{"entity":{"id":"advanced-melanoma","kind":"cancer","name":"Advanced melanoma (unresectable stage III and stage IV)","aka":["Metastatic melanoma","Stage IV melanoma","Unresectable melanoma","First-line advanced melanoma"],"tldr":"Advanced melanoma has spread beyond what surgery can remove, and it is the cancer in which immunotherapy first proved it could cure some people: about half of those given nivolumab with ipilimumab are alive ten years later. If immunotherapy fails, options include a cell therapy grown from the patient's own immune cells, a virus injected into the tumour, and targeted pills for BRAF-mutant disease.","summary":"Until 2011 advanced melanoma was treated with dacarbazine, which shrank about one tumour in ten, or high-dose interleukin-2, which produced rare durable remissions at great toxicity; median survival was six to nine months. Ipilimumab (2010) was the first drug to lengthen survival, from 6.4 to 10.1 months, and produced a plateau with about one in five patients alive long term. PD-1 blockade then transformed the disease: in KEYNOTE-006 pembrolizumab beat ipilimumab with ten-year survival of 34.0 against 23.6 percent, and in CheckMate 067 nivolumab plus ipilimumab, nivolumab and ipilimumab gave ten-year survival of 43, 37 and 19 percent. RELATIVITY-047 (2022) added the LAG-3 antibody relatlimab to nivolumab and lengthened progression-free survival from 4.6 to 10.1 months with about a third of the severe toxicity of the ipilimumab combination.\n\nFirst-line choice therefore lies between nivolumab-ipilimumab (deepest and longest data, most toxic), nivolumab-relatlimab (less toxic, no proven survival advantage over nivolumab alone) and anti-PD-1 monotherapy for frail patients, with treatment stopped after two years or after a confirmed complete response (KEYNOTE-006). BRAF-mutant patients are treated with immunotherapy first and BRAF-MEK inhibitors second on the DREAMseq result, unless rapid control is needed. Asymptomatic brain metastases respond to nivolumab-ipilimumab (intracranial clinical benefit 57 percent in CheckMate 204) and are treated with drugs first, with radiosurgery for symptomatic or progressing lesions; the details are on the brain metastases page.\n\nAfter PD-1 failure, tumour-infiltrating lymphocyte therapy produced responses in 31 percent of heavily pretreated patients in C-144-01, and the Dutch randomised trial found progression-free survival of 7.2 against 3.1 months for TIL versus ipilimumab; lifileucel became the first approved cell therapy for a solid tumour in February 2024. The oncolytic virus RP1 (vusolimogene oderparepvec) with nivolumab was approved in 2026 for PD-1-refractory disease, and ipilimumab-based combinations, clinical trials and, for the rare KIT-mutant tumour, imatinib remain options. Fianlimab plus cemiplimab, the PRAME-directed bispecific brenetafusp, the PRAME TCR-T cell therapy IMA203, faecal microbiota transplantation to reverse PD-1 resistance and first-line lifileucel with pembrolizumab (TILVANCE-301) are in phase 3 or pivotal trials.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Melanoma","links":[{"label":"CheckMate 067 ten-year results (NEJM 2025)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2407417"},{"label":"KEYNOTE-006 ten-year follow-up (Annals of Oncology 2024)","url":"https://www.annalsofoncology.org/article/S0923-7534(24)03910-3/fulltext"},{"label":"Dutch TIL trial (NEJM 2022)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2210233"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Melanoma"}],"tags":["subtype-page"],"related":["secondary-brain-tumours","braf-v600-melanoma","uveal-melanoma"],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","til-therapy","oncolytic-virus","lag3-blockade","tcr-t","radiosurgery-srs"],"targets":["pd1","ctla4","lag3","braf","kit","prame"],"drugs":["nivolumab","ipilimumab","pembrolizumab","relatlimab-nivolumab","lifileucel","vusolimogene-oderparepvec","talimogene-laherparepvec","dacarbazine","aldesleukin"],"companies":[],"institutions":[],"pathways":["pd1-checkpoint","ras-mapk"],"terms":["fixed-duration","brain-metastases","irae"],"trials":["checkmate-067","relativity-047","keynote-006","dreamseq","checkmate-204","c-144-01","combi-d","cobrim","columbus"],"people":["jedd-wolchok","james-larkin","caroline-robert","hussein-tawbi","f-stephen-hodi","michael-postow","antoni-ribas"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"skin","burden":"Roughly