Chapter 25 - EGFRC797S mutation and fourth-generation EGFR tyrosine kinase inhibitors

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are developed and commonly applied to patients with EGFR-mutations. EGFR-TKIs bring significant benefits and improve the overall survival of nonsmall cell lung cancer (NSCLC) patients, harboring EGFR mutations. First-generation or second-generation EGFR-TKIs are effective for NSCLC patients with 19Del and L858R mutations. But almost all cases, disease recurrence is observed after 1–2years of treatment due to an acquired resistance to first- and second-generation EGFR-TKIs. The most common acquired resistance mechanism is the EGFR T790M mutation in Exon 20. The FDA approved Osimertinib, a third-generation EGFR-TKI, to the market for NSCLC patients with T790M mutation. Other third-generation selective EGFRTKIs have been demonstrated to tackle T790M mutation. An additionally acquired resistance C797S mutation is observed that diminished the activity of third-generation EGFR-TKI. The development of new EGFR-TKIs remains an unmet challenge to overcome the C797S mutation. The latest development of fourth-generation EGFR-TKIs against C97S mutation is discussed in this chapter. Different strategies for tackling C797 mutation by EGFR-TKIs, the results of in vitro and in vivo studies, are highlighted here.