Treatment Strategies for Non-Small Cell Lung Cancer Harboring Common and Uncommon EGFR Mutations: Drug Sensitivity Based on Exon Classification, and Structure-Function Analysis

SIMPLE SUMMARY: The advent of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) has led to a dramatic improvement in the prognosis of patients having advanced EGFR-mutant non-small cell lung cancer (NSCLC). NSCLCs harboring “common” EGFR mutations, including exon 19 deletions and exon 21 L858R mutation substitutions, are sensitive to EGFR-TKIs. However, NSCLCs harboring “uncommon” EGFR mutations have poor sensitivity to EGFR-TKIs, and patients harboring uncommon mutations often experience poor outcomes. Here, we review the current EGFR-TKI therapy and the development of treatment strategies, including combined treatment and the exploration of new drugs. In addition, we discuss EGFR-TKI sensitivity based on structure-function analysis. ABSTRACT: The identification of epidermal growth factor receptor (EGFR) mutations and development of EGFR tyrosine kinase inhibitors (EGFR-TKIs) have dramatically improved the prognosis of advanced EGFR-mutated non-small cell lung cancer (NSCLC), setting a landmark in precision oncology. Exon 19 deletions and exon 21 L858R substitutions, which comprise the majority of common EGFR mutations, are predictors of good sensitivity to EGFR-TKIs. However, not all cancers harboring EGFR mutations are sensitive to EGFR-TKIs. Most patients harboring uncommon EGFR mutations demonstrate a poorer clinical response than those harboring common EGFR mutations. For example, cancers harboring exon 20 insertions, which represent approximately 4–12% of EGFR mutations, are generally insensitive to first- and second-generation EGFR-TKIs. Although understanding the biology of uncommon EGFR mutations is essential for developing treatment strategies, there is little clinical data because of their rarity. Moreover, clarifying the acquired resistance of EGFR-mutated NSCLC may lead to more precise treatments. Sequencing and structure-based analyses of EGFRmutated NSCLC have revealed resistance mechanisms and drug sensitivity. In this review, we discuss the strategies in development for treating NSCLC harboring common and uncommon EGFR mutations. We will also focus on EGFR-TKI sensitivity in patients harboring EGFR mutations based on the structural features.