title: Predictive factors for EGFR-tyrosine kinase inhibitor retreatment in patients with EGFR-mutated non-small-cell lung cancer - A multicenter retrospective SEQUENCE study.
abstract: Acquired resistance occurs in most non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations experiencing a response to EGFR-tyrosine kinase inhibitor (TKI) initially. We investigated EGFR-TKI retreatment in patients who had previously received EGFR-TKI followed by chemotherapy.
  
  
  
  This was a retrospective multicenter study. Patients with locally advanced or metastatic adenocarcinoma or TTF-1 (+) NSCLC, positive EGFR sensitive mutation, and EGFR-TKI reuse after initial EGFR-TKI followed by chemotherapy were enrolled. The objectives were to assess the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) of EGFR TKI switched retreatment.
  
  
  
  In total, 205 patients were enrolled, with a median age of 61.8 years (range 31.4-92.9). There was a larger proportion of females (62.9%) than males, and more never-smokers (73.2%) than ever-smokers. In the initial EGFR-TKI administration, 57.6% of patients showed a complete response (CR) or partial response (PR), and 34.6% had stable disease (SD); in the second-line chemotherapy, 13.7% had PR, and 58.0% had SD; in the EGFR-TKI retreatment, 7.3% had PR, and 37.1% had SD. The median PFS of first-line EGFR-TKI was 8.0 months (95% CI 7.3-8.2), and retreatment EGFR-TKI was 4.1 months (95% CI 2.7-4.6). The median OS since the start of the first-line EGFR-TKI therapy was 35.9 months (95% CI 28.8-50.9), and since the start of EGFR-TKI retreatment was 12.6 months (95% CI 10.4-20.9). In the univariable and multivariable regression analysis of factors associated with PFS of EGFR-TKI retreatment, time interval between the two EGFR TKIs equal to or more than 7 months was statistically significant (HR=0.62, 95% CI 0.44-0.86; HR=0.6, 95% CI 0.43-0.86), both p<0.01. Females with exon 21 mutation also showed a significant difference between the two groups (HR=0.51, 95% CI 0.30-0.86; HR=0.52 (0.31-0.88), both p<0.05).
  
  
  
  EGFR-TKI retreatment was effective in prolonging survival, and was shown to be a worthwhile option for EGFR-mutated NSCLC patients after failure of first-line EGFR-TKI and chemotherapy. The survival benefit was especially pronounced in patients with longer drug holidays from the initial EGFR-TKI and in females with the exon 21 mutation.
authors.affiliation: Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, and Faculty of Medicine, School of Medicine, National Yang-Ming University, Taiwan; Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address: august@vghtc.gov.tw.
authors.forename: Gee-Chen
authors.initials: GC
authors.lastname: Chang
authors.affiliation: Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan; Department of Critical Care Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Chien-Hua
authors.initials: CH
authors.lastname: Tseng
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan; Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Kuo-Hsuan
authors.initials: KH
authors.lastname: Hsu
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taiwan.
authors.forename: Chong-Jen
authors.initials: CJ
authors.lastname: Yu
authors.affiliation: Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Cheng-Ta
authors.initials: CT
authors.lastname: Yang
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Kun-Chieh
authors.initials: KC
authors.lastname: Chen
authors.affiliation: Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, and Faculty of Medicine, School of Medicine, National Yang-Ming University, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Tsung-Ying
authors.initials: TY
authors.lastname: Yang
authors.affiliation: Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, and Faculty of Medicine, School of Medicine, National Yang-Ming University, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jeng-Sen
authors.initials: JS
authors.lastname: Tseng
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taiwan.
authors.forename: Chien-Ying
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Wei-Yu
authors.initials: WY
authors.lastname: Liao
authors.affiliation: Department of Respiratory Therapy, China Medical University and Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Te-Chun
authors.initials: TC
authors.lastname: Hsia
authors.affiliation: Division of Pulmonary and Critical Care, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chih-Yen
authors.initials: CY
authors.lastname: Tu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Meng-Chih
authors.initials: MC
authors.lastname: Lin
authors.affiliation: Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Ying-Huang
authors.initials: YH
authors.lastname: Tsai
authors.affiliation: Department of Pulmonary and Critical Care Medicine Chiayi Chang-Gung Memorial Hospital, Taiwan.
authors.forename: Meng-Jer
authors.initials: MJ
authors.lastname: Hsieh
authors.affiliation: Department of Chest Medicine, Taipei AVeterans General Hospital, School of Medicine, National Yang-Ming Medical University, and School of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wen-Shuo
authors.initials: WS
authors.lastname: Wu
authors.affiliation: Department of Chest Medicine, Taipei AVeterans General Hospital, School of Medicine, National Yang-Ming Medical University, and School of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: ymchen@vghtpe.gov.tw.
authors.forename: Yuh-Min
authors.initials: YM
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology / Q000556:secondary*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019233:Retreatment; D012189:Retrospective Studies; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C000614412:NKX2-1 protein, human; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Adenocarcinoma; Drug holiday; EGFR TKI retreatment; EGFR mutation; Exon 21 mutation; Females; Lung cancer; Overall survival; Progression free survival