A 58-year-old woman from Delhi is diagnosed with metastatic melanoma (Stage IV) with multiple lung and liver metastases. BRAF mutation testing is positive. She has good performance status (ECOG 0). What is the drug of choice for first-line systemic therapy in this patient?

Explanation

## First-Line Therapy for BRAF-Mutant Metastatic Melanoma ### Targeted Therapy as Preferred Option **Key Point:** In BRAF-mutant metastatic melanoma, targeted therapy with BRAF + MEK inhibitors (dabrafenib + trametinib) is the preferred first-line approach, offering rapid response and superior progression-free survival compared to checkpoint inhibitors alone. ### Mechanism of Action - **Dabrafenib:** Selective BRAF V600E/K inhibitor - **Trametinib:** MEK1/2 inhibitor (prevents resistance via feedback activation of MAPK pathway) - **Rationale for combination:** Dual blockade prevents emergence of resistance mutations ### Evidence and Efficacy | Trial | Agents | Primary Endpoint | Outcome | Notes | |-------|--------|------------------|---------|-------| | **COMBI-v** | Dabrafenib + Trametinib vs. Vemurafenib | Overall Survival | Superior OS with combination | Landmark trial | | **COMBI-d** | Dabrafenib + Trametinib vs. Dabrafenib alone | PFS | Superior PFS with combination | Establishes MEK inhibitor benefit | | **KEYNOTE-006** | Pembrolizumab vs. Ipilimumab | OS | Pembrolizumab superior | Checkpoint inhibitor comparison | **High-Yield:** BRAF-mutant patients benefit more from targeted therapy (faster response, median PFS ~11 months) than checkpoint inhibitors alone (median PFS ~5-6 months). Checkpoint inhibitors are reserved for BRAF wild-type or as second-line after targeted therapy resistance. ### Dosing Regimen - **Dabrafenib:** 150 mg orally twice daily - **Trametinib:** 2 mg orally once daily - Continue until progression or unacceptable toxicity ### Toxicity Profile Common adverse events: - Pyrexia (40–50%), rash, fatigue - Hyperglycemia, hepatotoxicity - Retinal vein occlusion (rare but serious) - Monitoring: LFTs, glucose, ophthalmology baseline ### Clinical Pearl Sequencing strategy: BRAF-mutant patients typically receive targeted therapy first-line, then transition to checkpoint inhibitors (nivolumab ± ipilimumab) at progression. This sequential approach maximizes benefit from both drug classes. **Warning:** Do NOT use checkpoint inhibitors as first-line monotherapy in BRAF-mutant patients — they are less effective than targeted therapy and delay optimal treatment. [cite:NCCN Melanoma Guidelines 2023; COMBI-v Trial]