one in ten melanomas presents with or progresses to unresectable or metastatic disease; before 2011 median survival was under a year, and about half of patients treated with the nivolumab and ipilimumab combination are now alive at ten years.","subtypes":["Unresectable stage III (in-transit or nodal disease beyond surgery)","Stage IV M1a to M1c (skin, nodes, lung, other viscera)","Stage IV M1d (brain metastases; see the brain metastases page)","BRAF V600-mutant advanced melanoma (targeted therapy option)","PD-1-refractory melanoma (cell therapy, oncolytic virus, trials)","Acral and mucosal primaries (lower immunotherapy response rates)"],"biomarkers":["BRAF V600 mutation (decides the targeted-therapy option)","Lactate dehydrogenase (prognostic and part of staging)","PD-L1 expression (weakly predictive; not used to withhold therapy)","Tumour mutational burden and interferon-gamma signature (exploratory)","NRAS and KIT mutations (trial eligibility, imatinib in KIT-mutant disease)","HLA-A*02:01 (tebentafusp eligibility in uveal melanoma only)"],"standardOfCare":[{"setting":"First line, fit patient","approach":"Nivolumab plus ipilimumab (CheckMate 067) or nivolumab plus relatlimab (RELATIVITY-047); anti-PD-1 monotherapy where toxicity must be minimised (KEYNOTE-006). Immunotherapy first even when BRAF-mutant (DREAMseq).","refs":["checkmate-067","relativity-047","keynote-006","dreamseq","nivolumab","ipilimumab","relatlimab-nivolumab","pembrolizumab"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"BRAF V600-mutant, after immunotherapy or when rapid control is needed","approach":"Dabrafenib-trametinib, encorafenib-binimetinib or vemurafenib-cobimetinib.","refs":["braf-v600-melanoma","dabrafenib-trametinib","encorafenib","binimetinib","columbus","combi-d","cobrim"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Brain metastases","approach":"Nivolumab plus ipilimumab first for asymptomatic lesions (CheckMate 204); radiosurgery for symptomatic or progressing lesions; dabrafenib-trametinib in BRAF-mutant disease needing fast control. See the brain metastases page.","refs":["checkmate-204","secondary-brain-tumours","radiosurgery-srs","nivolumab","ipilimumab"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"After PD-1 failure","approach":"Lifileucel TIL therapy (C-144-01); RP1 with nivolumab; ipilimumab-based combinations; clinical trials; imatinib for KIT-mutant tumours.","refs":["lifileucel","c-144-01","til-therapy","vusolimogene-oderparepvec","ipilimumab","imatinib"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Treatment duration","approach":"Stop anti-PD-1 therapy after two years or after a confirmed complete response; most remissions hold off treatment (KEYNOTE-006).","refs":["keynote-006","fixed-duration"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}},{"setting":"Oligometastatic disease","approach":"Surgery or radiosurgery for isolated metastases alongside systemic therapy; isolated limb perfusion for limb-confined disease.","refs":["radiosurgery-srs","isolated-limb-perfusion"],"guideline":{"version":"NCCN Guidelines: Melanoma: Cutaneous","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492"}}],"stateOfArt":["About half of patients treated with nivolumab plus ipilimumab are alive at ten years, the longest immunotherapy follow-up in any cancer.","Lifileucel is the first approved cell therapy for a solid tumour and RP1 the second approved oncolytic virus, both for PD-1-refractory disease.","Immunotherapy first, targeted therapy second is the settled sequence for BRAF-mutant disease."],"history":[{"year":1975,"title":"Dacarbazine approved: about one in ten tumours respond","refs":["dacarbazine"]},{"year":1998,"title":"High-dose interleukin-2 approved for rare durable remissions","refs":["aldesleukin"]},{"year":2010,"title":"Ipilimumab is the first drug to lengthen survival in advanced melanoma","refs":["ipilimumab"]},{"year":2014,"title":"Pembrolizumab and nivolumab approved; KEYNOTE-006 shows PD-1 beats CTLA-4 blockade","refs":["pembrolizumab","nivolumab","keynote-006"]},{"year":2015,"title":"CheckMate 067: nivolumab plus ipilimumab; T-VEC first oncolytic