Journal article
Menin Inhibition With Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101)
Journal of clinical oncology, Vol.43(1), pp.75-84
01/2025
DOI: 10.1200/JCO.24.00826
PMCID: PMC11687943
PMID: 39121437
Abstract
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.PURPOSERevumenib, 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.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.METHODSAUGMENT-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.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.RESULTSFrom 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.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.CONCLUSIONRevumenib 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.
Details
- Title: Subtitle
- Menin Inhibition With Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101)
- Creators
- Ghayas C Issa - The University of Texas MD Anderson Cancer CenterIbrahim Aldoss - City Of Hope National Medical CenterMichael J Thirman - University of ChicagoJohn DiPersio - Washington University in St. LouisMartha Arellano - Emory UniversityJames S Blachly - The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research InstituteGabriel N Mannis - Stanford UniversityAlexander Perl - University of PennsylvaniaDavid S Dickens - University of IowaChristine M McMahon - University of Colorado HealthElie Traer - Oregon Health & Science UniversityC Michel Zwaan - Princess Máxima CenterCarolyn S Grove - Sir Charles Gairdner HospitalRichard Stone - Dana-Farber Cancer InstitutePaul J Shami - Huntsman Cancer InstituteIoannis Mantzaris - Albert Einstein College of MedicineMatthew Greenwood - Royal North Shore HospitalNeerav Shukla - Memorial Sloan Kettering Cancer CenterBranko Cuglievan - The University of Texas MD Anderson Cancer CenterTibor Kovacsovics - Goodyear (United States)Yu Gu - Synta Pharmaceuticals (United States)Rebecca G Bagley - Synta Pharmaceuticals (United States)Kate Madigan - Synta Pharmaceuticals (United States)Yakov Chudnovsky - Synta Pharmaceuticals (United States)Huy Van NguyenNicole McNeer - Synta Pharmaceuticals (United States)Eytan M Stein - Memorial Sloan Kettering Cancer Center
- Resource Type
- Journal article
- Publication Details
- Journal of clinical oncology, Vol.43(1), pp.75-84
- DOI
- 10.1200/JCO.24.00826
- PMID
- 39121437
- PMCID
- PMC11687943
- NLM abbreviation
- J Clin Oncol
- ISSN
- 1527-7755
- eISSN
- 1527-7755
- Publisher
- LIPPINCOTT WILLIAMS & WILKINS
- Grant note
- Syndax Pharmaceuticals, Inc.
The authors would like to thank the study participants, their families, all investigational site members involved in this study, and Alex Bataller, MD, PhD for assistance with the gene expression figure. Writing and editorial support were provided under the direction of the authors by Ella A. Kasanga, PhD, PMP, and Stephanie Roulias, ELS, of MedThink SciCom, and funded by Syndax Pharmaceuticals, Inc.
- Language
- English
- Electronic publication date
- 08/09/2024
- Date published
- 01/2025
- Academic Unit
- Stead Family Department of Pediatrics; Hematology/Oncology
- Record Identifier
- 9984696659302771
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