T-DM1治疗HER-2突变肺癌患者:一项II期篮式研究结果 | 引经据典[10] · 协和呼吸
本/期/解/读
T-DM1治疗HER-2突变肺癌患者:一项II期篮式研究结果
Ado-Trastuzumab Emtansine for Patients With HER2-
Mutant Lung Cancers: Results From a Phase II Basket Trial
作者:
Bob T. Li, et. al
翻译:
北京协和医院呼吸内科 高晓星 徐燕
文献来源:
J Clin Oncol, 2018: JCO2018779777.
DOI:
10.1200/JCO.2018.77.9777.
目 的
肺癌人群中2%存在人表皮生长因子受体2(HER2,ERBB2)突变。我们对HER2突变的肺癌队列进行了一项II期篮式研究,以了解T-DM1【注】对于HER2突变的肺癌患者的疗效。
注:T-DM1(ado-trastuzumab emtansine)为一种HER2抗体与微管抑制剂的偶联物,其中HER2抗体trastuzumab即为曲妥珠单抗,微管抑制剂又称DM1,故其简称T-DM1被广泛应用。
方 法
符合条件的受试者接受3周方案静脉T-DM1治疗直至病情进展,药物剂量为3.6mg/kg。依据实体瘤疗效评价标准(RECIST,版本1.1)对于患者的疗效进行评估,采用西蒙两级优化设计,主要终点为总体有效率,其他终点包括无进展生存期和药物副作用。HER2基因突变的检测手段包括高通量测序、荧光原位杂交、免疫组化及蛋白质谱分析。
结 果
本研究纳入病情进展的18例HER2基因突变的晚期肺癌患者,在使用T-DM1前的系统治疗方案中位数为2(区间为0-4)。T-DM1治疗的部分缓解率为44%(95%可信区间为22%-69%),达到了主要终点。在HER2基因20号外显子插入突变,激酶、跨膜及胞外结构域点突变的患者中有应答,同时2名患者存在HER2基因扩增。HER2免疫组化(0~++)对药物有效率无预测价值,蛋白质谱分析发现药物有效患者HER2蛋白表达较低。中位无进展生存期为5个月(95%可信区间为3-9个月)。药物不良反应包括1-2级输液反应,血小板减少症,肝转氨酶升高,但没有患者因药物不良反应或死亡而终止该研究。
图1 患者最佳疗效瀑布图(依据“实体肿瘤疗效评价标准”判断)
注:横坐标—患者;纵坐标—患者最佳疗效;蓝色—部分缓解,黄色—疾病稳定,灰色—疾病进展。
图2 患者无疾病进展生存时间
注:横坐标—治疗时间;纵坐标—患者;蓝色—部分缓解,黄色—疾病稳定,灰色—疾病进展,→箭头 —维持稳定,红色—获得部分缓解的起始时间。
表 HER2检测结果分析
注:FISH—荧光原位杂交;HER2—人表皮生长因子受体2;IHC—免疫组化;NA—无数据;NGS—高通量测序。
结 论
对于HER2突变的肺癌患者而言,T-DM1被证实为一种有效药物,这是针对HER2基因突变肺癌人群的首个阳性试验。但该药物的使用及研究仍需进一步证实。
原文摘要
Purpose
Human epidermal growth factor receptor 2 (HER2, ERBB2)–activating mutations occur in 2% of lung cancers. We assessed the activity of ado-trastuzumab emtansine, a HER2-targeted antibody-drug conjugate, in a cohort of patients with HER2-mutant lung cancers as part of a phase II basket trial.
Patients and Methods
Patients received ado-trastuzumab emtansine at 3.6 mg/kg intravenously every 3 weeks until progression. The primary end point was overall response rate using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A Simon two-stage optimal design was used. Other end points included progression-free survival and toxicity. HER2 testing was performed on tumor tissue by next generation sequencing, fluorescence in situ hybridization, immunohistochemistry, and protein mass spectrometry.
Results
We treated 18 patients with advanced HER2-mutant lung adenocarcinomas. The median number of prior systemic therapies was two (range, zero to four prior therapies). The partial response rate was 44% (95% CI, 22% to 69%), meeting the primary end point. Responses were seen in patients with HER2 exon 20 insertions and point mutations in the kinase, transmembrane, and extracellular domains. Concurrent HER2 amplification was observed in two patients. HER2 immunohistochemistry ranged from 0 to 2+ and did not predict response, and responders had low HER2 protein expression measured by mass spectrometry. The median progression-free survival was 5 months
(95% CI, 3 to 9 months). Toxicities included grade 1 or 2 infusion reactions, thrombocytopenia, and elevated hepatic transaminases. No patient stopped therapy as a result of toxicity or died on study.
Conclusion
Ado-trastuzumab emtansine is an active agent in patients with HER2-mutant lung cancers. This is the first positive trial in this molecular subset of lung cancers. Further use and study of this agent are warranted.
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作者介绍
高晓星
北京协和医院内科住院医师
临床医学博士,2015年毕业至今在北京协和医院内科工作,2018年夏被派往加州大学旧金山分校访问学习。
往期经典
文字来源:高晓星 徐燕
栏目负责:黄 慧
版面编辑:陈珂琪
图片来源:部分来源于网络,如有侵权,请联系删除
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