Advanced melanoma (unresectable stage III and stage IV)
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.
Overview
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.
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.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowFainting or palpitations
Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
- Emergency services nowHypophysitis or adrenal crisis
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
- Check before combiningFood and drink: Dabrafenib + trametinib
Dabrafenib: take on an empty stomach. Trametinib: take on an empty stomach; both cause pyrexia.
- Check before combiningFood and drink: Imatinib
Take with a meal and a large glass of water.
- Check before combiningFood and drink: Pembrolizumab
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
- Check before combiningHeart rhythm (QT): Encorafenib
Known QT prolongation. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.
See all on the product pages:BinimetinibDabrafenib + trametinibEncorafenibImatinibIpilimumabNivolumabPembrolizumabRelatlimab + nivolumab·Printable cards in the navigator
Anatomy and lymph node drainage
- Epidermis (in situ)
- Basal layer (melanocytes, basal cells)
- Keratinocytes (squamous)
- Dermis (invasive; Breslow depth)
- Merkel cells (dermal-epidermal)
- Dermal vessels (Kaposi)
- Acral and mucosal sites
- Nodes: sentinel node in the draining basin
- Nodes: regional basin (axilla, groin, neck)
Each skin cancer comes from a different cell layer: melanocytes and basal cells at the base of the epidermis, keratinocytes above them, Merkel cells and blood vessels in the dermis; depth of invasion decides the risk.
- Epidermis (in situ)
- Basal layer (melanocytes, basal cells)BRAF V600-mutant advanced melanoma (targeted therapy option)
- Keratinocytes (squamous)
- Dermis (invasive; Breslow depth)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)
- Merkel cells (dermal-epidermal)
- Dermal vessels (Kaposi)
- Acral and mucosal sitesAcral and mucosal primaries (lower immunotherapy response rates)
- sentinel node in the draining basin
- regional basin (axilla, groin, neck)
Same organ: Melanoma, Basal cell carcinoma, Cutaneous squamous cell carcinoma, Merkel cell carcinoma, Kaposi sarcoma, Skin cancer (all types), BRAF V600-mutant melanoma, Stage III melanoma (after surgery), Stage IIB and IIC melanoma, Mucosal melanoma, Acral melanoma, Advanced cutaneous squamous cell carcinoma, Locally advanced and metastatic basal cell carcinoma, Dermatofibrosarcoma protuberans
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.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
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).
Dabrafenib-trametinib, encorafenib-binimetinib or vemurafenib-cobimetinib.
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.
Lifileucel TIL therapy (C-144-01); RP1 with nivolumab; ipilimumab-based combinations; clinical trials; imatinib for KIT-mutant tumours.
Stop anti-PD-1 therapy after two years or after a confirmed complete response; most remissions hold off treatment (KEYNOTE-006).
Surgery or radiosurgery for isolated metastases alongside systemic therapy; isolated limb perfusion for limb-confined disease.
Subtypes & biomarkers
top- 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)
- 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)
How often this target appears
- 1975Dacarbazine approved: about one in ten tumours respond
- 1998High-dose interleukin-2 approved for rare durable remissions
- 2010Ipilimumab is the first drug to lengthen survival in advanced melanoma
- 2014Pembrolizumab and nivolumab approved; KEYNOTE-006 shows PD-1 beats CTLA-4 blockade
- 2015CheckMate 067: nivolumab plus ipilimumab; T-VEC first oncolytic virus
- 2018CheckMate 204: immunotherapy doublet works in the brain
- 2022RELATIVITY-047: nivolumab plus relatlimab approved; Dutch trial shows TIL beats ipilimumab
- 2024Lifileucel: first approved cell therapy for a solid tumour
- 2025CheckMate 067 ten-year results: 43 percent alive on the combination
- 2026RP1 with nivolumab approved for PD-1-refractory melanoma
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 35 changes by month →- 2026-09-17This recordAdvanced melanoma (unresectable stage III and stage IV)Facts on this page last checked
When this page itself was last checked or edited.
