Revumenib Demonstrates Clinical Benefit Among Patients With High-Risk, R/R KMT2Ar Acute Leukemia

Phase 1/2 Results from the AUGMENT Study

Revumenib, an oral, small molecule inhibitor of the menin-lysine methyltransferase 2A (KMT2A) interaction, demonstrated high remission rates with a predictable safety profile among patients with relapsed/refractory (R/R) KMT2Ar acute leukemia, according to results from the AUGMENT trial.

“[Acute myeloid leukemia] (AML), [acute lymphocytic leukemia], or mixed phenotype acute leukemia (MPAL) with KMT2A rearrangements (KMT2Ar) are associated with drug resistance and poor prognosis. The proportion of patients who achieve remission after 3 or more lines of therapy is < 10% in adults,” stated first study author Ghayas Issa, MD, The University of Texas MD Anderson Cancer Center, Houston, Texas, and colleagues.

This phase 1/2 open-label, dose-escalation and expansion study examined the use of revumenib for patients with R/R leukemias with KMT2Ar or NPM1 mutation and was conducted across 22 clinical sites in 5 countries. Eligible patients included those aged 30 days and older with R/R KMT2Ar acute leukemia or with AML and nucleophosmin 1 (NPM1) mutation, an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 to 2 for adults (on a scale from 0 to 5, with higher scores indicating greater disability) or a Karnofsky/Lansky score of more than 50 for children (on a scale from 0 to 100, with lower scores indicating greater disability), and bone marrow blasts ≥ 5% or reappearance of blasts in peripheral blood.

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. Primary end points included the rate of complete remission (CR) or CR with partial hematologic recovery (CR + CRh) and the evaluation of safety and tolerability of revumenib. At a prespecified interim analysis, the safety profile was assessed in all KMT2Ar treated patients, and efficacy was assessed in those with centrally confirmed KMT2Ar. Investigators noted the separate NPM1 cohort of the trial is ongoing. From October 1, 2021, to July 24, 2023, 94 patients with KMT2Ar acute leukemia received at least 1 dose of revumenib and were included in the safety population. This patient population included 78 patients (83%) with AML, 14 (14.9%) with ALL, and 2 (2.1%) patients with acute leukemia of ambiguous lineage. The median age was 37 years (range, 1.3 to 75), with 71 adults and 23 children (<18 years).

Results demonstrated an overall response rate of 63.2% (95% [confidence interval] CI, 49.3 to 75.6), with 15 of 22 patients (68.2%) having no detectable residual disease. Study authors noted that responses were rapid, with a median time to first overall response of 0.95 months (range, 0.9 to 2) and a median time to CR + CRh of 1.9 months (range, 0.9 to 4.6). The median duration of CR + CRh was 6.4 months (95% CI, 3.4 to not reached). With a median follow-up of 6.1 months (range, 0.3 to 18.6), the median overall survival was 8 months (95% CI, 4.1 to 10.9).

Overall, 93 patients (98.9%) had treatment-emergent adverse events with revumenib. Treatment-emergent adverse events leading to dose reduction or discontinuation occurred in 9.6% and 12.8% of patients, respectively. Adverse events that led to treatment discontinuation included septic shock (2%), respiratory failure (2%), intracranial hemorrhage (1%), sudden death (1%), AML (1%), cardiac failure (1%), febrile neutropenia (1%), myocardial ischemia (1%), pneumonia (1%), nausea (1%), and vomiting (1%). It was noted that, except for nausea and vomiting, these adverse events would generally not respond to dose modification.

Furthermore, it was noted that no patients discontinued revumenib because of prolongation of the QTc interval or differentiation syndrome. Adverse events while receiving revumenib or within 30 days of the last dose that led to death (grade 5) were reported in 14 of 94 patients (14.9%).

“In this phase 2 study, the oral menin inhibitor revumenib led to substantially greater rates of remission compared with historical controls in patients with high-risk, R/R KMT2Ar acute leukemia,” concluded Dr Issa and colleagues.

“Although sample sizes were small, efficacy was observed across subgroups, including age, lineage, prior venetoclax, and KMT2A translocation partner,” they added.

Source:

Issa G, Aldoss I, Thirman M, et al. Menin inhibition with revumenib for KMT2A-rearranged relapsed or refractory acute leukemia (AUGMENT-101). JCO. Published online August 9, 2024. doi: 10.1200/JCO.24.00826