{"entity":{"id":"uveal-melanoma","kind":"cancer","name":"Uveal melanoma","aka":["Ocular melanoma","Choroidal melanoma","Intraocular Melanoma"],"tldr":"A melanoma inside the eye that is biologically unrelated to skin melanoma: different mutations, no response to standard immunotherapy, and a tendency to spread to the liver years later. Tebentafusp is the first drug ever to extend survival in the metastatic disease.","summary":"Uveal melanoma arises from melanocytes of the choroid, ciliary body or iris and is driven by GNAQ/GNA11 (or CYSLTR2/PLCB4) mutations activating Gαq signalling, with metastatic risk set by BAP1 loss and monosomy 3 (gene-expression class 2, PRAME expression) versus SF3B1 and EIF1AX mutations (lower risk). The primary tumour is controlled by plaque brachytherapy or proton beam in most cases (COMS showed equivalence to enucleation), but about half of patients relapse, typically in the liver, with a median survival historically under a year.\n\nUnlike cutaneous melanoma, the tumour mutational burden is low and checkpoint inhibitors give response rates around 5%. Tebentafusp, a gp100×CD3 ImmTAC restricted to HLA-A*02:01, was the first therapy to improve overall survival in metastatic uveal melanoma (IMCgp100-202, 2021; approved 2022). Liver-directed therapy (percutaneous hepatic perfusion with melphalan, approved 2023 as Hepzato; radioembolisation; resection) controls hepatic disease. Darovasertib (PKC inhibitor) with crizotinib is in phase 2/3 in metastatic and neoadjuvant settings.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Uveal_melanoma","links":[{"label":"NCCN Guidelines: Uveal Melanoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1488"},{"label":"Tebentafusp IMCgp100-202 (NEJM 2021)","url":"https://doi.org/10.1056/NEJMoa2103485"},{"label":"Ocular Melanoma Foundation","url":"https://ocularmelanoma.org/"}],"tags":["gap-fill","skin","eye","rare"],"related":["mucosal-melanoma","acral-melanoma","advanced-melanoma"],"cancers":[],"sections":[],"technologies":["t-cell-engager","brachytherapy","proton-therapy","percutaneous-hepatic-perfusion","radioembolisation-tare","mri"],"targets":["gp100","cd3","pd1","ctla4","prame"],"drugs":["tebentafusp","melphalan","ipilimumab","nivolumab","brenetafusp"],"companies":["immunocore","bioinvent-international","aura-biosciences","ionctura"],"institutions":[],"pathways":["ras-mapk"],"terms":["hla-a02-restriction","crs","uveal-melanoma-prognostic-markers","bap1-loss","sf3b1-mutation"],"trials":["nct07804186","nct07015190","nct06581406","nct05022901","nct05987332","nct06007690"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["pigment-cell-and-melanoma-research"],"dependsOn":[],"notes":[],"group":"skin","burden":"About 5-7 per million per year (the most common primary eye cancer in adults); half of patients eventually develop metastases, almost always in the liver.","subtypes":["Choroidal melanoma (~90%)","Ciliary body melanoma","Iris melanoma (best prognosis)","GEP class 1A/1B (low risk) vs class 2 (high risk)","BAP1-mutant / monosomy 3 (high metastatic risk)"],"biomarkers":["GNAQ / GNA11 mutations","BAP1 loss and monosomy 3","SF3B1, EIF1AX (lower risk)","Gene-expression profile (DecisionDx-UM class 1/2) and PRAME","HLA-A*02:01 (tebentafusp eligibility)","Liver MRI surveillance"],"standardOfCare":[{"setting":"Primary tumour","approach":"Plaque brachytherapy (I-125 or Ru-106) or proton beam radiotherapy for most; enucleation for large tumours; prognostic biopsy for GEP/chromosome 3.","refs":["brachytherapy","proton-therapy"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Uveal Melanoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1488"}},{"setting":"Surveillance","approach":"Risk-adapted liver imaging (MRI/ultrasound) every 6-12 months for high-risk GEP class 2 / monosomy 3; no proven adjuvant