title: A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer.
abstract: BACKGROUND
  Continuation or 'switch' maintenance therapy is commonly used in patients with advancd non-small-cell lung cancer (NSCLC). Here, we evaluated the efficacy of the telomerase inhibitor, imetelstat, as switch maintenance therapy in patients with advanced NSCLC.
  
  
  METHODS
  The primary end point of this open-label, randomized phase II study was progression-free survival (PFS). Patients with non-progressive, advanced NSCLC after platinum-based doublet (first-line) chemotherapy (with or without bevacizumab), any histology, with Eastern Cooperative Oncology Group performance status 0-1 were eligible. Randomization was 2 : 1 in favor of imetelstat, administered at 9.4 mg/kg on days 1 and 8 of a 21-day cycle, or observation. Telomere length (TL) biomarker exploratory analysis was carried out in tumor tissue by quantitative PCR (qPCR) and telomerase fluorescence in situ hybridization.
  
  
  RESULTS
  Of 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control [hazard ratio (HR) = 0.844; 95% CI 0.54-1.31; P = 0.446]. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41-1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14-1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11-1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39-1.88; and HR = 0.51; 95% CI 0.2-1.28; P = 0.145).
  
  
  CONCLUSIONS
  Maintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat.
authors.affiliation: Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa alberto.chiappori@moffitt.org.
authors.forename: A A
authors.initials: AA
authors.lastname: Chiappori
authors.affiliation: Department of Oncology, Kaiser Permanente Medical Center, Vallejo.
authors.forename: T
authors.initials: T
authors.lastname: Kolevska
authors.affiliation: Research Consortium, Sarah Cannon Research Institute, Nashville.
authors.forename: D R
authors.initials: DR
authors.lastname: Spigel
authors.affiliation: Thoracic Department, Cancer Care Associates of Fresno Medical Group, Fresno.
authors.forename: S
authors.initials: S
authors.lastname: Hager
authors.affiliation: Oncology Hematology Department, Kaiser Permanente Northwest, Portland.
authors.forename: M
authors.initials: M
authors.lastname: Rarick
authors.affiliation: Karmanos Cancer Institute, Detroit, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gadgeel
authors.affiliation: CHUM-Hopital Notre-Dame, Montreal, Quebec, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Blais
authors.affiliation: Department of Oncology, Asklepios Fachkliniken Muenchen-Gauting, Gauting, Bayern, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Von Pawel
authors.affiliation: Sarah Cannon Florida Cancer Specialists, Bonita Springs, USA.
authors.forename: L
authors.initials: L
authors.lastname: Hart
authors.affiliation: Department of Thoracic Oncology, LungenClinic Grosshansdorf, member of the German Center for Lung Research (DZL), Grosshansdorf, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Reck
authors.affiliation: Department of Biostatistics, Geron Corporation, Menlo Park.
authors.forename: E
authors.initials: E
authors.lastname: Bassett
authors.affiliation: Department of Biostatistics, Geron Corporation, Menlo Park.
authors.forename: B
authors.initials: B
authors.lastname: Burington
authors.affiliation: Department of Oncology, University of Texas Southwestern Medical Center, Dallas, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Schiller
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007211:Indoles / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D060046:Maintenance Chemotherapy / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009841:Oligonucleotides; D016016:Proportional Hazards Models; D019098:Telomerase / Q000037:antagonists & inhibitors; D016615:Telomere / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D009841:Oligonucleotides; D009536:Niacinamide; D019098:Telomerase; C519562:imetelstat
keywords: biomarker; imetelstat; non-small-cell lung cancer