Department of Medicine, Division of Hematology, Oncology, Geffen School of Medicine, UCLA Medical Center, Los Angeles, California 90095, USA.
Clin Cancer Res. 2011 Nov 1;17(21):6905-13. doi: 10.1158/1078-0432.CCR-11-0288. Epub 2011 Oct 25.
Dasatinib is a potent, oral SRC-family kinase inhibitor with preclinical antiproliferative, antimetastatic, and antiosteoclastic activity suggesting dasatinib sensitivity in triple-negative, or basal-like, breast cancer cell lines. This phase 2 trial assessed efficacy and safety of single-agent dasatinib in patients with advanced triple-negative breast cancer (TNBC).
Female patients with measurable, locally advanced or metastatic TNBC initially received dasatinib 100 mg twice daily (BID); to improve tolerability, the protocol was amended and subsequent patients received 70 mg BID. Primary endpoint was Response Evaluation Criteria in Solid Tumors-defined objective response rate (ORR); secondary endpoints included progression-free survival (PFS), disease control rate (DCR), safety, and limited pharmacokinetics.
Of the 44 treated patients, 43 were response evaluable. ORR was 4.7%: two patients had confirmed partial responses lasting 14 and 58 weeks, respectively. Of 11 patients with stable disease, two continued for more than 16 weeks, thus protocol-defined DCR was 9.3%. Median PFS was 8.3 weeks (95% CI: 7.3-15.3). Five patients discontinued before first tumor assessment. No grade 4 adverse events (AE) were reported; grade 3 AEs occurring in more than 5% of patients were fatigue (9.1%), diarrhea, pleural effusion, and dyspnea (all 6.8%). Laboratory abnormalities were uncommon. Dasatinib at 100 mg BID was not well tolerated; rates of treatment interruption, dose reduction, and serious AEs were lower with dasatinib 70 mg BID.
Single-agent dasatinib has limited activity in unselected patients with TNBC. Dasatinib 70 mg BID was better tolerated than 100 mg BID. Future studies will investigate dasatinib in other breast cancer settings, including chemotherapy combinations.
达沙替尼是一种有效的、口服的 SRC 激酶家族抑制剂，具有抗增殖、抗转移和抗破骨活性，提示达沙替尼在三阴性或基底样乳腺癌细胞系中敏感。这项 2 期临床试验评估了单药达沙替尼治疗晚期三阴性乳腺癌（TNBC）患者的疗效和安全性。
女性可测量的局部晚期或转移性 TNBC 患者最初接受达沙替尼 100mg 每日两次（BID）；为了提高耐受性，方案进行了修改，随后的患者接受 70mg BID。主要终点是实体瘤反应评价标准定义的客观缓解率（ORR）；次要终点包括无进展生存期（PFS）、疾病控制率（DCR）、安全性和有限的药代动力学。
在 44 例接受治疗的患者中，43 例可进行疗效评估。ORR 为 4.7%：两名患者分别有确认的部分缓解，持续时间分别为 14 周和 58 周。11 例稳定疾病患者中，有 2 例持续时间超过 16 周，因此方案定义的 DCR 为 9.3%。中位 PFS 为 8.3 周（95%CI：7.3-15.3）。5 例患者在首次肿瘤评估前停药。无 4 级不良事件（AE）报告；3 级 AE 发生率超过 5%的有疲劳（9.1%）、腹泻、胸腔积液和呼吸困难（均为 6.8%）。实验室异常罕见。达沙替尼 100mg BID 耐受性不佳；达沙替尼 70mg BID 组的治疗中断、剂量减少和严重 AE 发生率较低。
单药达沙替尼在未经选择的 TNBC 患者中活性有限。达沙替尼 70mg BID 比 100mg BID 更耐受。未来的研究将在其他乳腺癌环境中研究达沙替尼，包括化疗联合治疗。
