title: Paclitaxel and bevacizumab with or without capecitabine   as first-line treatment for HER2-negative locally recurrent   or metastatic breast cancer: a multicentre, open-label,   randomised phase 2 trial.
abstract: BACKGROUND
  The addition of bevacizumab to paclitaxel or capecitabine has demonstrated improved progression-free survival (PFS) and objective response rate (ORR) as compared with chemotherapy alone in patients with HER2-negative locally recurrent or metastatic breast cancer (LR/MBC). We evaluated the efficacy and safety of first-line therapy of paclitaxel and bevacizumab with or without capecitabine in patients with HER2-negative LR/MBC.
  
  
  METHODS
  In this multicentre, open-label, randomised phase II trial, women with HER2-negative LR/MBC were randomly assigned in a 1:1 ratio to paclitaxel (90 mg/m2 intravenously [IV] on days 1, 8, and 15) and bevacizumab (10 mg/kg IV on days 1 and 15) every 4 weeks for six cycles, followed by bevacizumab (15 mg/kg IV on day 1) every 3 weeks (AT) or to paclitaxel (90 mg/m2 IV on days 1 and 8), bevacizumab (15 mg/kg IV on day 1) and capecitabine (825 mg/m2 orally twice daily on days 1–14) every 3 weeks for eight cycles, followed by bevacizumab and capecitabine at the same doses every 3 weeks (ATX). The primary end-point was investigator-assessed PFS. Secondary end-points included ORR, duration of response, overall survival (OS) and safety. Exploratory analyses were conducted to evaluate the impact of capecitabine on OS and to validate a novel prognostic model. This trial is registered with EudraCT, number 2006-006058-83.
  
  
  RESULTS
  Median PFS was significantly longer in ATX as compared with AT (11.2 months versus 8.4 months; stratified hazard ratio (HR), 0.52; 95% confidence interval (CI), 0.41–0.67; p < 0.0001). The ORR in ATX patients with measurable disease (n = 268) was higher than that in AT (69% versus 51%; p = 0.01). The median duration of response was 6.8 versus 5.4 months for, respectively, ATX and AT (p < 0.0001). Median OS was 24.2 months for ATX and 23.1 months for AT (p = 0.53). The increased rate of grade 3–4 adverse events related to the addition of capecitabine, being hand-foot syndrome (34% versus 0% for AT) and neutropenia (20% versus 12% for AT), generally did not preclude continuation of treatment. Exploratory analyses indicated that (1) patients receiving capecitabine at some line for treatment have significantly improved OS and (2) a prognostic model can classify patients into three risk groups associated with OS.
  
  
  CONCLUSIONS
  In patients with HER2-negative LR/MBC, addition of capecitabine to paclitaxel and bevacizumab significantly improved PFS, ORR and response duration. This combination was reasonably well tolerated and may be considered of use as first-line treatment in rapidly progressive disease.
  
  
  BACKGROUND
  F. Hoffmann-La Roche Ltd, the Netherlands.
authors.forename: S W
authors.initials: SW
authors.lastname: Lam
authors.forename: S M
authors.initials: SM
authors.lastname: de Groot
authors.forename: A H
authors.initials: AH
authors.lastname: Honkoop
authors.forename: A
authors.initials: A
authors.lastname: Jager
authors.forename: A J
authors.initials: AJ
authors.lastname: ten Tije
authors.forename: M M E M
authors.initials: MM
authors.lastname: Bos
authors.forename: S C
authors.initials: SC
authors.lastname: Linn
authors.forename: J
authors.initials: J
authors.lastname: van den Bosch
authors.forename: J R
authors.initials: JR
authors.lastname: Kroep
authors.forename: J J
authors.initials: JJ
authors.lastname: Braun
authors.forename: H
authors.initials: H
authors.lastname: van Tinteren
authors.forename: E
authors.initials: E
authors.lastname: Boven
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018450:Disease Progression; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; D017239:Paclitaxel; D005472:Fluorouracil