Melanoma
ICD-10 C43 · ICD-11 2C30

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

This protocol addresses patients with unresectable stage III or metastatic (stage IV) melanoma in whom molecular testing confirms the absence of a BRAF V600 mutation, excluding BRAF-targeted therapy and directing management toward other systemic approaches.

Clinical Scenario

Unresectable stage III or metastatic stage IV melanoma with confirmed BRAF V600 mutation absent (BRAF wild-type). Because BRAF-targeted agents are not applicable in this population, treatment strategy relies on immunotherapy-based regimens. Clinical trials such as CheckMate 066 established outcomes in this BRAF wild-type population compared with chemotherapy.

Treatment Approach — Partial Overview

In the second-line setting, management of this BRAF wild-type population centres on checkpoint inhibitor-based strategies, including both combination immunotherapy and monotherapy options; for patients with prior exposure to single-agent anti-PD-1 therapy, additional regimens may apply. The complete selection criteria, regimen details, and sequencing algorithm are available in the full protocol…

Instant Access to Structured Evidence-Based Regimens

References

  1. The superiority of nivolumab over dacarbazine (DTIC) chemotherapy for the first-line treatment of patients with BRAF-wild-type 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).
  2. Treatment options for the second-line setting depend on the therapy used in the first line and include ipilimumab–nivolumab [II, B], pembrolizumab [I, A; ESMO-MCBS v1.1 score: A/4], nivolumab [II, B], ipilimumab [II, B; ESMO-MCBS v1.1 score: 4] and BRAF–MEK inhibitor combination therapy for patients with BRAF-mutated melanoma [II, B; ESCAT score: I-A].
  3. If the first-line treatment was anti-PD-1 monotherapy or if patients had primary refractory disease following anti-PD-1 therapy, ipilimumab and ipilimumab–nivolumab are options based on results from the phase II SWOG S1616 trial.
  4. Nivolumab–relatlimab might also represent an option after failure of single-agent anti-PD-1 therapy [III, B; not EMA or FDA approved as second-line therapy].
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