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

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 (