脑转移 (BM) 是 HER2 阳性转移性乳腺癌 (BC) 的毁灭性并发症，迫切需要提供优化的局部和全身疾病控制的治疗策略。与曲妥珠单抗 emtansine 相比，抗体药物偶联物 (ADC) 曲妥珠单抗 deruxtecan (T-DXd) 改善了无进展生存期 (PFS) 和总生存期 (OS)，但有关颅内活性的数据有限。在 TUXEDO-1 的主要结果分析中，T-DXd 具有较高的颅内缓解率 (RR)。在这里，我们报告最终的 PFS 和 OS 结果。TUXEDO-1 招募了 HER2 阳性 BC 和活动性 BM（新诊断或进展）的成年患者，没有立即局部治疗的指征。主要终点是颅内 RR；次要终点包括 PFS、OS、安全性、生活质量 (QoL) 和神经认知功能。使用 Kaplan-Meier 方法估计 PFS 和 OS，并在符合方案的人群中进行分析。中位随访 26.5 个月时，中位 PFS 为 21 个月（95% CI 13.3-n.r.），中位 OS 尚未达到（95% CI 22.2-n.r.）。随着随访时间的延长，没有观察到新的安全信号。最常见的 3 级不良事件是疲劳（20%）。各一名患者出现 2 级间质性肺疾病和 3 级症状性左心室射血分数下降。治疗期间维持了生活质量。T-DXd 对 HER2 阳性 BC BM 患者的颅内和颅外疾病产生了延长的控制，这与关键试验的结果一致。这些结果支持 ADC 作为活动性 BM 系统治疗的概念。© 作者 2024。由牛津大学出版社代表神经肿瘤学会出版。

Brain metastases (BM) are a devastating complication of HER2-positive metastatic breast cancer (BC) and treatment strategies providing optimized local and systemic disease control are urgently required. The antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) and overall survival (OS) over trastuzumab emtansine but data regarding intracranial activity is limited. In the primary outcome analysis of TUXEDO-1, a high intracranial response rate (RR) was reported with T-DXd. Here, we report final PFS and OS results.TUXEDO-1 accrued adult patients with HER2-positive BC and active BM (newly diagnosed or progressing) without indication for immediate local therapy. The primary endpoint was intracranial RR; secondary endpoints included PFS, OS, safety, quality-of-life (QoL), and neurocognitive function. PFS and OS were estimated with the Kaplan-Meier method and analysed in the per-protocol population.At 26.5 months median follow-up, median PFS was 21 months (95% CI 13.3-n.r.) and median OS was not reached (95% CI 22.2-n.r.). With longer follow-up, no new safety signals were observed. The most common grade 3 adverse event was fatigue (20%). Grade 2 interstitial lung disease and a grade 3 symptomatic drop of left-ventricular ejection fraction were observed in one patient each. QoL was maintained over the treatment period.T-DXd yielded prolonged intra- and extracranial disease control in patients with active HER2-positive BC BM in line with results from the pivotal trials. These results support the concept of ADCs as systemic therapy for active BM.© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.