PHASE II STUDIES

Investigational New Drugs

, Volume 32, Issue 6, pp 1285-1294

A Phase II study of bevacizumab in combination with trastuzumab and docetaxel in HER2 positive metastatic breast cancer

  • Meng ZhaoAffiliated withDivision of Medical Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University’s Wexner Medical Center, Starling-Loving Hall
  • , Xueliang PanAffiliated withCenter for Biostatistics, The Ohio State University
  • , Rachel LaymanAffiliated withDivision of Medical Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University’s Wexner Medical Center, Starling-Loving Hall
  • , Maryam B. LustbergAffiliated withDivision of Medical Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University’s Wexner Medical Center, Starling-Loving Hall
  • , Ewa MrozekAffiliated withDivision of Medical Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University’s Wexner Medical Center, Starling-Loving Hall
  • , Erin R. MacraeAffiliated withDivision of Medical Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University’s Wexner Medical Center, Starling-Loving Hall
  • , Robert WesolowskiAffiliated withDivision of Medical Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University’s Wexner Medical Center, Starling-Loving Hall
  • , Sarah CarothersAffiliated withDivision of Medical Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University’s Wexner Medical Center, Starling-Loving Hall
  • , Shannon PuhallaAffiliated withUniversity of Pittsburgh Medical Center
    • , Charles L. ShapiroAffiliated withDivision of Medical Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University’s Wexner Medical Center, Starling-Loving Hall
    • , Bhuvaneswari RamaswamyAffiliated withDivision of Medical Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University’s Wexner Medical Center, Starling-Loving Hall Email author 

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Summary

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. Objectives 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. Materials and 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 %). Conclusion 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.

Keywords

Bevacizumab Trastuzumab Docetaxel Metastatic breast cancer HER2