title: Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis.
abstract: BACKGROUND
  The epidermal growth factor receptor (EGFR) signaling pathway is crucial for regulating tumorigenesis and cell survival and may be important in the development and progression of non-small cell lung cancer (NSCLC). We examined the impact of EGFR-tyrosine kinase inhibitors (TKIs) on progression-free survival (PFS) and overall survival (OS) in advanced NSCLC patients with and without EGFR mutations.
  
  
  METHODS
  Randomized trials that compared EGFR-TKIs monotherapy or combination EGFR-TKIs-chemotherapy with chemotherapy or placebo were included. We used published hazard ratios (HRs), if available, or derived treatment estimates from other survival data. Pooled estimates of treatment efficacy of EGFR-TKIs for the EGFR mutation-positive (EGFRmut(+)) and EGFR mutation-negative (EGFRmut(-)) subgroups were calculated with the fixed-effects inverse variance weighted method. All statistical tests were two-sided.
  
  
  RESULTS
  We included 23 eligible trials (13 front-line, 7 second-line, 3 maintenance; n = 14570). EGFR mutation status was known in 31% of patients. EGFR-TKIs treatment prolonged PFS in EGFRmut(+) patients, and EGFR mutation was predictive of PFS in all settings: The front-line hazard ratio for EGFRmut(+) was 0.43 (95% confidence interval [CI] = 0.38 to 0.49; P < .001), and the front-line hazard ratio for EGFRmut(-) was 1.06 (95% CI = 0.94 to 1.19; P = .35; P interaction < .001). The second-line hazard ratio for EGFRmut(+) was 0.34 (95% CI = 0.20 to 0.60; P < .001), and the second-line hazard ratio for EGFRmut(-) was 1.23 (95% CI = 1.05 to 1.46; P = .01; P interaction < .001). The maintenance hazard ratio for EGFRmut(+) was 0.15 (95% CI = 0.08 to 0.27; P < .001), and the maintenance hazard ratio for EGFRmut(-) was 0.81 (95% CI = 0.68 to 0.97; P = .02; P interaction < .001). EGFR-TKIs treatment had no impact on OS for EGFRmut(+) and EGFRmut(-) patients.
  
  
  CONCLUSIONS
  EGFR-TKIs therapy statistically significantly delays disease progression in EGFRmut(+) patients but has no demonstrable impact on OS. EGFR mutation is a predictive biomarker of PFS benefit with EGFR-TKIs treatment in all settings. These findings support EGFR mutation assessment before initiation of treatment. EGFR-TKIs should be considered as front-line therapy in EGFRmut(+) advanced NSCLC patients.
authors.affiliation: National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia. chihyang@ntu.edu.tw
authors.forename: Chee Khoon
authors.initials: CK
authors.lastname: Lee
authors.forename: Chris
authors.initials: C
authors.lastname: Brown
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gralla
authors.forename: Vera
authors.initials: V
authors.lastname: Hirsh
authors.forename: Sumitra
authors.initials: S
authors.lastname: Thongprasert
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Tsai
authors.forename: Eng Huat
authors.initials: EH
authors.lastname: Tan
authors.forename: James Chung-Man
authors.initials: JC
authors.lastname: Ho
authors.forename: Da Tong
authors.initials: da T
authors.lastname: Chu
authors.forename: Adel
authors.initials: A
authors.lastname: Zaatar
authors.forename: Jemela Anne
authors.initials: JA
authors.lastname: Osorio Sanchez
authors.forename: Vu Van
authors.initials: VV
authors.lastname: Vu
authors.forename: Joseph Siu Kie
authors.initials: JS
authors.lastname: Au
authors.forename: Akira
authors.initials: A
authors.lastname: Inoue
authors.forename: Siow Ming
authors.initials: SM
authors.lastname: Lee
authors.forename: Val
authors.initials: V
authors.lastname: Gebski
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
mesh_terms: D000077716:Afatinib; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality*; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D000077143:Docetaxel; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000068437:Pemetrexed; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage; D000093542:Gemcitabine
chemical_list: D005971:Glutamates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D043823:Taxoids; D000068437:Pemetrexed; D003841:Deoxycytidine; D000077143:Docetaxel; D000077716:Afatinib; D006147:Guanine; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D002945:Cisplatin; D000077156:Gefitinib; D000093542:Gemcitabine