title: First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations.
abstract: OBJECTIVE
  Somatic mutations in the epidermal growth factor receptor (EGFR) correlate with increased response in patients with non-small-cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). The multicenter iTARGET trial prospectively examined first-line gefitinib in advanced NSCLC patients harboring EGFR mutations and explored the significance of EGFR mutation subtypes and TKI resistance mechanisms.
  
  
  METHODS
  Chemotherapy-naïve patients with advanced NSCLC with >or= 1 clinical characteristic associated with EGFR mutations underwent direct DNA sequencing of tumor tissue EGFR exons 18 to 21. Patients found to harbor any EGFR mutation were treated with gefitinib 250 mg/d until progression or unacceptable toxicity. The primary outcome was response rate.
  
  
  RESULTS
  Ninety-eight patients underwent EGFR screening and mutations were detected in 34 (35%). EGFR mutations were primarily exon 19 deletions (53%) and L858R (26%) though 21% of mutation-positive cases had less common subtypes including exon 20 insertions, T790M/L858R, G719A, and L861Q. Thirty-one patients received gefitinib. The response rate was 55% (95% CI, 33 to 70) and median progression-free survival was 9.2 months (95% CI, 6.2 to 11.8). Therapy was well tolerated; 13% of patients had grade 3 toxicities including one grade 3 pneumonitis. Two patients with classic activating mutations exhibited de novo gefitinib resistance and had concurrent genetic anomalies usually associated with acquired TKI resistance, specifically the T790M EGFR mutation and MET amplification.
  
  
  CONCLUSIONS
  First-line therapy with gefitinib administered in a genotype-directed fashion to patients with advanced NSCLC harboring EGFR mutations results in very favorable clinical outcomes with good tolerance. This strategy should be compared with combination chemotherapy, the current standard of care.
authors.affiliation: Massachusetts General Hospital Cancer Center, 32 Fruit St, Yawkey Suite 7B, Boston, MA 02114, USA. lvsequist@partners.org
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.forename: Renato G
authors.initials: RG
authors.lastname: Martins
authors.forename: David
authors.initials: D
authors.lastname: Spigel
authors.forename: Steven M
authors.initials: SM
authors.lastname: Grunberg
authors.forename: Alexander
authors.initials: A
authors.lastname: Spira
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Joshi
authors.forename: David
authors.initials: D
authors.lastname: McCollum
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Evans
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.forename: Georgiana L
authors.initials: GL
authors.lastname: Kuhlmann
authors.forename: Moon
authors.initials: M
authors.lastname: Han
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Goldberg
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lynch
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018287:Carcinoma, Large Cell / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D016543:Central Nervous System Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011446:Prospective Studies; D011799:Quinazolines / Q000627:therapeutic use*; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib