# Advanced melanoma (unresectable stage III and stage IV)

Source: https://onco.cc/cancers/advanced-melanoma/  
OnCo record `advanced-melanoma` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

First-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.

After 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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: Metastatic melanoma; Stage IV melanoma; Unresectable melanoma; First-line advanced melanoma
- Tags: subtype-page
- 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)

## Standard of care

- First line, fit patient: 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). ([CheckMate 067](https://onco.cc/trials/checkmate-067/), [RELATIVITY-047](https://onco.cc/trials/relativity-047/), [KEYNOTE-006](https://onco.cc/trials/keynote-006/), [DREAMseq (ECOG-ACRIN EA6134)](https://onco.cc/trials/dreamseq/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Relatlimab + nivolumab](https://onco.cc/drugs/relatlimab-nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/))
- BRAF V600-mutant, after immunotherapy or when rapid control is needed: Dabrafenib-trametinib, encorafenib-binimetinib or vemurafenib-cobimetinib. ([BRAF V600-mutant melanoma](https://onco.cc/cancers/braf-v600-melanoma/), [Dabrafenib + trametinib](https://onco.cc/drugs/dabrafenib-trametinib/), [Encorafenib](https://onco.cc/drugs/encorafenib/), [Binimetinib](https://onco.cc/drugs/binimetinib/), [COLUMBUS](https://onco.cc/trials/columbus/), [COMBI-d](https://onco.cc/trials/combi-d/), [coBRIM](https://onco.cc/trials/cobrim/))
- Brain metastases: 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. ([CheckMate 204](https://onco.cc/trials/checkmate-204/), [Brain metastases (secondary brain tumours)](https://onco.cc/cancers/secondary-brain-tumours/), [Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/))
- After PD-1 failure: Lifileucel TIL therapy (C-144-01); RP1 with nivolumab; ipilimumab-based combinations; clinical trials; imatinib for KIT-mutant tumours. ([Lifileucel](https://onco.cc/drugs/lifileucel/), [C-144-01](https://onco.cc/trials/c-144-01/), [TIL therapy](https://onco.cc/technologies/til-therapy/), [Vusolimogene oderparepvec](https://onco.cc/drugs/vusolimogene-oderparepvec/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Imatinib](https://onco.cc/drugs/imatinib/))
- Treatment duration: Stop anti-PD-1 therapy after two years or after a confirmed complete response; most remissions hold off treatment (KEYNOTE-006). ([KEYNOTE-006](https://onco.cc/trials/keynote-006/), [Fixed-duration vs continuous therapy](https://onco.cc/terms/fixed-duration/))
- Oligometastatic disease: Surgery or radiosurgery for isolated metastases alongside systemic therapy; isolated limb perfusion for limb-confined disease. ([Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/), [Isolated limb perfusion and infusion](https://onco.cc/technologies/isolated-limb-perfusion/))

## State of the art

- 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.

## Open problems

- 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.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Melanoma
- CheckMate 067 ten-year results (NEJM 2025): https://www.nejm.org/doi/full/10.1056/NEJMoa2407417
- KEYNOTE-006 ten-year follow-up (Annals of Oncology 2024): https://www.annalsofoncology.org/article/S0923-7534(24)03910-3/fulltext
- Dutch TIL trial (NEJM 2022): https://www.nejm.org/doi/full/10.1056/NEJMoa2210233
- Wikipedia: https://en.wikipedia.org/wiki/Melanoma

## Connected records

- cancers: [Acral melanoma](https://onco.cc/cancers/acral-melanoma/), [BRAF V600-mutant melanoma](https://onco.cc/cancers/braf-v600-melanoma/), [Brain metastases (secondary brain tumours)](https://onco.cc/cancers/secondary-brain-tumours/), [Melanoma](https://onco.cc/cancers/melanoma/), [Mucosal melanoma](https://onco.cc/cancers/mucosal-melanoma/), [Uveal melanoma](https://onco.cc/cancers/uveal-melanoma/)
- technologies: [Faecal microbiota transplantation for PD-1 non-responders](https://onco.cc/technologies/fmt-checkpoint-nonresponders/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [Isolated limb perfusion and infusion](https://onco.cc/technologies/isolated-limb-perfusion/), [LAG-3 blockade](https://onco.cc/technologies/lag3-blockade/), [Oncolytic viruses](https://onco.cc/technologies/oncolytic-virus/), [Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/), [TCR-T cell therapy](https://onco.cc/technologies/tcr-t/), [TIL therapy](https://onco.cc/technologies/til-therapy/)
- targets: [BRAF](https://onco.cc/targets/braf/), [CTLA-4](https://onco.cc/targets/ctla4/), [KIT](https://onco.cc/targets/kit/), [LAG-3](https://onco.cc/targets/lag3/), [PD-1](https://onco.cc/targets/pd1/), [PRAME](https://onco.cc/targets/prame/)
- drugs: [Aldesleukin (high-dose IL-2)](https://onco.cc/drugs/aldesleukin/), [Binimetinib](https://onco.cc/drugs/binimetinib/), [Brenetafusp](https://onco.cc/drugs/brenetafusp/), [Cobimetinib](https://onco.cc/drugs/cobimetinib/), [Dabrafenib + trametinib](https://onco.cc/drugs/dabrafenib-trametinib/), [Dacarbazine](https://onco.cc/drugs/dacarbazine/), [EIK1001](https://onco.cc/drugs/eik1001/), [Encorafenib](https://onco.cc/drugs/encorafenib/), [Fianlimab](https://onco.cc/drugs/fianlimab/), [IMA203](https://onco.cc/drugs/ima203/), [Imatinib](https://onco.cc/drugs/imatinib/), [IO102-IO103](https://onco.cc/drugs/io102-io103/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Lifileucel](https://onco.cc/drugs/lifileucel/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Relatlimab + nivolumab](https://onco.cc/drugs/relatlimab-nivolumab/), [Talimogene laherparepvec](https://onco.cc/drugs/talimogene-laherparepvec/), [Tunlametinib](https://onco.cc/drugs/tunlametinib/), [Vemurafenib](https://onco.cc/drugs/vemurafenib/), [Vusolimogene oderparepvec](https://onco.cc/drugs/vusolimogene-oderparepvec/)
- pathways: [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- terms: [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/), [Fixed-duration vs continuous therapy](https://onco.cc/terms/fixed-duration/), [Immune-related adverse events (irAEs)](https://onco.cc/terms/irae/)
- trials: [A Study of Subcutaneous Nivolumab + Relatlimab Fixed-dose Combination (FDC) in Previously Untreated Metastatic or Unresectable Melanoma](https://onco.cc/trials/nct05625399/), [A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With NRAS-mutant Melanoma (SEACRAFT-2)](https://onco.cc/trials/seacraft-2/), [C-144-01](https://onco.cc/trials/c-144-01/), [CheckMate 067](https://onco.cc/trials/checkmate-067/), [CheckMate 204](https://onco.cc/trials/checkmate-204/), [coBRIM](https://onco.cc/trials/cobrim/), [COLUMBUS](https://onco.cc/trials/columbus/), [COMBI-d](https://onco.cc/trials/combi-d/), [Comparing Tunlametinib Capsules and Combination Chemotherapy in Advanced NRAS-mutant Melanoma](https://onco.cc/trials/nct06008106/), [DREAMseq (ECOG-ACRIN EA6134)](https://onco.cc/trials/dreamseq/), [Fianlimab + cemiplimab phase 3 (first-line melanoma)](https://onco.cc/trials/fianlimab-phase3-melanoma/), [IO102-IO103 in Combination With Pembrolizumab Versus Pembrolizumab Alone in Advanced Melanoma (IOB-013 / KN-D18)](https://onco.cc/trials/nct05155254/), [KEYNOTE-006](https://onco.cc/trials/keynote-006/), [PRISM-MEL-301](https://onco.cc/trials/prism-mel-301/), [RELATIVITY-047](https://onco.cc/trials/relativity-047/), [Safety and Efficacy of EIK1001 in Combo With Pembro Versus Placebo and Pembro as First-Line Therapy in Patients With Advanced Melanoma](https://onco.cc/trials/nct06697301/), [Study to Investigate Lifileucel Regimen Plus Pembrolizumab Compared With Pembrolizumab Alone in Participants With Untreated Advanced Melanoma.](https://onco.cc/trials/nct05727904/), [SUPRAME-ACTengine® IMA203 vs. Investigator's Choice of Treatment in Previously Treated, Unresectable or Metastatic Cutaneous Melanoma](https://onco.cc/trials/nct06743126/)
- people: [Antoni Ribas](https://onco.cc/people/antoni-ribas/), [Caroline Robert](https://onco.cc/people/caroline-robert/), [F. Stephen Hodi](https://onco.cc/people/f-stephen-hodi/), [Hussein A. Tawbi](https://onco.cc/people/hussein-tawbi/), [James Larkin](https://onco.cc/people/james-larkin/), [Jedd D. Wolchok](https://onco.cc/people/jedd-wolchok/), [Michael A. Postow](https://onco.cc/people/michael-postow/)

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