BAT8001 在人表皮生长因子受体 2 阳性乳腺癌患者中的安全性、耐受性和药代动力学：一项开放标签、剂量递增、I 期研究。
Safety, tolerability, and pharmacokinetics of BAT8001 in patients with HER2-positive breast cancer: An open-label, dose-escalation, phase I study.
机构信息
Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China.
Biology Research Department, Bio-Thera Solutions, Ltd., Guangzhou, Guangdong, 510060, P. R. China.
出版信息
Cancer Commun (Lond). 2021 Feb;41(2):171-182. doi: 10.1002/cac2.12135. Epub 2021 Feb 2.
BACKGROUND
The introductions of anti- human epidermal growth factor receptor-2 (HER2) agents have significantly improved the treatment outcome of patients with HER2-positive breast cancer. BAT8001 is a novel antibody-drug conjugate targeting human epidermal growth factor receptor-2 (HER2)-expressing cells composed of a trastuzumab biosimilar linked to the drug-linker Batansine. This dose-escalation, phase I study was designed to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of BAT8001 in patients with HER2-positive locally advanced or metastatic breast cancer.
METHODS
This trial was conducted in subjects with histologically confirmed HER2-positive breast cancer (having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1) using a 3 + 3 design of escalating BAT8001 doses. Patients received BAT8001 intravenously in a 21-day cycle, with dose escalation in 5 cohorts: 1.2, 2.4, 3.6, 4.8, and 6.0 mg/kg. The primary objective was to evaluate the safety and tolerability of BAT8001. Preliminary activity of BAT8001 was also assessed as a secondary objective.
RESULTS
Between March 2017 to May 2018, 29 HER2-positive breast cancer patients were enrolled. The observed dose-limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase. The maximum tolerated dose was determined to be 3.6 mg/kg. Grade 3 or greater adverse events (AEs) occurred in 14 (48.3%) of 29 patients, including thrombocytopenia in 12 (41.4%) patients, aspartate aminotransferase increased in 4 (13.8%) patients, γ-glutamyl transferase increased in 2 (6.9%) patients, alanine aminotransferase increased in 2 (6.9%) patients, diarrhea in 2 (6.9%) patients. Objective response was observed in 12 (41.4%; 95% confidence interval [CI] = 23.5%-61.1%) and disease control (including patients achieving objective response and stable disease) was observed in 24 (82.8%; 95% CI = 64.2%-94.2%) patients.
CONCLUSIONS
BAT8001 demonstrated favorable safety profiles, with promising anti-tumor activity in patients with HER2-positive locally advanced or metastatic breast cancer. BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2-positive breast cancer.
背景
抗人表皮生长因子受体 2（HER2）药物的引入显著改善了 HER2 阳性乳腺癌患者的治疗效果。BAT8001 是一种新型的针对表达人表皮生长因子受体 2（HER2）的细胞的抗体药物偶联物，由与药物接头巴坦辛连接的曲妥珠单抗生物类似物组成。这项剂量递增、I 期研究旨在评估 BAT8001 在 HER2 阳性局部晚期或转移性乳腺癌患者中的安全性、耐受性、药代动力学和初步抗肿瘤活性。
方法
这项试验在组织学确认的 HER2 阳性乳腺癌患者（具有可评估的病变和东部合作肿瘤学组体能状态 0 或 1）中进行，采用 3+3 设计递增 BAT8001 剂量。患者以 21 天为一个周期静脉注射 BAT8001，剂量递增 5 个队列：1.2、2.4、3.6、4.8 和 6.0mg/kg。主要目的是评估 BAT8001 的安全性和耐受性。BAT8001 的初步活性也作为次要目标进行评估。
结果
2017 年 3 月至 2018 年 5 月期间，共纳入 29 例 HER2 阳性乳腺癌患者。观察到的剂量限制性毒性为 4 级血小板减少症和 3 级转氨酶升高。确定最大耐受剂量为 3.6mg/kg。29 例患者中有 14 例（48.3%）发生 3 级或更高级别的不良事件（AE），包括 12 例（41.4%）血小板减少症、4 例（13.8%）天门冬氨酸氨基转移酶升高、2 例（6.9%）γ-谷氨酰转移酶升高、2 例（6.9%）丙氨酸氨基转移酶升高、2 例（6.9%）腹泻。12 例（41.4%；95%置信区间[CI] = 23.5%-61.1%）患者观察到客观缓解，24 例（82.8%；95%CI = 64.2%-94.2%）患者观察到疾病控制（包括客观缓解和稳定疾病的患者）。
结论
BAT8001 表现出良好的安全性特征，在 HER2 阳性局部晚期或转移性乳腺癌患者中具有有希望的抗肿瘤活性。BAT8001 有可能为转移性 HER2 阳性乳腺癌患者提供新的治疗选择。
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