Are all programmed cell death protein 1 inhibitors the same?

Programmed cell death protein 1 (PD-1) inhibitors have revolutionized the treatment of many cancers, seven of which are approved by the US Food and Drug Administration (FDA). No head-to-head phase 3 randomized controlled trials (RCTs) comparing PD-1 inhibitors have been conducted so it remains unknown whether clinically meaningful differences exist between them. Preclinical studies that have directly compared PD-1 inhibitors support a differentiating profile associated with toripalimab compared to pembrolizumab and nivolumab with regard to their PD-1 binding sites, binding orientations, and impact on T cell function. Findings of similar or greater benefit among patients with low/no PD-L1 expression versus high/intermediate PD-L1 expression with toripalimab plus chemotherapy were also observed in advanced nasopharyngeal carcinoma and non-small cell lung cancer for both overall survival and progression-free survival. However, determination of clinically-meaningful differences between PD-1 inhibitors requires sufficiently powered head-to-head RCTs.