FDA Approves Ziftomenib for NPM1+ R/R Acute Myeloid Leukemia

The FDA has approved ziftomenib (Komzifti) for the treatment of adult patients with relapsed/refractory acute myeloid leukemia (AML) with a susceptible NPM1 mutation who have no satisfactory alternative treatment options.¹

This regulatory decision was supported by data from the phase 1/2 KOMET-001 trial (NCT04067336), which met its primary end point of complete remission (CR) plus CR with full or partial hematologic recovery (CRh) rate with the use of ziftomenib in patients with relapsed/refractory AML. Findings supporting the approval showed that at a median follow-up of 4.2 months (range, 0.1-41.2 months), patients experienced a CR plus CRh rate of 21.4% (95% CI, 14.2%-30.2%). The median duration of CR plus CRh was 5 months (95% CI, 1.9-8.1). The CR rate and CRh rates were 17.0% (95% CI, 10.5%-25.2%) and 4.5% (95% CI, 1.5%-10.1%), respectively.

Additionally, among evaluable patients (n = 66) who were transfusion dependent at baseline, 21.2% achieved red blood cell and platelet transfusion independence during any 56-day period after baseline. In evaluable patients who were transfusion-independent at baseline (n = 46), patients remained transfusion independent during any 56-day after baseline.

Findings from KOMET-001 were presented at the 2025 ASCO Annual Meeting and demonstrated durable responses and a manageable safety profile with ziftomenib in this molecularly defined AML population.2 In the phase 2 patient population (n = 92), at a median follow-up of 4.1 months (range, 0.1-19.7), the CR rate was 14%, and the CRh rate was 9%, translating to a combined CR/CRh rate of 23%. The median time to CR/CRh was 2.8 months (range, 1.0-15.0). Patients also achieved a median duration of CR/CRh of 3.7 months (95% CI, 1.9-not evaluable), as well as a restricted mean duration of CR/CRh of 4.3 months (95% CI, 3.1-5.6).

Additionally, the overall response rate was 33%, and the median time to overall response was 1.9 months (range, 0.8-3.7). Furthermore, the median duration of overall response was 4.6 months (95% CI, 2.8-11.4), and the restricted mean duration of overall response was 5.9 months (95% CI, 4.4-7.5). Moreover, 63% of patients achieved minimal residual disease (MRD) negativity.

What was the design of the KOMET-001 trial?

The first-in-human, open-label, dose-escalation and -validation/expansion KOMET-001 trial enrolled patients at least 18 years of age with relapsed or refractory AML, defined as the re-emergence of a bone marrow blast level of at least 5%.3 Eligible patients had progressed on or were ineligible for standard-of-care therapies, including hematopoietic stem cell transplant (HSCT).

In the phase 1b portion, patients were required to have AML harboring either KMT2A rearrangements or NPM1 mutations; phase 2 enrollment was limited to those with NPM1 mutations. Key inclusion criteria included an ECOG performance status of 0 to 2, a life expectancy of at least 2 months, and adequate liver and kidney function.

Patients were excluded if they had acute promyelocytic leukemia, chronic myelogenous leukemia in blast crisis, a donor lymphocyte infusion within 30 days of enrollment, clinically active central nervous system leukemia, or if they had undergone HSCT without adequate hematologic recovery.

Phase 1a served as the dose-escalation portion, and phase 1b functioned as dose-validation and expansion. In phase 2, patients with NPM1-mutant relapsed/refractory AML received ziftomenib at the recommended phase 2 dose (RP2D) determined in earlier cohorts.

The trial’s primary end points included determination of the maximum tolerated dose and RP2D (phase 1a), safety and minimal biologically effective dose (phase 1b), and CR/CRh rate (phase 2).2,3 Key secondary end points in the phase 2 portion were duration of CR/CRh, CR/CRh MRD negativity, transfusion independence, and adverse effects (AEs).

What was the safety profile of ziftomenib in KOMET-001?

Among patients in the phase 2 population, any-grade treatment-emergent AEs (TEAEs) were reported in all patients, and grade 3 or higher TEAEs occurred in 93% of patients.2 The most commonly observed TEAEs were anemia (any-grade, 22%; grade ≥ 3, 20%), febrile neutropenia (26%; 26%), thrombocytopenia (20%; 20%), diarrhea (29%; 1%), nausea (25%; 1%), hypokalemia (24%; 13%), differentiation syndrome (25%; 15%), pruritus (23%; 0%), peripheral edema (25%; 0%), and pneumonia (21%; 14%). In total, 3% of patients discontinued treatment because of AEs related to ziftomenib.

References

1. FDA approves ziftomenib for relapsed or refractory acute myeloid leukemia with a NPM1 mutation. FDA. November 13, 2025. Accessed November 13, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ziftomenib-relapsed-or-refractory-acute-myeloid-leukemia-npm1-mutation
2. Wang E, Montesinos P, Issa G, et al. 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. J Clin Oncol. 2025;43(suppl_16):6506. doi:10.1200/JCO.2025.43.16_suppl.6506
3. First in human study of ziftomenib in relapsed or refractory acute myeloid leukemia. ClinicalTrials.gov. Updated April 18, 2025. Accessed June 2, 2025. https://clinicaltrials.gov/study/NCT04067336