The DEBBRAH trial: Trastuzumab deruxtecan in HER2-positive and HER2-low breast cancer patients with leptomeningeal carcinomatosis.

IF 12.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Med Pub Date : 2024-09-04 DOI:10.1016/j.medj.2024.08.001

Marta Vaz Batista, José Manuel Pérez-García, Laia Garrigós, José Ángel García-Sáenz, Patricia Cortez, Fabricio Racca, Salvador Blanch, Manuel Ruiz-Borrego, Adela Fernández-Ortega, María Fernández-Abad, Vega Iranzo, María Gion, Griselda Martrat, Daniel Alcalá-López, Jhudit Pérez-Escuredo, Miguel Sampayo-Cordero, Antonio Llombart-Cussac, Sofia Braga, Javier Cortés

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Abstract

Background: 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.

Methods: 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.

Findings: 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.

Conclusions: 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.

Funding: This work was funded by Daiichi Sankyo/AstraZeneca. This trial is registered with ClinicalTrials.gov: NCT04420598.

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DEBBRAH 试验：曲妥珠单抗德鲁替康治疗 HER2 阳性和 HER2 阳性低的乳腺癌脑膜癌肿患者。

背景：多发性脑膜病（LMD）与生存率低和生活质量下降有关。曲妥珠单抗德鲁司坦（T-DXd）在人类表皮生长因子受体2（HER2）阳性和HER2低下的晚期乳腺癌（ABC）中显示出显著的颅内和颅外活性。DEBBRAH 试验的目的是评估该药物在有脑转移（BMs）和/或 LMD 病史的 HER2 阳性和 HER2 低度晚期乳腺癌患者中的疗效和安全性。在此，我们报告了第5组患者的结果，其中特别包括了经病理证实的LMD患者：这项单臂、开放标签、五组群的 2 期试验在组群 5 中招募了七名患者，每 21 天静脉注射一次 5.4 mg/kg T-DXd，直到疾病进展或出现不可接受的毒性。主要终点是总生存期（OS）。主要次要终点包括无进展生存期（PFS）和安全性：截至数据截止日（2023 年 4 月 4 日），中位随访时间为 12.0 个月（2.5-18.6 个月）。中位OS为13.3个月（95%置信区间[CI]，5.7-NA，P 结论：T-DXd显示出了良好的抗肿瘤前景：T-DXd 在 HER2 阳性和 HER2 低的 ABC 患者中显示出良好的抗肿瘤活性，这些患者既往未经治疗，病理证实为 LMD。这些令人鼓舞的数据值得进一步研究，以满足这一难以治疗的疾病的未满足需求：本研究由第一制药/阿斯利康资助。该试验已在 ClinicalTrials.gov 注册：NCT04420598。

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来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

期刊介绍： Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically. Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.