Royal Marsden National Health Service Foundation Trust, The Institute of Cancer Research, Sutton, Surrey, UK.
J Clin Oncol. 2011 Apr 1;29(10):1271-9. doi: 10.1200/JCO.2010.31.0367. Epub 2011 Mar 7.
The hepatocyte growth factor/c-MET axis is implicated in tumor cell proliferation, survival, and angiogenesis. ARQ 197 is an oral, selective, non-adenosine triphosphate competitive c-MET inhibitor. A phase I trial of ARQ 197 was conducted to assess safety, tolerability, and target inhibition, including intratumoral c-MET signaling, apoptosis, and angiogenesis.
Patients with solid tumors amenable to pharmacokinetic and pharmacodynamic studies using serial biopsies, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and circulating endothelial cell (CEC) and circulating tumor cell (CTC) enumeration were enrolled.
Fifty-one patients received ARQ 197 at 100 to 400 mg twice per day. ARQ 197 was well tolerated, with the most common toxicities being grade 1 to 2 fatigue, nausea, and vomiting. Dose-limiting toxicities included grade 3 fatigue (200 mg twice per day; n = 1); grade 3 mucositis, palmar-plantar erythrodysesthesia, and hypokalemia (400 mg twice per day; n = 1); and grade 3 to 4 febrile neutropenia (400 mg twice per day, n = 2; 360 mg twice per day, n = 1). The recommended phase II dose was 360 mg twice per day. ARQ 197 systemic exposure was dose dependent and supported twice per day oral dosing. ARQ 197 decreased phosphorylated c-MET, total c-MET, and phosphorylated focal adhesion kinase and increased terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) staining in tumor biopsies (n = 15). CECs decreased in 25 (58.1%) of 43 patients, but no significant changes in DCE-MRI parameters were observed after ARQ 197 treatment. Of 15 patients with detectable CTCs, eight (53.3%) had ≥ 30% decline in CTCs after treatment. Stable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST), ≥ 4 months was observed in 14 patients, with minor regressions in gastric and Merkel cell cancers.
ARQ 197 safely inhibited intratumoral c-MET signaling. Further clinical evaluation focusing on combination approaches, including an erlotinib combination in non-small-cell lung cancer, is ongoing.
肝细胞生长因子/c-MET 轴参与肿瘤细胞的增殖、存活和血管生成。ARQ 197 是一种口服、选择性、非三磷酸腺苷竞争 c-MET 抑制剂。进行了一项 ARQ 197 的 I 期试验，以评估安全性、耐受性和目标抑制作用，包括肿瘤内 c-MET 信号、细胞凋亡和血管生成。
纳入了可进行药代动力学和药效学研究的实体瘤患者，包括使用连续活检、动态对比增强磁共振成像（DCE-MRI）以及循环内皮细胞（CEC）和循环肿瘤细胞（CTC）计数。
51 名患者接受了 100 至 400 mg 每日两次的 ARQ 197 治疗。ARQ 197 耐受性良好，最常见的毒性为 1 至 2 级疲劳、恶心和呕吐。剂量限制性毒性包括 3 级疲劳（200 mg 每日两次；n=1）；3 级粘膜炎、手掌-足底红斑感觉异常和低钾血症（400 mg 每日两次；n=1）；以及 3 至 4 级发热性中性粒细胞减少症（400 mg 每日两次，n=2；360 mg 每日两次，n=1）。推荐的 II 期剂量为 360 mg 每日两次。ARQ 197 全身暴露与剂量相关，并支持每日两次口服给药。ARQ 197 降低了肿瘤活检中磷酸化 c-MET、总 c-MET 和磷酸化粘着斑激酶的水平，并增加了末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸-生物素切口末端标记（TUNEL）染色（n=15）。在 43 名可检测到 CEC 的患者中，有 25 名（58.1%）患者的 CEC 下降，但在 ARQ 197 治疗后未观察到 DCE-MRI 参数的显著变化。在 15 名可检测到 CTC 的患者中，有 8 名（53.3%）患者的 CTC 下降了≥30%。14 名患者根据实体瘤反应评估标准（RECIST）定义为疾病稳定，≥4 个月，胃和 Merkel 细胞癌有轻微消退。
ARQ 197 安全地抑制了肿瘤内 c-MET 信号。正在进行针对包括非小细胞肺癌中厄洛替尼联合治疗在内的联合治疗方法的进一步临床评估。
