title: Mechanisms of Acquired Resistance to AZD9291: A Mutation-Selective, Irreversible EGFR Inhibitor.
abstract: BACKGROUND
  AZD9291, a third-generation and mutation-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is active against patients with EGFR-mutant non-small-cell lung cancer (NSCLC) who failed prior treatment with EGFR TKIs. However, acquired resistance to AZD9291 is inevitable. In this study, we identified the mechanisms of acquired resistance to AZD9291 in EGFR-mutant NSCLC.
  
  
  METHODS
  Four NSCLC patients with both an EGFR exon 19 deletion and the EGFR mutation after developing acquired resistance to first-generation EGFR TKIs received AZD9291 at doses of 20 to 80 mg/day in a phase I trial (NCT01802632). Paired tumor samples before and after treatment were obtained to evaluate EGFR modifications, alternative pathway activation, and histologic transformation. Genetic alterations were analyzed using Sanger sequencing, fluorescence in situ hybridization, real-time polymerase chain reaction, and targeted exome sequencing.
  
  
  RESULTS
  All four patients achieved a partial response (median duration of response, 9 months [range, 9-11 months]) and subsequently showed resistance to AZD9291. EGFR-mutant clones depopulated AZD9291-resistant tumors to below 1% (baseline, 14%-36%) in three patients with progression: one with the loss of EGFR-double mutant clones and two accompanied by transformation to small-cell carcinoma and focal fibroblast growth factor receptor 1 (FGFR1) amplification, respectively. EGFR-mutant clones remained and the EGFR ligand was overexpressed in one patient with focal progression to AZD9291.
  
  
  CONCLUSIONS
  Acquired resistance mechanisms of AZD9291 in patients with EGFR-mutant NSCLC who failed treatment with first-generation EGFR TKIs include the loss of EGFR-mutant clones plus alternative pathway activation or histologic transformation and EGFR ligand-dependent activation.
authors.affiliation: Departments of *Internal Medicine and ‡Pathology, Seoul National University Hospital, Seoul, Republic of Korea; and †Laboratory for Biologic Therapy of Cancer, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Tae Min
authors.initials: TM
authors.lastname: Kim
authors.forename: Ahnah
authors.initials: A
authors.lastname: Song
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.forename: Soyeon
authors.initials: S
authors.lastname: Kim
authors.forename: Yong-Oon
authors.initials: YO
authors.lastname: Ahn
authors.forename: Bhumsuk
authors.initials: B
authors.lastname: Keam
authors.forename: Yoon Kyung
authors.initials: YK
authors.lastname: Jeon
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Doo Hyun
authors.initials: DH
authors.lastname: Chung
authors.forename: Dae Seog
authors.initials: DS
authors.lastname: Heo
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage* / Q000494:pharmacology; D000814:Aniline Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D017321:Clinical Trials, Phase I as Topic; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D016896:Treatment Outcome; D007211:Indoles; D011743:Pyrimidines
chemical_list: D000178:Acrylamides; D000814:Aniline Compounds; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines; C512478:EGFR protein, human