A phase II trial of a selective c-Met inhibitor tivantinib (ARQ 197) monotherapy as a second- or third-line therapy in the patients with metastatic gastric cancer
A phase II trial of a selective c-Met inhibitor tivantinib (ARQ 197) monotherapy as a second- or third-line therapy in the patients with metastatic gastric cancer
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DOI：
10.1007/s10637-013-0057-2
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发表时间：
2014-04-01
影响因子：
3.4
通讯作者：
Boku, Narikazu
中科院分区：
文献类型：
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作者：
Kang, Yoon-Koo;Muro, Kei;Boku, Narikazu
背景Tivantinib是一种选择性的、非ATP竞争性的c-Met小分子抑制剂，目前正在开发用于多种癌症，包括非小细胞肺癌和肝细胞癌。c-Met的激活在转移性胃癌（MGC）中经常被发现，并且与预后不良相关。在这项单组研究中，我们评估了tivantinib单药治疗既往接受过治疗的亚洲MGC患者的疗效。这是评价选择性c-Met抑制剂对MGC疗效的试验的第一份临床报告。患者和方法入选标准包括：MGC至少有一个可测量的病灶; 1或2个既往化疗方案; ECOG PS 0或1。Tivantinib每日口服给药。主要终点是疾病控制率（DCR）。收集治疗前肿瘤组织以评价与疗效相关的生物标志物。结果30例患者（包括1/2例既往胃切除术患者）接受了tivantinib治疗：中位年龄62.5岁; ECOG PS 0/1（8/22）; 1/2既往方案（16/14）。未观察到客观缓解，DCR为36.7%。中位无进展生存期为43天（95% CI：29.0-92.0）。13例患者（43.3%）发生了3级或4级不良事件，其中中性粒细胞减少（N = 4）和贫血（N = 4）被认为与药物相关。2例患者（6.9%）观察到c-Met基因扩增。未发现疗效与生物标志物（包括c-Met基因扩增、c-Met、p-Met和HGF表达）之间存在明显关系。结论替凡替尼单药治疗既往治疗过的MGC疗效不佳，需要进一步研究预测性生物标志物和/或与其他化疗药物联合治疗MGC。
Background Tivantinib is a selective, non-ATP competitive, small-molecule inhibitor of c-Met and is under development in several cancers including non-small cell lung and hepatocellular carcinoma. Activation of c-Met has been frequently found in metastatic gastric cancer (MGC) and is associated with poor prognosis. In this single-arm study, we evaluated the efficacy of tivantinib monotherapy in Asian patients with previously treated MGC. This is the first clinical report from the trials evaluating the efficacy of a selective c-Met inhibitor for MGC. Patients and methods Eligibility criteria included: MGC with at least one measurable lesion; 1 or 2 prior chemotherapy regimens; and ECOG PS 0 or 1. Tivantinib was daily administered orally. The primary endpoint was the disease control rate (DCR). Pre-treatment tumor tissue was collected to evaluate the biomarkers related to efficacy. Results Thirty patients, including 12 patients with prior gastrectomy, received tivantinib: median age 62.5 years; ECOG PS 0/1 (8/22); 1/2 prior regimen (16/14). No objective response was observed, and DCR was 36.7 %. Median progression-free survival was 43 days (95 % CI: 29.0-92.0). Grade 3 or 4 adverse events occurred in 13 patients (43.3 %), in whom neutropenia (N = 4) and anemia (N = 4) were recognized as drug-related. c-Met gene amplification was observed in 2 patients (6.9 %). No obvious relationship was identified between efficacy and biomarkers including gene amplification of c-Met, expression of c-Met, p-Met and HGF. Conclusion Tivantinib as a monotherapy showed a modest efficacy in previously treated MGC, and further studies taking account of predictive biomarkers and/or combination with other chemotherapy may be needed in MGC.