Emerging therapeutic strategies for enhancing sensitivity and countering resistance to programmed cell death protein 1 or programmed death‐ligand 1 inhibitors in non–small cell lung cancer

Abstract

AbstractThe availability of agents targeting the programmed cell death protein 1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) immune checkpoint has transformed treatment of advanced and/or metastatic non–small cell lung cancer (NSCLC). However, a substantial proportion of patients treated with these agents do not respond or experience only a brief period of clinical benefit. Even among those whose disease responds, many subsequently experience disease progression. Consequently, novel approaches are needed that enhance antitumor immunity and counter resistance to PD‐(L)1 inhibitors, thereby improving and/or prolonging responses and patient outcomes, in both PD‐(L)1 inhibitor‐sensitive and inhibitor‐resistant NSCLC. Mechanisms contributing to sensitivity and/or resistance to PD‐(L)1 inhibitors in NSCLC include upregulation of other immune checkpoints and/or the presence of an immunosuppressive tumor microenvironment, which represent potential targets for new therapies. This review explores novel therapeutic regimens under investigation for enhancing responses to PD‐(L)1 inhibitors and countering resistance, and summarizes the latest clinical evidence in NSCLC.