Background
Phase 1 (dose escalation + dose validation/expansion), open-label, multi-cohort trial. N=83 patients with R/R AML at 22 hospitals in France, Italy, Spain, and the USA. Ziftomenib (KO-539) is a selective oral menin inhibitor targeting the menin–MLL1 protein-protein interaction, with preclinical activity in menin-dependent AML driven by KMT2A rearrangements (KMT2A-r) and NPM1 mutations. Phase 1a enrolled all molecular subtypes for dose escalation (50–1000 mg QD). Phase 1b enrolled patients with KMT2A-r or NPM1 mutations and randomly assigned (1:1) to 200 mg vs 600 mg QD parallel cohorts to select the recommended phase 2 dose (RP2D). Published Lancet Oncology 2024.
Interventions and follow up
Regimen: Ziftomenib 200–800 mg PO once daily (oral menin inhibitor, continuous) in R/R NPM1-mutated or KMT2A-rearranged AML
Primary endpoint: Phase 1a: MTD or RP2D; Phase 1b: safety, remission rates, PK supporting RP2D selectio
mFollow up: 22.3 months (IQR 15.4–30.2)
Primary endpoint: Phase 1a: MTD or RP2D; Phase 1b: safety, remission rates, PK supporting RP2D selectio
mFollow up: 22.3 months (IQR 15.4–30.2)
Results
RP2D: 600 mg QD (selected based on safety, PK/PD, and clinical activity; no responses at 200 mg)
CR/CRh at RP2D (all evaluable, KMT2A-r + NPM1-mut combined, N=36): 25% (9/36)
CR at RP2D (NPM1-mutated only, N=20): 35% (7/20)
KMT2A-rearranged enrollment: Halted due to differentiation syndrome rate and severity — KMT2A-r patients excluded from phase 2
CR/CRh at RP2D (all evaluable, KMT2A-r + NPM1-mut combined, N=36): 25% (9/36)
CR at RP2D (NPM1-mutated only, N=20): 35% (7/20)
KMT2A-rearranged enrollment: Halted due to differentiation syndrome rate and severity — KMT2A-r patients excluded from phase 2
Adverse events
Overall: 68/83 patients had serious AEs; treatment-related deaths 2 (differentiation syndrome ×1, cardiac arrest ×1).
Menin-class effect: Differentiation syndrome grade ≥3 15% — key safety signal that halted the KMT2A-rearranged cohort.
Hematologic: Anemia grade ≥3 24%, thrombocytopenia 13%.
Infectious: Febrile neutropenia grade ≥3 22%, pneumonia 19%, sepsis 12%.
Menin-class effect: Differentiation syndrome grade ≥3 15% — key safety signal that halted the KMT2A-rearranged cohort.
Hematologic: Anemia grade ≥3 24%, thrombocytopenia 13%.
Infectious: Febrile neutropenia grade ≥3 22%, pneumonia 19%, sepsis 12%.
Conclusions
Ziftomenib 600 mg QD (RP2D) achieved a 35% CR rate in NPM1-mutated R/R AML, supporting a meaningful single-agent response in a heavily pretreated population. Differentiation syndrome limited further development in KMT2A-rearranged disease, confining phase 2 to NPM1-mutated patients.
Key Limitations
Early-phase design: Phase 1 single-arm with N=83; efficacy estimates (CR/CRh) rest on small evaluable subsets and lack a randomized comparator.
KMT2A-r halted: Enrollment of KMT2A-rearranged patients was discontinued due to differentiation syndrome rate/severity, restricting phase 2 to NPM1-mutated disease.
Differentiation syndrome: Grade ≥3 in 15% with treatment-related death; mandates monitoring and prompt management.
Maturity: Durability, MRD response, and OS remain immature pending phase 2 readout.
KMT2A-r halted: Enrollment of KMT2A-rearranged patients was discontinued due to differentiation syndrome rate/severity, restricting phase 2 to NPM1-mutated disease.
Differentiation syndrome: Grade ≥3 in 15% with treatment-related death; mandates monitoring and prompt management.
Maturity: Durability, MRD response, and OS remain immature pending phase 2 readout.
Clinical Context
Ziftomenib is one of several menin inhibitors in development for NPM1-mutated and KMT2A-rearranged AML. Revumenib (AUGMENT-101) received FDA approval in November 2024 for R/R KMT2A-rearranged acute leukemia, establishing the menin-inhibitor class. Ziftomenib's KOMET-007/008 frontline combination programs (with 7+3 or venetoclax/azacitidine) are ongoing. Differentiation syndrome is a recognized class effect requiring prophylaxis and prompt treatment. Allo-SCT remains the consolidative goal for eligible responders. ELN 2022 recognizes NPM1 mutation as a key actionable molecular target. FDA/EMA approval of ziftomenib was pending at the time of this publication. ESMO-MCBS: not assigned.