在2012年12月3日在线出版的《临床肿瘤学杂志》(Journal of ClinicalOncology)杂志上，发表了美国国家癌症研究所泌尿肿瘤学部Ramaprasad Srinivasan博士的一项临床II期试验结果，该研究对foretinib用于乳头状肾细胞癌患者的疗效与安全性进行了评价。Foretinib对于晚期乳头状肾细胞癌患者具有活性，并且其毒性可控，对存在胚系MET基因突变的患者具有较高的缓解率。业已认为，乳头状肾细胞癌(PRCC)患者的MET基因会出现激活突变或扩增。研究人员最终发现，Foretinib是一种靶点为MET、VEGF、RON、 AXL以及TIE-2受体的多激酶口服抑制剂。该研究得到了葛兰素史克公司的支持。
按不同的foretinib剂量安排，研究人员将招募的患者分为两个队列：A组，在每14天中的第1至第5天内每日服用一次foretinib，每次240 mg (间歇给药组)；B组，每日80 mg(每日给药组)。同时按MET通路活化的原理，对患者进行分类(胚系或体细胞MET突变，MET [7q31]扩增，或发生于7号染色体上)。该研究主要终点为总缓解率(ORR)。
这项研究共招募了74例患者，每个剂量组37例。按照实体瘤疗效评价标准(RECIST) 1.0版本，患者总缓解率为13.5%，平均无进展存活期为9.3个月，目前尚未获得患者的平均整体存活期。研究人员发现，出现胚系MET基因突变为病情缓解情况的强预测因素(10例患者中有5例患者存在胚系MET基因突变vs 57 例患者中有5例患者不存在胚系MET基因突变)。与foretinib相关的各级最常见不良事件为疲劳、高血压、胃肠道毒性以及非致死性肺栓塞。(生物谷Bioon.com)
doi: 10.1200/JCO.2012.43.3383
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Phase II and Biomarker Study of the Dual MET/VEGFR2 Inhibitor Foretinib in Patients With Papillary Renal Cell Carcinoma
Toni K. Choueiri, Ulka Vaishampayan, Jonathan E. Rosenberg, Theodore F. Logan, Andrea L. Harzstark, Ronald M. Bukowski, Brian I. Rini, Sandy Srinivas, Mark N. Stein, Laurel M. Adams, Lone H. Ottesen, Kevin H. Laubscher, Laurie Sherman, David F. McDermott, Naomi B. Haas, Keith T. Flaherty, Robert Ross, Peter Eisenberg, Paul S. Meltzer, Maria J. Merino, Donald P. Bottaro, W. Marston Linehan and Ramaprasad Srinivasan
Purpose Foretinib 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 methods Patients 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). Results Overall, 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. Conclusion Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations.
