Metastatic Melanoma — BRAF V600-Mutant

Sequencing for BRAF V600-mutant metastatic melanoma: front-line immunotherapy (nivolumab + ipilimumab or anti-PD-1 monotherapy) is preferred for overall survival, with BRAF/MEK-targeted combination therapy reserved for immunotherapy failure or rapidly progressive high-LDH disease. Both strategies cross over on progression before further therapy or a clinical trial.

Pace of disease: is upfront immunotherapy appropriate, or is rapid cytoreduction needed?

• Immunotherapy-appropriate tempo → Immunotherapy (nivolumab + ipilimumab, or anti-PD-1 monotherapy)
• Rapid progression / high LDH → BRAF/MEK inhibitor combination (dabrafenib + trametinib, or encorafenib + binimetinib)

1L: Immunotherapy (nivolumab + ipilimumab, or anti-PD-1 monotherapy)

Preferred first line for durable, potentially treatment-free survival (DREAMseq showed superior overall survival vs targeted-first). Nivolumab + ipilimumab gives the highest response but substantial immune-related toxicity; anti-PD-1 monotherapy (or nivolumab + relatlimab) is a lower-toxicity alternative.

Evidence: CheckMate 067 · KEYNOTE-006

• Progression → BRAF/MEK inhibitor combination (dabrafenib + trametinib, or encorafenib + binimetinib)

1L: BRAF/MEK inhibitor combination (dabrafenib + trametinib, or encorafenib + binimetinib)

Reserved for rapidly progressive, symptomatic, or high-LDH/high-burden disease needing fast cytoreduction, or when immunotherapy is contraindicated. High, rapid response rates; monitor pyrexia (dabrafenib + trametinib) and manage per protocol.

Evidence: COMBI-d

• Progression → Immunotherapy (nivolumab + ipilimumab, or anti-PD-1 monotherapy)

2L: BRAF/MEK inhibitor combination (dabrafenib + trametinib, or encorafenib + binimetinib)

For progression after front-line immunotherapy. Provides rapid disease control in BRAF V600-mutant disease.

• Progression → Further therapy: clinical trial, tumor-infiltrating lymphocytes, or cytotoxic chemotherapy

2L: Immunotherapy (nivolumab + ipilimumab, or anti-PD-1 monotherapy)

For progression after front-line BRAF/MEK-targeted therapy; a substantial fraction of patients still derive durable benefit from checkpoint blockade.

Evidence: CheckMate 067 · KEYNOTE-006

• Progression → Further therapy: clinical trial, tumor-infiltrating lymphocytes, or cytotoxic chemotherapy

3L+: Further therapy: clinical trial, tumor-infiltrating lymphocytes, or cytotoxic chemotherapy

After both immunotherapy and BRAF/MEK-targeted therapy: strongly prioritize a clinical trial or lifileucel (TIL therapy) where available; cytotoxic chemotherapy (temozolomide/dacarbazine) has limited activity and is palliative.