Dasatinib as a Single Agent in Triple-Negative Breast Cancer: Results of an Open-Label Phase 2 Study
Dasatinib as a Single Agent in Triple-Negative Breast Cancer: Results of an Open-Label Phase 2 Study
复制标题
DOI：
10.1158/1078-0432.ccr-11-0288
复制
发表时间：
2011-11-01
影响因子：
11.5
通讯作者：
Goldstein, Lori J.
中科院分区：
文献类型：
--
作者：
Finn, Richard S.;Bengala, Carmelo;Goldstein, Lori J.
目的：达沙替尼是一种有效的口服src家族激酶抑制剂，具有临床前抗增殖、抗转移和抗破骨活性，表明达沙替尼对三阴性或基底样乳腺癌细胞系敏感。该2期临床试验评估了单药达沙替尼在晚期三阴性乳腺癌（TNBC）患者中的疗效和安全性。实验设计：可测量的、局部晚期或转移性TNBC的女性患者最初接受达沙替尼100mg，每日两次（BID）；为了提高耐受性，对方案进行了修改，随后患者接受了70 mg BID。主要终点为实体瘤反应评价标准——定义客观反应率（ORR）；次要终点包括无进展生存期（PFS）、疾病控制率（DCR）、安全性和有限药代动力学。结果：44例患者中，43例可评价疗效。ORR为4.7%：两名患者确认部分缓解持续时间分别为14周和58周。在11例病情稳定的患者中，2例持续超过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止治疗。无4级不良事件（AE）报告；超过5%的患者发生3级不良事件，包括疲劳（9.1%）、腹泻、胸腔积液和呼吸困难（均为6.8%）。实验室异常不常见。达沙替尼100mg BID耐受不良；达沙替尼70mg BID组的治疗中断率、剂量减少率和严重不良事件发生率较低。结论：单药达沙替尼在未选择的TNBC患者中具有有限的活性。达沙替尼70mg BID比100mg BID耐受性好。未来的研究将调查达沙替尼在其他乳腺癌情况下的作用，包括化疗组合。临床癌症研究；17 (21);6905 - 13所示。AACR (C) 2011。
Purpose: 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).Experimental Design: 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.Results: 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.Conclusions: 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. Clin Cancer Res; 17(21); 6905-13. (C)2011 AACR.