This protocol covers amelanocytic melanoma that has progressed to unresectable stage III or stage IV (distant metastasis) and where molecular testing has confirmed the absence of a BRAF V600 mutation (BRAF wild-type). This distinction directly shapes available first-line options and limits what is approved in subsequent lines.
Unresectable stage III or stage IV (metastatic) cutaneous melanoma confirmed as BRAF wild-type (BRAF V600 mutation absent). PD-1 blockade is a standard-of-care option in the first-line setting regardless of BRAF status; however, for BRAF wild-type disease, approved second-line options are notably limited — making the first-line choice especially consequential.
First-line management for this presentation involves immunotherapy, with the preferred regimen depending on whether a rapid response is clinically required and, for at least one option, on a specific tumour biomarker result. The full structured regimen — including agent selection criteria and sequencing — is available via the link below.
Based on these trials, PD-1 blockade is now an SoC option for all patients, regardless of tumour BRAF status, in the first-line setting.
For BRAF-WT melanoma, approved second-line options are very limited.
For patients with unresectable disease, first-line ipilimumab+nivolumab [ESMO-MCBS v1.1 score: A/4] is a preferred option for all patients regardless of BRAF status when this can be safely delivered for the first few months (i.e. when a rapid response is not required due to aggressive/symptomatic disease) [I, A].
First-line nivolumab [I, A; ESMO-MCBS v1.1 score: A/4] or pembrolizumab [I, A; ESMO-MCBS v1.1 score: A/4] is also recommended.
Nivolumab+relatlimab can be offered as first-line treatment but EMA approval is only for patients with tumour cell PD-L1 expression <1% [I, B; ESMO-MCBS v1.1 score: 3; EMA approved for PD-L1 expression <1%, FDA approval is regardless of PD-L1 expression].
DOI: 10.1016/j.annonc.2024.11.006 View source ↗