Phase II and Biomarker Study of the Dual MET/VEGFR2 Inhibitor Foretinib in Patients With Papillary Renal Cell Carcinoma
Phase II and Biomarker Study of the Dual MET/VEGFR2 Inhibitor Foretinib in Patients With Papillary Renal Cell Carcinoma
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DOI：
10.1200/jco.2012.43.3383
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发表时间：
2013-01-10
影响因子：
45.3
通讯作者：
Srinivasan, Ramaprasad
中科院分区：
文献类型：
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作者：
Choueiri, Toni K.;Vaishampayan, Ulka;Srinivasan, Ramaprasad
目的福维替尼是一种针对MET、血管内皮生长因子、RON、Ax1和Tie-2受体的口服多激酶抑制剂。乳头状肾细胞癌(PRCC)患者中存在MET的激活突变或扩增。本研究的目的是评价福维替尼治疗原发性肝癌的疗效和安全性。患者和方法患者分为A组和B组，A组每天240 mg，每14天1~5天给药1次，B组每天80 mg，每日给药。根据MET通路的激活(胚系或体细胞MET突变、MET[7q31]扩增或7号染色体获得)对患者进行分层。主要终点是总有效率(ORR)。结果共纳入74例患者，每组37例。实体瘤反应评估标准(RECIST)1.0的ORR为13.5%，中位无进展生存期为9.3个月，未达到中位总生存期。胚系MET突变的存在对疗效具有很高的预测性(57例有胚系MET突变和无胚系MET突变的患者中，分别有5例和5例)。与福维替尼相关的任何级别的最常见不良事件是乏力、高血压、胃肠道毒性和非致死性肺栓。结论福维替尼在晚期PRCC患者中具有活性，毒性特征可控，在生殖系MET突变患者中有较高的应答率。J Clin Oncol31：181-186。(C)2012年美国临床肿瘤学会
PurposeForetinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC.Patients and MethodsPatients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR).ResultsOverall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli.ConclusionForetinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations. J Clin Oncol 31:181-186. (C) 2012 by American Society of Clinical Oncology