title: Phase II study of preoperative gefitinib in clinical stage I non-small-cell lung cancer.
abstract: OBJECTIVE
  Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have proven efficacy in advanced non-small-cell lung cancer (NSCLC). Their role in early-stage NSCLC has not been established. Our purpose was to explore the use of preoperative gefitinib in clinical stage I NSCLC to assess tumor response, toxicity, and clinical and molecular predictors of response.
  
  
  METHODS
  Patients received gefitinib 250 mg/d for up to 28 days, followed by mediastinoscopy and surgical resection in an open-label, single-arm study. Tumor response was evaluated by Response Evaluation Criteria in Solid Tumors. Blood samples and tumor biopsies were collected and analyzed for transforming growth factor alpha level, EGFR protein expression, EGFR gene copy number, and EGFR (exon 19 to 21) and KRAS mutations.
  
  
  RESULTS
  Thirty-six patients completed preoperative treatment (median duration, 28 days; range, 27 to 30 days). Median follow-up time is 2.1 years (range, 0.86 to 3.46 years). Three patients experienced grade 3 toxicities (rash, diarrhea, and elevated ALT). Tumors demonstrated EGFR-positive protein expression in 83%, high gene copy number in 59%, EGFR mutations in 17%, and KRAS mutations in 17%. Tumor shrinkage was more frequent among women and nonsmokers. Partial response was seen in four patients (11%), and disease progression was seen in three patients (9%). The strongest predictor of response was EGFR mutation.
  
  
  CONCLUSIONS
  Preoperative window therapy with gefitinib is a safe and feasible regimen in early NSCLC and provides a trial design that may better inform predictors of treatment response or sensitivity.
authors.affiliation: University Ave, Toronto, Ontario, Canada M5G 2M9.
authors.forename: Humberto
authors.initials: H
authors.lastname: Lara-Guerra
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Waddell
authors.forename: Maria A
authors.initials: MA
authors.lastname: Salvarrey
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Joshua
authors.forename: Catherine T
authors.initials: CT
authors.lastname: Chung
authors.forename: Narinder
authors.initials: N
authors.lastname: Paul
authors.forename: Scott
authors.initials: S
authors.lastname: Boerner
authors.forename: Akira
authors.initials: A
authors.lastname: Sakurada
authors.forename: Olga
authors.initials: O
authors.lastname: Ludkovski
authors.forename: Clement
authors.initials: C
authors.lastname: Ma
authors.forename: Jeremy
authors.initials: J
authors.lastname: Squire
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.forename: Natasha B
authors.initials: NB
authors.lastname: Leighl
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D057234:Preoperative Period; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib