title: Pemetrexed versus gefitinib as a second-line treatment in advanced nonsquamous nonsmall-cell lung cancer patients harboring wild-type EGFR (CTONG0806): a multicenter randomized trial.
abstract: BACKGROUND
  CTONG0806 assessed the efficacy of pemetrexed versus gefitinib as second-line treatment in advanced nonsquamous nonsmall-cell lung cancer (NSCLC) harboring wild-type epidermal growth factor receptor (EGFR).
  
  
  METHODS
  Patients with locally advanced or metastatic nonsquamous NSCLC harboring wild-type EGFR, detected by direct sequencing, and previously treated with platinum-based chemotherapy were randomized to receive gefitinib (250 mg/day) orally or pemetrexed (500 mg/m(2)) i.v. on day 1 of a 21-day cycle until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). The Independent Review Committee (IRC) evaluated all pictorial data.
  
  
  RESULTS
  From February 2009 to August 2012, 161 patients were enrolled, and 157 were assessable (81 in the gefitinib arm, 76 in the pemetrexed arm). Baseline characteristics were balanced between the two arms. The median PFSs were 4.8 versus 1.6 months in the pemetrexed and gefitinib arms, respectively [hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.40-0.75, P < 0.001] as confirmed by IRC evaluation (5.6versus 1.7 months, HR 0.53, 95% CI 0.38-0.75, P < 0.001). The median overall survival (OS) showed a trend of superiority in the pemetrexed arm (12.4 versus 9.6 months, HR 0.72, 95% CI 0.49-1.04, P = 0.077). Quality-of-life assessment showed no marked difference between the arms. No unexpected adverse events were found. Of 108 patients with sufficient DNA samples, EGFR mutation status was re-tested by Scorpion amplification refractory mutation system (ARMS); 32 (29.6%) tested positive (19 in the pemetrexed arm, 13 in the gefitinib arm; median PFS: 8.1 versus 7.0 months, HR 0.94, 95% CI 0.43-2.08, P = 0.877).
  
  
  CONCLUSIONS
  CTONG0806 is the first trial to show significant improvement in PFS and an improved OS trend with pemetrexed compared with gefitinib as second-line setting treatment of EGFR wild-type advanced nonsquamous NSCLC. ARMS is superior to direct sequencing in excluding false-negative patients.
  
  
  BACKGROUND
  NCT00891579.
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Pulmonary Oncology, Jilin Provincial Cancer Hospital, Changchun.
authors.forename: Y
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou.
authors.forename: J-J
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang.
authors.forename: M-F
authors.initials: MF
authors.lastname: Zhao
authors.affiliation: Department of Respiratory Medicine, Perking Union Medical Hospital, Beijing.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou.
authors.forename: X-C
authors.initials: XC
authors.lastname: Zhang
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou.
authors.forename: Z-H
authors.initials: ZH
authors.lastname: Chen
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou.
authors.forename: H-H
authors.initials: HH
authors.lastname: Yan
authors.affiliation: Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing.
authors.forename: Y
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Medical Oncology, Hunan Cancer Hospital, Changsha.
authors.forename: J-H
authors.initials: JH
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, The First People's Hospital of Foshan, Foshan, China.
authors.forename: W-N
authors.initials: WN
authors.lastname: Feng
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou.
authors.forename: C-R
authors.initials: CR
authors.lastname: Xu
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Chen
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou.
authors.forename: W-Z
authors.initials: WZ
authors.lastname: Zhong
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang.
authors.forename: Y-P
authors.initials: YP
authors.lastname: Liu
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou. Electronic address: syylwu@live.cn.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000077156:Gefitinib; D005971:Glutamates / Q000627:therapeutic use*; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000068437:Pemetrexed; D011799:Quinazolines / Q000627:therapeutic use*
chemical_list: D005971:Glutamates; D011799:Quinazolines; D000068437:Pemetrexed; D006147:Guanine; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: TKI; chemotherapy; clinical trial; non-small-cell lung cancer; second-line therapy; wild-type EGFR