title: A randomized, double-blind, placebo-controlled phase 2 study of tigatuzumab (CS-1008) in combination with carboplatin/paclitaxel in patients with chemotherapy-naïve metastatic/unresectable non-small cell lung cancer.
abstract: BACKGROUND
  Tigatuzumab, a humanized monoclonal DR5 agonist antibody induces apoptosis in human cancer cell lines. The objective of this study was to investigate the antitumor effects of tigatuzumab combined with carboplatin/paclitaxel in chemotherapy-naïve patients with metastatic/unresectable non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Patients with histologically or cytologically confirmed NSCLC stage IIIB/IV disease by RECIST (version 1.0) and ECOG-PS 0-1 were enrolled at 15 European sites. Patients received tigatuzumab or placebo intravenously with carboplatin/paclitaxel every 3 weeks (1 cycle) for up to 6 cycles. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate and safety.
  
  
  RESULTS
  97 patients were analyzed for efficacy (49 tigatuzumab; 48 placebo). Median PFS (95% CI) was 5.4 months (3.3, 6.6) for tigatuzumab compared with 4.3 months (4.1, 5.8) for placebo. Median OS (95% CI) was 8.4 months (6.9, 16.3) for tigatuzumab versus 9.0 months (7.6, 14.5) for placebo. 12 patients (24.5%) in the tigatuzumab arm and 11 patients (22.9%) in the placebo arm had partial response. No patient had complete response. In a prospectively-defined Fc gamma receptor genotype subset (n=25), there was a non-significant trend toward increased PFS with tigatuzumab versus placebo (HR=0.47; 95% CI: 0.16, 1.35) but no difference in OS. Tigatuzumab was well tolerated. However, grade 3/4 neutropenia was reported in 10 patients (20.4%) receiving tigatuzumab compared with 4 patients (8.3%) receiving placebo.
  
  
  CONCLUSIONS
  Tigatuzumab was well tolerated but did not improve efficacy of carboplatin/paclitaxel in systemic therapy-naïve, unselected advanced NSCLC patients.
authors.affiliation: LungClinic Grosshansdorf, Member of the German Centre for Lung Research (DZL), Grosshansdorf, Germany. Electronic address: dr.martin.reck@web.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
authors.forename: Maciej
authors.initials: M
authors.lastname: Krzakowski
authors.forename: Ewa
authors.initials: E
authors.lastname: Chmielowska
authors.forename: Martin
authors.initials: M
authors.lastname: Sebastian
authors.forename: Dietrich
authors.initials: D
authors.lastname: Hadler
authors.forename: Tara
authors.initials: T
authors.lastname: Fox
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Jon
authors.initials: J
authors.lastname: Greenberg
authors.forename: Robert A
authors.initials: RA
authors.lastname: Beckman
authors.forename: Joachim
authors.initials: J
authors.lastname: von Pawel
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005060:Europe; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009503:Neutropenia / Q000209:etiology; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D010919:Placebos; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D010919:Placebos; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C552861:tigatuzumab; D016190:Carboplatin; D017239:Paclitaxel
keywords: Chemotherapy; DR5; Efficacy; Lung; NSCLC; Phase II; Tigatuzumab