title: A Phase II study of bevacizumab in combination with trastuzumab and docetaxel in HER2 positive metastatic breast cancer.
abstract: BACKGROUND
  Preclinical and early clinical data support the use of Vascular Epithelial Growth Factor (VEGF)-targeted therapy with trastuzumab in Human Epidermal Receptor 2 (HER2) positive breast cancer. Adding bevacizumab to a taxane (docetaxel or paclitaxel) improves progression free survival (PFS) of metastatic breast cancer (MBC) patients.
  
  
  OBJECTIVE
  We evaluated the efficacy and feasibility of combining bevacizumab with trastuzumab and docetaxel in patients with HER2- positive MBC who received 0-1 prior chemotherapy regimens for metastatic disease. The primary end point was PFS.
  
  
  METHODS
  Eligible patients received bevacizumab (15 mg/kg), trastuzumab (8 mg/kg loading dose followed by 6 mg/kg), and docetaxel (100 mg/m2 initially, later amended to 75 mg/m2) every three weeks for six cycles and then were allowed to receive bevacizumab and trastuzumab alone. Results Thirteen (50%) of 26 patients enrolled completed all 6 cycles of bevacizumab, trastuzumab and docetaxel and went on to receive bevacizumab and trastuzumab alone (median: 11 cycles). The most common grade 3 or 4 toxicities include: neutropenia (8%), septic death (4%), infection not associated with neutropenia (15%), fatigue (27%), mylagia and/or arthraligia (20%), and hand-foot syndrome (8%). One patient (4%) and six patients (23%) developed grade 3 and grade 2 hypertension, respectively. Two (8%) patients had transient grade 2 drop in Left Ventricular Ejection Fraction (LVEF) with full recovery later. The median progression free survival (PFS) was 14.3 months (95% CI: 9.3-35 months), the objective response rate (ORR), defined as the best response of complete response (CR) or partial response (PR) was (12/26) 46%. The clinical benefit rate (CBR), defined as the best response of CR or PR or stable disease (SD) for at least 24 weeks, was (18/26) 69% (95% CI: 48-86%).
  
  
  CONCLUSIONS
  The combination of bevacizumab, trastuzumab and docetaxel is well tolerated and is clinically active in patients with HER2-positive MBC, with response rate and PFS comparable to previous reports utilizing higher dose of docetaxel (100 mg/m2). Recent randomized trials did not demonstrate additional overall survival (OS) benefit of adding bevacizumab to trastuzumab and docetaxel despite an improvement in PFS. Identification of predictive biomarkers and careful patient selection should be incorporated in further investigation of anti-VEGF in breast cancer.
authors.affiliation: Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University's Wexner Medical Center, Starling-Loving Hall, 320 W 10th Ave, Columbus, OH, 43210, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhao
authors.forename: Xueliang
authors.initials: X
authors.lastname: Pan
authors.forename: Rachel
authors.initials: R
authors.lastname: Layman
authors.forename: Maryam B
authors.initials: MB
authors.lastname: Lustberg
authors.forename: Ewa
authors.initials: E
authors.lastname: Mrozek
authors.forename: Erin R
authors.initials: ER
authors.lastname: Macrae
authors.forename: Robert
authors.initials: R
authors.lastname: Wesolowski
authors.forename: Sarah
authors.initials: S
authors.lastname: Carothers
authors.forename: Shannon
authors.initials: S
authors.lastname: Puhalla
authors.forename: Charles L
authors.initials: CL
authors.lastname: Shapiro
authors.forename: Bhuvaneswari
authors.initials: B
authors.lastname: Ramaswamy
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D000077143:Docetaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C508053:ERBB2 protein, human