Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Clin Cancer Res. 2011 Nov 1;17(21):6897-904. doi: 10.1158/1078-0432.CCR-11-0070. Epub 2011 Sep 8.
SRC-family kinases (SFK) are involved in numerous oncogenic signaling pathways. A phase 2 trial of dasatinib, a potent oral tyrosine kinase inhibitor of SFKs, was carried out in patients with human epidermal growth factor receptor 2-positive (HER2+) and/or hormone receptor-positive (HR+) advanced breast cancer.
Patients with measurable tumors and progression after chemotherapy and HER2 and/or HR-targeted agents in adjuvant or metastatic settings (maximum of two prior metastatic setting regimens) received twice daily dasatinib. Primary endpoint was Response Evaluation Criteria in Solid Tumors-defined response rate. Secondary endpoints included toxicity and limited pharmacokinetics.
Seventy patients (55 years median age) were treated, 83% of HER2+ patients had received prior HER2-directed therapy, and 61% of HR+ patients had received prior endocrine therapy in the advanced setting. Dasatinib starting dose was reduced from 100 to 70 mg twice daily to limit toxicity. Median therapy duration was 1.8 months in both dose groups and most discontinuations were due to progression. Of 69 evaluable patients, three had confirmed partial responses and six had stable disease for 16 weeks or more (disease control rate = 13.0%); all nine of these tumors were HR+ (two were also HER2+). The most common drug-related toxicities were gastrointestinal complaints, headache, asthenia, and pleural effusion. Grade 3-4 toxicity occurred in 37% of patients and was comparable between doses; drug-related serious adverse events were less frequent with 70 mg twice daily than 100 mg twice daily.
Limited single-agent activity was observed with dasatinib in patients with advanced HR+ breast cancer.
Src 家族激酶（SFK）参与许多致癌信号通路。一项针对达沙替尼的 2 期临床试验，达沙替尼是一种强效的 SFK 口服酪氨酸激酶抑制剂，在人表皮生长因子受体 2 阳性（HER2+）和/或激素受体阳性（HR+）的晚期乳腺癌患者中进行。
有可测量肿瘤且在化疗后、HER2 和/或 HR 靶向药物（辅助或转移性治疗中最多两种转移性治疗方案）后进展的患者接受每日两次达沙替尼治疗。主要终点是实体瘤反应评估标准定义的反应率。次要终点包括毒性和有限的药代动力学。
70 例（中位年龄 55 岁）患者接受了治疗，83%的 HER2+患者接受了先前的 HER2 定向治疗，61%的 HR+患者在晚期接受了先前的内分泌治疗。为了限制毒性，达沙替尼的起始剂量从 100mg 每日两次减少到 70mg 每日两次。两个剂量组的中位治疗持续时间均为 1.8 个月，大多数停药是由于进展。在 69 例可评估患者中，有 3 例患者有确认的部分缓解，6 例患者有稳定的疾病持续 16 周或更长时间（疾病控制率=13.0%）；所有这 9 例肿瘤均为 HR+（其中 2 例也是 HER2+）。最常见的药物相关毒性是胃肠道不适、头痛、乏力和胸腔积液。37%的患者出现 3-4 级毒性，两个剂量组之间相似；与 100mg 每日两次相比，70mg 每日两次时药物相关严重不良事件的发生频率较低。
在 HR+晚期乳腺癌患者中，达沙替尼的单一药物活性有限。
