Over the last decade, the treatment of advanced
non-small cell lung cancer (NSCLC) has undergone rapid changes with innovations in oncogene-directed
therapy and
immune checkpoint inhibitors. In patients with
epidermal growth factor receptor (EGFR) gene mutant (EGFRm) NSCLC, newer-generation
tyrosine kinase inhibitors (TKIs) are providing unparalleled survival benefit and tolerability. Unfortunately, most patients will experience
disease progression and thus an urgent need exists for improved subsequent lines of
therapies. The concurrent revolution in
immune checkpoint inhibitor (ICI)
therapy is providing novel treatment options with improved clinical outcomes in wild-type EGFR (EGFRwt) NSCLC; however, the application of ICI
therapy to advanced EGFRm NSCLC patients is controversial. Early studies demonstrated the inferiority of ICI monotherapy to EGFR TKI
therapy in the first line setting and inferiority to
chemotherapy in the second line setting. Additionally, combination ICI and EGFR TKI
therapies have demonstrated increased toxicities, and EGFR TKI
therapy given after first-line ICI
therapy has been correlated with severe adverse events. Nonetheless, combination
therapies including dual-ICI blockade and ICI,
chemotherapy, and
angiogenesis inhibitor combinations are areas of active study with some intriguing signals in preliminary studies. Here, we review previous and ongoing clinical studies of ICI
therapy in advanced EGFRm NSCLC. We discuss advances in understanding the differences in the
tumor biology and tumor microenvironment (TME) of EGFRm NSCLC
tumors that may lead to novel approaches to enhance ICI efficacy. It is our goal to equip the reader with a knowledge of current
therapies, past and current clinical trials, and active avenues of research that provide the promise of novel approaches and improved outcomes for patients with advanced EGFRm NSCLC.