Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.
TriHealth Physician Partners, Cincinnati, OH, USA.
Cancer Chemother Pharmacol. 2019 Aug;84(2):327-336. doi: 10.1007/s00280-019-03879-2. Epub 2019 Jun 1.
Epidermal growth factor receptor variant III (EGFRvIII) is expressed in a significant percentage of primary and recurrent glioblastoma (GBM), a common malignant primary brain tumor in adults. AMG 595 is an antibody-drug conjugate comprising a fully human, anti-EGFRvIII monoclonal antibody linked to DM1. The study goals were to assess safety, tolerability, and pharmacokinetics of AMG 595 in GBM.
In this phase 1, first-in-human, open-label, sequential-dose, exploration study, adults with recurrent GBM received AMG 595 once every 3 weeks (Q3W) according to incremental dosing cohorts (0.5-3.0 mg/kg). Primary endpoints were to assess safety, the incidence of dose-limiting toxicities (DLTs), objective response (per Macdonald criteria), evaluate pharmacokinetics, and estimate the maximum tolerated dose (MTD).
Of 382 patients screened, 32 were enrolled and received ≥ 1 dose of AMG 595. Ten patients experienced 18 DLTs (all grade 4 thrombocytopenia), and the MTD was 2.0 mg/kg. Twenty-eight patients (88%) experienced ≥ 1 treatment-related adverse event (AE); the most common AEs were thrombocytopenia (50%) and fatigue (25%). Grade ≥ 3 treatment-related AEs occurred in 17 patients (53%); 11 (34%) had serious treatment-emergent AEs, and none were considered treatment related. Pharmacokinetic profiles indicated low levels of circulating unconjugated antibody and cytotoxin, dose-proportional increases in plasma exposures for the conjugated antibody over the studied range, and less than twofold accumulation following multiple Q3W dosing. Two patients (6%) had partial responses; 15 (47%) had stable disease.
AMG 595 exhibited favorable pharmacokinetics and is a unique therapy with possible benefit for some patients with EGFRvIII-mutated GBM with limited therapeutic options.
表皮生长因子受体变体 III（EGFRvIII）在相当一部分原发性和复发性胶质母细胞瘤（GBM）中表达，GBM 是成人中常见的恶性原发性脑肿瘤。AMG 595 是一种抗体药物偶联物，由与人 EGFRvIII 完全结合的单克隆抗体与 DM1 组成。该研究的目的是评估 AMG 595 在 GBM 中的安全性、耐受性和药代动力学。
在这项首次人体、开放性、序贯剂量、探索性研究中，复发性 GBM 患者根据递增剂量队列（0.5-3.0mg/kg）每 3 周（Q3W）接受一次 AMG 595 治疗。主要终点是评估安全性、剂量限制性毒性（DLT）发生率、客观缓解（根据 Macdonald 标准）、评估药代动力学和估计最大耐受剂量（MTD）。
在筛选的 382 名患者中，有 32 名入组并接受了至少 1 剂 AMG 595。10 名患者出现 18 例 DLT（均为 4 级血小板减少症），MTD 为 2.0mg/kg。28 名患者（88%）发生了≥1 次与治疗相关的不良事件（AE）；最常见的 AE 是血小板减少症（50%）和疲劳（25%）。17 名患者（53%）发生了≥3 级与治疗相关的 AE；11 名（34%）发生了严重的治疗突发 AE，但均与治疗无关。药代动力学特征表明，循环未结合抗体和细胞毒素水平较低，在所研究范围内，结合抗体的血浆暴露呈剂量比例增加，多次 Q3W 给药后累积不到两倍。2 名患者（6%）有部分缓解；15 名患者（47%）疾病稳定。
AMG 595 表现出良好的药代动力学特性，是一种独特的治疗方法，对一些 EGFRvIII 突变的 GBM 患者可能有一定的疗效，这些患者的治疗选择有限。
