title: Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS).
abstract: OBJECTIVE
  The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status.
  
  
  METHODS
  In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS.
  
  
  RESULTS
  OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio [HR], 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation-positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation-negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation-positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09).
  
  
  CONCLUSIONS
  EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation-positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment.
authors.affiliation: Kinki University School of Medicine, Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukuoka
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Wu
authors.forename: Sumitra
authors.initials: S
authors.lastname: Thongprasert
authors.forename: Patrapim
authors.initials: P
authors.lastname: Sunpaweravong
authors.forename: Swan-Swan
authors.initials: SS
authors.lastname: Leong
authors.forename: Virote
authors.initials: V
authors.lastname: Sriuranpong
authors.forename: Tsu-Yi
authors.initials: TY
authors.lastname: Chao
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Da-Tong
authors.initials: DT
authors.lastname: Chu
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.forename: Emma L
authors.initials: EL
authors.lastname: Duffield
authors.forename: Yuri
authors.initials: Y
authors.lastname: Rukazenkov
authors.forename: Georgina
authors.initials: G
authors.lastname: Speake
authors.forename: Haiyi
authors.initials: H
authors.lastname: Jiang
authors.forename: Alison A
authors.initials: AA
authors.lastname: Armour
authors.forename: Ka-Fai
authors.initials: KF
authors.lastname: To
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
authors.forename: Tony S K
authors.initials: TS
authors.lastname: Mok
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001208:Asia; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008175:Lung Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D017239:Paclitaxel / Q000008:administration & dosage; D018579:Patient Selection; D057285:Precision Medicine; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D018570:Risk Assessment; D012307:Risk Factors; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D016190:Carboplatin; C512478:EGFR protein, human; D066246:ErbB Receptors; D017239:Paclitaxel; D000077156:Gefitinib