The discovery of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI), such as gefitinib and erlotinib, has produced remarkable clinical response in a sub-population of lung cancer patients harboring the sensitizing EGFR mutations (L858R or exon 19 deletion). However, their successful clinical application is significantly hindered by the development of acquired resistance predominantly caused by the secondary EGFR T790M mutation, usually occurring within a year after the initial TKI therapy. Second generation irreversible EGFR TKIs have been developed to bind covalently to Cys-797 of the EGFR kinase binding domain in order to bypass these EGFR T790M mutations. However, these irreversible EGFR TKIs are not sufficiently effective against the resistant cells in vivo at clinically achievable drug concentrations. In order to overcome resistant mutations and also to reduce toxic effects, highly potent third generation EGFR TKIs have been designed against EGFR T790M-bearing cancer while sparing the wild-type receptor. However, acquired resistance to the third generation TKIs has already been reported, which is mediated by the induction of another secondary EGFR C797S mutation and in some instances MET amplification. This chapter summarizes the current research in the development of EGFR TKIs, mainly focusing on pharmacological properties, safety and clinical status.
Keywords: Afatinib, Dacomitinib, Drug Resistance, Epidermal Growth Factor Receptor (EGFR), Gefitinib, Molecular-Targeted Therapy, Mutant Selective EGFR Inhibitor, Osimertinib, Non-Small Cell Lung Cancer, Tyrosine Kinase Inhibitor.