Precision oncology in advanced melanoma: molecular landscapes and personalized therapy recommendations from the Molecular Tumor Board Freiburg.

Immune checkpoint inhibitors (ICIs) and BRAF/MEK kinase inhibitors have substantially improved survival in advanced melanoma; however, therapeutic resistance and severe toxicities underscore the ongoing need for alternative strategies. Here, we evaluate the clinical utility of multi-omic profiling, biomarker-stratified recommendations, and survival outcomes within a prospective cohort of 98 patients with advanced cutaneous or uveal melanoma evaluated by the Molecular Tumor Board Freiburg (MTB-FR) between 2021 and 2024. Completed profiling revealed at least one potential actionable target beyond classical BRAF V600 mutations in 83.8% of cases. Alterations in NRAS, atypical BRAF variants, CDK4/6 pathway amplifications, and DNA-damage response (DDR) gene mutations most frequently guided board recommendations. Biomarker-stratified therapies were recommended for 68.4% of patients, and personalized immunotherapy combinations for 72.4%. The treatment implementation rate was 33.8% (n = 27), achieving an overall disease control rate (DCR) of 42.9% and an overall response rate (ORR) of 10.7%. These findings demonstrate that comprehensive molecular profiling in a real-world setting uncovers actionable alterations, providing viable subsequent treatment avenues that may optimize outcomes for heavily pretreated melanoma patients beyond established standards of care. Ultimately, prospective, randomized, biomarker-driven trials remain essential to validate whether these individualized diagnostic strategies translate into a reproducible survival benefit.