一项评估甲磺酸艾日布林联合曲妥珠单抗和帕妥珠单抗治疗人表皮生长因子受体 2（HER2）阳性转移性乳腺癌的疗效、毒性及基因组改变对疗效影响的 II 期研究。
A phase II study of efficacy, toxicity, and the potential impact of genomic alterations on response to eribulin mesylate in combination with trastuzumab and pertuzumab in women with human epidermal growth factor receptor 2 (HER2)+ metastatic breast cancer.
机构信息
The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Yawkey 1259, Boston, MA, 02215, USA.
出版信息
Breast Cancer Res Treat. 2021 Sep;189(2):411-423. doi: 10.1007/s10549-021-06329-x. Epub 2021 Jul 24.
PURPOSE
There are limited data on trastuzumab-pertuzumab (HP)-based treatments beyond the first-line, HER2+ metastatic breast cancer (MBC) setting. We conducted a phase II study of eribulin mesylate, which extends survival in MBC, with HP in patients with previously treated HER2+ MBC to evaluate efficacy, toxicity, and genomic alterations driving therapeutic response.
METHODS
After a run-in phase for eribulin dosing, two cohorts were enrolled (Cohort A-no prior pertuzumab; Cohort B-prior pertuzumab). All patients received eribulin 1.4 mg/m on days 1, 8 with standard-dose HP on day 1 (21-day cycles). The primary endpoint was objective response rate (ORR). Genomic characterization via whole exome sequencing (WES) was completed on tumor DNA and matched germline DNA from 19 patients.
RESULTS
The six-patient run-in established a dose of eribulin 1.4 mg/m with HP. Cohorts A and B enrolled 17 and 7 patients, respectively. Accrual stopped early due to an evolving treatment landscape and slow enrollment. The ORR was 26.3% (95% Confidence Interval [CI] 9.2-51.2%) in Cohort A and 0% in Cohort B (95% CI 0-41.0%). WES revealed more frequent alterations in TP53 (p < 0.05, q > 0.05) in patients without clinical benefit (disease control for < 24 weeks) which was not significant after multiple hypothesis correction.
CONCLUSION
Eribulin-HP had manageable toxicity and modest clinical activity in patients without prior pertuzumab exposure. This study provides a preliminary landscape of somatic alterations in this patient cohort. Our data add to the literature on how genomic alterations may predict for therapy response/resistance, as we work to individualize choices in a quickly evolving HER2+ MBC treatment landscape.
TRIAL REGISTRATION
www.clinicaltrials.gov , NCT01912963. Registered 24 July 2013.
目的
在二线及以上 HER2+转移性乳腺癌（MBC）治疗中，曲妥珠单抗-帕妥珠单抗（HP）的治疗数据有限。我们进行了一项亚甲磺酸艾日布林的 II 期研究，该研究显示亚甲磺酸艾日布林可延长 MBC 患者的生存时间，在先前接受过治疗的 HER2+MBC 患者中与 HP 联合使用，以评估疗效、毒性和驱动治疗反应的基因组改变。
方法
在亚甲磺酸艾日布林剂量调整的引入阶段后，招募了两个队列（队列 A-无先前的帕妥珠单抗；队列 B-先前有过帕妥珠单抗）。所有患者接受艾日布林 1.4mg/m2 治疗，第 1、8 天，第 1 天接受标准剂量的 HP（21 天周期）。主要终点为客观缓解率（ORR）。对 19 名患者的肿瘤 DNA 和匹配的种系 DNA 进行了全外显子组测序（WES）的基因组特征分析。
结果
六名患者的引入阶段确定了亚甲磺酸艾日布林 1.4mg/m2 与 HP 联合使用的剂量。队列 A 和 B 分别入组了 17 名和 7 名患者。由于治疗领域的不断发展和入组缓慢，提前停止了入组。队列 A 的 ORR 为 26.3%（95%置信区间 [CI] 9.2-51.2%），队列 B 为 0%（95% CI 0-41.0%）。WES 显示，在无临床获益（疾病控制时间<24 周）的患者中，TP53 改变更频繁（p<0.05，q>0.05），但在经过多次假设校正后并不显著。
结论
在没有先前暴露于帕妥珠单抗的患者中，艾日布林-HP 的毒性可管理，且具有适度的临床活性。这项研究提供了该患者队列中体细胞改变的初步情况。我们的数据增加了关于基因组改变如何预测治疗反应/耐药性的文献，因为我们努力在 HER2+MBC 治疗领域快速发展的情况下，使治疗选择个体化。
试验注册
www.clinicaltrials.gov，NCT01912963。2013 年 7 月 24 日注册。
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