Tucatinib Combined With Ado-Trastuzumab Emtansine in Advanced ERBB2/HER2-PositiveMetastatic Breast Cancer A Phase 1b Clinical Trial
Tucatinib Combined With Ado-Trastuzumab Emtansine in Advanced ERBB2/HER2-PositiveMetastatic Breast Cancer A Phase 1b Clinical Trial
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DOI：
10.1001/jamaoncol.2018.1812
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发表时间：
2018-09-01
期刊：
影响因子：
28.4
通讯作者：
Hamilton, Erika
中科院分区：
文献类型：
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作者：
Borges, Virginia F.;Ferrario, Cristiano;Hamilton, Erika
对于使用曲妥珠单抗、pertuzumab和ado-trastuzumab emtansine(T-DM1)治疗后疾病进展的患者，重要的治疗选择有限。Tucatinib是一种口服、有效的人类表皮生长因子受体2(HER2)特异性酪氨酸激酶抑制剂(TKI)，正在开发用于ERBB2/HER2阳性乳腺癌的新疗法。目的确定Tucatinib联合T-DM1治疗ERBB2/HER2阳性转移性乳腺癌有脑转移和无脑转移患者的最大耐受量。2018年1月至3月，图卡替尼300 mg或350 mg口服，每日两次，共21天，T-DM1 3.6 mg/kg静脉注射，每21天一次。用RECIST 1.1评估安全性、药代动力学和反应。图卡替尼的最大耐受量被确定为每天两次，每次300毫克，限量毒性反应为350毫克，每天两次。药代动力学分析表明，T-DM1不存在药物-药物相互作用。在以最大耐受量治疗的50名患者中，无论因果关系如何，出现的不良事件包括恶心(36名患者；72%)、腹泻(30名患者；60%)、疲劳(28名患者；56%)、鼻出血(22名患者；44%)、头痛(22名患者；44%)、呕吐(21名患者；42%)、便秘(21名患者；42%)和食欲下降(20名患者；40%)；大多数不良事件为1级或2级。与图卡替尼有关的3级及以上毒性反应包括血小板减少(7名；14%)和肝脏转移性炎症(6名；结论：在本研究中，Tucatinib联合T-DM1似乎具有可接受的毒性，并且在有或没有脑转移的严重预治疗的ERBB2/HER2阳性转移性乳腺癌患者中显示出初步的抗肿瘤活性。
IMPORTANCE Treatment options for patients with disease progression after treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1) are limited. Tucatinib is an oral, potent, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor (TKI) being developed as a novel treatment for ERBB2/HER2-positive breast cancer.OBJECTIVE To determine the maximum tolerated dosage of tucatinib in combination with T-DM1 in the treatment of patients with ERBB2/HER2-positivemetastatic breast cancer with and without brain metastases.DESIGN, SETTING, AND PARTICIPANTS In this phase 1b open-label, multicenter, clinical trial, 57 participants enrolled between January 22, 2014, and June 22, 2015, were 18 years of age or older with ERBB2/HER2-positivemetastatic breast cancer previously treated with trastuzumab and a taxane. Data were analyzed between January and March 2018.INTERVENTIONS Tucatinib 300mg or 350mg administered orally twice per day for 21 days and T-DM1 3.6 mg/kg administered intravenously once every 21 days.MAIN OUTCOMES AND MEASURES Safety assessments, pharmacokinetics, and responsewere assessed using RECIST 1.1 every 2 cycles for 6 cycles, followed by every 3 cycles.RESULTS Fifty-seven T-DM1-naive patients (median [IQR] 51 [44.0-63.0] years of age) who had undergone a median of 2 earlier HER2 therapies (range, 1-3) were treated. The tucatinib maximum tolerated dosage was determined to be 300mg administered twice per day with dose-limiting toxic reactions seen at 350mg twice per day. Pharmacokinetic analysis showed that there was no drug-drug interaction with T-DM1. Adverse events seen among the 50 patients treated at the maximum tolerated dosage regardless of causality included nausea (36 patients; 72%), diarrhea (30 patients; 60%), fatigue (28 patients; 56%), epistaxis (22 patients; 44%), headache (22 patients; 44%), vomiting (21 patients; 42%), constipation (21 patients; 42%), and decreased appetite (20 patients; 40%); the majority of adverse events were grade 1 or 2. Tucatinib-related toxic reactions that were grade 3 and above included thrombocytopenia (7 patients; 14%) and hepatic transaminitis (6 patients; 12%).CONCLUSIONS AND RELEVANCE In this study, tucatinib in combination with T-DM1 appeared to have acceptable toxicity and to show preliminary antitumor activity among heavily pretreated patients with ERBB2/HER2-positivemetastatic breast cancer with and without brain metastases.