JCO：贝伐单抗联合多西他赛及曲妥珠单抗不能改善乳腺癌患者无进展生存率

在2013年4月8日在线出版的《临床肿瘤学杂志》(Journal of Clinical Oncology)上，意大利米兰San Raffaele医院的Luca Gianni发文对AVEREL临床III期试验的结果进行了报告，AVEREL [阿瓦斯汀(贝伐单抗)联合赫赛汀(曲妥珠单抗)/多西他赛治疗HER2呈阳性的转移性乳腺癌患者]临床试验主要针对人表皮生长因子受体2(HER2)呈阳性的局部复发性/转移性乳腺癌(LR/MBC)患者，评价含贝伐单抗的一线治疗方案在此类患者中的应用情况。

AVEREL研究对象为HER2呈阳性的LR/MBC可测量/可评价患者，这些患者均未曾因LR/MBC接受过曲妥珠单抗或化疗方案治疗，根据患者所接受的前期辅助性曲妥珠单抗治疗、前期(新)辅助紫杉醇治疗、激素受体状态以及患者的病情评定结果，研究人员对参试患者进行了分层，患者在接受100 mg/m2多西他赛及负荷剂量为8 mg/kg的曲妥珠单抗联合治疗后，随机接受6 mg/kg曲妥珠单抗联合或不联合15 mg/kg的贝伐单抗治疗，每3周对所有患者进行给药。研究主要终点为无进展生存率(PFS)。其他终点包括总生存率、缓解率(RR)、安全性、生活治疗以及转化医学研究。

研究人员对治疗组424例患者间的基线特征进行了平衡。研究发现，多数患者存在内脏转移，43%的患者无病间隔期小于12个月，85%的患者病情可测。中位随访时间为26个月。根据研究人员评价，PFS风险比为0.82 (95% CI, 0.65至1.02; P = .0775; 中位PFS, 无贝伐单抗组13.7个月 v 贝伐单抗组16.5 个月; 72%的患者存在PFS事件)。根据独立评审委员会评价，PFS风险比为0.72 (95% CI, 0.54至 0.94; P = .0162; 中位 PFS分别为, 13.9个月 v 16.8 个月; 53%的患者存在PFS事件)。RR则分别为70%及74%(P = .3492)。含贝伐单抗治疗组更常见≥ 3级发热性中性粒细胞减少症及高血压。较高的血浆血管内皮生长因子A(VEGF-A)含量基线值与较大的贝伐单抗获益有关(无统计学意义上的显著性)。

最终经研究人员评价，贝伐单抗联合多西他赛及曲妥珠单抗方案并未显著改善患者PFS。此外，血浆VEGF-A的潜在预测值与在HER2呈阴性的LR/MBC患者结果一致，可据此进行前瞻性评价。
与乳腺癌相关的拓展阅读：

• Ann Intern Med：三苯氧胺和雷洛昔芬用于乳腺癌预防可获得"广泛获益"
• ASO：香港中文大学谢文杰发现纤维化病灶为乳腺癌不良预后因素
• J Clin Oncol：侵润性小叶乳腺癌：曲妥单抗疗效如何？
• 侵润性小叶乳腺癌：曲妥单抗疗效如何？
• JCO：乳腺癌“AVEREL”临床试验的阴性结果
• ANN INTERN MED：乳腺癌的药物性预防
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AVEREL: A Randomized Phase III Trial Evaluating Bevacizumab in Combination With Docetaxel and Trastuzumab as First-Line Therapy for HER2-Positive Locally Recurrent/Metastatic Breast Cancer.
PURPOSE
The AVEREL trial [A Study of Avastin (Bevacizumab) in Combination With Herceptin (Trastuzumab)/Docetaxel in Patients With HER2-Positive Metastatic Breast Cancer] evaluated first-line bevacizumab-containing therapy for human epidermal growth factor receptor 2 (HER2) -positive locally recurrent/metastatic breast cancer (LR/MBC).
PATIENTS AND METHODS
Patients with measurable/evaluable HER2-positive LR/MBC who had not received trastuzumab or chemotherapy for LR/MBC were stratified by prior adjuvant trastuzumab, prior (neo)adjuvant taxane, hormone receptor status, and measurable disease and were randomly assigned to receive docetaxel 100 mg/m2 plus trastuzumab 8 mg/kg loading dose followed by 6 mg/kg either with bevacizumab 15 mg/kg or without bevacizumab, all administered every 3 weeks. The primary end point was progression-free survival (PFS). Additional end points included overall survival, response rate (RR), safety, quality of life, and translational research.
Results
Baseline characteristics of the 424 patients were balanced between treatment arms. Most patients had visceral metastases, 43% had a disease-free interval less than 12 months, and 85% had measurable disease. Median follow-up was 26 months. The hazard ratio for investigator-assessed PFS was 0.82 (95% CI, 0.65 to 1.02; P = .0775; median PFS, 13.7 v 16.5 months in the non-bevacizumab and bevacizumab arms, respectively; PFS events in 72%). The Independent Review Committee-assessed PFS hazard ratio was 0.72 (95% CI, 0.54 to 0.94; P = .0162; median PFS, 13.9 v 16.8 months, respectively; PFS events in 53%). The RR was 70% versus 74%, respectively (P = .3492). Grade ≥ 3 febrile neutropenia and hypertension were more common with bevacizumab-containing therapy. High baseline plasma vascular endothelial growth factor A (VEGF-A) concentrations were associated with greater bevacizumab benefit (not statistically significant).
CONCLUSION
Combining bevacizumab with docetaxel and trastuzumab did not significantly improve investigator-assessed PFS. The potential predictive value of plasma VEGF-A is consistent with findings in HER2-negative LR/MBC, warranting prospective evaluation.