title: A phase II study of erlotinib monotherapy in pre-treated non-small cell lung cancer without EGFR gene mutation who have never/light smoking history: re-evaluation of EGFR gene status (NEJ006/TCOG0903).
abstract: OBJECTIVE
  Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are particularly effective in non-small cell lung cancer (NSCLC) patients harboring active EGFR mutations. However, some studies have reported survival benefits in NSCLC patients with wild-type EGFR upon erlotinib treatment. This trial was conducted to evaluate the efficacy of erlotinib monotherapy and investigate the predictive values of several biomarkers.
  
  
  METHODS
  Patients with previously treated NSCLC but without EGFR gene mutations that had never or light smoked were eligible for this study. Gene status screening was performed using the PNA-LNA PCR clamp method. Erlotinib was administered until disease progression or unacceptable toxicities occurred. EGFR gene status was re-evaluated using the fragment method to detect exon 19 deletions and the Cycleave-PCR method to detect point mutations. Expression of hepatocyte growth factor (HGF), Met, and thymidylate synthase (TS) were evaluated using immunohistochemistry.
  
  
  RESULTS
  Forty-seven patients were enrolled in the study between March 2010 and November 2011. Objective response rate (ORR) and disease control rate (DCR) were 15.2% and 41.3%. Re-evaluations for EGFR gene were performed in 32 tumor samples. EGFR gene mutations were found in eight samples (5:exon 19 deletion, 2:G719X, 1:L858R). Six patients had PR and two had SD among these eight patients. A total of 24 patients were confirmed as wild-type EGFR using different methods. ORR and DCR were 4.2% and 41.7%. The median progression free survival (PFS) and median survival times were 2.0 and 6.0 months, respectively. Patients with tumors expressing HGF showed shorter PFS but not MET or TS.
  
  
  CONCLUSIONS
  Re-examination of EGFR gene status using different detecting method or different sample should be considered to grasp a chance of erlotinib treatment after first line treatment. In confirmed EGFR wild NSCLC, negative HGF staining could be a biomarker for longer PFS by erlotonib treatment.
authors.affiliation: Department of Medical Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Department of Medical Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Department of Respiratory Medicine, Miyagi Cancer Center, Natori, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Maemondo
authors.affiliation: Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, Tochigi, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Hirosaki Central Hospital, Hirosaki, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Okudera
authors.affiliation: Division of Respiratory Medicine, Ishikawa Prefectural Central Hospital, Kanazawa, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Demura
authors.affiliation: Obihiro-Kousei General Hospital, Obihiro, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Takamura
authors.affiliation: Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Morikawa
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Gemma
authors.affiliation: Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ishimoto
authors.affiliation: Division of Respirology, NTT Medical Center Tokyo, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Usui
authors.affiliation: Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Harada
authors.affiliation: Division of Respiratory Medicine, Niigata University Medical and Dental Hospital, Niigata, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miura
authors.affiliation: Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, Asahikawa, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Department of Pathology, Miyagi Cancer Center, Natori, Japan.
authors.forename: Ikuro
authors.initials: I
authors.lastname: Sato
authors.affiliation: Department of Medical Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Department of Medical Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan. Electronic address: yasosj@med.niigata-u.ac.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Saijo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D015415:Biomarkers; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019233:Retreatment; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; C066855:HGF protein, human; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D017228:Hepatocyte Growth Factor; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: EGFR-TKI; Erlotinib; HGF; Re-evaluation; Wild type EGFR