FDA Approves Ziftomenib in NPM1+ Relapsed/Refractory Acute Myeloid Leukemia

The FDA has granted approval to the menin inhibitor ziftomenib (Komzifti) for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) harboring NPM1 mutations with no appropriate alternative treatment options.¹

How Effective is Ziftomenib in R/R AML?

According to results from the phase 2 open-label, single-arm, multicenter KOMET-001 trial (NCT04067336), upon which this approval is based², the rate of complete remission (CR) plus CR with partial hematologic recovery (CRh; CR+CRh) was 21.4% (95% CI, 14.2-30.2; P = .0058)³, and the duration of CR+CRh was 5 months (95% CI, 1.9-8.1). The median follow-up was 4.2 months (range, 0.1-41.2). Additionally, the CR rate was 17.0% (95% CI, 10.5-25.2) with a CRh rate of 4.5% (95% CI, 1.5-10.1).

In this trial, 66 patients were dependent on red blood cell (RBC) and/or platelet transfusions at baseline. Of these patients, 21.2% (n = 14) became independent of RBC and platelet transfusions during any 56-day period after baseline. Moreover, 46 patients were dependent on both RBC and platelet transfusions, 26.1% of whom (n = 12) remained transfusion independent during any 56-day period after baseline.

The primary end point of KOMET-001 was met, according to data published in the Journal of Clinical Oncology, which also reveal that 61% of patients were negative for measurable residual disease. The overall response rate (ORR) was 33% (95% CI, 23%-43%) with a median duration of 4.6 months (95% CI, 2.8-7.4).

Median time to first overall response was 1.9 months (range, 0.8-3.7), and median overall survival (OS) was 6.6 months (95% CI, 3.6-8.6). Out of those who responded to treatment, median OS was 18.4 months (95% CI, 8.6-not estimable [NE]). At the time of data cutoff, 9 patients remained on treatment with ziftomenib, 2 of whom had undergone subsequent allogeneic stem cell transplant.

Patients received ziftomenib monotherapy at 600 mg once daily, which is the dose recommended by the FDA.

Ziftomenib Safety Data

Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 86 out of 92 patients (93%) who received ziftomenib. The most common TEAEs, occurring in at least 10% of patients, were febrile neutropenia (n = 24; 26%), anemia (n = 18; 20%), thrombocytopenia (n = 18; 20%), differentiation syndrome (n = 14; 15%), decreased platelet count (n = 14; 15%), neutropenia (n = 13; 14%), pneumonia (n = 13; 14%), sepsis (n = 13; 14%), and hypokalemia (n = 12; 13%).

Treatment-emergent hematologic toxicities of any grade occurring in at least 10% of patients included febrile neutropenia (n = 24; 26%), anemia (n = 20; 22%), thrombocytopenia (n = 18; 20%), decreased platelet count (n = 14; 15%), and neutropenia (n = 13; 14%). Most patients (n = 73; 79%) experienced serious TEAEs, the most common of which was febrile neutropenia, which occurred in 21% of patients (n = 19).

Adverse events (AEs) directly related to ziftomenib occurred in 64 patients (70%); of these patients, 37 (40%) had grade 3 or higher AEs. Ziftomenib-related hematologic toxicities occurring in 5% or more patients included neutropenia (n = 6; 7%) and anemia (n = 5; 5%). Additionally, dose interruptions occurred in 33% of patients (n = 30), and dose reductions occurred in 3% (n = 3). Three patients discontinued study treatment due to ziftomenib-related AEs.

QTc prolongation related to ziftomenib occurrerd in 3 patients (3%), including 1 instance that was grade 2 and 2 that were grade 3; all patients who experienced QTc prolongations were taking additional medications associated with QTc prolongation and had either electrolyte abnormalities or previous atrial fibrillation.

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. Kura Oncology and Kyowa Kirin announce publication of pivotal ziftomenib data in relapsed/refractory NPM1-mutated AML in the Journal of Clinical Oncology. Kura Oncology, Inc. September 25, 2025. Accessed November 13, 2025. https://ir.kuraoncology.com/news-releases/news-release-details/kura-oncology-and-kyowa-kirin-announce-publication-pivotal
3. Wang ES, Montesinos P, Foran J, et al. Ziftomenib in relapsed or refractory NPM1-mutated AML. J Clin Oncol. 2025;43(31):3381-3390. doi:10.1200/JCO-25-01694