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Belzutifan在ccRCC中的临床作用
作者:小柯机器人 发布时间:2021/4/25 13:44:49

美国德克萨斯州德克萨斯大学安德森分校癌症中心Eric Jonasch、美国达纳-法伯癌症研究所和哈佛医学院Toni K. Choueiri研究组合作取得最新进展。他们进行了一项1期试验和生物标志物分析,并发现belzutifan抑制缺氧诱导因子2α(HIF-2α)在肾细胞癌中的作用。该研究于2021年4月22日发表于国际一流学术期刊《自然-医学》杂志上。

HIF-2α是一种转录因子,经常在透明细胞肾细胞癌(ccRCC)中积累,导致与癌变有关的基因发生组成型激活。Belzutifan(MK-6482,以前称为PT2977)是一种有效的选择性HIF-2α小分子抑制剂。在这项人类第一个1期研究(NCT02974738)中,评估了belzutifan的最大耐受剂量、安全性、药代动力学、药效学和抗肿瘤活性。患者患有晚期实体瘤(剂量升高队列)或先前接受过治疗的晚期ccRCC(剂量扩展队列)。在ccRCC患者中,Belzutifan使用3+ 3剂量递增设计口服给药,然后以推荐的2期剂量(RP2D)进行扩展。

在剂量递增队列中(n = 43),每天一次至多160μmg的剂量没有发生剂量限制性毒性,并且未达到最大耐受剂量;RP2D每天120mg。在所有剂量下均观察到血浆促红细胞生成素减少。促红细胞生成素浓度与belzutifan血浆浓度相关。每天接受120μmg ccRCC的患者(n = 55),确定的客观缓解率为25%(全部为局部缓解),中位无进展生存期为14.5个月。最常见的≥3级不良事件为贫血(27%)和缺氧(16%)。

研究表明,Belzutifan具有良好的耐受性,并在大量接受预处理的患者中显示出初步的抗肿瘤活性,这表明抑制HIF-2α可能为ccRCC提供有效的治疗方法。

附:英文原文

Title: Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis

Author: Toni K. Choueiri, Todd M. Bauer, Kyriakos P. Papadopoulos, Elizabeth R. Plimack, Jaime R. Merchan, David F. McDermott, M. Dror Michaelson, Leonard J. Appleman, Sanjay Thamake, Rodolfo F. Perini, Naseem J. Zojwalla, Eric Jonasch

Issue&Volume: 2021-04-22

Abstract: Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor that frequently accumulates in clear cell renal cell carcinoma (ccRCC), resulting in constitutive activation of genes involved in carcinogenesis. Belzutifan (MK-6482, previously known as PT2977) is a potent, selective small molecule inhibitor of HIF-2α. Maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of belzutifan were evaluated in this first-in-human phase 1 study (NCT02974738). Patients had advanced solid tumors (dose-escalation cohort) or previously treated advanced ccRCC (dose-expansion cohort). Belzutifan was administered orally using a 3+3 dose-escalation design, followed by expansion at the recommended phase 2 dose (RP2D) in patients with ccRCC. In the dose-escalation cohort (n=43), no dose-limiting toxicities occurred at doses up to 160mg once daily, and the maximum tolerated dose was not reached; the RP2D was 120mg once daily. Plasma erythropoietin reductions were observed at all doses; erythropoietin concentrations correlated with plasma concentrations of belzutifan. In patients with ccRCC who received 120mg once daily (n=55), the confirmed objective response rate was 25% (all partial responses), and the median progression-free survival was 14.5 months. The most common grade ≥3 adverse events were anemia (27%) and hypoxia (16%). Belzutifan was well tolerated and demonstrated preliminary anti-tumor activity in heavily pre-treated patients, suggesting that HIF-2α inhibition might offer an effective treatment for ccRCC.

DOI: 10.1038/s41591-021-01324-7

Source: https://www.nature.com/articles/s41591-021-01324-7

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex