Facts and Hopes: Toward the Next Quantum Leap in Melanoma.

Outcomes from advanced melanoma, the deadliest of the skin cancers arising from melanocytes and capable of widely metastasizing, have greatly improved, with death rates decreasing for patients with American Joint Committee on Cancer stage 4 melanoma by 3% to 5% annually over the past 10 years. This improvement is a result of advances in both targeted therapy and immunotherapy. BRAF and MEK inhibitors for advanced melanoma have led the way for targeted cancer strategies and first-in-class approvals for immune checkpoint blockers targeting CTLA4, PD-1, and LAG3; T-cell engager therapy targeting the antigen gp100; and tumor-infiltrating lymphocyte therapy. All of these have contributed to enhanced outcomes, including long-term durable responses in up to half of patients with advanced disease. In addition, adjuvant and neoadjuvant approaches are reducing the risk of relapse in patients with stage II and III disease. Because of its immunogenicity and defined targetable mutations, melanoma drug development has led the way for novel approaches in cancer research. Yet additional approaches are needed for patients with recurrent or nonresponsive disease or rare subtypes, including mucosal, acral, and uveal melanomas. Progress in modified T cells, including T-cell receptor, chimeric antigen receptor T-cell (CAR-T), and CRISPR gene editing strategies, holds promise for future therapeutics. Continued understanding of the molecular and immune tumor microenvironment and heterogeneity, as well as understanding the microbiome and numerous diverse approaches to topics ranging from prevention to mechanisms of treatment resistance and novel therapeutic approaches, will optimize opportunities to further decrease melanoma mortality.