Immune checkpoint inhibitors in melanoma define a new era in immunotherapy aiming for cure

Breaking tolerance represents a major paradigm shift that marks the beginning of a new era in immunotherapy. The impact of the first checkpoint inhibitors, i.e., anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) and anti-PD1/anti-PDL1 (programmed death-1 receptor and its ligand PD-L1) is unprecedented. In advanced melanoma, response rates are about 12 % for anti-CTLA-4 and about 40 % for anti-PD1. Most importantly, these responses are remarkably durable and have a clear impact on survival. In melanoma anti-CTLA4 (ipilimumab) was approved in 2011 and the anti-PD1 molecules pembrolimumab and nivolumab in 2014. The combination of ipilimumab and nivolumab has further significantly improved response rates and impact of progression-free survival (PFS) in stage IV disease. Various combinations with checkpoint inhibitors with agonists, cytokines, and vaccines will be explored to improve results in the coming years. Ipilimumab has already been evaluated in the adjuvant setting (EORTC 18071) and was 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) is scheduled to start in the first quarter of 2015 as is the case for nivolumab in patients with resected stage IIIB/C-IV disease.