在2012年12月3日在線(xiàn)出版的《臨床腫瘤學(xué)雜志》(Journal of ClinicalOncology)雜志上,，發(fā)表了美國(guó)國(guó)家癌癥研究所泌尿腫瘤學(xué)部Ramaprasad Srinivasan博士的一項(xiàng)臨床II期試驗(yàn)結(jié)果，該研究對(duì)foretinib用于乳頭狀腎細(xì)胞癌患者的療效與安全性進(jìn)行了評(píng)價(jià),。Foretinib對(duì)于晚期乳頭狀腎細(xì)胞癌患者具有活性,，并且其毒性可控，對(duì)存在胚系MET基因突變的患者具有較高的緩解率,。業(yè)已認(rèn)為,，乳頭狀腎細(xì)胞癌(PRCC)患者的MET基因會(huì)出現(xiàn)激活突變或擴(kuò)增。研究人員最終發(fā)現(xiàn),，F(xiàn)oretinib是一種靶點(diǎn)為MET,、VEGF、RON,、 AXL以及TIE-2受體的多激酶口服抑制劑,。該研究得到了葛蘭素史克公司的支持。
按不同的foretinib劑量安排,，研究人員將招募的患者分為兩個(gè)隊(duì)列：A組,，在每14天中的第1至第5天內(nèi)每日服用一次foretinib，每次240 mg (間歇給藥組),；B組,，每日80 mg(每日給藥組),。同時(shí)按MET通路活化的原理，對(duì)患者進(jìn)行分類(lèi)(胚系或體細(xì)胞MET突變,，MET [7q31]擴(kuò)增,，或發(fā)生于7號(hào)染色體上)。該研究主要終點(diǎn)為總緩解率(ORR),。
這項(xiàng)研究共招募了74例患者,，每個(gè)劑量組37例。按照實(shí)體瘤療效評(píng)價(jià)標(biāo)準(zhǔn)(RECIST) 1.0版本,，患者總緩解率為13.5%,，平均無(wú)進(jìn)展存活期為9.3個(gè)月，目前尚未獲得患者的平均整體存活期,。研究人員發(fā)現(xiàn),，出現(xiàn)胚系MET基因突變?yōu)椴∏榫徑馇闆r的強(qiáng)預(yù)測(cè)因素(10例患者中有5例患者存在胚系MET基因突變vs 57 例患者中有5例患者不存在胚系MET基因突變)。與foretinib相關(guān)的各級(jí)最常見(jiàn)不良事件為疲勞,、高血壓,、胃腸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.
