title: A phase II trial of gefitinib monotherapy in pretreated patients with advanced non-small cell lung cancer not harboring activating EGFR mutations: implications of sensitive EGFR mutation test.
abstract: OBJECTIVE
  Efficacy of gefitinib therapy strongly depends on epidermal growth factor receptor (EGFR) mutation status in patients with non-small cell lung cancer (NSCLC). However, cumulative data from many clinical studies demonstrated that some patients with wild-type (WT) EGFR also responded to gefitinib with durable disease control rate (DCR). The aim of this trial was to evaluate the efficacy and toxicity of gefitinib in NSCLC patients with WT EGFR who failed previous chemotherapy.
  
  
  METHODS
  Patients with advanced or recurrent NSCLC whose tumors have WT EGFR were eligible. Gefitinib (250 mg/day) was administered until disease progression or unacceptable toxicity occurred. The primary end point was DCR at 8 weeks.
  
  
  RESULTS
  A total of 85 patients (53 men and 32 women; median age, 60 years; range 30-86) were enrolled between October 2010 and May 2013. Seventy-four patients (87.1 %) had adenocarcinoma. Forty-two patients (49.4 %) were treated with gefitinib as second-line chemotherapy. Eleven patients showed partial response, and 21 had stable disease. Thus, objective response rate was 12.9 %, and DCR at 8 weeks was 37.6 %. The median progression-free survival (PFS) and overall survival were 1.9 and 10.9 months, respectively. Skin rash was the most common side effect. It is of note that patients with skin rash of any grade had improved PFS with gefitinib as compared with patients experiencing no skin rash (median PFS: 3.0 vs. 1.7 months, P = 0.004). One patient developed interstitial lung disease (grade 2). Of 11 gefitinib responders, 6 patients were identified as having tumor with activating EGFR mutation by peptide nucleic acid (PNA)-mediated PCR clamping method. Regarding the outcomes of the 79 patients, excluding 6 positive mutations, the response rate was 6.3 %, and DCR at 8 weeks was 31.8 %.
  
  
  CONCLUSIONS
  Small proportion of NSCLC patients with the WT EGFR benefits with gefitinib. Optimized diagnosis through more sensitive bioassay could have major consequences in terms of the selection of candidate for EGFR TKI in patients with WT EGFR by direct sequencing.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea.
authors.forename: Moon Ki
authors.initials: MK
authors.lastname: Choi
authors.forename: Jung Yong
authors.initials: JY
authors.lastname: Hong
authors.forename: Won Jin
authors.initials: WJ
authors.lastname: Chang
authors.forename: Moon Jin
authors.initials: MJ
authors.lastname: Kim
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Kim
authors.forename: Hyun Ae
authors.initials: HA
authors.lastname: Jung
authors.forename: In-Gu
authors.initials: IG
authors.lastname: Do
authors.forename: Yoon-la
authors.initials: YL
authors.lastname: Choi
authors.forename: Jong-Mu
authors.initials: JM
authors.lastname: Sun
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Ahn
authors.forename: Keunchil
authors.initials: K
authors.lastname: Park
authors.forename: Myung-Ju
authors.initials: MJ
authors.lastname: Ahn
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics; D011446:Prospective Studies; D011799:Quinazolines / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib