Department of Neurology at The Feinberg School of Medicine at Northwestern University and The Malnati Brain Tumor Institute at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA.
Department of Anesthesiology, Emeritus Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Neuro Oncol. 2023 Mar 14;25(3):557-565. doi: 10.1093/neuonc/noac195.
Patients with human epidermal growth factor receptor 2-positive (HER2-positive) cancers have a high incidence of central nervous system (CNS) spread, but unfortunately systemic trastuzumab which targets the HER2 receptor has little CNS penetration. The purpose of this study was to determine the maximum-tolerated dose of intrathecal trastuzumab and its efficacy in patients with HER2-positive leptomeningeal disease (LMD).
This multicenter study enrolled 34 LMD patients in a combined phase I/II study in treating patients with intrathecal trastuzumab. Any HER2-positive histology was allowed in the phase I; the phase II was limited to HER2-positive breast cancer.
Intrathecal trastuzumab was well-tolerated, with one dose limiting toxicity of grade 4 (arachnoiditis) occurring at the 80 mg twice weekly dose. The recommended phase II dose was 80 mg intrathecally twice weekly. Twenty-six patients at dose level 80 mg were included in evaluation for efficacy: partial response was seen in 5 (19.2%) patients, stable disease was observed in 13 (50.0%), and 8 (30.8%) of the patients had progressive disease. Median overall survival (OS) for phase II dose treated patients was 8.3 months (95% CI 5.2-19.6). The phase II HER2-positive breast cancer patients median OS was 10.5 months (95% CI 5.2-20.9). Pharmacokinetic (PK) studies were limited in the setting of concurrent systemic trastuzumab administration, however, did show stable cerebrospinal fluid (CSF) concentrations with repeated dosing suggest that trastuzumab does not accumulate in the CSF in toxic concentrations.
This study suggests promise for potentially improved outcomes of HER-positive LMD patients when treated with intrathecal trastuzumab while remaining safe and well-tolerated for patients.
人表皮生长因子受体 2 阳性（HER2 阳性）癌症患者中枢神经系统（CNS）转移发生率高，但遗憾的是，针对 HER2 受体的曲妥珠单抗全身治疗对 CNS 的穿透力有限。本研究旨在确定鞘内注射曲妥珠单抗的最大耐受剂量及其在 HER2 阳性脑膜疾病（LMD）患者中的疗效。
这项多中心研究在一项治疗鞘内曲妥珠单抗的 I/II 期联合研究中纳入了 34 例 LMD 患者。I 期允许任何 HER2 阳性组织学；II 期仅限于 HER2 阳性乳腺癌。
鞘内曲妥珠单抗耐受性良好，80mg 每周两次的剂量出现 1 例 4 级（蛛网膜炎）剂量限制毒性。推荐的 II 期剂量为 80mg 每周两次鞘内注射。26 例 80mg 剂量水平的患者纳入疗效评估：5 例（19.2%）患者部分缓解，13 例（50.0%）患者病情稳定，8 例（30.8%）患者疾病进展。接受 II 期剂量治疗的患者中位总生存期（OS）为 8.3 个月（95%CI 5.2-19.6）。II 期 HER2 阳性乳腺癌患者的中位 OS 为 10.5 个月（95%CI 5.2-20.9）。在同时给予曲妥珠单抗全身治疗的情况下，药代动力学（PK）研究受到限制，但重复给药显示稳定的脑脊液（CSF）浓度表明曲妥珠单抗在 CSF 中不会以有毒浓度积累。
本研究表明，鞘内注射曲妥珠单抗可能为 HER 阳性 LMD 患者带来更好的预后，同时对患者安全且耐受性良好。
