EGFRC797S mutation and fourth-generation EGFR tyrosine kinase inhibitors

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 1–2 years 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.