LAUSR

Programmed death-1 (PD-1) pathway inhibitors have revolutionized the treatment of locally advanced and advanced non-small cell lung cancer (NSCLC). Response to these agents can be durable, but most patients will go on to develop resistance after initial tumor regression or prolonged disease stability. In patients with ‘acquired oligo-resistance,’ in whom progression is limited to two or less disease sites, local therapy may be an effective management strategy. For those experiencing systemic progression, immunotherapy based combinations are currently under investigation. Translational work has uncovered neoantigen loss and antigen processing/presentation defects as mediators of resistance to PD-1 axis inhibitors NSCLC. In other tumor types, defects in IFN- γ signaling, upregulation of alternative immune checkpoint pathways, and various tumor genomic or epigenetic changes have been implicated. In this review, we propose clinical criteria, highlight emerging management strategies, and discuss mechanistic insights into acquired resistance to PD-1 axis inhibitors in NSCLC.