Harbeck Nadia, Ciruelos Eva, Jerusalem Guy, Müller Volkmar, Niikura Naoki, Viale Giuseppe, Bartsch Rupert, Kurzeder Christian, Higgins Michaela J, Connolly Roisin M, Baron-Hay Sally, Gión María, Guarneri Valentina, Bianchini Giampaolo, Wildiers Hans, Escrivá-de-Romaní Santiago, Prahladan Manoj, Bridge Helen, Kuptsova-Clarkson Nataliya, Scotto Nana, Verma Sunil, Lin Nancy U
Breast Center, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Munich, LMU University Hospital, Munich, Germany.
Hospital Universitario 12 de Octubre, Madrid, Spain.
Nat Med. 2024 Dec;30(12):3717-3727. doi: 10.1038/s41591-024-03261-7. Epub 2024 Sep 13.
Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2-positive (HER2) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2 mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs (n = 263) and no BMs (n = 241)) treated with one or more prior anti-HER2-based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9-67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9-65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5-68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade ≥3: 3%) of patients with BMs and 13% (grade ≥3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2 mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761 .
在患有人类表皮生长因子受体2阳性（HER2）晚期/转移性乳腺癌（mBC）且脑转移（BMs）稳定或活跃（未治疗/先前治疗且病情进展）的小样本或回顾性患者队列中，已观察到曲妥珠单抗德鲁昔单抗（T-DXd）的颅内活性。3b/4期DESTINY-Breast12研究调查了T-DXd在HER2 mBC患者中的情况，据我们所知，这是在这种情况下对T-DXd在BMs患者中进行的最大规模前瞻性研究。接受过一种或多种基于抗HER2方案治疗的患者（稳定/活跃的BMs患者（n = 263）和无BMs患者（n = 241））接受T-DXd（5.4 mg/kg）治疗。主要终点为无进展生存期（PFS；BMs队列）和根据实体瘤疗效评价标准1.1版的客观缓解率（ORR）（非BMs队列）。其他终点包括中枢神经系统（CNS）PFS、ORR、至第二次进展时间、CNS ORR（BMs队列）、新的有症状CNS转移的发生率（非BMs队列）、进展时间、缓解持续时间、总生存期和安全性（两个队列）。对于这项单臂、开放标签研究未进行正式的假设检验。在BMs队列中，12个月的PFS为61.6%（95%置信区间（CI）：54.9 - 67.6），12个月的CNS PFS为58.9%（95% CI：51.9 - 65.3）。在非BMs队列中，ORR为62.7%（95% CI：56.5 - 68.8）。51%（BMs队列）和49%（非BMs队列）的患者发生3级或更高等级的不良事件。研究者报告的间质性肺疾病/肺炎在有BMs的患者中发生率为16%（≥3级：3%），在无BMs的患者中发生率为13%（≥3级：1%）。这些数据显示T-DXd具有显著且持久的总体和颅内活性，支持其用于先前接受过治疗的HER2 mBC患者，无论基线BMs是稳定还是活跃。临床试验注册号：NCT04739761 。
