Ziftomenib (menin inhibitor) + venetoclax/azacitidine drives 46% CRc and frequent MRD negativity in R/R NPM1-mut AML

Ziftomenib is a potent, selective, oral menin inhibitor evaluated with venetoclax (BCL-2 inhibitor) plus azacitidine (hypomethylating agent) in KOMET-007, a Phase 1a/1b dose-escalation/expansion study in adults with relapsed/refractory (R/R) NPM1-mutated AML (n=67; median age 66; median 1 prior line; 55% prior venetoclax; 22% prior transplant; NCT05735184). At the selected ziftomenib 600mg dose, composite complete remission (CRc) was 46% (22/48) with central MRD negativity (<0.01%) in 67% (12/18) of MRD-evaluable responders; CRc was 70% (16/23) in venetoclax-naïve vs 24% (6/25) in venetoclax-exposed patients, with MRD negativity 75% (9/12) vs 50% (3/6), respectively; median duration of response was 8.6 months and median OS was not reached. Grade ≥3 TEAEs ≥20% were leukopenia (34%), thrombocytopenia (28%), febrile neutropenia (25%), and neutropenia (25%); QTc prolongation occurred in 6 patients (1 ziftomenib-related, grade 1) and differentiation syndrome in 2 patients (grade 3), all managed—benchmarked against commonly used VEN/HMA salvage in R/R AML where responses are often ~30% with median OS ~6 months, the venetoclax-naïve CRc rate here looks meaningfully higher, while venetoclax-exposed outcomes appear closer to what you’d expect from salvage.