Ji Dongmei, Shen Weina, Zhang Jian, Cao Junning, Li Wenhua, Lam Lisa H, Wu Fan, Wang Bei, Li Zao, Sun Guofang, Hu Xichun, Chen Shang-Chiung
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
Genentech, Inc., South San Francisco, CA, USA.
Medicine (Baltimore). 2020 Oct 30;99(44):e22886. doi: 10.1097/MD.0000000000022886.
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that retains the antitumor effects of trastuzumab while also delivering the cytotoxic antimicrotubule agent, DM1, directly to tumor cells that overexpress human epidermal growth factor receptor 2. The pharmacokinetic (PK) profile of T-DM1 has been well characterized in Western, Asian, and Japanese patients; this single-center, phase I study (NCT03153163) examined the PK of T-DM1 and safety specifically in Chinese patients.
Patients with locally advanced or metastatic breast cancer, previously treated with trastuzumab and a taxane, received open-label T-DM1 at 3.6 mg/kg every 3 weeks. Serum T-DM1 and total trastuzumab, and plasma DM1 were evaluated, and PK parameters were calculated using standard noncompartmental approaches. Adverse events (AEs) were assessed, and immunogenicity was evaluated by measuring antidrug antibodies to T-DM1.
Among 11 Chinese patients, mean (±standard deviation) PK parameters (maximum serum concentration, 77.6 ± 17.4 μg/mL; clearance 11.0 ± 2.6 mL/d/kg; terminal half-life 3.8 ± 1.0 days) were similar to those previously reported in Western and Japanese patients. One patient transiently developed antidrug antibodies, which did not appear to influence safety or PK. T-DM1 was generally well tolerated. Grade 3-4 AEs occurred in 7 patients (63.6%) and serious AEs occurred in 4 patients (36.4%). Platelet count decrease was the most common all-grade AE (10/11; 90.9%), grade 3-4 AE (5/11; 45.5%), and serious AE (3/11; 27.3%), but did not appear to be associated with any clinically significant bleeding events.
T-DM1 PK in Chinese patients was consistent with those in global and Asian populations, supporting its use in patients with advanced human epidermal growth factor receptor 2-positive breast cancer following progression on trastuzumab and a taxane. The safety profile of T-DM1 was consistent with prior experience.
曲妥珠单抗-emtansine（T-DM1）是一种抗体药物偶联物，它保留了曲妥珠单抗的抗肿瘤作用，同时还能将细胞毒性抗微管药物DM1直接递送至过度表达人表皮生长因子受体2的肿瘤细胞。T-DM1的药代动力学（PK）特征已在西方、亚洲和日本患者中得到充分表征；这项单中心I期研究（NCT03153163）专门研究了中国患者中T-DM1的PK和安全性。
局部晚期或转移性乳腺癌患者，既往接受过曲妥珠单抗和紫杉烷治疗，每3周接受一次3.6mg/kg的开放标签T-DM1治疗。评估血清T-DM1和总曲妥珠单抗以及血浆DM1，并使用标准非房室方法计算PK参数。评估不良事件（AE），并通过测量针对T-DM1的抗药物抗体来评估免疫原性。
在11名中国患者中，平均（±标准差）PK参数（最大血清浓度，77.6±17.4μg/mL；清除率11.0±2.6mL/d/kg；末端半衰期3.8±1.0天）与先前在西方和日本患者中报告的参数相似。1名患者短暂产生了抗药物抗体，这似乎并未影响安全性或PK。T-DM1总体耐受性良好。7名患者（63.6%）发生3-4级AE，4名患者（36.4%）发生严重AE。血小板计数降低是最常见的所有级别AE（10/11；90.9%）、3-4级AE（5/11；45.5%）和严重AE（3/11；27.3%），但似乎与任何具有临床意义的出血事件无关。
中国患者中T-DM1的PK与全球和亚洲人群一致，支持其在曲妥珠单抗和紫杉烷治疗后进展的晚期人表皮生长因子受体2阳性乳腺癌患者中的应用。T-DM1的安全性概况与先前经验一致。
