Menin Inhibition With Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101).

IF 42.1 1区医学 Q1 ONCOLOGY

Journal of Clinical Oncology Pub Date : 2025-01-01 Epub Date: 2024-08-09 DOI:10.1200/JCO.24.00826

Ghayas C Issa, Ibrahim Aldoss, Michael J Thirman, John DiPersio, Martha Arellano, James S Blachly, Gabriel N Mannis, Alexander Perl, David S Dickens, Christine M McMahon, Elie Traer, C Michel Zwaan, Carolyn S Grove, Richard Stone, Paul J Shami, Ioannis Mantzaris, Matthew Greenwood, Neerav Shukla, Branko Cuglievan, Tibor Kovacsovics, Yu Gu, Rebecca G Bagley, Kate Madigan, Yakov Chudnovsky, Huy Van Nguyen, Nicole McNeer, Eytan M Stein

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引用次数: 0

Abstract

Purpose: Revumenib, an oral, small molecule inhibitor of the menin-lysine methyltransferase 2A (KMT2A) interaction, showed promising efficacy and safety in a phase I study of heavily pretreated patients with KMT2A-rearranged (KMT2Ar) acute leukemia. Here, we evaluated the activity of revumenib in individuals with relapsed/refractory (R/R) KMT2Ar acute leukemia.

Methods: AUGMENT-101 is a phase I/II, open-label, dose-escalation and expansion study of revumenib conducted across 22 clinical sites in five countries (ClinicalTrials.gov identifier: NCT04065399). We report results from the phase II, registration-enabling portion. Individuals age ≥30 days with R/R KMT2Ar acute leukemia or with AML and nucleophosmin 1 (NPM1) mutation were enrolled. Revumenib was administered once every 12 hours, at 163 mg (95 mg/m² if weight <40 kg) with a strong cytochrome P450 inhibitor, in 28-day cycles. The primary end points were the rate of complete remission (CR) or CR with partial hematologic recovery (CR + CRh) and safety. At a prespecified interim analysis, safety was assessed in all KMT2Ar treated patients; efficacy was assessed in those with centrally confirmed KMT2Ar. The separate NPM1 cohort of the trial is ongoing.

Results: From October 1, 2021, to July 24, 2023, N = 94 patients (median [range] age, 37 [1.3-75] years) were treated. Grade ≥3 adverse events included febrile neutropenia (37.2%), differentiation syndrome (16.0%), and QTc prolongation (13.8%). In the efficacy-evaluable patients (n = 57), the CR + CRh rate was 22.8% (95% CI, 12.7 to 35.8), exceeding the null hypothesis of 10% (P = .0036). Overall response rate was 63.2% (95% CI, 49.3 to 75.6), with 15 of 22 patients (68.2%) having no detectable residual disease.

Conclusion: Revumenib led to high remission rates with a predictable safety profile in R/R KMT2Ar acute leukemia. To our knowledge, this trial represents the largest evaluation of a targeted therapy for these patients.

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用Revumenib抑制Menin治疗KMT2A累及的复发性或难治性急性白血病（AUGMENT-101）。

研究目的Revumenib是一种口服的门苷-赖氨酸甲基转移酶2A（KMT2A）相互作用小分子抑制剂，在一项针对KMT2A重排（KMT2Ar）急性白血病重度预处理患者的I期研究中显示出良好的疗效和安全性。在此，我们评估了 revumenib 在复发/难治（R/R）KMT2Ar 急性白血病患者中的活性：AUGMENT-101是revumenib的一项I/II期、开放标签、剂量递增和扩展研究，在5个国家的22个临床研究机构进行（ClinicalTrials.gov标识符：NCT04065399）。我们报告的是 II 期注册促成部分的结果。年龄≥30天的R/R KMT2Ar急性白血病患者或急性髓细胞白血病患者以及核糖蛋白1 (NPM1)突变者均被纳入研究。Revumenib每12小时给药一次，剂量为163毫克（如果体重为KMT2Ar，剂量为95毫克/平方米）；对中心确诊的KMT2Ar患者进行疗效评估。该试验的独立 NPM1 队列正在进行中：从2021年10月1日到2023年7月24日，N = 94名患者（中位年龄[范围]为37 [1.3-75]岁）接受了治疗。≥3级不良事件包括发热性中性粒细胞减少（37.2%）、分化综合征（16.0%）和QTc延长（13.8%）。在疗效有效的患者（n = 57）中，CR + CRh 率为 22.8%（95% CI，12.7 至 35.8），超过了 10%的无效假设（P = .0036）。总体反应率为63.2%（95% CI，49.3至75.6），22名患者中有15名（68.2%）未检测到残留疾病：结论：Revumenib治疗R/R KMT2Ar急性白血病的缓解率高，且安全性可预测。据我们所知，该试验是针对这些患者的靶向治疗的最大规模评估。

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

Journal of Clinical Oncology 医学-肿瘤学

CiteScore

41.20

自引率

2.20%

发文量

8215

审稿时长

2 months

期刊介绍： The Journal of Clinical Oncology serves its readers as the single most credible, authoritative resource for disseminating significant clinical oncology research. In print and in electronic format, JCO strives to publish the highest quality articles dedicated to clinical research. Original Reports remain the focus of JCO, but this scientific communication is enhanced by appropriately selected Editorials, Commentaries, Reviews, and other work that relate to the care of patients with cancer.