Comparative effectiveness of different interventions in metastatic melanoma: A network meta-analysis.

294 Background: Multiple therapeutic options are available for metastatic melanoma, including immune checkpoint inhibitors (ICIs) and BRAF/MEK-targeted therapies, yet optimal treatment selection remains unclear. Methods: We conducted a network meta-analysis synthesizing randomized controlled trials examining metastatic melanoma treatment efficacy. Primary outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events. Network meta-analyses estimated hazard ratios and odds ratios with 95% confidence intervals. Results: Combination nivolumab plus ipilimumab achieved five-year OS of 55.7% with 52.2% response rates versus 34.3% OS and 31.6% response with monotherapy. Pembrolizumab monotherapy showed median OS of 32.7 months versus 15.9 months with ipilimumab. Combined BRAF-MEK inhibition significantly improved PFS (HR: 0.58 versus BRAF alone) and OS (HR: 0.67) compared with monotherapy. Triple therapy combining targeted therapy with immunotherapy demonstrated longer PFS than BRAF/MEK alone (HR: 0.76) but with increased adverse events. Immune-related adverse events occurred in 93.2% with combination immunotherapy versus 81.9% with monotherapy. In specialized populations, uveal melanoma patients achieved superior outcomes with dual immunotherapy (12.4% objective response, 16.3-month OS) versus monotherapy (3.4% response, 9.8-month OS). Acral melanoma patients showed worse prognosis (15-month median OS) but demonstrated anti-PD-1 superiority over anti-CTLA-4 (53% versus 34% one-year survival). Conclusions: Combination immunotherapy provides greatest efficacy with higher toxicity; BRAF/MEK inhibitors offer rapid disease control. Immunotherapy is preferred first-line treatment for most patients regardless of BRAF status 7. Optimal outcomes require individualized selection based on mutation status, disease burden, and patient factors.