Zhao Meng, Pan Xueliang, Layman Rachel, Lustberg Maryam B, Mrozek Ewa, Macrae Erin R, Wesolowski Robert, Carothers Sarah, Puhalla Shannon, Shapiro Charles L, Ramaswamy Bhuvaneswari
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.
Invest New Drugs. 2014 Dec;32(6):1285-94. doi: 10.1007/s10637-014-0122-5. Epub 2014 Jun 5.
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.
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.
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%).
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.
临床前和早期临床数据支持在人表皮生长因子受体2（HER2）阳性乳腺癌中使用针对血管内皮生长因子（VEGF）的曲妥珠单抗靶向治疗。在紫杉烷（多西他赛或紫杉醇）中添加贝伐单抗可改善转移性乳腺癌（MBC）患者的无进展生存期（PFS）。
我们评估了在接受过0 - 1种转移性疾病化疗方案的HER2阳性MBC患者中，将贝伐单抗与曲妥珠单抗和多西他赛联合使用的疗效和可行性。主要终点是PFS。
符合条件的患者每三周接受一次贝伐单抗（15 mg/kg）、曲妥珠单抗（8 mg/kg负荷剂量，随后为6 mg/kg）和多西他赛（最初100 mg/m²，后来调整为75 mg/m²），共六个周期，然后允许单独接受贝伐单抗和曲妥珠单抗。结果：26例入组患者中有13例（50%）完成了贝伐单抗、曲妥珠单抗和多西他赛的所有6个周期，并继续单独接受贝伐单抗和曲妥珠单抗（中位数：11个周期）。最常见的3级或4级毒性包括：中性粒细胞减少（8%）、感染性死亡（4%）、与中性粒细胞减少无关的感染（15%）、疲劳（27%）、肌痛和/或关节痛（20%）以及手足综合征（8%）。1例患者（4%）和6例患者（23%）分别出现3级和2级高血压。2例（8%）患者左心室射血分数（LVEF）出现短暂2级下降，随后完全恢复。中位无进展生存期（PFS）为14.3个月（95%CI：9.3 - 35个月），客观缓解率（ORR）定义为完全缓解（CR）或部分缓解（PR）的最佳反应为（12/26）46%。临床获益率（CBR）定义为CR或PR或疾病稳定（SD）至少24周的最佳反应为（18/26）69%（95%CI：48 - 86%）。
贝伐单抗、曲妥珠单抗和多西他赛联合使用耐受性良好，在HER2阳性MBC患者中具有临床活性，缓解率和PFS与之前使用更高剂量多西他赛（100 mg/m²）的报道相当。最近的随机试验未显示在曲妥珠单抗和多西他赛中添加贝伐单抗能带来额外的总生存期（OS）获益，尽管PFS有所改善。在乳腺癌抗VEGF的进一步研究中应纳入预测生物标志物的识别和仔细的患者选择。
