title: Randomized phase II study of ixabepilone or paclitaxel plus carboplatin in patients with non-small-cell lung cancer prospectively stratified by beta-3 tubulin status.
abstract: OBJECTIVE
  Retrospective studies have reported that tumor expression of the beta-3 tubulin (β3T) isoform is an unfavorable prognostic factor in non-small-cell lung cancer (NSCLC) treated with tubulin-inhibiting chemotherapy. Ixabepilone is a tubulin-inhibiting agent with low susceptibility to multiple resistance mechanisms including β3T isoform expression in several tumor models. This randomized phase II study evaluated ixabepilone-based chemotherapy in stage IIIb/IV NSCLC, compared with paclitaxel-based chemotherapy. Tumor specimens were prospectively evaluated for β3T expression.
  
  
  METHODS
  Patients were stratified by β3T status (positive v negative) and randomly assigned at a ratio of 1:1 to receive ixabepilone (32 mg/m(2)) and carboplatin (area under concentration-time curve [AUC], 6) or paclitaxel (200 mg/m(2)) and carboplatin (AUC, 6) for up to six cycles. The primary end point was progression-free survival (PFS) in the β3T-positive subgroup.
  
  
  RESULTS
  Ninety-five patients (β3T positive, 52; β3T negative, 43) received ixabepilone plus carboplatin; 96 patients (β3T positive, 49; β3T negative, 47) received paclitaxel plus carboplatin. No significant differences in median PFS were observed between arms for either subgroup (β3T positive, 4.3 months in both arms; β3T negative, 5.8 v 5.3 months). Ixabepilone did not significantly improve overall survival (OS) for the β3T-positive subset or the overall population. Adverse events were similar between the two arms and comparable with those in previous studies.
  
  
  CONCLUSIONS
  There was no predictive value of β3T in differentiating clinical activity of ixabepilone- or paclitaxel-containing regimens. Ixabepilone did not improve PFS or OS in patients with β3T-positive tumors. β3T-positive patients had worse PFS relative to β3T-negative patients, regardless of treatment; hence, β3T expression seems to be a negative prognostic factor, but not a predictive factor, in advanced NSCLC treated with either ixabepilone or paclitaxel platinum-based doublets.
authors.affiliation: Division of Hematology/Oncology, University of Maryland Greenebaum Cancer Center, Baltimore, MD21201-1595, USA. medelman@umm.edu
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Edelman
authors.forename: Claus-Peter
authors.initials: CP
authors.lastname: Schneider
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Tsai
authors.forename: Heung-Tae
authors.initials: HT
authors.lastname: Kim
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Quoix
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Luft
authors.forename: Remigiusz
authors.initials: R
authors.lastname: Kaleta
authors.forename: Pralay
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: Ovidiu C
authors.initials: OC
authors.lastname: Trifan
authors.forename: Laura
authors.initials: L
authors.lastname: Whitaker
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry / Q000188:drug therapy* / Q000556:secondary; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D034261:Epothilones / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D011237:Predictive Value of Tests; D011446:Prospective Studies; D016896:Treatment Outcome; D014404:Tubulin / Q000032:analysis*; D050257:Tubulin Modulators / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; D034261:Epothilones; D014404:Tubulin; D050257:Tubulin Modulators; D016190:Carboplatin; C430592:ixabepilone; D017239:Paclitaxel