Immune checkpoint inhibitors, particularly anti-PD-1-based
immune checkpoint inhibitors, have dramatically improved outcomes for patients with advanced
melanoma and are currently deemed a standard of care.
Ipilimumab/
nivolumab is the first combination of
immune checkpoint inhibitors to improve progression-free survival and overall survival in the first-line setting, with durable responses and the longest median overall survival, 72.1 months, of any
drug therapy approved for advanced
melanoma. However, its use is limited by the high rate of severe (grade 3-4) treatment-related adverse events. More recently, the novel
immune checkpoint inhibitor combination of
nivolumab/
relatlimab (anti-PD-1/anti-LAG3) showed improved progression-free survival compared with
nivolumab alone in the first-line setting and was well tolerated; thus, it is likely this combination will be added to the armamentarium as a first-line treatment for advanced
melanoma. These changes in the treatment landscape have several treatment implications for decision-making. The choice of first-line systemic
drug therapy, and the decision between
immune checkpoint inhibitor monotherapy or combination
therapy, requires a comprehensive assessment of disease-related factors and patient characteristics. Despite this striking progress, many patients' disease still progresses. Several new agents and therapeutic approaches are under investigation in clinical trials. Intralesional treatments hold promise for accessible
metastases, although their broad application in the clinic will be limited. Prognostic and predictive
biomarkers, as well as strategies to reduce treatment-related toxicities and overcome resistance, are required and are now the focus of clinical and translational research.