title: The safety and efficacy of osimertinib for the treatment of EGFR T790M mutation positive non-small-cell lung cancer.
abstract: First- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the evidence-based first-line treatment for metastatic non-small-cell lung cancers (NSCLCs) that harbor sensitizing EGFR mutations (i.e. exon 19 deletions or L858R). However, acquired resistance to EGFR TKI monotherapy occurs invariably within a median time frame of one year. The most common form of biological resistance is through the selection of tumor clones harboring the EGFR T790M mutation, present in >50% of repeat biopsies. The presence of the EGFR T790M mutation negates the inhibitory activity of gefitinib, erlotinib, and afatinib. A novel class of third-generation EGFR TKIs has been identified by probing a series of covalent pyrimidine EGFR inhibitors that bind to amino-acid residue C797 of EGFR and preferentially inhibit mutant forms of EGFR versus the wild-type receptor. We review the rapid clinical development and approval of the third-generation EGFR TKI osimertinib for treatment of NSCLCs with EGFR-T790M.
authors.affiliation: a Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center , Harvard Medical School , Boston , MA , USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: a Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center , Harvard Medical School , Boston , MA , USA.
authors.forename: Xiuning
authors.initials: X
authors.lastname: Le
authors.affiliation: a Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center , Harvard Medical School , Boston , MA , USA.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
mesh_terms: D000178:Acrylamides; D000814:Aniline Compounds; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D017322:Clinical Trials, Phase II as Topic; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D014018:Tissue Distribution; D007211:Indoles; D011743:Pyrimidines
chemical_list: D000178:Acrylamides; D000814:Aniline Compounds; D066246:ErbB Receptors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines; C512478:EGFR protein, human
keywords: EGFR; T790M; TKI; adenocarcinoma; kinase inhibitor; lung cancer; mutation; osimertinib; resistance