therapy.","refs":["mri"]},{"setting":"Metastatic, HLA-A*02:01-positive","approach":"Tebentafusp weekly (OS 21.7 vs 16.0 months vs investigator's choice); manage cytokine release and rash.","refs":["tebentafusp"],"guideline":{"nccn":"Category 1","esmoMcbs":"4","version":"NCCN Guidelines: Uveal Melanoma"}},{"setting":"Metastatic, HLA-A*02:01-negative or liver-dominant","approach":"Percutaneous hepatic perfusion with melphalan (FOCUS trial; approved 2023), radioembolisation, hepatic resection; ipilimumab-nivolumab (~15% response); clinical trials (darovasertib-crizotinib).","refs":["percutaneous-hepatic-perfusion","melphalan","radioembolisation-tare","ipilimumab","nivolumab"]}],"stateOfArt":["Tebentafusp is the first TCR-based bispecific approved in any cancer and the first drug to improve survival in metastatic uveal melanoma.","Liver-directed therapy has a randomised trial (FOCUS) behind percutaneous hepatic perfusion.","Gene-expression profiling reliably separates patients who will and will not metastasise, but there is still no adjuvant therapy that helps them.","Gαq-pathway inhibition (darovasertib ± crizotinib) is the leading targeted strategy."],"history":[{"year":2001,"title":"COMS: brachytherapy equals enucleation for medium tumours","refs":["brachytherapy"]},{"year":2004,"title":"Gene-expression classes 1 and 2 predict metastasis (Onken, Harbour)","refs":[]},{"year":2009,"title":"GNAQ mutations discovered (Van Raamsdonk); GNA11 in 2010","refs":[]},{"year":2010,"title":"BAP1 loss drives metastasis (Harbour, Science)","refs":[]},{"year":2021,"title":"Tebentafusp improves overall survival (NEJM)","refs":["tebentafusp"]},{"year":2022,"title":"Tebentafusp approved","note":"FDA January 2022; EMA April 2022.","refs":["tebentafusp"]},{"year":2023,"title":"Percutaneous hepatic perfusion (Hepzato) approved","refs":["percutaneous-hepatic-perfusion","melphalan"]}],"pipeline":["tebentafusp","percutaneous-hepatic-perfusion","brenetafusp","darovasertib"],"openProblems":["Half of patients metastasise with no adjuvant therapy despite accurate prediction.","Tebentafusp only for HLA-A*02:01 (about 45% of white patients, fewer elsewhere) and gives few objective responses despite OS benefit.","Liver-tropic metastasis biology poorly understood.","Vision-preserving local therapy still causes radiation retinopathy."],"parent":"melanoma"},"route":"/cancers/uveal-melanoma/","neighbours":{"cancer":[{"id":"acral-melanoma","kind":"cancer","name":"Acral melanoma","route":"/cancers/acral-melanoma/"},{"id":"advanced-melanoma","kind":"cancer","name":"Advanced melanoma (unresectable stage III and stage IV)","route":"/cancers/advanced-melanoma/"},{"id":"conjunctival-melanoma","kind":"cancer","name":"Conjunctival melanoma","route":"/cancers/conjunctival-melanoma/"},{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"},{"id":"mucosal-melanoma","kind":"cancer","name":"Mucosal melanoma","route":"/cancers/mucosal-melanoma/"},{"id":"skin-cancer","kind":"cancer","name":"Skin cancer (all types)","route":"/cancers/skin-cancer/"}],"technology":[{"id":"brachytherapy","kind":"technology","name":"Brachytherapy","route":"/technologies/brachytherapy/"},{"id":"ldr-seed-brachytherapy","kind":"technology","name":"Low-dose-rate seed brachytherapy","route":"/technologies/ldr-seed-brachytherapy/"},{"id":"mri","kind":"technology","name":"MRI","route":"/technologies/mri/"},{"id":"percutaneous-hepatic-perfusion","kind":"technology","name":"Percutaneous hepatic perfusion (chemosaturation)","route":"/technologies/percutaneous-hepatic-perfusion/"},{"id":"proton-therapy","kind":"technology","name":"Proton therapy","route":"/technologies/proton-therapy/"},{"id":"proton-therapy-systems","kind":"technology","name":"Proton therapy machines: cyclotrons, synchrotrons and single-room systems","route":"/technologies/proton-therapy-systems/"},{"id":"radioembolisation-tare","kind":"technology","name":"Radioembolisation (TARE / SIRT, yttrium-90)","route":"/technologies/radioembolisation-tare/"},{"id":"t-cell-engager","kind":"technology","name":"T-cell engagers (bispecific)","route":"/technologies/t-cell-engager/"}],"target":[{"id":"cd3","kind":"target","name":"CD3","route":"/targets/cd3/"},{"id":"ctla4","kind":"target","name":"CTLA-4","route":"/targets/ctla4/"},{"id":"cysltr2","kind":"target","name":"CYSLTR2","route":"/targets/cysltr2/"},{"id":"ddx43","kind":"target","name":"DDX43","route":"/targets/ddx43/"},{"id":"eif1ax","kind":"target","name":"EIF1AX","route":"/targets/eif1ax/"},{"id":"gna11","kind":"target","name":"GNA11","route":"/targets/gna11/"},{"id":"gnaq","kind":"target","name":"GNAQ","route":"/targets/gnaq/"},{"id":"gp100","kind":"target","name":"gp100 (PMEL)","route":"/targets/gp100/"},{"id":"hla-a","kind":"target","name":"HLA-A","route":"/targets/hla-a/"},{"id":"mbd4","kind":"target","name":"MBD4","route":"/targets/mbd4/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"prame","kind":"target","name":"PRAME","route":"/targets/prame/"}],"drug":[{"id":"brenetafusp","kind":"drug","name":"Brenetafusp","route":"/drugs/brenetafusp/"},{"id":"darovasertib","kind":"drug","name":"Darovasertib","route":"/drugs/darovasertib/"},{"id":"ipilimumab","kind":"drug","name":"Ipilimumab","route":"/drugs/ipilimumab/"},{"id":"melphalan","kind":"drug","name":"Melphalan (including hepatic delivery system)","route":"/drugs/melphalan/"},{"id":"hepzato","kind":"drug","name":"Melphalan hepatic delivery system","route":"/drugs/hepzato/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"tebentafusp","kind":"drug","name":"Tebentafusp","route":"/drugs/tebentafusp/"}],"company":[{"id":"aura-biosciences","kind":"company","name":"Aura Biosciences","route":"/companies/aura-biosciences/"},{"id":"bioinvent-international","kind":"company","name":"BioInvent International","route":"/companies/bioinvent-international/"},{"id":"delcath","kind":"company","name":"Delcath Systems","route":"/companies/delcath/"},{"id":"immunocore","kind":"company","name":"Immunocore","route":"/companies/immunocore/"},{"id":"ionctura","kind":"company","name":"iOnctura","route":"/companies/ionctura/"}],"pathway":[{"id":"organ-tropism-seed-soil","kind":"pathway","name":"Organ tropism: seed and soil","route":"/pathways/organ-tropism-seed-soil/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"term":[{"id":"bap1-loss","kind":"term","name":"BAP1 loss","route":"/terms/bap1-loss/"},{"id":"crs","kind":"term","name":"Cytokine release syndrome (CRS)","route":"/terms/crs/"},{"id":"hla-a02-restriction","kind":"term","name":"HLA-A*02:01 restriction","route":"/terms/hla-a02-restriction/"},{"id":"rare-cancers","kind":"term","name":"Rare cancers","route":"/terms/rare-cancers/"},{"id":"seed-and-soil-hypothesis","kind":"term","name":"Seed and soil hypothesis of metastasis (Paget)","route":"/terms/seed-and-soil-hypothesis/"},{"id":"sf3b1-mutation","kind":"term","name":"SF3B1 mutation","route":"/terms/sf3b1-mutation/"},{"id":"uveal-melanoma-prognostic-markers","kind":"term","name":"Uveal melanoma prognostic markers (GNAQ/GNA11, monosomy 3, gene-expression class)","route":"/terms/uveal-melanoma-prognostic-markers/"}],"trial":[{"id":"nct05907954","kind":"trial","name":"(Neo)Adjuvant IDE196 (Darovasertib) in Patients With Localized Ocular Melanoma","route":"/trials/nct05907954/"},{"id":"nct07636785","kind":"trial","name":"A Phase 1 and 2 Study of VMD-102 in Hepatocellular Carcinoma and Other Solid Tumors","route":"/trials/nct07636785/"},{"id":"nct06007690","kind":"trial","name":"A Phase 3 Randomized, Masked, Controlled Trial to Evaluate Efficacy and Safety of Belzupacap Sarotalocan (AU-011) Treatment Compared to Sham Control in Subjects With Primary Indeterminate Lesions or Small Choroidal Melanoma","route":"/trials/nct06007690/"},{"id":"nct05415072","kind":"trial","name":"A