EGFR-TKIs have changed the landscape of metastatic NSCLC treatment with a significant improvement in survival of EGFRm patients compared to wild-type EGFR. Even with the newer third generation EGFR TKIs like, Osimertinib, which has proven efficacy against the resistance mutation of EGFRm T790M, progression eventually occurs. There are limited treatment options for patients with metastatic EGFRm NSCLC with other acquired resistance. Therefore, novel therapeutic combination strategies are being researched to overcome potential resistance to EGFR-TKI-targeted therapy. The ICIs targeting the programmed cell death-1 pathway in patients with EGFRm NSCLC were greatly anticipated based on preclinical studies showing increased PD-L1 expression. In clinical settings, this increased expression did not translate into a survival benefit. Treatment with ICIs failed to positively affect EGFRm patients because of multiple reasons: nonsynonymous tumor mutational burden, lower PD-L1 expression in tumors, and cancer cells utilizing alternate immune escape mechanisms. The NCCN guidelines currently do not recommend immunotherapy in patients with metastatic EGFRm NSCLC. Recently, a subgroup analysis in the IMpower150 study provided a signal for overall survival of atezolizumab with bevacizumab plus chemotherapy in EGFRm-TKI progressed patients. Based on these encouraging findings, several combinations of ICIs and EGFR-TKIs are being evaluated in TKI-failed EGFRm patients. These regimens might provide a favorable therapeutic effect by combining higher response rates of TKIs and durable disease control of ICIs. However, further research is warranted to understand the exact underlying molecular and cellular mechanisms responsible for the clinical benefits. In this article, we explored the TKI failed metastatic EGFRm NSCLC, reviewed the available clinical data of ICI use in metastatic EGFRm NSCLC, and discussed its emerging role as a combination regimen in this patient population.
Keywords: Epidermal growth factor receptors; immune checkpoint inhibitors; non-small cell lung cancer; programed cell death-1; programmed cell death ligand-1; tyrosine kinase inhibitors.