title: Phase II trial of mapatumumab, a fully human agonist monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer.
abstract: BACKGROUND
  This phase II study examined the efficacy of mapatumumab in combination with paclitaxel and carboplatin in patients with non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  Patients with stage IIIB or stage IV advanced primary NSCLC were randomly assigned (1:1:1) to receive up to 6 courses of standard-dose paclitaxel and carboplatin or a combination of paclitaxel, carboplatin, and mapatumumab (10 mg/kg or 30 mg/kg). Primary efficacy end points were overall response rate and median progression-free survival (PFS). Secondary efficacy end points included disease control rate, overall survival (OS), time to response, and duration of response. Exploratory studies included evaluation of historical biopsy materials for TRAIL-R1 expression by immunohistochemical analysis and serum levels of M30, a marker of apoptosis, before and after the first 2 doses of mapatumumab. Safety parameters, including adverse events (AEs), laboratory tests, and immunogenicity, were assessed.
  
  
  RESULTS
  The majority of patients had stage IV disease (79%) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (58%); baseline characteristics were similar across treatment arms. No improvements in response or disease control rates, PFS, or OS were gained from the addition of mapatumumab. Adverse events in the mapatumumab arms were generally consistent with toxicities seen in the carboplatin and paclitaxel control arm. Levels of M30 were highly variable, and consistent patterns were not seen across treatment arms.
  
  
  CONCLUSIONS
  This study showed no clinical benefit from adding mapatumumab to carboplatin and paclitaxel in unselected patients with NSCLC. The combination was generally well tolerated. The possibility of subgroups sensitive to mapatumumab is discussed.
authors.affiliation: Department of Oncology, Asklepios-Fachkliniken München-Gauting, Munich, Germany. Electronic address: j.pawel@asklepios.com.
authors.forename: Joachim
authors.initials: J
authors.lastname: von Pawel
authors.affiliation: Alabama Oncology, Birmingham, AL.
authors.forename: Jimmie H
authors.initials: JH
authors.lastname: Harvey
authors.affiliation: Tennessee Oncology, Sarah Cannon Research Institute, Nashville, TN.
authors.forename: David R
authors.initials: DR
authors.lastname: Spigel
authors.affiliation: Department of Medical Oncology, Institute of Oncology "Prof. Dr. Alexandru Trestioreanu", Bucharest, Romania.
authors.forename: Mircea
authors.initials: M
authors.lastname: Dediu
authors.affiliation: Department of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
authors.affiliation: Department of Radiotherapy I-Medical Oncology, Prof Dr Ion Chircuta Institute of Oncology, Cluj, Romania.
authors.forename: Cristina L
authors.initials: CL
authors.lastname: Cebotaru
authors.affiliation: Preclinical Research, Rockville, MD.
authors.forename: Robin C
authors.initials: RC
authors.lastname: Humphreys
authors.affiliation: Department of Biostatistics, Rockville, MD.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Gribbin
authors.affiliation: Clinical Research, Human Genome Sciences, Rockville, MD.
authors.forename: Norma Lynn
authors.initials: NL
authors.lastname: Fox
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO.
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D016190:Carboplatin; D017239:Paclitaxel; C507357:mapatumumab
keywords: Carboplatin/paclitaxel combination; Death receptors; Targeted biological agent