Hope and Challenges: Immunotherapy in EGFR-Mutant NSCLC Patients

EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. Sadly, remission is transient, and no approved effective treatment options are available for EGFR-TKI-advanced EGFR-mutant NSCLCs. Although immunotherapy with immune checkpoint inhibitors (ICIs) induces sustained cancer remission in a subset of NSCLCs, ICI therapy exhibits limited activity in most EGFR-mutant NSCLCs. Mechanistically, the strong oncogenic EGFR signaling in EGFR-mutant NSCLCs contributes to a non-inflamed tumor immune microenvironment (TIME), characterized by a limited number of CD8⁺ T cell infiltration, a high number of regulatory CD4⁺ T cells, and an increased number of inactivated infiltrated T cells. Additionally, EGFR-mutant NSCLC patients are generally non-smokers with low levels of PD-L1 expression and tumor mutation burden. Promisingly, a small population of EGFR-mutant NSCLCs still durably respond to ICI therapy. The hope of ICI therapy from pre-clinical studies and clinical trials is reviewed in EGFR-mutant NSCLCs. The challenges of application ICI therapy in EGFR-mutant NSCLCs are also reviewed.