Efficacy and safety of dasatinib with trastuzumab and paclitaxel in first line HER2-positive metastatic breast cancer: results from the phase II GEICAM/2010-04 study
Efficacy and safety of dasatinib with trastuzumab and paclitaxel in first line HER2-positive metastatic breast cancer: results from the phase II GEICAM/2010-04 study
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DOI：
10.1007/s10549-018-05100-z
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发表时间：
2019-04-01
影响因子：
3.8
通讯作者：
Ruiz-Borrego, Manuel
中科院分区：
文献类型：
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作者：
Ocana, Alberto;Gil-Martin, Marta;Ruiz-Borrego, Manuel
背景 很大一部分 HER2 阳性转移性乳腺癌患者对曲妥珠单抗没有反应。达沙替尼和曲妥珠单抗的组合已在临床前模型中显示出协同作用。方法我们进行了一项 II 期试验，将达沙替尼 100mg 每日一次与曲妥珠单抗 2mg/kg 和紫杉醇 80mg/m(2) 每周组合。主要目标是客观缓解率（ORR），次要目标包括安全性、其他疗效参数以及肿瘤组织、血液样本和皮肤活检中的药效学。结果从2013年6月至2015年12月，纳入了29名患者。中位周期数为 12 (1-49)。只有 6 名患者因不良事件而停药。 ORR 为 79.3% (95% CI 60.3-92)，临床获益率为 82.8% (95% CI 64.2-94.2)。中位进展时间为 23.9 个月（95% CI 14.9-未达到 [NR]），中位无进展生存期为 23.9 个月（95% CI 10.3-NR）。未发现 4 级毒性。 3级毒性包括：射血分数降低、中性粒细胞减少、低钠血症、疲劳和感觉神经病变以及一种左心室收缩功能障碍。外周血单核细胞中磷酸化 (p)-SRC 减少。表皮角质形成细胞中磷酸化的SRC、ERK和AKT也减少。结论达沙替尼可以安全地与曲妥珠单抗和紫杉醇联合使用。该组合具有活性，ORR 接近 80%。试验注册：NCT01306942，EudraCT 2010-023304-27。
BackgroundAn important proportion of HER2-positive metastatic breast cancer patients do not respond to trastuzumab. The combination of dasatinib and trastuzumab has shown to be synergistic in preclinical models.MethodsWe conducted a phase II trial combining dasatinib 100mg once daily with trastuzumab 2mg/kg and paclitaxel 80mg/m(2) weekly. Primary objective was objective response rate (ORR) and secondary included safety, other efficacy parameters and pharmacodynamics in tumour tissue, blood samples and skin biopsies.ResultsFrom June 2013 to December 2015, 29 patients were included. Median number of cycles was 12 (1-49). Only 6 patients discontinued due to adverse events. ORR was 79.3% (95% CI 60.3-92), clinical benefit rate 82.8% (95% CI 64.2-94.2). Median time to progression 23.9 months (95% CI 14.9-not reached [NR]), median progression-free survival 23.9months (95% CI 10.3-NR). No grade 4 toxicity was seen. Grade 3 toxicities included: ejection fraction decrease, neutropenia, hyponatremia, fatigue and sensory neuropathy and one left ventricular systolic dysfunction. Phosphorylated (p)-SRC was reduced in peripheral blood mononuclear cells. Phosphorylated SRC, ERK and AKT were also reduced in epidermal keratinocytes.ConclusionsDasatinib can be safely combined with trastuzumab and paclitaxel. The combination is active with an ORR of almost 80%. Trial registration: NCT01306942, EudraCT 2010-023304-27.