Cutaneous Melanoma: Systemic Therapy

Cutaneous Melanoma: overview

This algorithm covers systemic therapy for cutaneous melanoma across the adjuvant, metastatic, and later-line settings. For resected high-risk disease (stage IIB to III), options are adjuvant pembrolizumab or nivolumab (CheckMate 238 / KEYNOTE-054), adjuvant dabrafenib plus trametinib for BRAF-mutant tumors (COMBI-AD), or neoadjuvant pembrolizumab (S1801).

For metastatic disease treated with first-line immunotherapy, the chart lists nivolumab plus ipilimumab (CheckMate 067), nivolumab plus relatlimab (RELATIVITY-047), and anti-PD-1 monotherapy (KEYNOTE-006). RELATIVITY-047 showed improved progression-free survival and, with longer follow-up, overall survival for LAG-3 plus PD-1 blockade versus nivolumab alone, and KEYNOTE-006 showed durable survival benefit for pembrolizumab over ipilimumab. For BRAF V600-mutant disease, targeted options are dabrafenib plus trametinib (COMBI-d) or encorafenib plus binimetinib (COLUMBUS), which improved progression-free and overall survival over vemurafenib. In later lines, lifileucel (TIL therapy) is shown after anti-PD-1 therapy, and BRAF/MEK inhibition or a clinical trial is used if not given earlier, depending on prior sequence.

Trials behind this algorithm

• CheckMate 238 trial Ascierto PA et al, Lancet Oncol, 2020; PMID:32961119
• COMBI-AD trial Dummer R et al, NEJM, 2020; PMID:32877599
• CheckMate 067 trial Larkin J et al, NEJM, 2019 PMID:31562797
• RELATIVITY-047 Tawbi HA et al, JCO, 2025; PMID: 39671533
• KEYNOTE-006 Long GV et al, Ann Oncol, 2024; PMID: 39306585
• COMBI-d trial Long GV et al, J Ann Onc, 2017; PMID:28475671
• COLUMBUS Dummer R et al, JCO, 2022; PMID: 35862871

Background reading: Melanoma board review notes.