Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center, Lebanon, NH.
KU Leuven and Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.
Clin Breast Cancer. 2019 Feb;19(1):47-57. doi: 10.1016/j.clbc.2018.09.012. Epub 2018 Oct 9.
Trebananib, a peptide-Fc fusion protein, blocks angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. Trebananib plus trastuzumab and paclitaxel was evaluated in human epidermal growth factor receptor 2-positive breast cancer in an open-label phase 1b clinical study.
Women with human epidermal growth factor receptor 2-positive breast cancer received weekly paclitaxel (80 mg/m), trastuzumab (8 mg/m then 6 mg/kg every 3 weeks), and intravenous trebananib (10 mg/kg or 30 mg/kg weekly) beginning week 2. The primary end point was the incidence of dose-limiting toxicities. Secondary end points included incidence of adverse events (AEs), pharmacokinetics, and tumor response (objective response and duration of response).
Forty women were enrolled; 2 experienced dose-limiting toxicities (grade 3 ocular transient ischemic attack [10 mg/kg cohort] and grade 3 elevation in γ-glutamyl transferase [30 mg/kg cohort]). The most common treatment-emergent AEs were peripheral edema (n = 28), diarrhea (n = 27), alopecia (n = 26), fatigue (n = 24), and nausea (n = 24). Maximum observed concentration and area under the concentration-time curve increased proportionally with the trebananib dose. Objective response was confirmed in 31 patients. In the 10 mg/kg cohort, 16 patients (80%) experienced partial response, and none experienced complete response. In the 30 mg/kg cohort, 12 patients (71%) experienced partial response and 3 (18%) experienced complete response. Median (95% confidence interval) duration of response in the 10 and 30 mg/kg cohorts was 12.6 (4.3-20.2) and 16.6 (8.2-not estimable) months, respectively.
This phase 1b study showed that trebananib was tolerated with manageable AEs at a dose up to 30 mg/kg weekly. Trebananib demonstrated anticancer activity, as indicated by objective response and duration of response.
Trebananib 是一种肽-Fc 融合蛋白，通过抑制血管生成素-1/2 与受体酪氨酸激酶 Tie2 的结合来抑制血管生成。在一项开放标签的 1b 期临床研究中，评估了 Trebananib 联合曲妥珠单抗和紫杉醇治疗人表皮生长因子受体 2 阳性乳腺癌。
人表皮生长因子受体 2 阳性乳腺癌患者每周接受紫杉醇（80mg/m）、曲妥珠单抗（8mg/m，然后每 3 周 6mg/kg）和静脉注射 Trebananib（10mg/kg 或 30mg/kg 每周），从第 2 周开始。主要终点是剂量限制毒性的发生率。次要终点包括不良反应（AE）的发生率、药代动力学和肿瘤反应（客观反应和反应持续时间）。
共入组 40 例患者；2 例患者发生剂量限制毒性（30mg/kg 队列中 1 例为 3 级眼短暂性缺血发作，10mg/kg 队列中 1 例为 3 级 γ-谷氨酰转移酶升高）。最常见的治疗相关不良事件为外周水肿（28 例）、腹泻（27 例）、脱发（26 例）、疲劳（24 例）和恶心（24 例）。最大观察浓度和浓度-时间曲线下面积与 Trebananib 剂量成正比增加。在 31 例患者中确认了客观反应。在 10mg/kg 队列中，16 例（80%）患者有部分缓解，无完全缓解。在 30mg/kg 队列中，12 例（71%）患者有部分缓解，3 例（18%）患者有完全缓解。10mg/kg 和 30mg/kg 队列的中位（95%置信区间）反应持续时间分别为 12.6（4.3-20.2）和 16.6（8.2-不可估计）个月。
这项 1b 期研究表明，Trebananib 每周最高达 30mg/kg 的剂量耐受良好，不良反应可管理。Trebananib 表现出抗癌活性，表现在客观反应和反应持续时间上。
