First-Line Treatment for Unresectable Stage III or Metastatic Stage IV Melanoma Without BRAF V600 Mutation

Clinical Scenario

This protocol addresses patients with unresectable stage III or metastatic stage IV melanoma in whom BRAF V600 mutation is absent (BRAF wild-type). Because these patients lack the molecular target for BRAF-directed therapy, immune checkpoint inhibitor-based strategies represent the backbone of first-line systemic treatment.

Treatment Approach

First-line management centres on immune checkpoint inhibitor therapy. Both combination and monotherapy approaches are available, with regimen selection guided by clinical factors such as disease pace and urgency of response.

The full protocol specifies which regimens are preferred, under which conditions each applies — including the threshold at which combination therapy is favoured over monotherapy — and how regulatory approvals bear on the choice. Dosing, sequencing, and the complete decision algorithm are contained in the structured regimen below.

Instant Access to Structured Evidence-Based Regimens

References

The superiority of nivolumab over dacarbazine (DTIC) chemotherapy (ChT) for the first-line treatment of patients with BRAF-wild-type (WT) melanoma was demonstrated in the prospective randomised CheckMate 066 trial, with an HR for death of 0.42 (99.79% CI 0.25-0.73, P < 0.001) and an HR for death or progression of disease of 0.43 (95% CI 0.34-0.56, P < 0.001).
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].

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