For a 64‑year‑old patient with completely resected stage III cutaneous melanoma harboring a BRAF V600E/K mutation, what are the recommended first‑line adjuvant therapies and how should I choose between pembrolizumab (Keytruda) and dabrafenib (Tafinlar) + trametinib (Mekinist)?

Adjuvant Therapy for BRAF V600E/K-Positive Resected Stage III Melanoma

For your 64-year-old patient with completely resected stage III BRAF V600E/K-positive melanoma, I recommend pembrolizumab 200 mg IV every 3 weeks (or 400 mg every 6 weeks) for 52 weeks as first-line adjuvant therapy, prioritizing its superior tolerability profile with only 14.7% grade 3-4 adverse events and 10% treatment discontinuation rate compared to dabrafenib plus trametinib's 41% grade 3-4 toxicity and 26% discontinuation rate, while delivering equivalent survival benefit. 1

Three Equally Valid First-Line Options

ASCO guidelines establish three evidence-based adjuvant regimens for BRAF V600E/K-positive stage III melanoma, all with strong recommendation strength and high-quality evidence: 1

• Pembrolizumab 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks for 52 weeks 1, 2
• Nivolumab 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks for 52 weeks 1, 2
• Dabrafenib 150 mg PO twice daily + trametinib 2 mg PO once daily for 52 weeks 1

Efficacy: Comparable Survival Outcomes

All three regimens demonstrate robust efficacy in BRAF-mutant disease: 1

• Pembrolizumab (KEYNOTE-054): RFS hazard ratio 0.57, delivering approximately 14% absolute improvement in 3-year RFS across all BRAF subgroups 2
• Nivolumab (CheckMate 238): RFS hazard ratio 0.66 versus ipilimumab, with consistent benefit in BRAF-mutant cohorts 1, 2
• Dabrafenib + trametinib (COMBI-AD): RFS hazard ratio 0.47 (approximately 19% absolute 3-year RFS gain) AND overall survival hazard ratio 0.57, providing preliminary OS benefit evidence 1

The COMBI-AD trial is the only adjuvant study demonstrating statistically significant OS improvement (HR 0.57, P=0.0006), though this does not establish superiority over immunotherapy in the absence of head-to-head comparisons. 1

Toxicity: The Critical Differentiator

The toxicity profiles diverge dramatically and should drive your decision: 1

Regimen	Grade 3-4 AEs	Treatment Discontinuation
Pembrolizumab	14.7%	10%
Nivolumab	14.4%	8%
Dabrafenib + trametinib	41%	26%

• Anti-PD-1 toxicities include immune-related colitis, hepatitis, pneumonitis, endocrinopathies, and dermatologic events—some may persist after discontinuation but occur less frequently 1, 2
• Targeted therapy toxicities include pyrexia (often severe), skin rash, hepatic dysfunction, and cardiac toxicity—all resolve rapidly upon discontinuation but occur in 41% of patients at grade 3-4 severity 1, 3

Clinical Decision Algorithm

Choose pembrolizumab or nivolumab when: 1

• The patient prioritizes lower treatment-related toxicity (14.4-14.7% vs 41% grade 3-4 events)
• The patient values lower discontinuation risk (8-10% vs 26%)
• The patient desires potential for durable responses extending beyond treatment completion
• The patient has cardiovascular comorbidities (targeted therapy carries cardiac toxicity risk)

Choose dabrafenib + trametinib when: 1

• The patient has absolute contraindications to immunotherapy (active autoimmune disease requiring systemic immunosuppression)
• The patient cannot tolerate immunotherapy due to prior severe immune-related adverse events
• The patient has rapidly progressive disease requiring faster disease control (targeted therapy provides more rapid initial response in first 6-12 months) 4

Critical Implementation Details

• Initiate therapy within 13 weeks post-surgery—this was the maximum interval allowed in pivotal trials 4
• Complete surgical resection with negative margins is mandatory before starting any adjuvant therapy 4
• BRAF testing must be performed in accredited laboratories and specifically identify V600E and V600K mutations—other BRAF variants lack proven benefit with targeted therapy 2, 4

Common Pitfalls to Avoid

• Do not use vemurafenib monotherapy—it failed to meet primary endpoints in the BRIM8 trial and lacks FDA approval for adjuvant use 1
• Do not use ipilimumab monotherapy—CheckMate 238 demonstrated nivolumab superiority with lower toxicity 1
• Do not use dabrafenib + trametinib for non-V600E/K BRAF mutations—no efficacy data exist for other variants 1
• Do not delay BRAF testing—results must be available before finalizing adjuvant therapy selection 2

Special Consideration: Sentinel Node Metastases <1 mm

If your patient had microscopic sentinel node metastases <1 mm in diameter, note that such patients were excluded from KEYNOTE-054, CheckMate 238, and COMBI-AD trials. 1 These patients typically have excellent prognosis (5-year survival >80%) and observation may be appropriate after thorough risk-benefit discussion. 4

Management of Future Recurrence

• Patients who relapse after adjuvant targeted therapy respond excellently to subsequent anti-PD-1 therapy, with high response rates documented in real-world cohorts 4, 5
• Oligometastatic recurrence (1-3 lesions) warrants consideration for surgical resection or stereotactic radiation combined with systemic therapy 4

Patient-Reported Outcomes

The COMBI-AD trial demonstrated that dabrafenib + trametinib did not negatively impact quality-of-life scores during treatment, with no clinically meaningful differences in EQ-5D-3L visual analogue scale or utility scores between active treatment and placebo groups throughout the 12-month treatment phase and long-term follow-up. 3 However, this must be weighed against the substantially higher objective toxicity burden (41% grade 3-4 events). 1