Overview of Melanoma Treatment
Melanoma treatment has been revolutionized by targeted therapies and immunotherapy. For BRAF V600-mutated melanoma (approximately 50% of cases), combination BRAF/MEK inhibition provides rapid tumor responses. For unresectable or metastatic disease, checkpoint inhibitors targeting PD-1 (pembrolizumab, nivolumab) or CTLA-4 (ipilimumab) have dramatically improved survival outcomes.
Treatment Strategies by Molecular Subtype
BRAF V600-Mutated Melanoma (50%)
- Combination BRAF + MEK inhibition: Dabrafenib + Trametinib OR Vemurafenib + Cobimetinib
- Superior to BRAF inhibitor monotherapy
BRAF Wild-Type Melanoma
- Checkpoint inhibitor monotherapy or combination
- Pembrolizumab or Nivolumab single agent
- Nivolumab + Ipilimumab combination for higher response rates
Adjuvant Therapy (Stage III Resected)
- Pembrolizumab or Nivolumab for 1 year
- Dabrafenib + Trametinib for BRAF-mutated disease
Epidemiology & Impact
Melanoma is the fifth most common cancer in the United States, with approximately 100,640 new invasive cases and 8,290 deaths expected in 2024. Incidence has risen sharply over the past four decades, increasing approximately 1.5% per year, driven by UV exposure and improved detection. The median age at diagnosis is 66 years, though melanoma has a notably younger age distribution compared to most solid tumors. The overall five-year survival rate is 94%, reflecting the high proportion of early-stage disease, but survival for distant metastatic melanoma has improved from approximately 10% to over 30% in the immunotherapy era. Risk factors include UV exposure (both chronic and intermittent/blistering sunburns), fair skin phenotype, multiple atypical nevi, family history, and immunosuppression. Approximately 10% of melanomas arise in a familial context, with CDKN2A being the most commonly mutated high-penetrance susceptibility gene.
Molecular Biology & Biomarkers
Melanoma is characterized by a high somatic mutation burden (driven by UV mutagenesis), which contributes to its immunogenicity and responsiveness to checkpoint inhibitor therapy. The major molecular subtypes defined by The Cancer Genome Atlas (TCGA) include BRAF-mutant (~50%, predominantly V600E), RAS-mutant (~28%, predominantly NRAS Q61), NF1-mutant (~14%), and triple wild-type (~8%). BRAF V600 mutations are targetable with BRAF/MEK inhibitor combinations, which produce rapid responses in 65-70% of patients. Acral and mucosal melanomas have distinct molecular profiles with lower mutation burdens, frequent KIT mutations or amplifications, and generally poorer responses to immunotherapy. Uveal melanoma, while histologically distinct, harbors GNAQ/GNA11 mutations in >80% of cases and has a unique metastatic tropism to the liver. The tumor microenvironment classification — including T-cell inflamed versus non-inflamed phenotypes — is an emerging predictor of immunotherapy response and is guiding combination strategy development.
Evolving Treatment Landscape
The melanoma treatment landscape has been revolutionized more dramatically than perhaps any other solid tumor. Prior to 2011, metastatic melanoma had no therapies demonstrating an overall survival benefit. The sequential approvals of ipilimumab (anti-CTLA-4, 2011), pembrolizumab and nivolumab (anti-PD-1, 2014), and their combinations have fundamentally changed outcomes. The nivolumab + ipilimumab combination achieves 5-year survival rates of approximately 52% in metastatic melanoma. The first-in-class LAG-3 inhibitor combination (nivolumab + relatlimab, Opdualag) provides another frontline option. In 2024, lifileucel (Amtagvi) became the first FDA-approved TIL (tumor-infiltrating lymphocyte) cell therapy, representing an entirely new modality for immunotherapy-refractory patients. The adjuvant setting has been equally transformed, with pembrolizumab and nivolumab reducing recurrence risk by 40-50% in resected stage III disease. Neoadjuvant immunotherapy is emerging as a paradigm-shifting approach, with the NADINA trial demonstrating that neoadjuvant nivolumab + ipilimumab followed by surgery achieves pathological complete responses in ~60% of patients, potentially sparing selected patients from adjuvant therapy.
Approved Melanoma Therapies
Treatment Selection Strategies
BRAF-Mutated Melanoma
For BRAF V600-mutated unresectable or metastatic melanoma, both targeted therapy (BRAF + MEK inhibition) and immunotherapy are options. Combination BRAF/MEK inhibition provides rapid responses but eventual resistance. Checkpoint inhibitors may provide more durable responses. Treatment choice depends on disease burden, need for rapid response, and patient factors.
Checkpoint Inhibitor Selection
For BRAF wild-type or patients preferring immunotherapy, single-agent anti-PD-1 (pembrolizumab or nivolumab) has lower toxicity than combination ipilimumab + nivolumab. However, combination therapy has higher response rates (58% vs 44%) and improved progression-free survival in CheckMate 067, at the cost of increased immune-related adverse events.