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Treatment Options for Unresectable Stage III, Stage IV, and Recurrent Melanoma
Source: Melanoma Treatment (PDQ®)–Health Professional Version, National Cancer Institute.
Source updated: May 2, 2025 · Captured 2026-09-09.
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Context: Treatment of Unresectable Stage III, Stage IV, and Recurrent Melanoma
Treatment options for unresectable stage III, stage IV, and recurrent melanoma include the following:
Immunotherapy.
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Immunotherapy. › Checkpoint inhibitors.
Anti–programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) therapy.
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Immunotherapy. › Checkpoint inhibitors. › Anti–programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) therapy.
Pembrolizumab.
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Immunotherapy. › Checkpoint inhibitors. › Anti–programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) therapy.
Nivolumab.
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Immunotherapy. › Checkpoint inhibitors.
Anti–cytotoxic T-lymphocyte antigen-4 (CTLA-4) therapy.
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Immunotherapy. › Checkpoint inhibitors. › Anti–cytotoxic T-lymphocyte antigen-4 (CTLA-4) therapy.
Ipilimumab.
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Immunotherapy.
High-dose interleukin-2 (IL-2).
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Immunotherapy. › Dual checkpoint inhibition.
CTLA-4 inhibitor plus PD-1 inhibitor.
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Immunotherapy. › Dual checkpoint inhibition.
LAG-3 inhibitor plus PD-1 inhibitor.
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Signal transduction inhibitors.
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Signal transduction inhibitors.
BRAF inhibitors (for patients who test positive for the BRAF V600 pathogenic variant).
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Signal transduction inhibitors. › BRAF inhibitors (for patients who test positive for the BRAF V600 pathogenic variant).
Vemurafenib.
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Signal transduction inhibitors. › BRAF inhibitors (for patients who test positive for the BRAF V600 pathogenic variant).
Dabrafenib.
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Signal transduction inhibitors.
Mitogen-activated protein kinase (MEK) inhibitors.
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Signal transduction inhibitors. › Mitogen-activated protein kinase (MEK) inhibitors.
Trametinib.
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Signal transduction inhibitors. › Mitogen-activated protein kinase (MEK) inhibitors.
Cobimetinib.
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Signal transduction inhibitors.
Combination therapy with signal transduction inhibitors.
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Signal transduction inhibitors. › Combination therapy with signal transduction inhibitors.
BRAF inhibitor plus MEK inhibitors.
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Signal transduction inhibitors. › Combination therapy with signal transduction inhibitors. › BRAF inhibitor plus MEK inhibitors.
Dabrafenib plus trametinib.
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Signal transduction inhibitors. › Combination therapy with signal transduction inhibitors. › BRAF inhibitor plus MEK inhibitors.
Vemurafenib plus cobimetinib.
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Signal transduction inhibitors. › Combination therapy with signal transduction inhibitors. › BRAF inhibitor plus MEK inhibitors.
Encorafenib plus binimetinib.
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Signal transduction inhibitors.
Combination signal transduction inhibitor therapy plus PD-L1 inhibitor.
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Signal transduction inhibitors. › Combination signal transduction inhibitor therapy plus PD-L1 inhibitor.
Cobimetinib and vemurafenib plus atezolizumab.
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Tumor-infiltrating lymphocyte (TIL) therapy.
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Intralesional therapy.
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Intralesional therapy.
Talimogene laherparepvec (T-VEC).
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Adjunctive local/regional therapy including surgical resection.
Adjunctive local/regional therapy including surgical resection.
Isolated limb infusion (ILI).
Palliative therapy.
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Targeted therapy with single agents or combination therapy (under clinical evaluation).
Combinations of immunotherapy and targeted therapy (under clinical evaluation).
Intralesional injections (e.g., oncolytic viruses) (under clinical evaluation).
Complete surgical resection of all known disease versus best medical therapy (under clinical evaluation).
Isolated limb perfusion for unresectable extremity melanoma (under clinical evaluation).
Systemic therapy for unresectable disease (under clinical evaluation).
Two approaches—checkpoint inhibition and targeting the mitogen-activated protein kinase (MAPK) pathway—improved progression-free survival (PFS) and overall survival (OS) in randomized trials. Anti–PD-1 monotherapy (pembrolizumab or nivolumab) improved efficacy outcomes with better safety profiles when compared with treatment using single-agent anti–CTLA-4 (ipilimumab) or investigator choice of chemotherapy. The combination of anti–PD-1 and anti–CTLA-4 immunotherapies (nivolumab and ipilimumab) also prolongs PFS and OS compared with ipilimumab, but the combination is associated with significant toxicity. The efficacy seen with immunotherapy is independent of BRAF variant status.
Combinations of BRAF and MEK inhibitors have consistently shown superior efficacy compared with BRAF monotherapy. Improved PFS was seen when a PD-L1 inhibitor (atezolizumab) was added to the combination of a BRAF plus MEK inhibitor (vemurafenib plus cobimetinib); however, data on OS are immature. Further questions remain regarding triplet therapy, including how it compares with monotherapy checkpoint inhibition and if the concurrent administration is superior to sequential therapy (NCT02224781).
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Because of the rapid development of new agents, combinations, and remaining questions, patients and their physicians are encouraged to consider a clinical trial for initial treatment and at the time of progression. Ongoing clinical trials address the following issues:
The value of sequencing therapies, such as immunotherapy and targeted therapy.
Optimal doses of combination immunotherapy to decrease toxicity and preserve efficacy.
How to select the patients who will benefit from combination immunotherapy versus monotherapy.
The role of PD-L1 expression as a biomarker for efficacy.
The role of maintenance therapy.
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