Vorasidenib和ivosidenib在IDH1突变低级别胶质瘤的围手术期随机化1期试验。
Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial.
发表日期：2023 Feb 23
作者：
Ingo K Mellinghoff, Min Lu, Patrick Y Wen, Jennie W Taylor, Elizabeth A Maher, Isabel Arrillaga-Romany, Katherine B Peters, Benjamin M Ellingson, Marc K Rosenblum, Saewon Chun, Kha Le, Ania Tassinari, Sung Choe, Youssef Toubouti, Steven Schoenfeld, Shuchi S Pandya, Islam Hassan, Lori Steelman, Jennifer L Clarke, Timothy F Cloughesy
来源：
NATURE MEDICINE
摘要：
Vorasidenib和ivosidenib能够抑制异柠檬酸脱氢酶（mIDH）的突变形式，并且已显示出对mIDH神经胶质瘤的初步临床活性。我们在围手术期1期试验中评估了这两种药物的作用机制，旨在探索复发性低级别胶质瘤的作用机制，并选择一种分子用于3期试验。主要终点是测量49名接受随机治疗的mIDH1-R132H非强化胶质瘤患者的肿瘤组织中D-2-羟基戊二酸（2-HG）的浓度，该代谢产物来自mIDH酶，治疗前分别给予vorasidenib（每日一次50mg或10mg）、ivosidenib（每日一次500mg或每天两次250mg）或不治疗。使用vorasidenib 50mg q.d.和ivosidenib 500mg q.d.治疗的患者在肿瘤2-HG浓度方面分别降低了92.6%（95%可信区间（CrI）为76.1-97.6）和91.1%（95%CrI为72.0-97.0）。两种药物均耐受良好，随访仍在进行中。在探索性分析中，2-HG减少与DNA 5-羟甲基脱氧胞苷、“倾向神经”和“干细胞”基因表达签名的逆转、肿瘤细胞增殖和免疫细胞激活的降低相关联。Vorasidenib具有脑渗透和更一致的2-HG抑制能力，因此被用于进行mIDH LGGs患者的3期测试。资助方为Agios Pharmaceuticals, Inc.和Servier Pharmaceuticals LLC；ClinicalTrials.gov编号为NCT03343197。 ©2023年作者/独家许可Springer Nature America, Inc.
Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDH glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of D-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1-97.6) and 91.1% (95% CrI, 72.0-97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of 'proneural' and 'stemness' gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.