title: Impact of Specific Epidermal Growth Factor Receptor (EGFR) Mutations and Clinical Characteristics on Outcomes After Treatment With EGFR Tyrosine Kinase Inhibitors Versus Chemotherapy in EGFR-Mutant Lung Cancer: A Meta-Analysis.
abstract: OBJECTIVE
  We examined the impact of different epidermal growth factor receptor (EGFR) mutations and clinical characteristics on progression-free survival (PFS) in patients with advanced EGFR-mutated non-small-cell lung cancer treated with EGFR tyrosine kinase inhibitors (TKIs) as first-line therapy.
  
  
  METHODS
  This meta-analysis included randomized trials comparing EGFR TKIs with chemotherapy. We calculated hazard ratios (HRs) and 95% CIs for PFS for the trial population and prespecified subgroups and calculated pooled estimates of treatment efficacy using the fixed-effects inverse-variance-weighted method. All statistical tests were two sided.
  
  
  RESULTS
  In seven eligible trials (1,649 patients), EGFR TKIs, compared with chemotherapy, significantly prolonged PFS overall (HR, 0.37; 95% CI, 0.32 to 0.42) and in all subgroups. For tumors with exon 19 deletions, the benefit was 50% greater (HR, 0.24; 95% CI, 0.20 to 0.29) than for tumors with exon 21 L858R substitution (HR, 0.48; 95% CI, 0.39 to 0.58; Pinteraction < .001). Never-smokers had a 36% greater benefit (HR, 0.32; 95% CI, 0.27 to 0.37) than current or former smokers (HR, 0.50; 95% CI, 0.40 to 0.63; Pinteraction < .001). Women had a 27% greater benefit (HR, 0.33; 95% CI, 0.28 to 0.38) than men (HR, 0.45; 95% CI, 0.36 to 0.55; treatment-sex interaction P = .02). Performance status, age, ethnicity, and tumor histology did not significantly predict additional benefit from EGFR TKIs.
  
  
  CONCLUSIONS
  Although EGFR TKIs significantly prolonged PFS overall and in all subgroups, compared with chemotherapy, greater benefits were observed in those with exon 19 deletions, never-smokers, and women. These findings should enhance drug development and economic analyses, as well as the design and interpretation of clinical trials.
authors.affiliation: Chee Khoon Lee, Pei Ni Ding, Sarah J. Lord, and Val Gebski, National Health and Medical Research Council Clinical Trials Centre, The University of Sydney; Chee Khoon Lee and Matthew Links, Cancer Care Centre, St George Hospital; Pei Ni Ding, Liverpool Hospital; Sarah J. Lord, School of Medicine, The University of Notre Dame; Nick Pavlakis, Royal North Shore Hospital, Sydney, Australia; Yi-Long Wu, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong; Caicun Zhou, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China; Akira Inoue, Tohoku University Hospital, Sendai; Tetsuya Mitsudomi, Kinki University School of Medicine, Osaka-Sayama, Japan; Rafael Rosell, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Barcelona, Spain; Richard J. Gralla, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY; James Chih-Hsin Yang, Graduate Institute of Oncology, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chee Khoon
authors.initials: CK
authors.lastname: Lee
authors.affiliation: Chee Khoon Lee, Pei Ni Ding, Sarah J. Lord, and Val Gebski, National Health and Medical Research Council Clinical Trials Centre, The University of Sydney; Chee Khoon Lee and Matthew Links, Cancer Care Centre, St George Hospital; Pei Ni Ding, Liverpool Hospital; Sarah J. Lord, School of Medicine, The University of Notre Dame; Nick Pavlakis, Royal North Shore Hospital, Sydney, Australia; Yi-Long Wu, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong; Caicun Zhou, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China; Akira Inoue, Tohoku University Hospital, Sendai; Tetsuya Mitsudomi, Kinki University School of Medicine, Osaka-Sayama, Japan; Rafael Rosell, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Barcelona, Spain; Richard J. Gralla, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY; James Chih-Hsin Yang, Graduate Institute of Oncology, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Wu
authors.affiliation: Chee Khoon Lee, Pei Ni Ding, Sarah J. Lord, and Val Gebski, National Health and Medical Research Council Clinical Trials Centre, The University of Sydney; Chee Khoon Lee and Matthew Links, Cancer Care Centre, St George Hospital; Pei Ni Ding, Liverpool Hospital; Sarah J. Lord, School of Medicine, The University of Notre Dame; Nick Pavlakis, Royal North Shore Hospital, Sydney, Australia; Yi-Long Wu, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong; Caicun Zhou, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China; Akira Inoue, Tohoku University Hospital, Sendai; Tetsuya Mitsudomi, Kinki University School of Medicine, Osaka-Sayama, Japan; Rafael Rosell, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Barcelona, Spain; Richard J. Gralla, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY; James Chih-Hsin Yang, Graduate Institute of Oncology, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Pei Ni
authors.initials: PN
authors.lastname: Ding
authors.affiliation: Chee Khoon Lee, Pei Ni Ding, Sarah J. Lord, and Val Gebski, National Health and Medical Research Council Clinical Trials Centre, The University of Sydney; Chee Khoon Lee and Matthew Links, Cancer Care Centre, St George Hospital; Pei Ni Ding, Liverpool Hospital; Sarah J. Lord, School of Medicine, The University of Notre Dame; Nick Pavlakis, Royal North Shore Hospital, Sydney, Australia; Yi-Long Wu, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong; Caicun Zhou, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China; Akira Inoue, Tohoku University Hospital, Sendai; Tetsuya Mitsudomi, Kinki University School of Medicine, Osaka-Sayama, Japan; Rafael Rosell, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Barcelona, Spain; Richard J. Gralla, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY; James Chih-Hsin Yang, Graduate Institute of Oncology, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lord
authors.affiliation: Chee Khoon Lee, Pei Ni Ding, Sarah J. Lord, and Val Gebski, National Health and Medical Research Council Clinical Trials Centre, The University of Sydney; Chee Khoon Lee and Matthew Links, Cancer Care Centre, St George Hospital; Pei Ni Ding, Liverpool Hospital; Sarah J. Lord, School of Medicine, The University of Notre Dame; Nick Pavlakis, Royal North Shore Hospital, Sydney, Australia; Yi-Long Wu, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong; Caicun Zhou, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China; Akira Inoue, Tohoku University Hospital, Sendai; Tetsuya Mitsudomi, Kinki University School of Medicine, Osaka-Sayama, Japan; Rafael Rosell, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Barcelona, Spain; Richard J. Gralla, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY; James Chih-Hsin Yang, Graduate Institute of Oncology, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Akira
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Chee Khoon Lee, Pei Ni Ding, Sarah J. Lord, and Val Gebski, National Health and Medical Research Council Clinical Trials Centre, The University of Sydney; Chee Khoon Lee and Matthew Links, Cancer Care Centre, St George Hospital; Pei Ni Ding, Liverpool Hospital; Sarah J. Lord, School of Medicine, The University of Notre Dame; Nick Pavlakis, Royal North Shore Hospital, Sydney, Australia; Yi-Long Wu, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong; Caicun Zhou, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China; Akira Inoue, Tohoku University Hospital, Sendai; Tetsuya Mitsudomi, Kinki University School of Medicine, Osaka-Sayama, Japan; Rafael Rosell, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Barcelona, Spain; Richard J. Gralla, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY; James Chih-Hsin Yang, Graduate Institute of Oncology, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Caicun
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Chee Khoon Lee, Pei Ni Ding, Sarah J. Lord, and Val Gebski, National Health and Medical Research Council Clinical Trials Centre, The University of Sydney; Chee Khoon Lee and Matthew Links, Cancer Care Centre, St George Hospital; Pei Ni Ding, Liverpool Hospital; Sarah J. Lord, School of Medicine, The University of Notre Dame; Nick Pavlakis, Royal North Shore Hospital, Sydney, Australia; Yi-Long Wu, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong; Caicun Zhou, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China; Akira Inoue, Tohoku University Hospital, Sendai; Tetsuya Mitsudomi, Kinki University School of Medicine, Osaka-Sayama, Japan; Rafael Rosell, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Barcelona, Spain; Richard J. Gralla, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY; James Chih-Hsin Yang, Graduate Institute of Oncology, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
authors.affiliation: Chee Khoon Lee, Pei Ni Ding, Sarah J. Lord, and Val Gebski, National Health and Medical Research Council Clinical Trials Centre, The University of Sydney; Chee Khoon Lee and Matthew Links, Cancer Care Centre, St George Hospital; Pei Ni Ding, Liverpool Hospital; Sarah J. Lord, School of Medicine, The University of Notre Dame; Nick Pavlakis, Royal North Shore Hospital, Sydney, Australia; Yi-Long Wu, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong; Caicun Zhou, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China; Akira Inoue, Tohoku University Hospital, Sendai; Tetsuya Mitsudomi, Kinki University School of Medicine, Osaka-Sayama, Japan; Rafael Rosell, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Barcelona, Spain; Richard J. Gralla, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY; James Chih-Hsin Yang, Graduate Institute of Oncology, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
