Immune Checkpoint Inhibitors in Melanoma Provide the Cornerstones for Curative Therapies

Immunotherapy has been revolutionalized by the concept of breaking tolerance. It represents a major paradigm shift that marks the beginning of a new era. The impact of the first checkpoint inhibitors, ie, anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) and anti-PD-1/ anti-PD-L1 (programmed death-1 receptor and its ligand, PD-L1) is unprecedented. In only 5 years advanced melanoma has been transformed from an incurable disease into a curable disease, and we are only at the beginning of discovering its transversal impact throughout solid tumor oncology. In advanced melanoma response rates are about 12% for anti-CTLA-4 and about 40% for anti-PD-1, and are remarkably durable, hence their impact on survival. In melanoma anti-CTLA-4 (ipilimumab) was approved in 2011 and anti-PD-1 (pembrolimumab) in 2014. Another anti-PD-1 antibody (nivolumab) has been recently approved based on phase III trial results in metastatic melanoma without BRAF mutation. Ipilimumab already has been evaluated in the adjuvant setting (European Organization for Research and Treatment of Cancer [EORTC] 18071) and shown to significantly improve recurrence-free survival in stage III patients at high risk of relapse. An adjuvant trial to evaluate pembrolizumab in this population (EORTC 1325) was started in early 2015.