The role of EGFR mutations in sensitivity of PD-1/PD-L1 blockade in non-small cell lung cancer.

In non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) is one of the most prevalent driver gene, whose expression and recurrent mutations are closely related to the prognosis of patients. EGFR tyrosine kinase inhibitors (EGFR-TKIs) are ones of the most used among the first line treatment of NSCLC, but their efficacy is significantly reduced due to the inevitable development of acquired EGFR-TKI resistance. Consequently, searching for innovative drugs to overcome this challenge is urgent. Immune checkpoint inhibitors such as antibodies against the programmed cell death protein-1 (PD-1) or its ligand (PD-L1), have exhibited remarkable potential in NSCLC therapy. While the response rates of PD-1/PD-L1 blockade in EGFR-mutated NSCLC patients remain controversial. To gain deeper insights, we first analyzed the different therapeutic effect of PD-1/PD-L1 blockade between EGFR wild-type and mutated NSCLC patients. Meanwhile, the factors and the mechanisms that affect therapeutic effect of PD-1/PD-L1 blockade were summarized, including PD-1/PD-L1 expression levels, the tumor microenvironment (TME), and the adoption of combination therapy strategies. Furthermore, we comprehensively evaluated the combinatorial therapeutic effect with established synergistic potential within these factors. Moreover, we further explored the potential of PD-1/PD-L1 as a predictive biomarker for EGFR mutations by conducting a systematic and multidimensional analysis, aiming to refine therapeutic decision-making and facilitate personalized treatment strategies for EGFR-mutated NSCLC. Additionally, we also discussed the novel strategies that could alleviate the EGFR-TKIs resistance in NSCLC base on PD-1/PD-L1 immune inhibitors, shedding light on challenges facing future research.