Leptomeningeal metastatic disease (LMD) is a severe complication of solid cancers with poor outcomes and limited treatment options. The antibody–drug conjugate patritumab deruxtecan (HER3-DXd) demonstrated efficacy in breast and lung cancers, and HER3 is involved in central nervous system metastases, particularly in parenchymal colonization. In this study, we investigated HER3-DXd efficacy and safety in patients with LMD in cohort 3 of the TUXEDO-3 phase 2 trial. Key eligibility criteria included age ≥18 years, treatment-naive LMD or LMD progressing after radiotherapy from any solid tumor and Eastern Cooperative Oncology Group performance status of 0–2. Between January and July 2024, 20 evaluable patients (nine with type I and 11 with type II LMD) were accrued and received HER3-DXd 5.6 mg kg⁻¹ intravenously every 3 weeks. Main primary tumor types included breast (60%) and lung (30%) cancers. Median follow-up time was 5.4 months. The primary endpoint was met with 65.0% patients alive after 3 months. The Kaplan–Meier-estimated 3-month and 6-month overall survival rates were 69.6% and 58.9%, respectively. Overall response rate was 11.1% for intracranial, 30.8% for extracranial and 26.3% for overall lesions. Clinical benefit rate was 50.0% for intracranial, 38.5% for extracranial and 47.4% for overall lesions. Neurological symptoms and quality of life remained stable or improved during study treatment. No new neurological adverse events were observed. The most common adverse events of any grade were anemia (nine (40.9%) patients, one (4.5%) grade ≥3), nausea (seven (31.8%) patients, no grade ≥3), neutropenia (six (27.3%) patients, three (13.6%) grade ≥3), diarrhea (six (27.3%) patients, one (4.5%) grade ≥3), asthenia (six (27.3%) patients, no grade ≥3) and thrombocytopenia and headache (five (22.7%) patients, one (4.5%) grade ≥3 each). TUXEDO-3 showed clinically relevant HER3-DXd activity in patients with LMD. ClinicalTrials.gov identifier: NCT05865990.

软脑膜转移性疾病 （LMD） 是实体癌的一种严重并发症，预后不良且治疗选择有限。抗体-药物偶联物 patritumab deruxtecan （HER3-DXd） 在乳腺癌和肺癌中显示出疗效，并且 HER3 参与中枢神经系统转移，尤其是在实质定植中。在这项研究中，我们调查了 TUXEDO-3 2 期试验队列 3 中 LMD 患者的 HER3-DXd 疗效和安全性。主要资格标准包括年龄 ≥18 岁、未接受过治疗的 LMD 或任何实体瘤放疗后进展的 LMD 以及 0-2 的东部肿瘤合作组体能状态。在 2024 年 1 月至 7 月期间，共招募了 20 名可评估患者 （9 名 I 型和 11 名 II 型 LMD），并接受了每 3 周静脉注射 HER3-DXd 5.6 mg kg ⁻¹ 。主要的原发性肿瘤类型包括乳腺癌 （60%） 和肺癌 （30%）。中位随访时间为 5.4 个月。达到主要终点，3 个月后存活率为 65.0%。Kaplan-Meier 估计的 3 个月和 6 个月总生存率分别为 69.6% 和 58.9%。颅内总缓解率为 11.1%，颅外为 30.8%，总病灶为 26.3%。颅内临床获益率为 50.0%，颅外为 38.5%，总病灶为 47.4%。在研究治疗期间，神经系统症状和生活质量保持稳定或改善。未观察到新的神经系统不良事件。 任何级别最常见的不良事件是贫血（9 例 （40.9%） 患者，1 例 （4.5%） ≥3 级）、恶心（7 例 （31.8%） 患者，无 ≥3 级）、中性粒细胞减少症（6 例 （27.3%） 患者，3 例 （13.6%） ≥3 级）、腹泻（6 例 （27.3%） 患者，1 例 （4.5%） ≥3 级）、乏力（6 例 （27.3%） 患者，无 ≥3 级）以及血小板减少症和头痛（5 例 （22.7%） 患者，各 1 例 （4.5%） ≥3 级）。TUXEDO-3 在 LMD 患者中显示出临床相关的 HER3-DXd 活性。ClinicalTrials.gov 标识符：NCT05865990。