title: Relationship between EGFR expression, EGFR mutation status, and the efficacy of chemotherapy plus cetuximab in FLEX study patients with advanced non-small-cell lung cancer.
abstract: BACKGROUND
  The phase III FLEX study (NCT00148798) in advanced non-small-cell lung cancer indicated that the survival benefit associated with the addition of cetuximab to cisplatin and vinorelbine was limited to patients whose tumors expressed high levels of epidermal growth factor receptor (EGFR) (immunohistochemistry score of ≥200; scale 0-300). We assessed whether the treatment effect was also modulated in FLEX study patients by tumor EGFR mutation status.
  
  
  METHODS
  A tumor mutation screen of EGFR exons 18 to 21 included 971 of 1125 (86%) FLEX study patients. Treatment outcome in low and high EGFR expression groups was analyzed across efficacy endpoints according to tumor EGFR mutation status.
  
  
  RESULTS
  Mutations in EGFR exons 18 to 21 were detected in 133 of 971 tumors (14%), 970 of which were also evaluable for EGFR expression level. The most common mutations were exon 19 deletions and L858R (124 of 133 patients; 93%). In the high EGFR expression group (immunohistochemistry score of ≥200), a survival benefit for the addition of cetuximab to chemotherapy was demonstrated in patients with EGFR wild-type (including T790M mutant) tumors. Although patient numbers were small, those in the high EGFR expression group whose tumors carried EGFR mutations may also have derived a survival benefit from the addition of cetuximab to chemotherapy. Response data suggested a cetuximab benefit in the high EGFR expression group regardless of EGFR mutation status.
  
  
  CONCLUSIONS
  The survival benefit associated with the addition of cetuximab to first-line chemotherapy for advanced non-small-cell lung cancer expressing high levels of EGFR is not limited by EGFR mutation status.
authors.affiliation: *Department of Medical Oncology, Institut de Cancerologie de l'Ouest, Centre René Gauducheau, Saint-Herblain, France; †Department of Medicine I, Medical University of Vienna, Vienna, Austria; ‡HOPE Directorate, St James's Hospital, Dublin, Ireland; §Department of Pathology, Aberdeen Royal Infirmary, Aberdeen, United Kingdom; ‖Institute of Pathology, University of Witten/Herdecke and HELIOS Hospital Wuppertal, Wuppertal, Germany; ¶Global Biostatistics, #Biomarker Technologies & Operations, and **Translational Innovation Platform Oncology, Merck KGaA, Darmstadt, Germany; and ††University Health Network, Department of Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Douillard
authors.forename: Robert
authors.initials: R
authors.lastname: Pirker
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: O'Byrne
authors.forename: Keith M
authors.initials: KM
authors.lastname: Kerr
authors.forename: Stephan
authors.initials: S
authors.lastname: Störkel
authors.forename: Anja
authors.initials: A
authors.lastname: von Heydebreck
authors.forename: Hans Jürgen
authors.initials: HJ
authors.lastname: Grote
authors.forename: Ilhan
authors.initials: I
authors.lastname: Celik
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics; D000068818:Cetuximab; D002945:Cisplatin / Q000008:administration & dosage; D004252:DNA Mutational Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000032:analysis* / Q000235:genetics*; D005091:Exons; D006801:Humans; D008175:Lung Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics; D017384:Sequence Deletion; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014747:Vinblastine; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab; D002945:Cisplatin; D000077235:Vinorelbine