Vaz Batista Marta, Pérez-García José Manuel, Garrigós Laia, García-Sáenz José Ángel, Cortez Patricia, Racca Fabricio, Blanch Salvador, Ruiz-Borrego Manuel, Fernández-Ortega Adela, Fernández-Abad María, Iranzo Vega, Gion María, Martrat Griselda, Alcalá-López Daniel, Pérez-Escuredo Jhudit, Sampayo-Cordero Miguel, Llombart-Cussac Antonio, Braga Sofia, Cortés Javier
Hospital Professor Doutor Fernando Fonseca EPE, Lisbon, Portugal; Medica Scientia Innovation Research (MEDSIR) - Oncoclínicas&Co, Jersey City, NJ, USA.
Medica Scientia Innovation Research (MEDSIR) - Oncoclínicas&Co, Jersey City, NJ, USA; International Breast Cancer Center (IBCC), Pangaea Oncology, Quiron Group, Barcelona, Spain.
Med. 2025 Jan 10;6(1):100502. doi: 10.1016/j.medj.2024.08.001. Epub 2024 Sep 11.
Leptomeningeal disease (LMD) is associated with poor survival and diminished quality of life. Trastuzumab deruxtecan (T-DXd) has shown remarkable intracranial and extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). The DEBBRAH trial was designed to evaluate its efficacy and safety in patients with HER2-positive and HER2-low ABC with a history of brain metastases (BMs) and/or LMD. Here, we report results from cohort 5, which specifically included patients with pathologically confirmed LMD.
This single-arm, open-label, five-cohort, phase 2 trial enrolled seven patients in cohort 5 who received 5.4 mg/kg T-DXd intravenously every 21 days until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Key secondary endpoints included progression-free survival (PFS) and safety profile.
At data cutoff (April 4, 2023), the median duration of follow-up was 12.0 months (range, 2.5-18.6). The median OS was 13.3 months (95% confidence interval [CI], 5.7-NA, p < 0.001), meeting the primary endpoint. The median PFS was 8.9 months (95% CI, 2.1-NA). Two (28.6%) of seven patients remained on treatment after 18.6 and 11.9 months, respectively. Of the five patients who progressed and died, none had intracranial progression or clinical worsening of leptomeningeal symptoms. Notably, 71.4% (95% CI, 29.0-96.3) achieved prolonged stabilization (≥24 weeks) by response evaluation criteria in solid tumors (RECIST) v.1.1. No unexpected safety signals and no treatment-related deaths were observed.
T-DXd showed promising antitumor activity in patients with HER2-positive and HER2-low ABC with previously untreated, pathologically confirmed LMD. These encouraging data warrant further investigation to address the unmet need in this difficult-to-treat condition.
This work was funded by Daiichi Sankyo/AstraZeneca. This trial is registered with ClinicalTrials.gov: NCT04420598.
软脑膜疾病（LMD）与生存率低和生活质量下降相关。曲妥珠单抗德鲁昔单抗（T-DXd）在人表皮生长因子受体2（HER2）阳性和HER2低表达的晚期乳腺癌（ABC）中显示出显著的颅内和颅外活性。DEBBRAH试验旨在评估其在有脑转移（BMs）和/或LMD病史的HER2阳性和HER2低表达ABC患者中的疗效和安全性。在此，我们报告队列5的结果，该队列专门纳入了经病理证实患有LMD的患者。
这项单臂、开放标签、五队列的2期试验在队列5中纳入了7名患者，他们每21天接受5.4mg/kg的T-DXd静脉注射，直至疾病进展或出现不可接受的毒性。主要终点是总生存期（OS）。关键次要终点包括无进展生存期（PFS）和安全性。
在数据截止（2023年4月4日）时，中位随访时间为12.0个月（范围2.5 - 18.6个月）。中位OS为13.3个月（95%置信区间[CI]，5.7 - NA，p < 0.001），达到主要终点。中位PFS为8.9个月（95% CI，2.1 - NA）。7名患者中有2名（28.6%）分别在18.6个月和11.9个月后仍在接受治疗。在5名病情进展和死亡的患者中，没有一人出现颅内进展或软脑膜症状的临床恶化。值得注意的是，根据实体瘤疗效评价标准（RECIST）v.1.1，71.4%（95% CI，29.0 - 96.3）的患者实现了长期病情稳定（≥24周）。未观察到意外的安全信号，也没有与治疗相关的死亡。
T-DXd在先前未经治疗、经病理证实患有LMD的HER2阳性和HER2低表达ABC患者中显示出有前景的抗肿瘤活性。这些令人鼓舞的数据值得进一步研究，以满足这种难治性疾病中未满足的需求。
本研究由第一三共/阿斯利康资助。该试验已在ClinicalTrials.gov注册：NCT04420598。
