In a 64-year-old patient with resected stage III cutaneous melanoma, should we perform BRAF (B‑Raf proto‑oncogene) V600 mutation testing, and how would a positive versus negative result influence adjuvant therapy decisions such as continuing pembrolizumab versus switching to dabrafenib + trametinib?

BRAF Mutation Testing and Its Significance in Stage III Melanoma

Mandatory BRAF Testing Requirement

BRAF V600 mutation testing is mandatory for all patients with resected stage III melanoma and must be performed before finalizing adjuvant therapy decisions. 1

The testing determines eligibility for targeted therapy with dabrafenib plus trametinib, which represents an equally effective alternative to immunotherapy for BRAF-mutant disease. 1, 2

Testing Specifications

• Test for BRAF V600E and V600K mutations specifically, as these are the actionable mutations with FDA-approved targeted therapies. 1
• Testing must be performed in accredited (certified) institutes with careful quality controls, as drivers are actionable and directly impact clinical decisions. 1
• If BRAF is wild-type at the V600 locus, sequencing for other minor BRAF mutations (class II and III) plus NRAS and c-kit mutations is recommended to confirm wild-type status and identify patients for future clinical trials. 1

Treatment Algorithm Based on BRAF Status

For BRAF V600E/K Mutation-Positive Disease:

Both anti-PD-1 immunotherapy (pembrolizumab or nivolumab) and dabrafenib plus trametinib combination are equally valid first-line adjuvant options. 1, 2

• Pembrolizumab 200 mg IV every 3 weeks or 400 mg IV every 6 weeks for 52 weeks (RFS HR 0.57,3-year RFS gain 14.4%). 1
• Nivolumab 240 mg IV every 2 weeks or 480 mg IV every 4 weeks for 52 weeks (RFS HR 0.66 vs ipilimumab). 1, 2
• Dabrafenib 150 mg PO twice daily plus trametinib 2 mg PO once daily for 52 weeks (RFS HR 0.47,3-year RFS gain 19%, OS HR 0.57). 1, 3

Critical Decision Points Between Immunotherapy vs Targeted Therapy:

Choose dabrafenib plus trametinib when:

• Patient cannot tolerate or has contraindications to immunotherapy. 1
• Rapid disease control is needed (targeted therapy acts faster than immunotherapy). 4
• Patient preference after informed discussion of toxicity profiles.

Choose anti-PD-1 immunotherapy when:

• Lower treatment discontinuation rate is desired (8-10% for immunotherapy vs 26% for targeted therapy). 1
• Lower grade 3-4 toxicity is preferred (14.4-14.7% for immunotherapy vs 41% for targeted therapy). 1
• Potential for durable response after treatment completion is prioritized.

For BRAF Wild-Type Disease:

Anti-PD-1 immunotherapy is the only evidence-based adjuvant option. 2

• Pembrolizumab or nivolumab for 52 weeks using the same dosing schedules as above. 2
• Dabrafenib plus trametinib is NOT an option for BRAF wild-type patients. 1

Prognostic Significance of BRAF Mutations

• BRAF V600 mutations are present in approximately 40% of stage III melanomas. 5
• BRAF-mutant status is independently associated with worse overall survival (median OS 1.4 years vs 2.8 years for wild-type, HR 1.9). 5
• This worse prognosis underscores the importance of effective adjuvant therapy in BRAF-mutant patients. 5

Efficacy Data Supporting Treatment Decisions

COMBI-AD Trial (Dabrafenib + Trametinib):

• 3-year RFS: 58% vs 39% placebo (HR 0.47). 3
• 3-year OS: 86% vs 77% placebo (HR 0.57, though did not cross prespecified interim boundary). 3
• Reduced distant metastasis rate: 25% vs 35% placebo. 1
• Quality of life was maintained during treatment with no clinically meaningful deterioration. 6

KEYNOTE-054 Trial (Pembrolizumab):

• RFS HR 0.57 across all BRAF subgroups (mutant and wild-type showed similar benefit). 1
• Distant metastasis as first recurrence at 18 months: 17% vs 30% placebo. 1

CheckMate 238 Trial (Nivolumab):

• RFS HR 0.66 vs high-dose ipilimumab, with consistent benefit across BRAF-mutant and wild-type subgroups. 1

Common Pitfalls and How to Avoid Them

• Do not delay BRAF testing until after starting immunotherapy – testing must be completed before finalizing adjuvant therapy selection. 1
• Do not use vemurafenib monotherapy – it is not FDA-approved for adjuvant therapy and inferior to combination therapy. 1
• Do not assume all BRAF mutations are actionable – only V600E and V600K mutations have proven benefit with dabrafenib plus trametinib. 1
• Do not use dabrafenib plus trametinib for resected stage IV disease – this was excluded from COMBI-AD, though nivolumab has evidence in this setting. 1

Monitoring During Adjuvant Therapy

For Targeted Therapy (Dabrafenib + Trametinib):

• Monitor for pyrexia (most common adverse event), skin rash, liver dysfunction, and cardiac toxicity. 2
• Grade 3-4 adverse events occur in 41% of patients. 1

For Immunotherapy:

• Monitor for immune-related adverse events including colitis, hepatitis, pneumonitis, endocrinopathies, and dermatologic toxicities. 2
• Grade 3-4 adverse events occur in 14.4-14.7% of patients. 1

Emerging Role of ctDNA Monitoring

• Baseline ctDNA detection post-resection identifies patients at markedly higher risk of recurrence (RFS HR 2.91-2.98 for ctDNA-positive patients). 7
• Patients with persistently positive or molecular relapse ctDNA have median RFS of only 5-8 months despite adjuvant therapy. 7
• ctDNA monitoring may guide future therapeutic interventions, though not yet standard of care. 7

Treatment Initiation Timing

• Adjuvant therapy should be initiated within 13 weeks post-surgery with complete surgical resection and negative margins mandatory before starting. 2