Pharmacokinetic (PK) assessment of revumenib in patients with relapsed/refractory (R/R) acute leukemias harboring a <i>KMT2A</i> rearrangement ( <i>KMT2A</i> r) or <i>NPM1</i> mutation ( <i>NPM1</i> m): Impact of food and concomitant medications.

Abstract

6528 Background: Revumenib is a first-in-class, oral, potent, and selective inhibitor of the menin-KMT2A interaction that disrupts multiple drivers of leukemogenesis such as KMT2A rearrangements ( KMT2A r) and NPM1 mutations ( NPM1 m). Revumenib is approved in the United States in patients 1 year and older for the treatment of R/R acute leukemia with a KMT2A translocation or R/R acute myeloid leukemia with a susceptible NPM1 mutation who have no satisfactory alternative treatment options. Given the severity of disease, frequent polypharmacy, and variable clinical status in this population, dosing flexibility is essential to support consistent treatment delivery and optimize outcomes. This analysis characterizes the PK of revumenib and its major metabolite (M1), with emphasis on factors that may influence dosing flexibility, including food and concomitant medications such as CYP3A4 inhibitors (CYP3A4i) and gastric acid–reducing agents such as antacids, H2 blockers (H2Bs), and proton pump inhibitors (PPIs). Methods: PK data were obtained from 286 adult (≥18 years) and 49 pediatric (&lt;18 years) patients with KMT2A r or NPM1 m acute leukemia enrolled in the phase 1/2 AUGMENT-101 trial (NCT04065399) following single and multiple doses of revumenib. Non-compartmental analyses were performed in selected subgroups, while population PK modeling was conducted using data from all patients to systematically quantify PK variability and evaluate covariate effects. Results: As compared to fasted state, a low-fat meal (400–500 calories with &lt;25% fat content) reduced revumenib C max and AUC by 27% and 12%, respectively, and M1 C max and AUC by 14% and 18%, respectively, although exposure ranges overlapped under fasted and fed (low-fat meal) conditions. Median T max was unchanged for revumenib and delayed by 1.8 hours for M1. Co-administration with strong CYP3A4i (eg, voriconazole, posaconazole, itraconazole) resulted in ~2-fold increase in revumenib C max and AUC, whereas moderate CYP3A4i (eg, fluconazole, isavuconazole) had no meaningful effect. M1 exposure was unaffected by strong or moderate CYP3A4i. Approximately 52% of patients received antacids, H2Bs, or PPIs; revumenib and M1 C max and AUC were not altered, consistent with the high solubility of revumenib across physiological pH range (1.2–6.8). Conclusions: Revumenib exposure increases ~2-fold with strong CYP3A4i, supporting dose reduction in this setting, while M1 exposure remains unaffected. Low-fat meals do not cause clinically meaningful changes in revumenib or M1 PK. Similarly, antacids, H2Bs, and PPIs, which are frequently used in this patient population, had no impact on revumenib or M1 PK. These findings reinforce the flexible administration of revumenib that may support treatment adherence and patient convenience. Clinical trial information: NCT04065399 .