EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for non-small cell lung cancer (NSCLC) patients harboring sensitive mutations. Sadly, remission is transient, and no approved effective treatment options are available for EGFR-TKI-advanced -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 -mutant NSCLCs. Mechanistically, the strong oncogenic EGFR signaling in -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, -mutant NSCLC patients are generally non-smokers with low levels of PD-L1 expression and tumor mutation burden. Promisingly, a small population of -mutant NSCLCs still durably respond to ICI therapy. The hope of ICI therapy from pre-clinical studies and clinical trials is reviewed in -mutant NSCLCs. The challenges of application ICI therapy in -mutant NSCLCs are also reviewed.