TY - JOUR
T1 - Menin Inhibition With Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101)
AU - Issa, Ghayas C.
AU - Aldoss, Ibrahim
AU - Thirman, Michael J.
AU - Dipersio, John
AU - Arellano, Martha
AU - Blachly, James S.
AU - Mannis, Gabriel N.
AU - Perl, Alexander
AU - Dickens, David S.
AU - Mcmahon, Christine M.
AU - Traer, Elie
AU - Zwaan, C. Michel
AU - Grove, Carolyn S.
AU - Stone, Richard
AU - Shami, Paul J.
AU - Mantzaris, Ioannis
AU - Greenwood, Matthew
AU - Shukla, Neerav
AU - Cuglievan, Branko
AU - Kovacsovics, Tibor
AU - Gu, Yu
AU - Bagley, Rebecca G.
AU - Madigan, Kate
AU - Chudnovsky, Yakov
AU - Nguyen, Huy Van
AU - Mcneer, Nicole
AU - Stein, Eytan M.
PY - 2025/1
Y1 - 2025/1
N2 - 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.
AB - 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.
KW - Mll
KW - Hox
KW - Aml
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=uwapure5-25&SrcAuth=WosAPI&KeyUT=WOS:001386096300002&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1200/JCO.24.00826
DO - 10.1200/JCO.24.00826
M3 - Article
C2 - 39121437
SN - 0732-183X
VL - 43
SP - 75
EP - 84
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 1
M1 - JCO.24.00826
ER -