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FDA Approves Ziftomenib for Acute Myeloid Leukemia

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The treatment landscape for acute myeloid leukemia (AML) has recently seen a significant development with the U.S. Food and Drug Administration (FDA) granting full approval to ziftomenib (Komzifti™) for adult patients diagnosed with relapsed or refractory (R/R) AML who harbor a susceptible NPM1 (Nucleophosmin 1) mutation and have no satisfactory alternative treatment options. This landmark decision, announced on November 13, 2025, introduces a novel, once-daily, targeted oral therapy to a patient population historically characterized by poor outcomes and limited effective options at relapse1,2.

The Critical Role of the NPM1 Mutation in AML

Acute myeloid leukemia is a heterogeneous hematologic malignancy. The presence of specific genetic alterations is critical for disease classification, prognosis, and therapeutic targeting. The NPM1 gene, which is involved in ribosome biogenesis and genomic stability, is the most frequently mutated gene in adult AML, affecting approximately 30% of cases3.

Wild-type NPM1 protein is predominantly localized in the nucleolus. However, mutations in NPM1 (most commonly Type A, B, and D) lead to a loss of the nucleolar localization signal and the creation of a new nuclear export signal. This results in the aberrant cytoplasmic mislocalization of the mutant NPM1 protein4. This cytoplasmic accumulation disrupts normal cellular functions and is a major oncogenic driver, promoting leukemogenesis through altered gene expression, including the upregulation of key transcription factors like HOXA and MEIS15.

While NPM1-mutated AML is often associated with a favorable prognosis in the frontline setting, patients who relapse or are refractory to initial therapy face markedly diminished survival rates, often with less than a 10% complete response rate to subsequent chemotherapy6,7.

Ziftomenib: A Potent and Selective Menin Inhibitor

Ziftomenib is a small-molecule, potent, and highly selective menin inhibitor8. Its mechanism of action directly addresses the core oncogenic driver of NPM1-mutated AML.

Mechanism of Action

The protein menin (encoded by the MEN1 gene) forms a crucial complex with the Lysine [K]-specific Methyltransferase 2A (KMT2A, formerly MLL) protein. This Menin-KMT2A complex is aberrantly recruited to the promoters of leukemogenic genes, such as HOXA and MEIS1, when NPM1 is mutated and cytoplasmic5.

Ziftomenib works by specifically disrupting the interaction between menin and KMT2A. By preventing the formation of this complex, ziftomenib effectively downregulates the expression of the HOX/MEIS1 transcriptional program. This downstream inhibition leads to the terminal differentiation and apoptosis of the leukemic blasts, thereby exerting its anti-leukemic activity8,9.

Pivotal Efficacy and Safety Data: The KOMET-001 Trial

The FDA approval of ziftomenib is primarily supported by the data from the pivotal Phase 2 portion of the global, multicenter, open-label, single-arm KOMET-001 trial (NCT04067336)1,10. The trial evaluated ziftomenib monotherapy at a recommended phase 2 dose (RP2D) of 600 mg once daily in a heavily pretreated cohort of adults with R/R NPM1-mutated AML1.

Key Efficacy Outcomes

The primary efficacy endpoint was the rate of Complete Remission (CR) plus CR with Partial Hematologic Recovery (CRh). Secondary endpoints included the duration of CR+CRh, the rate of conversion from transfusion dependence to independence, and minimal residual disease (MRD) negativity1,10.

The efficacy population included 112 adult patients with R/R NPM1-mutated AML, with a median follow-up of 4.2 months (range, 0.1 to 41.2 months)1.

Response MetricValue (95% Confidence Interval)Median Duration
CR + CRh Rate21.4% (14.2, 30.2)15.0 months (1.9, 8.11
Complete Remission (CR) Rate17.0% (10.5, 25.2)1–
CR with Partial Hematologic Recovery (CRh) Rate4.5% (1.5, 10.1)1–
Transfusion Independence Rate21.2%1 (Among 66 patients dependent at baseline)–
MRD Negativity Rate (Among CR/CRh responders tested)65%2–

Source: FDA Approval and KOMET-001 Trial Data (Adapted)1,2

Notably, the trial data indicated that clinically meaningful response rates were comparable regardless of previous therapy, including prior treatment with venetoclax or prior hematopoietic stem cell transplantation (HSCT)2. For responders (patients achieving a complete or composite complete response), the median overall survival was 16.4 months (95% CI: 9.6, 20.4), compared to 3.5 months (95% CI: 2.5, 4.0) for non-responders2.

Safety Profile

The safety profile observed in the KOMET-001 trial showed that ziftomenib was generally well-tolerated. Common Grade treatment-emergent adverse events (TEAEs) included cytopenias, such as febrile neutropenia, anemia, and thrombocytopenia1,10.

