Metastatic melanoma: BRAF / IO first-line reasoning

Learning objectives

1. Identify the BRAF V600 status, performance status, organ function, and disease-burden inputs needed before metastatic melanoma first-line treatment selection.
2. Explain why dual checkpoint inhibition (nivolumab + ipilimumab) is the standard immunotherapy backbone, when single-agent anti-PD-1 is preferred, and where BRAF-targeted combinations fit.
3. Recognize parallel obligations — autoimmune history, brain MRI for active CNS disease, infection / hepatitis screening — that do not change the canonical IO call but change the safety plan.

At a glance

• BRAF V600E/K testing is required before the first-line plan because it routes patients between IO and targeted strategies.
• Nivolumab + ipilimumab is the canonical IO backbone for fit patients without contraindications; relatlimab + nivolumab is an alternative dual checkpoint combination.
• Encorafenib + binimetinib (or dabrafenib + trametinib) is the canonical BRAF-targeted track for V600-mutant disease — typically used when IO is contraindicated or rapid response is needed.
• Active brain metastases, autoimmune disease, organ-failure-grade comorbidities, and pregnancy status are parallel obligations that shape the safety plan even when the systemic regimen is unchanged.
• This chapter is an OpenOnco-authored learning aid, not official ESMO content or a CME-credit activity.

Diagnostic and biomarker minimum

Before drafting the first-line plan in metastatic melanoma the chapter expects confirmed metastatic histology, BRAF V600E/K testing on the metastatic lesion or, when not feasible, on the primary tumor with discussion of discordance risk, baseline performance status and organ function, LDH and disease-burden inputs (CheckMate-067 prognostic signal), brain MRI when CNS symptoms are present, and an autoimmune-history review before any checkpoint inhibitor. The chapter is explicit that NRAS and KIT testing are useful for sequencing but not for routing the first-line IO-versus-targeted decision.

Linked entities

Section sources

• SRC-NCCN-MELANOMA-2025 NCCN Cutaneous Melanoma
• SRC-ESMO-MELANOMA-2024 ESMO Cutaneous Melanoma

First-line IO decision logic

OpenOnco keeps nivolumab + ipilimumab as the canonical first-line IO backbone for fit metastatic melanoma patients without absolute contraindications to dual checkpoint inhibition (CheckMate-067). Single-agent pembrolizumab is the canonical default when the patient cannot tolerate the higher autoimmune risk of dual IO (KEYNOTE-006). Relatlimab + nivolumab (anti-LAG-3 + anti-PD-1) is an additional dual-checkpoint option with a different toxicity profile (RELATIVITY-047). The chapter expects the learner to weigh autoimmune history, organ function, and disease tempo against these three IO options before reaching for targeted therapy.

Linked entities

Section sources

• SRC-CHECKMATE-067-LARKIN-2019 Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma
• SRC-KEYNOTE-006-ROBERT-2015 Pembrolizumab versus Ipilimumab in Advanced Melanoma
• SRC-RELATIVITY-047-TAWBI-2022 Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma

When BRAF-targeted therapy moves to first line

BRAF V600E/K-mutant disease pulls dabrafenib + trametinib or encorafenib + binimetinib into the canonical first-line conversation. The OpenOnco model uses targeted therapy first when rapid response is needed (high tumor burden, symptomatic disease, organ-threatening progression) or when IO is contraindicated (active uncontrolled autoimmune disease, recent organ transplantation, severe baseline immune dysfunction). The default in BRAF-mutant disease without these features remains IO first because durable IO responses outperform the duration of targeted-therapy benefit in most prospective evidence.

Linked entities

Section sources

• SRC-COMBI-D-LONG-2014 Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma
• SRC-COMBI-V-ROBERT-2015 Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib
• SRC-COLUMBUS-DUMMETT-2018 Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial

Common traps

Do not treat regimen selection as the whole task. A history of moderate or severe autoimmune disease is a parallel obligation that may move dual IO down the list even in a fit BRAF-wild-type patient. Active brain metastases are a treatment-planning emergency that pulls upfront stereotactic radiosurgery and dexamethasone planning into the conversation; the systemic IO choice may not change but the safety plan does. Hepatitis B/C reactivation risk requires baseline screening before any checkpoint inhibitor. None of these alter the canonical first-line call by themselves but missing them changes the trajectory of care.

Linked entities

Section sources

• SRC-NCCN-MELANOMA-2025 NCCN Cutaneous Melanoma
• SRC-ESMO-MELANOMA-2024 ESMO Cutaneous Melanoma

Worked synthetic cases

• patient_melanoma_braf_v600_nivo_ipi BRAF V600 mutant melanoma: IO chosen as 1L - IO-first reasoning in BRAF-mutant disease examples/patient_melanoma_braf_v600_nivo_ipi.json
• patient_melanoma_braf_v600_dab_tram BRAF V600 mutant melanoma: targeted therapy as 1L - rapid-response targeted route examples/patient_melanoma_braf_v600_dab_tram.json
• patient_melanoma_braf_wt_pembro_mono BRAF wild-type melanoma: single-agent pembrolizumab - single-agent IO selection, autoimmune-history weighting examples/patient_melanoma_braf_wt_pembro_mono.json