Wolchok et al.1 and Hamid et al.2 report in the Journal the results of phase 1 clinical trials showing that the combination of PD-1 and CTLA-4 antibody blockers leads to improved treatment outcomes in patients with melanoma, without an escalation of toxic effects. The results of these trials are striking and complementary. In the trial by Hamid et al., a PD-1 monoclonal antibody was administered in patients who had had a relapse after CTLA-4 antibody monotherapy (ipilimumab); the authors found that durable and clinically significant responses were as common and robust as were those observed in patients who had not received ipilimumab therapy previously. Thus, progression of melanoma after anti-CTLA-4 therapy does not preclude a response to anti-PD-1 therapy. Wolchok et al., who in part report similar data for sequential CTLA-4 and PD-1 antibody therapy, also tested concomitant administration and found that at the maximum tolerated dose, 53% of patients with advanced, treatment-resistant melanoma had objective tumor responses, with tumor regression of at least 80% in every patient who had a response. Surprisingly and importantly, the use of ipilimumab and either one of two PD-1 monoclonal antibodies — whether the PD-1 and CTLA-4 antibodies were given sequentially or together — resulted in a rate and severity of adverse events that were no higher than those observed with the individual drugs alone…
