Immune Checkpoint Inhibitors vs. Targeted Therapy in BRAF‐Mutated Melanoma: A Systematic Review

Background Skin cancer is a common malignancy. Although melanoma represents only 3% of cases, it causes 65% skin cancer–related deaths, with incidence rising worldwide. Melanoma’s severity stems from alterations in the MAPK pathway, triggered by BRAF mutations in 50% of melanoma cases. Immune checkpoint inhibitors (CPIs) and targeted therapy (TT) are therapeutic advancements that enhance survival outcomes in melanoma. However, the relative benefits of these therapies as first‐line treatment remain unclear. This systematic review assesses patient outcomes with CPI versus TT to determine optimal first‐line therapy for BRAF‐mutated melanoma. Methods The search consisted of four databases (Cochrane, PubMed, Scopus, and WOS) from Inception to May 2025, following the PRISMA guideline. STROBE and CARE tools assessed reporting quality for observational studies and case reports, respectively. Therapies were categorized as CPI (anti‐CTLA‐4: e.g., ipilimumab; anti‐PD‐1: e.g., pembrolizumab; dual inhibition anti‐CTLA‐4/anti‐PD‐1 immunotherapy: e.g., ipilimumab/nivolumab) or TT (BRAFi monotherapy: e.g., vemurafenib; BRAFi/MEKi combination: e.g., dabrafenib/trametinib). This categorization allowed clinical practice and guideline‐aligned comparative analysis. Results Thirteen studies, with over 5150 patients, directly compared CPI (anti‐CTLA‐4, anti‐PD‐1, or both) and TT (BRAFi, MEKi, or both). While TT demonstrated superior ORR, CPI, especially anti‐PD‐1 or dual immune blockade immunotherapy, consistently outperformed TT in long‐term metrics such as OS. Weighted quantitative analysis demonstrates that CPI therapy is associated with 47%, 53%, and 48% reduction in 1‐year, 2‐year, and overall mortality risk compared to TT. CPI is also associated with less frequent but more severe adverse events, specifically irAEs (e.g., hepatitis and colitis). Conclusions Immune checkpoint inhibitors and TT exhibit different advantages in the treatment of BRAF‐mutated melanoma. Current evidence identifies immune checkpoint inhibitors as the preferred treatment for BRAF‐mutated melanoma due to a significantly increased overall survival and more sustainable responses compared to TT, although TT remains favored in immunocompromised populations as well as those with poor prognostic factors requiring rapid response.