Department of Medicine, University of California, Los Angeles, California.
Department of Medicine, University of California, San Francisco, California.
Clin Cancer Res. 2017 Apr 15;23(8):1910-1919. doi: 10.1158/1078-0432.CCR-16-1418. Epub 2016 Oct 10.
The MET/HGF pathway regulates cell proliferation and survival and is dysregulated in multiple tumors. Emibetuzumab (LY2875358) is a bivalent antibody that inhibits HGF-dependent and HGF-independent MET signaling. Here, we report dose escalation results from the first-in-human phase I trial of emibetuzumab. The study comprised a 3+3 dose escalation for emibetuzumab monotherapy (Part A) and in combination with erlotinib (Part A2). Emibetuzumab was administered i.v. every 2 weeks (Q2W) using a flat dosing scheme. The primary objective was to determine a recommended phase II dose (RPTD) range; secondary endpoints included tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. Twenty-three patients with solid tumors received emibetuzumab monotherapy at 20, 70, 210, 700, 1,400, and 2,000 mg and 14 non-small cell lung cancer (NSCLC) patients at 700, 1,400, and 2,000 mg in combination with erlotinib 150 mg daily. No dose-limiting toxicities and related serious or ≥ grade 3 adverse events were observed. The most common emibetuzumab-related adverse events included mild diarrhea, nausea, and vomiting, and mild to moderate fatigue, anorexia, and hypocalcemia in combination with erlotinib. Emibetuzumab showed linear PK at doses >210 mg. Three durable partial responses were observed, one for emibetuzumab (700 mg) and two for emibetuzumab + erlotinib (700 mg and 2,000 mg). Both of the responders to emibetuzumab + erlotinib had progressed to prior erlotinib and were positive for MET protein tumor expression. Based on tolerability, PK/PD analysis, and preliminary clinical activity, the RPTD range for emibetuzumab single agent and in combination with erlotinib is 700 to 2,000 mg i.v. Q2W. .
MET/HGF 通路调节细胞增殖和存活，在多种肿瘤中失调。Emibetuzumab（LY2875358）是一种双价抗体，可抑制 HGF 依赖性和 HGF 非依赖性 MET 信号。在此，我们报告了首例人体 I 期临床试验的剂量递增结果，该试验包括 emibetuzumab 单药治疗（A 部分）和与厄洛替尼联合治疗（A2 部分）的 3+3 剂量递增。Emibetuzumab 采用静脉输注，每 2 周一次（Q2W），采用平剂量方案。主要目标是确定推荐的 II 期剂量（RPTD）范围；次要终点包括耐受性、药代动力学（PK）、药效学（PD）和抗肿瘤活性。23 例实体瘤患者接受了 20、70、210、700、1400 和 2000 mg 的 emibetuzumab 单药治疗，14 例非小细胞肺癌（NSCLC）患者接受了 700、1400 和 2000 mg 的 emibetuzumab 单药治疗，同时接受了 150 mg 厄洛替尼每日治疗。未观察到剂量限制毒性和相关严重或≥3 级不良事件。最常见的与 emibetuzumab 相关的不良事件包括轻度腹泻、恶心和呕吐，以及轻度至中度疲劳、厌食和低钙血症，与厄洛替尼联合使用时还会出现这些症状。在剂量>210mg 时，Emibetuzumab 显示出线性 PK。观察到 3 例持久的部分缓解，其中 1 例为 emibetuzumab（700mg），2 例为 emibetuzumab + erlotinib（700mg 和 2000mg）。对 emibetuzumab + erlotinib 有反应的两名患者均已进展至先前的 erlotinib 治疗，且对 MET 蛋白肿瘤表达呈阳性。基于耐受性、PK/PD 分析和初步临床活性，emibetuzumab 单药和与 erlotinib 联合使用的 RPTD 范围为 700 至 2000mg，静脉输注，每 2 周一次。