Phase I/II Study of DYP688 in Patients With Metastatic Uveal Melanoma and Other GNAQ/11 Mutant Melanomas","route":"/trials/nct05415072/"},{"id":"nct06717126","kind":"trial","name":"A Randomised Phase II Study of Roginolisib in Patients With Advanced/Metastatic Uveal Melanoma","route":"/trials/nct06717126/"},{"id":"nct06581406","kind":"trial","name":"A Randomized, Phase 2/3 Study to Investigate the Efficacy and Safety of RP2 in Combination With Nivolumab in Immune Checkpoint Inhibitor-Naïve Adult P","route":"/trials/nct06581406/"},{"id":"nct03611868","kind":"trial","name":"A Study of APG-115 in as a Monotherapy or Combination With Pembrolizumab in Patients With Metastatic Melanomas or Advanced Solid Tumors","route":"/trials/nct03611868/"},{"id":"nct06940739","kind":"trial","name":"A Study to Investigate the Safety and Efficacy of IOV-3001 in Adults With Advanced Melanoma Who Will Receive Lifileucel","route":"/trials/nct06940739/"},{"id":"nct05022901","kind":"trial","name":"An Open-Label Expanded Access Study of the Melphalan/Hepatic Delivery System (HDS) in Patients With Hepatic Dominant Ocular Melanoma","route":"/trials/nct05022901/"},{"id":"nct06784648","kind":"trial","name":"Different Doses of BI-1607 in Combination With Pembrolizumab and Ipilimumab, in Participants With Unresectable or Metastatic Melanoma","route":"/trials/nct06784648/"},{"id":"nct07627698","kind":"trial","name":"Dual-Target CSPG4/GD2 CAR-NK Cells for Advanced Melanoma","route":"/trials/nct07627698/"},{"id":"nct07136181","kind":"trial","name":"Evaluation of the Safety, Efficacy, and Pharmacokinetics of NBM-BMX in Patients With Metastatic Uveal Melanoma","route":"/trials/nct07136181/"},{"id":"nct02678572","kind":"trial","name":"FOCUS","route":"/trials/nct02678572/"},{"id":"nct05987332","kind":"trial","name":"IDE196 (Darovasertib) in Combination With Crizotinib as First-line Therapy in Metastatic Uveal Melanoma","route":"/trials/nct05987332/"},{"id":"nct07015190","kind":"trial","name":"Neoadjuvant Darovasertib in Primary Uveal Melanoma","route":"/trials/nct07015190/"},{"id":"nct06519266","kind":"trial","name":"PHP in Combination With IPI1/NIVO3 Compared to IPI3/NIVO1 Only in Patients With Uveal Melanoma Liver Metastases","route":"/trials/nct06519266/"},{"id":"nct03172299","kind":"trial","name":"Prevention of Neovascular Glaucoma by Intravitreal Injections of Anti-VEGF in Patients Treated with Proton Therapy for a Large Choroidal Melanoma","route":"/trials/nct03172299/"},{"id":"nct07804186","kind":"trial","name":"Study of Adjuvant Darovasertib and Crizotinib in Participants With Primary Non-metastatic Uveal Melanoma","route":"/trials/nct07804186/"},{"id":"nct03947385","kind":"trial","name":"Study of IDE196 in Patients With Solid Tumors Harboring GNAQ/11 Mutations or PRKC Fusions","route":"/trials/nct03947385/"}],"journal":[{"id":"melanoma-research","kind":"journal","name":"Melanoma research","route":"/journals/melanoma-research/"},{"id":"pigment-cell-and-melanoma-research","kind":"journal","name":"Pigment cell & melanoma research","route":"/journals/pigment-cell-and-melanoma-research/"}],"person":[{"id":"paul-nathan","kind":"person","name":"Paul Nathan","route":"/people/paul-nathan/"},{"id":"richard-carvajal","kind":"person","name":"Richard D. Carvajal","route":"/people/richard-carvajal/"},{"id":"sapna-patel","kind":"person","name":"Sapna P. Patel","route":"/people/sapna-patel/"}],"collection":[{"id":"melanoma-research-alliance","kind":"collection","name":"Melanoma Research Alliance (MRA)","route":"/collections/melanoma-research-alliance/"}],"institution":[{"id":"clatterbridge","kind":"institution","name":"The Clatterbridge Cancer Centre NHS Foundation Trust","route":"/institutions/clatterbridge/"}],"biomarker":[{"id":"hla-a-02-01","kind":"biomarker","name":"HLA-A*02:01 (HLA typing for TCR therapies)","route":"/biomarkers/hla-a-02-01/"}]}}