PD-1/PD-L1 Blockade Therapy in Advanced Non-Small-Cell Lung Cancer: Current Status and Future Directions

The use of immune checkpoint inhibitors (ICIs) has become one of the most promising approaches in the field of cancer therapy. Unlike the current therapies that target tumor cells, such as chemotherapy, radiotherapy, or targeted therapy, ICIs directly restore the exhausted host antitumor immune responses mediated by the tumors. Among multiple immune modulators identified, the programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) axis leading to the exhaustion of T-cell immunity in chronic infections and tumors has been widely investigated. Therefore, blocking antibodies targeting PD-1 or PD-L1 have been developed and approved for the treatment of various advanced cancers, including non-small-cell lung cancer (NSCLC), making them the most successful ICIs. Compared with chemotherapy or radiotherapy, PD-1/PD-L1 blockade therapy significantly improves the durable response rate and prolongs long-term survival with limited adverse effects in both monotherapy and combination therapy for advanced NSCLC. However, extensive challenges exist for further clinical applications, such as a small fraction of benefit population, primary and acquired resistance, the lack of predictive and prognostic biomarkers, and treatment-related adverse effects. In this article, we summarize the latest clinical applications of PD-1/PD-L1 blockade therapy in advanced NSCLC worldwide, as well as in China, and discuss the bottlenecks related to the use of this therapy in clinical practice. An exploration of the underlying mechanism of PD-1/PD-L1 blockade therapy and biomarker identification will maximize the application of ICIs in advanced NSCLC and facilitate bedside-to-bench studies in cancer immunotherapy as well. IMPLICATIONS FOR PRACTICE: Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) display apparent benefits for the treatment of advanced non-small-cell lung cancer (NSCLC). However, the clinical applications of these therapies are challenged by the limited benefit population with additional high economic burden and adverse events. This review discusses the bottlenecks of ICI therapy in clinical practice and provides appropriate guidance in the development of predictive biomarkers, the establishment of the criteria for combining PD-1/PD-L1 blockade therapy with the existing therapies, and the management of adverse events observed both in monotherapy and combination therapy, which will help maximize the applications of ICIs in advanced NSCLC.