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

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 <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. 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/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 <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. 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. 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.