title: Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer.
abstract: OBJECTIVE
  The first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, are effective as first-line treatment of advanced nonsmall cell lung cancer (NSCLC) harboring activating EGFR mutations (deletions in exon 19 and exon 21 L858R mutation). EGFR T790 M resistance mutation (EGFR T790 M) ultimately emerged in most of these patients. The second and third-generation EGFR-TKIs were designed to have more potent inhibition of EGFR and to overcome EGFR T790 M. This review describes the recent developments of these novel EGFR-TKIs.
  
  
  RESULTS
  The second-generation EGFR-TKIs, afatinib and dacomitinib, irreversibly bind to the tyrosine kinase of EGFR and other ErbB-family members. Afatinib has been approved as first-line treatment of advanced NSCLC harboring activating EGFR mutations. Dacomitinib is under development. Third-generation EGFR-TKIs, AZD9291, CO-1686, and HM61713, inhibit both EGFR activating and resistance mutations, while sparing wild-type EGFR. In early-phase studies, these drugs demonstrated promising response rates against tumors with acquired EGFR T790 M.
  
  
  CONCLUSIONS
  Second-generation EGFR-TKI, afatinib, is available as first-line treatment of advanced NSCLC harboring activating EGFR mutations. Third-generation EGFR-TKIs are under development for tumors harboring acquired EGFR T790 M.
authors.affiliation: aDepartment of Oncology bDepartment of Urology cGraduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Bin-Chi
authors.initials: BC
authors.lastname: Liao
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Lin
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D000077156:Gefitinib