virus","refs":["checkmate-067","talimogene-laherparepvec"]},{"year":2018,"title":"CheckMate 204: immunotherapy doublet works in the brain","refs":["checkmate-204"]},{"year":2022,"title":"RELATIVITY-047: nivolumab plus relatlimab approved; Dutch trial shows TIL beats ipilimumab","refs":["relativity-047","relatlimab-nivolumab","til-therapy"]},{"year":2024,"title":"Lifileucel: first approved cell therapy for a solid tumour","refs":["lifileucel","c-144-01"]},{"year":2025,"title":"CheckMate 067 ten-year results: 43 percent alive on the combination","refs":["checkmate-067"]},{"year":2026,"title":"RP1 with nivolumab approved for PD-1-refractory melanoma","refs":["vusolimogene-oderparepvec"]}],"pipeline":["fianlimab-phase3-melanoma","fianlimab","prism-mel-301","brenetafusp","nct06743126","ima203","nct05727904","lifileucel","vusolimogene-oderparepvec","fmt-checkpoint-nonresponders","nct05155254","io102-io103","nct06697301","eik1001","seacraft-2","nct06008106","tunlametinib","nct05625399"],"openProblems":["About four in ten patients never respond to PD-1 blockade and no biomarker reliably identifies them.","Who needs the ipilimumab component and its toxicity, and whether relatlimab can replace it, has not been settled.","Acral, mucosal and uveal melanomas respond far less well and have few dedicated trials."],"parent":"melanoma"},"route":"/cancers/advanced-melanoma/","neighbours":{"cancer":[{"id":"acral-melanoma","kind":"cancer","name":"Acral melanoma","route":"/cancers/acral-melanoma/"},{"id":"braf-v600-melanoma","kind":"cancer","name":"BRAF V600-mutant melanoma","route":"/cancers/braf-v600-melanoma/"},{"id":"secondary-brain-tumours","kind":"cancer","name":"Brain metastases (secondary brain tumours)","route":"/cancers/secondary-brain-tumours/"},{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"},{"id":"mucosal-melanoma","kind":"cancer","name":"Mucosal melanoma","route":"/cancers/mucosal-melanoma/"},{"id":"uveal-melanoma","kind":"cancer","name":"Uveal melanoma","route":"/cancers/uveal-melanoma/"}],"technology":[{"id":"fmt-checkpoint-nonresponders","kind":"technology","name":"Faecal microbiota transplantation for PD-1 non-responders","route":"/technologies/fmt-checkpoint-nonresponders/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"isolated-limb-perfusion","kind":"technology","name":"Isolated limb perfusion and infusion","route":"/technologies/isolated-limb-perfusion/"},{"id":"lag3-blockade","kind":"technology","name":"LAG-3 blockade","route":"/technologies/lag3-blockade/"},{"id":"oncolytic-virus","kind":"technology","name":"Oncolytic viruses","route":"/technologies/oncolytic-virus/"},{"id":"radiosurgery-srs","kind":"technology","name":"Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)","route":"/technologies/radiosurgery-srs/"},{"id":"tcr-t","kind":"technology","name":"TCR-T cell therapy","route":"/technologies/tcr-t/"},{"id":"til-therapy","kind":"technology","name":"TIL therapy","route":"/technologies/til-therapy/"}],"target":[{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"ctla4","kind":"target","name":"CTLA-4","route":"/targets/ctla4/"},{"id":"kit","kind":"target","name":"KIT","route":"/targets/kit/"},{"id":"lag3","kind":"target","name":"LAG-3","route":"/targets/lag3/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"prame","kind":"target","name":"PRAME","route":"/targets/prame/"}],"drug":[{"id":"aldesleukin","kind":"drug","name":"Aldesleukin (high-dose IL-2)","route":"/drugs/aldesleukin/"},{"id":"binimetinib","kind":"drug","name":"Binimetinib","route":"/drugs/binimetinib/"},{"id":"brenetafusp","kind":"drug","name":"Brenetafusp","route":"/drugs/brenetafusp/"},{"id":"cobimetinib","kind":"drug","name":"Cobimetinib","route":"/drugs/cobimetinib/"},{"id":"dabrafenib-trametinib","kind":"drug","name":"Dabrafenib + trametinib","route":"/drugs/dabrafenib-trametinib/"},{"id":"dacarbazine","kind":"drug","name":"Dacarbazine","route":"/drugs/dacarbazine/"},{"id":"eik1001","kind":"drug","name":"EIK1001","route":"/drugs/eik1001/"},{"id":"encorafenib","kind":"drug","name":"Encorafenib","route":"/drugs/encorafenib/"},{"id":"fianlimab","kind":"drug","name":"Fianlimab","route":"/drugs/fianlimab/"},{"id":"ima203","kind":"drug","name":"IMA203","route":"/drugs/ima203/"},{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"io102-io103","kind":"drug","name":"IO102-IO103","route":"/drugs/io102-io103/"},{"id":"ipilimumab","kind":"drug","name":"Ipilimumab","route":"/drugs/ipilimumab/"},{"id":"lifileucel","kind":"drug","name":"Lifileucel","route":"/drugs/lifileucel/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"relatlimab-nivolumab","kind":"drug","name":"Relatlimab + nivolumab","route":"/drugs/relatlimab-nivolumab/"},{"id":"talimogene-laherparepvec","kind":"drug","name":"Talimogene laherparepvec","route":"/drugs/talimogene-laherparepvec/"},{"id":"tunlametinib","kind":"drug","name":"Tunlametinib","route":"/drugs/tunlametinib/"},{"id":"vemurafenib","kind":"drug","name":"Vemurafenib","route":"/drugs/vemurafenib/"},{"id":"vusolimogene-oderparepvec","kind":"drug","name":"Vusolimogene oderparepvec","route":"/drugs/vusolimogene-oderparepvec/"}],"pathway":[{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"term":[{"id":"brain-metastases","kind":"term","name":"Brain metastases (intracranial disease)","route":"/terms/brain-metastases/"},{"id":"fixed-duration","kind":"term","name":"Fixed-duration vs continuous therapy","route":"/terms/fixed-duration/"},{"id":"irae","kind":"term","name":"Immune-related adverse events (irAEs)","route":"/terms/irae/"}],"trial":[{"id":"nct05625399","kind":"trial","name":"A Study of Subcutaneous Nivolumab + Relatlimab Fixed-dose Combination (FDC) in Previously Untreated Metastatic or Unresectable Melanoma","route":"/trials/nct05625399/"},{"id":"seacraft-2","kind":"trial","name":"A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With NRAS-mutant Melanoma (SEACRAFT-2)","route":"/trials/seacraft-2/"},{"id":"c-144-01","kind":"trial","name":"C-144-01","route":"/trials/c-144-01/"},{"id":"checkmate-067","kind":"trial","name":"CheckMate 067","route":"/trials/checkmate-067/"},{"id":"checkmate-204","kind":"trial","name":"CheckMate 204","route":"/trials/checkmate-204/"},{"id":"cobrim","kind":"trial","name":"coBRIM","route":"/trials/cobrim/"},{"id":"columbus","kind":"trial","name":"COLUMBUS","route":"/trials/columbus/"},{"id":"combi-d","kind":"trial","name":"COMBI-d","route":"/trials/combi-d/"},{"id":"nct06008106","kind":"trial","name":"Comparing Tunlametinib Capsules and Combination Chemotherapy in Advanced NRAS-mutant Melanoma","route":"/trials/nct06008106/"},{"id":"dreamseq","kind":"trial","name":"DREAMseq (ECOG-ACRIN EA6134)","route":"/trials/dreamseq/"},{"id":"fianlimab-phase3-melanoma","kind":"trial","name":"Fianlimab + cemiplimab phase 3 (first-line melanoma)","route":"/trials/fianlimab-phase3-melanoma/"},{"id":"nct05155254","kind":"trial","name":"IO102-IO103 in Combination With Pembrolizumab Versus Pembrolizumab Alone in Advanced Melanoma (IOB-013 / KN-D18)","route":"/trials/nct05155254/"},{"id":"keynote-006","kind":"trial","name":"KEYNOTE-006","route":"/trials/keynote-006/"},{"id":"prism-mel-301","kind":"trial","name":"PRISM-MEL-301","route":"/trials/prism-mel-301/"},{"id":"relativity-047","kind":"trial","name":"RELATIVITY-047","route":"/trials/relativity-047/"},{"id":"nct06697301","kind":"trial","name":"Safety and Efficacy of EIK1001 in Combo With Pembro Versus Placebo and Pembro as First-Line Therapy in Patients With Advanced Melanoma","route":"/trials/nct06697301/"},{"id":"nct05727904","kind":"trial","name":"Study to Investigate Lifileucel Regimen Plus Pembrolizumab Compared With Pembrolizumab Alone in Participants With Untreated Advanced Melanoma.","route":"/trials/nct05727904/"},{"id":"nct06743126","kind":"trial","name":"SUPRAME-ACTengine® IMA203 vs. Investigator's Choice of Treatment in Previously Treated, Unresectable or Metastatic Cutaneous Melanoma","route":"/trials/nct06743126/"}],"person":[{"id":"antoni-ribas","kind":"person","name":"Antoni Ribas","route":"/people/antoni-ribas/"},{"id":"caroline-robert","kind":"person","name":"Caroline Robert","route":"/people/caroline-robert/"},{"id":"f-stephen-hodi","kind":"person","name":"F. Stephen Hodi","route":"/people/f-stephen-hodi/"},{"id":"hussein-tawbi","kind":"person","name":"Hussein A. Tawbi","route":"/people/hussein-tawbi/"},{"id":"james-larkin","kind":"person","name":"James Larkin","route":"/people/james-larkin/"},{"id":"jedd-wolchok","kind":"person","name":"Jedd D. Wolchok","route":"/people/jedd-wolchok/"},{"id":"michael-postow","kind":"person","name":"Michael A. Postow","route":"/people/michael-postow/"}]}}