A phase 3 study of revumenib plus venetoclax/azacitidine in adults with newly diagnosed <i>NPM1</i> -mutated or <i>KMT2A</i> -rearranged acute myeloid leukemia ineligible for intensive chemotherapy (EVOLVE-2/HO177/AMLSG35-24/ACT-HOV-AML-002).

Abstract

TPS6600 Background: Optimal treatment for patients (pts) with acute myeloid leukemia (AML) unfit for intensive chemotherapy (IC) remains challenging and depends on pt and disease characteristics and pt preference. In AML with a nucleophosmin-1 mutation ( NPM1 m) or lysine methyltransferase 2A ( KMT2A ) rearrangement ( KMT2A r), menin-KMT2A fusion proteins upregulate HOX/MEIS gene expression, resulting in hematopoietic differentiation arrest and leukemogenesis. Revumenib is a first-in-class, oral, potent, and selective inhibitor of the menin-KMT2A interaction. In the phase 1/2 AUGMENT-101 study (NCT04065399), revumenib monotherapy demonstrated clinically meaningful response rates and was generally well tolerated in pts with relapsed/refractory NPM1 m AML or KMT2A r acute leukemia. To further improve outcomes, combination regimens are being studied as front-line therapy for newly diagnosed (ND) pts. In the phase 1b Beat AML study (NCT03013998), revumenib plus venetoclax/azacitidine (VEN/AZA) demonstrated deep responses in pts ≥60 years (y) of age with ND NPM1 m or KMT2A r AML. EVOLVE-2 will assess whether revumenib plus VEN/AZA prolongs overall survival (OS) and improves complete remission (CR) rates in pts with ND NPM1 m or KMT2A r AML ineligible for IC. Methods: EVOLVE-2 is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial (NCT06652438/EU-CT 2024-512733-32-00). Eligible pts are ≥75 y of age (18–74 y with comorbidities), have ND AML with centrally confirmed NPM1 m or KMT2A r (excluding KMT2A partial tandem duplications/deletions), are ineligible for IC, and are AML treatment-naive. Pts will be randomized 1:1 to revumenib or placebo in combination with VEN/AZA and stratified by age (&lt;75 vs ≥75 y), genotype ( NPM1 m vs KMT2A r), and region (Europe vs Australia vs United States). In Cycle (C) 1, VEN is given daily on Days (D) 1–28 and AZA daily on D1–7, ± revumenib twice daily on D1–28. In C2+, responders (per 2022 European LeukemiaNet criteria) may adjust VEN based on remission status/count recovery. Treatment continues until disease progression, unacceptable toxicity, pt withdrawal, or death. The dual primary endpoints are OS and CR rate. Key secondary endpoints include event-free survival and rate of CR/CR with partial hematologic recovery (CRh). Other endpoints include rates of CRh and CR/CR with incomplete hematologic recovery (CRi), measurable residual disease (MRD) negativity (CR, CR/CRh, CR/CRi with MRD negativity), time to/duration of response, adverse events, time to hematopoietic recovery, and incidence of platelet and red blood cell transfusions. Overall, 448 pts will be enrolled. As of January 27, 2026, the study is open to enrollment. Clinical trial information: NCT06652438 .