Phase II Study of the Antibody Drug Conjugate Trastuzumab-DM1 for the Treatment of Human Epidermal Growth Factor Receptor 2 (HER2) -Positive Breast Cancer After Prior HER2-Directed Therapy
Phase II Study of the Antibody Drug Conjugate Trastuzumab-DM1 for the Treatment of Human Epidermal Growth Factor Receptor 2 (HER2) -Positive Breast Cancer After Prior HER2-Directed Therapy
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DOI：
10.1200/jco.2010.29.5865
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发表时间：
2011-02-01
影响因子：
45.3
通讯作者：
O'Shaughnessy, Joyce A.
中科院分区：
文献类型：
--
作者：
Burris, Howard A., III;Rugo, Hope S.;O'Shaughnessy, Joyce A.
抗体-药物偶联曲妥珠单抗-DM1 （T-DM1）结合了曲妥珠单抗的生物活性和靶向递送一种强效抗微生物小管药物DM1，用于人表皮生长因子受体2 （HER2）过表达的癌细胞。基于一项I期研究的结果显示，在先前接受曲妥珠单抗治疗的her2阳性转移性乳腺癌（MBC）患者中，每3周最大耐受剂量为3.6 mg/kg时T-DM1耐受性良好，并有疗效证据，我们进行了一项II期研究，以进一步确定T-DM1在该患者群体中的安全性和有效性。本报告描述了一项单臂II期研究（TDM4258g），该研究评估了静脉注射T-DM1 （3.6 mg/kg / 3周）对her2阳性MBC患者的有效性和安全性，这些患者在先前接受her2定向治疗后肿瘤进展，并且先前接受过化疗。结果112例患者随访bb0 = 12个月，独立评估客观有效率为25.9% （95% CI, 18.4% ~ 34.4%）。由于事件不足，中位反应持续时间未达到（95% CI下限，6.2个月），中位无进展生存时间为4.6个月（95% CI， 3.9至8.6个月）。回顾性中心检测（n = 74）证实her2阳性肿瘤（免疫组化3+或荧光原位杂交阳性）的患者应答率更高。通过HER2表达的定量逆转录酶聚合酶链反应，在肿瘤表达>=中位HER2水平的患者中，与HER2表达中位水平低于中位的患者相比，也观察到更高的应答率。T-DM1耐受性良好，无剂量限制性心脏毒性。大多数不良事件（ae）为1级或2级；最常见的>= 3级ae是低钾血症（8.9%）、血小板减少症（8.0%）和疲劳（4.5%）。结论T-DM1在重度预处理的her2阳性MBC患者中具有强大的单药活性，并且在推荐的II期剂量下具有良好的耐受性。中华临床杂志，29(3):398- 398。(C) 2010年由美国临床肿瘤学会出版
Purpose The antibody-drug conjugate trastuzumab-DM1 (T-DM1) combines the biologic activity of trastuzumab with targeted delivery of a potent antimicrotubule agent, DM1, to human epidermal growth factor receptor 2 (HER2)-overexpressing cancer cells. Based on results from a phase I study that showed T-DM1 was well tolerated at the maximum-tolerated dose of 3.6 mg/kg every 3 weeks, with evidence of efficacy, in patients with HER2-positive metastatic breast cancer (MBC) who were previously treated with trastuzumab, we conducted a phase II study to further define the safety and efficacy of T-DM1 in this patient population.Patients and Methods This report describes a single-arm phase II study (TDM4258g) that assessed efficacy and safety of intravenous T-DM1 (3.6 mg/kg every 3 weeks) in patients with HER2-positive MBC who had tumor progression after prior treatment with HER2-directed therapy and who had received prior chemotherapy.Results With a follow-up of >= 12 months among 112 treated patients, the objective response rate by independent assessment was 25.9% (95% CI, 18.4% to 34.4%). Median duration of response was not reached as a result of insufficient events (lower limit of 95% CI, 6.2 months), and median progression-free survival time was 4.6 months (95% CI, 3.9 to 8.6 months). The response rates were higher among patients with confirmed HER2-positive tumors (immunohistochemistry 3+ or fluorescent in situ hybridization positive) by retrospective central testing (n = 74). Higher response rates were also observed in patients whose tumors expressed >= median HER2 levels by quantitative reverse transcriptase polymerase chain reaction for HER2 expression, compared with patients who had less than median HER2 levels. T-DM1 was well tolerated with no dose-limiting cardiotoxicity. Most adverse events (AEs) were grade 1 or 2; the most frequent grade >= 3 AEs were hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%).Conclusion T-DM1 has robust single-agent activity in patients with heavily pretreated, HER2-positive MBC and is well tolerated at the recommended phase II dose. J Clin Oncol 29: 398-405. (C) 2010 by American Society of Clinical Oncology