title: Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib.
abstract: OBJECTIVE
  Most lung cancers with activating epidermal growth factor receptor (EGFR) mutations respond to gefitinib; however, resistance to this tyrosine kinase inhibitor (TKI) invariably ensues. The T790M mutation occurs in 50% and MET amplification in 20% of TKI-resistant tumors. Other secondary mutations (D761Y and L747S) are rare. Our goal was to determine the effects of erlotinib 150 mg/d in EGFR mutated patients resistant to gefitinib 250 mg/d, because the EGFR TKI erlotinib is given at a higher biologically active dose than gefitinib.
  
  
  METHODS
  Retrospective review of 18 EGFR mutated (exon 19 deletions, L858R, and L861Q) patients that were given gefitinib and subsequently erlotinib. Seven patients had tumor resampling after TKI therapy and were analyzed for secondary EGFR mutations and MET amplification.
  
  
  RESULTS
  Most patients (14 of 18) responded to gefitinib with median progression-free survival of 11 months (95% confidence interval, 4-16). After gefitinib resistance (de novo or acquired), 78% (14 of 18) of these patients displayed progressive disease while on erlotinib with progression-free survival of 2 months (95% confidence interval, 2-3). Six of 7 resampled patients acquired the T790M mutation, and 0 of 3 had MET amplification. Only 1 gefitinib-resistant patient with the acquired L858R-L747S EGFR, which in vitro is sensitive to achievable serum concentrations of erlotinib 150 mg/d, achieved a partial response to erlotinib.
  
  
  CONCLUSIONS
  In EGFR mutated tumors resistant to gefitinib 250 mg/d, a switch to erlotinib 150 mg/d does not lead to responses in most patients. These findings are consistent with preclinical models, because the common mechanisms of TKI resistance (T790M and MET amplification) in vitro are not inhibited by clinically achievable doses of gefitinib or erlotinib. Alternative strategies to overcome TKI resistance must be evaluated.
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. dbcosta@bidmc.harvard.edu
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
authors.forename: Kim-Son H
authors.initials: KS
authors.lastname: Nguyen
authors.forename: Byoung C
authors.initials: BC
authors.lastname: Cho
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.forename: David M
authors.initials: DM
authors.lastname: Jackman
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.forename: Beow Y
authors.initials: BY
authors.lastname: Yeap
authors.forename: Balázs
authors.initials: B
authors.lastname: Halmos
authors.forename: Joo H
authors.initials: JH
authors.lastname: Kim
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: Mark S
authors.initials: MS
authors.lastname: Huberman
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors; D011799:Quinazolines / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib