Merkel cell carcinoma immunotherapy: key questions in the era of immune checkpoint blockade

Merkel cell carcinoma (MCC) exemplifies the paradigm of immunogenic tumors that nonetheless develop sophisticated immune evasion mechanisms. This is in line with the observation that MCC exhibits remarkable susceptibility to immune checkpoint inhibitors (ICIs), with responses in approximately half of patients with advanced disease in the first-line setting. However, 40-50% of patients show primary ICI resistance, while 20-30% of patients develop acquired ICI resistance on initial disease control. Still, the advent of ICI therapy represents a revolutionary rather than evolutionary advance in MCC management, fundamentally transforming outcomes from the dismal prognosis associated with conventional chemotherapy to durable responses extending substantially beyond 2 years. Still, important questions remain: (1) Is programmed cell death protein-1 or programmed death-ligand 1 inhibition more effective? (2) How long should ICI treatment continue? (3) What is the best choice of salvage therapy for patients with primary or acquired ICI resistance? (4) Which combination regimens can increase the share of patients benefiting from ICI? (5) Which patient/tumor characteristics predict response and its duration? Finally, (6) which timing of ICI therapy, that is, the neoadjuvant, adjuvant or therapeutic setting, offers the optimal overall outcomes for patients with MCC? A number of recent studies provide initial, but unfortunately not yet definitive answers.