[Treatment of metastatic melanoma: update 2025]

Immune checkpoint inhibition and targeted therapy with BRAF/MEK inhibition for BRAF-mutated melanoma have significantly improved progression-free and overall survival in patients with metastatic melanoma. Current research focuses on novel treatment strategies for PD-1 resistance, neoadjuvant approaches, and cellular therapies. 10-year follow-up data of randomized clinical trials show that both combined CTLA-4 and PD-1 immune checkpoint inhibition and PD-1 immune checkpoint inhibition alone can achieve long-term survival in metastatic melanoma. Potential surrogate markers of long-term response include a progression-free survival at 3 years after start of treatment and a reduction in tumour burden of at least 80%. The management of PD-1 resistance remains a challenge. Advances in molecular pathology have led to the identification of new therapeutic targets. Several cellular therapies are currently being evaluated in clinical trials as alternatives for melanoma patients refractory to immune checkpoint inhibition or targeted BRAF/MEK inhibition. In BRAF-mutant melanoma, combined BRAF/MEK inhibition is an alternative to immune checkpoint inhibition. Real-world data and clinical trial results on treatment sequencing suggest that immune checkpoint inhibition may improve survival in the first line setting, particularly in the absence of prior adjuvant systemic therapy. Adjuvant treatment leads to improved progression-free survival in melanoma patients while overall survival data are still pending. Neoadjuvant treatment seems to be a promising alternative to conventional adjuvant therapy for specific subgroups of melanoma patients. Participation in clinical trials offers patients the best opportunity to benefit from the latest treatment options.