- 2026-08-06RegulatoryVusolimogene oderparepvecVusolimogene oderparepvec: approval (US)
Accelerated approval with nivolumab for unresectable/metastatic melanoma after anti-PD-1 (IGNYTE)
- 2026ApprovalVusolimogene oderparepvecVusolimogene oderparepvec approved in US
Unresectable/metastatic melanoma after anti-PD-1, with nivolumab (accelerated)
- 2026Trial resultFianlimab + cemiplimab phase 3 (first-line melanoma)Fianlimab + cemiplimab phase 3 (first-line melanoma) reported
Primary PFS endpoint not met; numerical +5.
- 2026MilestoneVusolimogene oderparepvecRP1 with nivolumab approved for PD-1-refractory melanoma
A milestone in how this cancer is treated.
- 2025MilestoneCheckMate 067CheckMate 067 ten-year results: 43 percent alive on the combination
A milestone in how this cancer is treated.
What is in development for Advanced melanoma (unresectable stage III and stage IV), drawn from the whole corpus: 24 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Drugs in phase 3 · 5
Technologies being tested · 1
Trials under way · 8
- PRISM-MEL-301 · phase 3 · Immunocore
- SUPRAME-ACTengine® IMA203 vs. Investigator's Choice of Treatment in Previously Treated, Unresectable or Metastatic Cutaneous Melanoma · phase 3 · Immatics US
- Study to Investigate Lifileucel Regimen Plus Pembrolizumab Compared With Pembrolizumab Alone in Participants With Untreated Advanced Melanoma. · phase 3 · Iovance Biotherapeutics, Inc.
- IO102-IO103 in Combination With Pembrolizumab Versus Pembrolizumab Alone in Advanced Melanoma (IOB-013 / KN-D18) · phase 3 · IO Biotech
- Safety and Efficacy of EIK1001 in Combo With Pembro Versus Placebo and Pembro as First-Line Therapy in Patients With Advanced Melanoma · phase 2/3 · Eikon Therapeutics
- A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With NRAS-mutant Melanoma (SEACRAFT-2) · phase 3 · Erasca
- Comparing Tunlametinib Capsules and Combination Chemotherapy in Advanced NRAS-mutant Melanoma · phase 3 · Shanghai Kechow Pharma, Inc.
- A Study of Subcutaneous Nivolumab + Relatlimab Fixed-dose Combination (FDC) in Previously Untreated Metastatic or Unresectable Melanoma · phase 3 · Bristol-Myers Squibb
Trials reported · 10
- Fianlimab + cemiplimab phase 3 (first-line melanoma) · phase 3 · 2026 · negative
- C-144-01 · phase 2 · 2021 · positive
- CheckMate 067 · phase 3 · 2015 · positive
- CheckMate 204 · phase 2 · 2018 · positive
- coBRIM · phase 3 · 2014 · positive
- COLUMBUS · phase 3 · 2018 · positive
- COMBI-d · phase 3 · 2014 · positive
- DREAMseq (ECOG-ACRIN EA6134) · phase 3 · 2021 · positive
- KEYNOTE-006 · phase 3 · 2015 · positive
- RELATIVITY-047 · phase 2/3 · 2022 · positive
Open problems and what is being done
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.
and how the field plans to fix it →What is being done about thisSide effects and quality of lifeAvailable now- Aldesleukin (high-dose IL-2)Approved
- Immune checkpoint inhibitorsStandard of care
In trials- RELATIVITY-047Positive
Ideas and roadmapsNothing recorded yet.
Background: Immune-related adverse events (irAEs). Also on OnCo: Side effects by symptom · Immune-related side effects · Toxicity compare · Survivorship planner.
Acral, mucosal and uveal melanomas respond far less well and have few dedicated trials.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
Houston · cancer center | United States | 0 | 6,724 | 95,007 | #2 | ||
Seoul · hospital | South Korea | none recorded | 0 | 1,312 | 17,172 | #3 | |
Rochester, MN · hospital | United States | 0 | 4,511 | 44,748 | #5 | ||
Villejuif · cancer center | France | none recorded | 0 | 1,855 | 31,182 | #6 | |
Seoul · hospital | South Korea | none recorded | 0 | 1,607 | 24,676 | #8 | |
Baltimore · cancer center | United States | 0 | 2,955 | 41,449 | #10 | ||
Berlin · university | Germany | none recorded | 0 | 1,563 | 17,749 | #12 | |
Boston · hospital | United States | 0 | 3,582 | 54,857 | #16 | ||
Cleveland · hospital | United States | 0 | 2,264 | 29,412 | #20 | ||
Seoul · hospital | South Korea | none recorded | 0 | 464 | 3,248 | #22 | |
Barcelona · cancer center | Spain | none recorded | 0 | 966 | 23,221 | none recorded | #28 |
Stanford · university | United States | 0 | 3,000 | 50,162 | #30 | ||
San Francisco · cancer center | United States | 0 | 2,800 | 46,704 | #33 | ||
Stockholm · university | Sweden | none recorded | 0 | 987 | 12,440 | #39 | |
Amsterdam · cancer center | Netherlands | none recorded | 0 | 1,451 | 25,873 | #45 |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with Advanced melanoma but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about Advanced melanoma
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example BRAF V600 mutation, Lactate dehydrogenase, PD-L1 expression, Tumour mutational burden and interferon-gamma signature, NRAS and KIT mutations), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include Unresectable stage III, Stage IV M1a to M1c, Stage IV M1d.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
First line, fit patient
- For my situation (first line, fit patient), which of the standard options do you recommend and why?Why: Guideline options include: 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).
- Am I a candidate for Nivolumab, Ipilimumab, Relatlimab + nivolumab or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of CheckMate 067 and RELATIVITY-047 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
BRAF V600-mutant, after immunotherapy or when rapid control is needed
- For my situation (braf v600-mutant, after immunotherapy or when rapid control is needed), which of the standard options do you recommend and why?Why: Guideline options include: Dabrafenib-trametinib, encorafenib-binimetinib or vemurafenib-cobimetinib.
- Am I a candidate for Dabrafenib + trametinib, Encorafenib, Binimetinib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of COLUMBUS and COMBI-d apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Brain metastases
- For my situation (brain metastases), which of the standard options do you recommend and why?Why: Guideline options include: 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.
- Am I a candidate for Nivolumab, Ipilimumab, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of CheckMate 204 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
After PD-1 failure
- For my situation (after pd-1 failure), which of the standard options do you recommend and why?Why: Guideline options include: Lifileucel TIL therapy (C-144-01); RP1 with nivolumab; ipilimumab-based combinations; clinical trials; imatinib for KIT-mutant tumours.
- Am I a candidate for Lifileucel, Vusolimogene oderparepvec, Ipilimumab or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of C-144-01 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Treatment duration
- For my situation (treatment duration), which of the standard options do you recommend and why?Why: Guideline options include: Stop anti-PD-1 therapy after two years or after a confirmed complete response; most remissions hold off treatment (KEYNOTE-006).
- How do the results of KEYNOTE-006 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Oligometastatic disease
- For my situation (oligometastatic disease), which of the standard options do you recommend and why?Why: Guideline options include: Surgery or radiosurgery for isolated metastases alongside systemic therapy; isolated limb perfusion for limb-confined disease.
Any stage
- Are there clinical trials I could join, for example of Fianlimab + cemiplimab phase 3 (first-line melanoma), Fianlimab, PRISM-MEL-301, Brenetafusp?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “About four in ten patients never respond to PD-1 blockade and no biomarker reliably identifies them”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Who needs the ipilimumab component and its toxicity, and whether relatlimab can replace it, has not been settled”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with Advanced melanoma, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
12targets
10drugs
21companies
14pathways
2terms
3trials
18people
7Latest papers
topQuery for this cancer: (TITLE:"Advanced melanoma" OR ABSTRACT:"Advanced melanoma" OR TITLE:"unresectable stage III and stage IV" OR ABSTRACT:"unresectable stage III and stage IV" OR TITLE:"Metastatic melanoma" OR ABSTRACT:"Metastatic melanoma" OR TITLE:"Stage IV melanoma" OR ABSTRACT:"Stage IV melanoma" OR TITLE:"Unresectable melanoma" OR ABSTRACT:"Unresectable melanoma" OR TITLE:"First-line advanced melanoma" OR ABSTRACT:"First-line advanced melanoma") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Advanced melanoma (unresectable stage III and stage IV), not a curated reading list.
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