"Advanced RCC after PD-1/PD-L1 and VEGF-TKI (LITESPARK-005)","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications"},{"date":"2025-05","type":"approval","region":"US","note":"Pheochromocytoma/paraganglioma","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications"},{"date":"2026-06-12","type":"approval","region":"US","note":"Adjuvant clear-cell RCC with pembrolizumab (LITESPARK-022)","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-pembrolizumab-adjuvant-treatment-renal-cell-carcinoma"},{"date":"2026-09-24","type":"approval","region":"US","note":"With lenvatinib, advanced renal cell carcinoma with a clear cell component","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-combination-lenvatinib-advanced-renal-cell-carcinoma-clear-cell-component"}]},"route":"/drugs/belzutifan/","neighbours":{"cancer":[{"id":"clear-cell-rcc","kind":"cancer","name":"Clear cell renal cell carcinoma","route":"/cancers/clear-cell-rcc/"},{"id":"hereditary-ppgl","kind":"cancer","name":"Hereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127)","route":"/cancers/hereditary-ppgl/"},{"id":"metastatic-ppgl","kind":"cancer","name":"Metastatic pheochromocytoma and paraganglioma","route":"/cancers/metastatic-ppgl/"},{"id":"neuroendocrine","kind":"cancer","name":"Neuroendocrine tumours","route":"/cancers/neuroendocrine/"},{"id":"pancreatic-net","kind":"cancer","name":"Pancreatic neuroendocrine tumours","route":"/cancers/pancreatic-net/"},{"id":"pheochromocytoma-paraganglioma","kind":"cancer","name":"Pheochromocytoma and paraganglioma (PPGL)","route":"/cancers/pheochromocytoma-paraganglioma/"},{"id":"rcc","kind":"cancer","name":"Renal cell carcinoma","route":"/cancers/rcc/"},{"id":"spinal-cord-tumours","kind":"cancer","name":"Spinal cord tumours (intramedullary and intradural)","route":"/cancers/spinal-cord-tumours/"}],"technology":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"arnt","kind":"target","name":"ARNT","route":"/targets/arnt/"},{"id":"hif1a","kind":"target","name":"HIF-1α (HIF1A)","route":"/targets/hif1a/"},{"id":"hif2a","kind":"target","name":"HIF-2α","route":"/targets/hif2a/"}],"company":[{"id":"merck","kind":"company","name":"Merck & Co. (MSD)","route":"/companies/merck/"}],"trial":[{"id":"nct05468697","kind":"trial","name":"A Study of Belzutifan (MK-6482) in Combination With Palbociclib Versus Belzutifan Monotherapy in Participants With Advanced Renal Cell Carcinoma (MK-6","route":"/trials/nct05468697/"},{"id":"nct04489771","kind":"trial","name":"A Study of Belzutifan (MK-6482) in Participants With Advanced Renal Cell Carcinoma (MK-6482-013)","route":"/trials/nct04489771/"},{"id":"nct05899049","kind":"trial","name":"A Study of Pembrolizumab (MK-3475) in Combination With Belzutifan (MK-6482) and Lenvatinib (MK-7902), or Pembrolizumab/Quavonlimab (MK-1308A) in Combination With Lenvatinib, vs Pembrolizumab and Lenvatinib, for Treatment of Advanced Clear Cell Renal Cell Carcinoma (MK-6482-012)-China Extension Study","route":"/trials/nct05899049/"},{"id":"nct03634540","kind":"trial","name":"A Trial of Belzutifan (PT2977, MK-6482) in Combination With Cabozantinib in Patients With Clear Cell Renal Cell Carcinoma (ccRCC) (MK-6482-003)","route":"/trials/nct03634540/"},{"id":"nct04924075","kind":"trial","name":"Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL","route":"/trials/nct04924075/"},{"id":"nct07405164","kind":"trial","name":"Extension Study for Participants in Studies That Include Belzutifan (MK-6482-043/LITESPARK-043)","route":"/trials/nct07405164/"},{"id":"litespark-005","kind":"trial","name":"LITESPARK-005","route":"/trials/litespark-005/"},{"id":"nct04586231","kind":"trial","name":"LITESPARK-011","route":"/trials/nct04586231/"},{"id":"litespark-012","kind":"trial","name":"LITESPARK-012","route":"/trials/litespark-012/"},{"id":"litespark-022","kind":"trial","name":"LITESPARK-022","route":"/trials/litespark-022/"},{"id":"nct04976634","kind":"trial","name":"Pembrolizumab Plus Lenvatinib in Combination With Belzutifan in Solid Tumors (MK-6482-016)","route":"/trials/nct04976634/"},{"id":"nct06428396","kind":"trial","name":"Study of Belzutifan (MK-6482) Plus Fulvestrant for ER+/HER2- Metastatic Breast Cancer (MK-6482-029/LITESPARK-029)","route":"/trials/nct06428396/"},{"id":"nct04626479","kind":"trial","name":"Substudy 03A: A Study of Immune and Targeted Combination Therapies in Participants With First Line (1L) Renal Cell Carcinoma (MK-3475-03A)","route":"/trials/nct04626479/"},{"id":"nct04626518","kind":"trial","name":"Substudy 03B: A Study of Immune and Targeted Combination Therapies in Participants With Second Line Plus (2L+) Renal Cell Carcinoma (MK-3475-03B/KEYMAKER-U03)","route":"/trials/nct04626518/"},{"id":"nct07049926","kind":"trial","name":"Substudy 03C: A Study of Combination Therapies in Participants With Renal Cell Carcinoma With Recurrent Disease During or After Anti-PD-(L)1 Therapy (","route":"/trials/nct07049926/"}],"term":[{"id":"angiogenesis","kind":"term","name":"Angiogenesis","route":"/terms/angiogenesis/"},{"id":"men1-hereditary-net","kind":"term","name":"MEN1 and hereditary neuroendocrine syndromes","route":"/terms/men1-hereditary-net/"},{"id":"sdh-deficiency","kind":"term","name":"SDH deficiency (SDHB immunohistochemistry loss)","route":"/terms/sdh-deficiency/"},{"id":"vhl-disease","kind":"term","name":"Von Hippel-Lindau disease","route":"/terms/vhl-disease/"}],"idea":[{"id":"idea-adjuvant-selection-rcc","kind":"idea","name":"Biomarker-selected adjuvant therapy in RCC (ctDNA, CAIX PET, gene signatures)","route":"/ideas/idea-adjuvant-selection-rcc/"}],"pathway":[{"id":"choline-metabolism-in-cancer","kind":"pathway","name":"Choline metabolism in cancer","route":"/pathways/choline-metabolism-in-cancer/"},{"id":"renal-cell-carcinoma-signalling","kind":"pathway","name":"Renal cell carcinoma (KEGG map)","route":"/pathways/renal-cell-carcinoma-signalling/"},{"id":"synthetic-lethality-map","kind":"pathway","name":"Synthetic lethality: paired dependencies","route":"/pathways/synthetic-lethality-map/"},{"id":"angiogenic-switch","kind":"pathway","name":"The angiogenic switch & tumour vessels","route":"/pathways/angiogenic-switch/"},{"id":"vegf-angiogenesis","kind":"pathway","name":"VEGF angiogenesis","route":"/pathways/vegf-angiogenesis/"},{"id":"hif-vhl","kind":"pathway","name":"VHL / HIF oxygen sensing","route":"/pathways/hif-vhl/"}],"person":[{"id":"laurence-albiges","kind":"person","name":"Laurence Albiges","route":"/people/laurence-albiges/"},{"id":"toni-choueiri","kind":"person","name":"Toni K. Choueiri","route":"/people/toni-choueiri/"},{"id":"william-kaelin","kind":"person","name":"William G. Kaelin Jr.","route":"/people/william-kaelin/"}],"paper":[{"id":"paper-belzutifan-vhl-jonasch-nejm-2021","kind":"paper","name":"Belzutifan for renal cell carcinoma and other tumours in von Hippel-Lindau disease","route":"/key-papers/paper-belzutifan-vhl-jonasch-nejm-2021/"},{"id":"paper-litespark-011-motzer-lancet-2026","kind":"paper","name":"Belzutifan plus lenvatinib versus cabozantinib in patients with previously treated advanced renal cell carcinoma (LITESPARK-011): an open-label, randomised, controlled, phase 3 trial","route":"/key-papers/paper-litespark-011-motzer-lancet-2026/"}],"institution":[{"id":"utsw-simmons","kind":"institution","name":"Harold C. Simmons Comprehensive Cancer Center, UT Southwestern","route":"/institutions/utsw-simmons/"}]}}