CTLA4 and metastatic melanoma: As a first-line treatment in metastatic melanoma, anti-CTLA-4 and anti-PD-1 have improved the OS rate of many patients [35]; however, the majority of patients treated with monotherapy are non-responsive [36], and combinations of anti-PD-1 with anti-CTLA-4 lead to grade III–V adverse events [37].