authors.affiliation: Chee Khoon Lee, Pei Ni Ding, Sarah J. Lord, and Val Gebski, National Health and Medical Research Council Clinical Trials Centre, The University of Sydney; Chee Khoon Lee and Matthew Links, Cancer Care Centre, St George Hospital; Pei Ni Ding, Liverpool Hospital; Sarah J. Lord, School of Medicine, The University of Notre Dame; Nick Pavlakis, Royal North Shore Hospital, Sydney, Australia; Yi-Long Wu, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong; Caicun Zhou, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China; Akira Inoue, Tohoku University Hospital, Sendai; Tetsuya Mitsudomi, Kinki University School of Medicine, Osaka-Sayama, Japan; Rafael Rosell, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Barcelona, Spain; Richard J. Gralla, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY; James Chih-Hsin Yang, Graduate Institute of Oncology, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Nick
authors.initials: N
authors.lastname: Pavlakis
authors.affiliation: Chee Khoon Lee, Pei Ni Ding, Sarah J. Lord, and Val Gebski, National Health and Medical Research Council Clinical Trials Centre, The University of Sydney; Chee Khoon Lee and Matthew Links, Cancer Care Centre, St George Hospital; Pei Ni Ding, Liverpool Hospital; Sarah J. Lord, School of Medicine, The University of Notre Dame; Nick Pavlakis, Royal North Shore Hospital, Sydney, Australia; Yi-Long Wu, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong; Caicun Zhou, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China; Akira Inoue, Tohoku University Hospital, Sendai; Tetsuya Mitsudomi, Kinki University School of Medicine, Osaka-Sayama, Japan; Rafael Rosell, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Barcelona, Spain; Richard J. Gralla, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY; James Chih-Hsin Yang, Graduate Institute of Oncology, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Matthew
authors.initials: M
authors.lastname: Links
authors.affiliation: Chee Khoon Lee, Pei Ni Ding, Sarah J. Lord, and Val Gebski, National Health and Medical Research Council Clinical Trials Centre, The University of Sydney; Chee Khoon Lee and Matthew Links, Cancer Care Centre, St George Hospital; Pei Ni Ding, Liverpool Hospital; Sarah J. Lord, School of Medicine, The University of Notre Dame; Nick Pavlakis, Royal North Shore Hospital, Sydney, Australia; Yi-Long Wu, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong; Caicun Zhou, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China; Akira Inoue, Tohoku University Hospital, Sendai; Tetsuya Mitsudomi, Kinki University School of Medicine, Osaka-Sayama, Japan; Rafael Rosell, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Barcelona, Spain; Richard J. Gralla, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY; James Chih-Hsin Yang, Graduate Institute of Oncology, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Val
authors.initials: V
authors.lastname: Gebski
authors.affiliation: Chee Khoon Lee, Pei Ni Ding, Sarah J. Lord, and Val Gebski, National Health and Medical Research Council Clinical Trials Centre, The University of Sydney; Chee Khoon Lee and Matthew Links, Cancer Care Centre, St George Hospital; Pei Ni Ding, Liverpool Hospital; Sarah J. Lord, School of Medicine, The University of Notre Dame; Nick Pavlakis, Royal North Shore Hospital, Sydney, Australia; Yi-Long Wu, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong; Caicun Zhou, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China; Akira Inoue, Tohoku University Hospital, Sendai; Tetsuya Mitsudomi, Kinki University School of Medicine, Osaka-Sayama, Japan; Rafael Rosell, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Barcelona, Spain; Richard J. Gralla, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY; James Chih-Hsin Yang, Graduate Institute of Oncology, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gralla
authors.affiliation: Chee Khoon Lee, Pei Ni Ding, Sarah J. Lord, and Val Gebski, National Health and Medical Research Council Clinical Trials Centre, The University of Sydney; Chee Khoon Lee and Matthew Links, Cancer Care Centre, St George Hospital; Pei Ni Ding, Liverpool Hospital; Sarah J. Lord, School of Medicine, The University of Notre Dame; Nick Pavlakis, Royal North Shore Hospital, Sydney, Australia; Yi-Long Wu, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong; Caicun Zhou, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China; Akira Inoue, Tohoku University Hospital, Sendai; Tetsuya Mitsudomi, Kinki University School of Medicine, Osaka-Sayama, Japan; Rafael Rosell, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Barcelona, Spain; Richard J. Gralla, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY; James Chih-Hsin Yang, Graduate Institute of Oncology, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan. chihyang@ntu.edu.tw.
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D018572:Disease-Free Survival; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D009154:Mutation; D016017:Odds Ratio; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases