| Setting | Treatment |
|---|---|
| IN SITU / STAGE IA lentigo maligna, or T1a <0.8 mm non-ulcerated | WLE 0.5–1 cm
wide local excision No SLNB, no systemic therapy — surveillance only
<5% sentinel-node positivity |
| STAGE IB–IIA T1b–T3a, 0.8–2 mm | WLE 1–2 cm by depth SLNB — discuss / offer at T1b, indicated from T2a No approved adjuvant therapy at stage IIA — surveillance |
| STAGE IIB/IIC, node-negative T3b–T4b, >2 mm, ulcerated or thick | WLE 2 cm + SLNB Node-negative → adjuvant pembrolizumab ×1 year (KEYNOTE-716)
RFS HR 0.65 — first anti-PD-1 to significantly improve RFS and distant-metastasis-free survival at stage II · adjuvant interferon is historical — do not offer |
| 🔴 STAGE III, MICROSCOPIC sentinel-node positive | ⚠⚠ NO reflexive completion node dissection (MSLT-II)
MSLT-II / DeCOG-SLT: no melanoma-specific survival benefit, real lymphoedema cost → nodal ultrasound surveillance instead Adjuvant systemic ×12 months → nivolumab (CheckMate-238) or pembrolizumab (KEYNOTE-054) BRAF V600E/K → dabrafenib + trametinib (COMBI-AD) |
| 🔴 STAGE III, MACROSCOPIC, resectable palpable nodal disease | NEOADJUVANT IMMUNOTHERAPY, not upfront surgery — the standard-of-care shift Ipilimumab + nivolumab ×2 → response-adapted surgery ± adjuvant (NADINA)
12/24-mo EFS 85.2%/77.3% vs 61.7%/55.7%, HR 0.40; ~60% needed no further therapy after 2 cycles · cost: grade ≥3 AEs 29.7% vs 14.7% Alternative → neoadjuvant pembrolizumab ×3 → surgery → adjuvant (SWOG S1801)
2-yr EFS 72% vs 49% |
| UNRESECTABLE III / STAGE IV any BRAF status, first line | Immunotherapy first Ipilimumab + nivolumab (CheckMate-067)
10-yr OS 43% vs 37% (nivo alone) vs 19% (ipi alone) — longest checkpoint-inhibitor follow-up in any tumour Nivolumab + relatlimab — a less toxic doublet (RELATIVITY-047)
mPFS 10.2 vs 4.6 mo; mature OS benefit at 3 yr (median 51.0 vs 34.1 mo, 3-yr OS 54.6% vs 48.0%) · reasonable frailer-patient alternative |
| 🔴 STAGE IV, BRAF-mutant — sequencing | Immunotherapy FIRST, even in BRAF-mutant disease (DREAMseq)
ipi+nivo → BRAF/MEK at progression gave 2-yr OS 72% vs 52% vs the reverse sequence Reserve BRAF/MEK for AFTER immunotherapy
except when rapid cytoreduction is needed for symptomatic / high-burden / high-LDH disease BRAF/MEK regimens — encorafenib + binimetinib (COLUMBUS) · dabrafenib + trametinib (COMBI-v) · vemurafenib + cobimetinib (coBRIM)
cross-trial comparison only, not head-to-head |
| 🔴 BRAIN METASTASES (M1d) | Asymptomatic, steroid-free → systemic IO upfront (CheckMate-204)
ipi+nivo in active brain mets — intracranial response 55%, sparing / deferring RT Symptomatic → radiation oncology early; SRS standard
IO benefit falls to 22% — for limited / symptomatic disease |
| ACRAL / MUCOSAL a different disease | ⚠ KIT is the actionable target here, not BRAF
KIT mutations in up to 36% acral / 39% mucosal (BRAF/NRAS only ~10–15%) Exon 11/13 KIT mutations → imatinib
exon 17 or amplification do NOT respond BRAF/MEK less effective in mucosal (NF1-loss resistance); anti-PD-1 activity lower in both; worse prognosis |
| UVEAL HLA-A*02:01-positive, unresectable/metastatic | ⚠ No BRAF, poor checkpoint response, HEPATOTROPIC — do NOT treat like cutaneous melanoma Tebentafusp
gp100×CD3 T-cell-receptor bispecific — median OS 21.6 vs 16.9 mo, HR 0.68 · HLA typing gatekeeps eligibility |