title: Update on recent preclinical and clinical studies of T790M mutant-specific irreversible epidermal growth factor receptor tyrosine kinase inhibitors.
abstract: The first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors (1/2G EGFR-TKIs) gefitinib, erlotinib, and afatinib have all been approved as standard first-line treatments for advanced EGFR mutation-positive non-small cell lung cancer. The third-generation (3G) EGFR-TKIs have been developed to overcome the EGFR T790M mutation, which is the most common mechanism of acquired resistance to 1/2G EGFR-TKI treatment. This resistance mutation develops in half of the patients who respond to 1/2G EGFR-TKI therapy. The structures of the novel 3G EGFR-TKIs are different from those of 1/2G EGFR-TKIs. Particularly, 3G EGFR-TKIs have lower affinity to wild-type EGFR, and are therefore associated with lower rates of skin and gastrointestinal toxicities. However, many of the adverse events (AEs) that are observed in patients receiving 3G EGFR-TKIs have not been observed in patients receiving 1/2G EGFR-TKIs. Although preclinical studies have revealed many possible mechanisms for these AEs, the causes of some AEs remain unknown. Many mechanisms of resistance to 3G EGFR-TKI therapy have also been reported. Here, we have reviewed the recent clinical and preclinical developments related to novel 3G EGFR-TKIs, including osimertinib, rociletinib, olmutinib, EGF816, and ASP8273.
authors.affiliation: Department of Oncology, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei, 100, Taiwan.|National Taiwan University Cancer Center, College of Medicine, National Taiwan University, Taipei, Taiwan.|Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Bin-Chi
authors.initials: BC
authors.lastname: Liao
authors.affiliation: Department of Oncology, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei, 100, Taiwan.|Department of Urology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Department of Oncology, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei, 100, Taiwan.|Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Jih-Hsiang
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Oncology, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei, 100, Taiwan. chihyang@ntu.edu.tw.|National Taiwan University Cancer Center, College of Medicine, National Taiwan University, Taipei, Taiwan. chihyang@ntu.edu.tw.|Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. chihyang@ntu.edu.tw.|Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan. chihyang@ntu.edu.tw.
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors
keywords: ASP8273; EGF816; Epidermal growth factor receptor; Non-small cell lung cancer; Olmutinib; Osimertinib; Rociletinib; T790M mutation; Tyrosine kinase inhibitor