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
{"title":"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）。","authors":"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","doi":"10.1200/JCO.24.00826","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>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 <i>KMT2A</i>-rearranged (<i>KMT2Ar</i>) acute leukemia. Here, we evaluated the activity of revumenib in individuals with relapsed/refractory (R/R) <i>KMT2Ar</i> acute leukemia.</p><p><strong>Methods: </strong>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 <i>KMT2Ar</i> acute leukemia or with AML and nucleophosmin 1 (<i>NPM1</i>) mutation were enrolled. Revumenib was administered once every 12 hours, at 163 mg (95 mg/m<sup>2</sup> 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 <i>KMT2Ar</i> treated patients; efficacy was assessed in those with centrally confirmed <i>KMT2Ar</i>. The separate <i>NPM1</i> cohort of the trial is ongoing.</p><p><strong>Results: </strong>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% (<i>P</i> = .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.</p><p><strong>Conclusion: </strong>Revumenib led to high remission rates with a predictable safety profile in R/R <i>KMT2Ar</i> acute leukemia. To our knowledge, this trial represents the largest evaluation of a targeted therapy for these patients.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"75-84"},"PeriodicalIF":42.1000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Menin Inhibition With Revumenib for <i>KMT2A</i>-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101).\",\"authors\":\"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\",\"doi\":\"10.1200/JCO.24.00826\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>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 <i>KMT2A</i>-rearranged (<i>KMT2Ar</i>) acute leukemia. Here, we evaluated the activity of revumenib in individuals with relapsed/refractory (R/R) <i>KMT2Ar</i> acute leukemia.</p><p><strong>Methods: </strong>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 <i>KMT2Ar</i> acute leukemia or with AML and nucleophosmin 1 (<i>NPM1</i>) mutation were enrolled. Revumenib was administered once every 12 hours, at 163 mg (95 mg/m<sup>2</sup> 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 <i>KMT2Ar</i> treated patients; efficacy was assessed in those with centrally confirmed <i>KMT2Ar</i>. The separate <i>NPM1</i> cohort of the trial is ongoing.</p><p><strong>Results: </strong>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% (<i>P</i> = .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.</p><p><strong>Conclusion: </strong>Revumenib led to high remission rates with a predictable safety profile in R/R <i>KMT2Ar</i> acute leukemia. To our knowledge, this trial represents the largest evaluation of a targeted therapy for these patients.</p>\",\"PeriodicalId\":15384,\"journal\":{\"name\":\"Journal of Clinical Oncology\",\"volume\":\" \",\"pages\":\"75-84\"},\"PeriodicalIF\":42.1000,\"publicationDate\":\"2025-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Clinical Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1200/JCO.24.00826\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/8/9 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1200/JCO.24.00826","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/9 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Menin Inhibition With Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101).
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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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.
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