First-Line Treatment for Unresectable Stage III or IV Cutaneous Melanoma with BRAF V600 Mutation
Clinical scenario
This protocol addresses patients with unresectable stage III or stage IV (metastatic) cutaneous melanoma in whom a BRAF V600 mutation has been confirmed. Both the extent of disease and the mutation status are central to treatment selection at this stage.
Treatment approach — partial overview
First-line management involves immunotherapy-based regimens as the primary pathway; for patients with a confirmed BRAF V600 mutation, targeted combination therapy represents an established alternative when immunotherapy is not suitable. The choice between pathways, preferred agent combinations, eligibility criteria, and sequencing logic are covered in full in the complete protocol.
References
DOI: 10.1016/j.annonc.2024.11.006
- For patients with unresectable disease, first-line ipilimumabenivolumab [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.
- If anti-PD-1-based therapy is not available or patients are considered ineligible for its use, BRAFieMEKi combination therapy (dabrafenibetrametinib [ESMO-MCBS v1.1 score: 5]; vemurafenibecobimetinib [ESMO-MCBS v1.1 score: A/5]; binimetinibeencorafenib [ESMO-MCBS v1.1 score: A/5]) is also an option in the first line for patients with BRAF-mutated melanoma [I; A; ESCAT score: I-A].
- For patients in whom the decision to treat with targeted therapy has been made, those who cannot receive a MEKi (e.g. due to cardiovascular comorbidities, a recent BM bleeding event, history of retinal detachment or other ophthalmological contraindications) can be offered encorafenib as monotherapy [II, B; not FDA or EMA approved].
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