MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-01-06 DOI:10.1038/s41467-024-55316-5

Mrinal Gounder, Melissa Johnson, Rebecca S. Heist, Geoffrey I. Shapiro, Sophie Postel-Vinay, Frederick H. Wilson, Elena Garralda, Gerburg Wulf, Caroline Almon, Salah Nabhan, Elia Aguado-Fraile, Peng He, Mathilde Romagnoli, Mohammad Hossain, Rohini Narayanaswamy, Amel Sadou-Dubourgnoux, Michael Cooper, Vasileios Askoxylakis, Howard A. Burris, Josep Tabernero

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Abstract

Homozygous MTAP deletion occurs in ~15% of cancers, making them vulnerable to decreases in the concentration of S-adenosylmethionine (SAM). AG-270/S095033 is an oral, potent, reversible inhibitor of methionine adenosyltransferase 2 A (MAT2A), the enzyme primarily responsible for the synthesis of SAM. We report results from the first-in-human, phase 1 trial of AG-270/S095033 as monotherapy in patients with advanced malignancies (ClinicalTrials.gov Identifier: NCT03435250). Eligible patients had tumors with homozygous deletion of CDKN2A/MTAP and/or loss of MTAP protein by immunohistochemistry. Patients received AG-270/S095033 once daily (QD) or twice daily (BID) in 28-day cycles. The primary objective was to assess the maximum tolerated dose (MTD) of AG-270/S095033. Secondary objectives included safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Forty patients were treated with AG-270/S095033. Plasma concentrations of AG-270/S095033 increased with dose. Maximal reductions in plasma SAM concentrations ranged from 54% to 70%. Analysis of paired tumor biopsies showed decreases in levels of symmetrically di-methylated arginine (SDMA) residues. Reversible increases in liver function tests, thrombocytopenia, anemia and fatigue were common treatment-related toxicities. Two partial responses were observed; five additional patients achieved radiographically confirmed stable disease for ≥16 weeks. AG-270/S095033 has a manageable safety profile. Our data provide preliminary evidence of clinical activity and proof-of-mechanism for MAT2A inhibition.

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MAT2A抑制剂AG-270/S095033用于晚期恶性肿瘤患者：一项I期试验

纯合子MTAP缺失发生在约15%的癌症中，使它们容易受到s -腺苷蛋氨酸（SAM）浓度降低的影响。AG-270/S095033是一种口服、有效、可逆的甲硫氨酸腺苷转移酶2a （MAT2A）抑制剂，该酶主要负责SAM的合成。我们报告了AG-270/S095033作为单药治疗晚期恶性肿瘤患者的首个人体一期试验结果（ClinicalTrials.gov标识符：NCT03435250）。通过免疫组化检测，符合条件的患者存在CDKN2A/MTAP纯合缺失和/或MTAP蛋白缺失。患者接受ag270 /S095033，每日1次（QD）或每日2次（BID），周期为28天。主要目的是评估AG-270/S095033的最大耐受剂量（MTD）。次要目标包括安全性、耐受性、药代动力学（PK）、药效学（PD）和疗效。40例患者接受AG-270/S095033治疗。AG-270/S095033血药浓度随剂量增加而升高。血浆SAM浓度最大降低幅度从54%到70%不等。配对肿瘤活检分析显示对称二甲基化精氨酸（SDMA）残基水平降低。肝功能检查可逆性增加、血小板减少、贫血和疲劳是常见的治疗相关毒性。观察到两个部分反应；另外5例患者经影像学证实病情稳定≥16周。AG-270/S095033具有可管理的安全配置文件。我们的数据为MAT2A抑制的临床活性和机制证明提供了初步证据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.