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

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.

FIG 1.

Flow diagram for participants with relapsed or refractory KMT2Ar acute leukemia who received revumenib. At the time of the interim analysis for the phase II KMT2Ar population, 95 patients were enrolled in the KMT2Ar cohorts. An additional 92 patients had been screened for inclusion in the study but failed the screening. The reasons for screening failure are listed in the Data Supplement (Table S4). ^aUpon review following data cutoff, these patients were confirmed to have elevated bone marrow blasts and were therefore included in the safety population. KMT2Ar, lysine methyltransferase 2A rearranged; PR, partial remission.

FIG 2.

Duration of treatment. Treatment course of revumenib in patients with KMT2Ar relapsed or refractory acute leukemia. Time to response, duration of treatment, and patient status by the data cutoff date for patients in the efficacy population (n = 57). Dotted lines indicate patients who resumed post-transplant maintenance at the time of data cutoff. CR, complete remission; CRh, CR with partial hematologic recovery; CRi, CR with incomplete hematologic recovery; CRp, CR with incomplete platelet recovery; HSCT, hematopoietic stem cell transplant; KMT2Ar, lysine methyltransferase 2A-rearranged; MLFS, morphological leukemia-free state; PR, partial remission.

FIG 3.

Duration of response and OS. The data cutoff date for this analysis was July 24, 2023. (A) The Kaplan-Meier estimate of duration of CR + CRh in 13 patients with CR + CRh. Duration of CR + CRh was defined as the date of first documented CR + CRh to the first documented confirmed relapse or death. The at-risk population at any specific time point was defined as patients with CR + CRh, up to that time point, who had not experienced relapse, death, or a censoring event. (B) The Kaplan-Meier estimate of overall survival in patients with KMT2Ar acute leukemia in the efficacy population. CR, complete remission; CRh, CR with partial hematologic recovery; KMT2Ar, lysine methyltransferase 2A-rearranged; NR, not reached: OS, overall survival.