A class effect for menin inhibitors is differentiation syndrome; in the KOMET-001 trial, differentiation syndrome occurred in 13% of the overall safety population (15% Grade3) and was reported as manageable with protocol-defined mitigation strategies1. Importantly, the prescribing information for ziftomenib does not include a Boxed Warning for QTc interval prolongation, which can be a key advantage for patients on multiple concurrent medications2.

Implications for R/R NPM1-Mutated AML

The FDA approval of ziftomenib marks a significant advance in precision medicine for AML. For adult patients with R/R NPM1-mutated AML, for whom treatment options have been severely limited, this targeted oral menin inhibitor provides a new, non-intensive therapeutic pathway.

The favorable safety profile, including manageable differentiation syndrome and the lack of a Boxed Warning for QTc prolongation, underscores its potential to improve outcomes for a vulnerable patient population, particularly those who are older or unable to tolerate intensive chemotherapy or transplant2. The achievement of durable, MRD-negative responses across various prior treatment exposure subgroups highlights ziftomenib’s potential to establish a new standard of care in this molecularly defined, high-unmet-need setting.

As clinical development continues, combination studies evaluating ziftomenib with intensive and non-intensive chemotherapy regimens are ongoing, with the potential to integrate menin inhibition into earlier lines of therapy for a broader range of patients with NPM1-mutated and KMT2A-rearranged AML11.

References (11)

  1. FDA Approves Ziftomenib for Relapsed or Refractory Acute Myeloid Leukemia with an NPM1 Mutation. U.S. Food and Drug Administration. November 13, 2025.  https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ziftomenib-relapsed-or-refractory-acute-myeloid-leukemia-npm1-mutation
  2. Kura Oncology and Kyowa Kirin Announce FDA Approval of KOMZIFTI™ (ziftomenib), the First and Only Once-Daily Targeted Therapy for Adults with Relapsed or Refractory NPM1-Mutated Acute Myeloid Leukemia. Kura Oncology, Inc. News Release. November 13, 2025.  https://www.globenewswire.com/news-release/2025/11/13/3187609/0/en/Kura-Oncology-and-Kyowa-Kirin-Announce-FDA-Approval-of-KOMZIFTI-ziftomenib-the-First-and-Only-Once-Daily-Targeted-Therapy-for-Adults-with-Relapsed-or-Refractory-NPM1-Mutated-Acute-.html
  3. Falini B, Brunetti L, Sportoletti P, Martelli MP. NPM1-mutated acute myeloid leukemia: from bench to bedside. Blood. 2020;136(15):1707-1721.  https://ashpublications.org/blood/article/136/15/1707/459468/NPM1-mutated-acute-myeloid-leukemia-from-bench-to
  4. Menin inhibitor ziftomenib (KO-539) synergizes with drugs targeting chromatin regulation or apoptosis and sensitizes acute myeloid leukemia with MLL rearrangement or NPM1 mutation to venetoclax. NIH. PMC.  https://pmc.ncbi.nlm.nih.gov/articles/PMC10543165/
  5. A 2024 Update on Menin Inhibitors. A New Class of Target Agents against KMT2A-Rearranged and NPM1-Mutated Acute Myeloid Leukemia. PubMed Central.  https://pmc.ncbi.nlm.nih.gov/articles/PMC11036224/
  6. Ziftomenib in Relapsed or Refractory NPM1-Mutated AML. Journal of Clinical Oncology. 2025;43(31):3381-3390.  https://ascopubs.org/doi/10.1200/JCO-25-01694
  7. Issa G, Bidikian A, Venugopal S, et al. Clinical outcomes associated with NPM1 mutations in patients with relapsed or refractory AML. Blood Adv. 2023 Mar 28;7(6):933-942.  https://ashpublications.org/bloodadvances/article/7/6/933/492576/Clinical-outcomes-associated-with-NPM1-mutations-in
  8. Komzifti (ziftomenib) dosing, indications, interactions, adverse effects, and more. Medscape Reference.  https://reference.medscape.com/drug/ziftomenib-4000546
  9. Ziftomenib in relapsed/refractory (R/R) NPM1-mutant acute myeloid leukemia (AML): Phase 1b/2 clinical activity and safety results from the pivotal KOMET-001 study. ASCO Publications.  https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6506
  10. First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia. ClinicalTrials.gov. Identifier: NCT04067336.  https://clinicaltrials.gov/study/NCT04067336
  11. Ziftomenib Combined with Intensive Induction (7+3) in Newly Diagnosed NPM1-m or KMT2A-r Acute Myeloid Leukemia: Interim Phase 1a Results from KOMET-007. Blood. 2024;144(Supplement 1):214.  https://ashpublications.org/blood/article/144/Supplement%201/214/530335/Ziftomenib-Combined-with-Intensive-Induction-7-3

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