FDA Approves Ziftomenib for R/R NPM1-Mutated AML

Ziftomenib (Komzifti; Kura Oncology and Kyowa Kirin), an oral, once-daily, selective menin inhibitor, has received approval from the FDA for the treatment of adult patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) harboring a susceptible NPM1 mutation.1,2

The FDA approved ziftomenib for relapsed acute myeloid leukemia with NPM1 mutations, marking the second menin inhibitor approved for this population. | Image credit: wladimir1804 - stock.adobe.com

This marks the second menin inhibitor to be approved for this indication,3 providing a new targeted pathway option for a high-risk population with historically poor outcomes. The approval is based on positive data from the pivotal phase 2 KOMET-001 trial, which demonstrated clinically meaningful response rates and a favorable benefit-risk profile in a heavily pretreated patient cohort.

The efficacy of ziftomenib was established in the KOMET-001 trial (NCT04067336), an open-label, single-arm, multicenter study enrolling 112 adults with R/R NPM1-mutated AML. The NPM1 mutation appears in approximately 30% of AML cases, making it the most commonly mutated gene for adult AML.4

Efficacy was measured by the composite response end point of complete remission (CR) plus CR with partial hematological recovery (CRh). The trial successfully met its primary end point, demonstrating a significant clinical benefit.

“Komzifti addresses a critical need for adult patients with R/R NPM1-[mutant] AML, many of whom are older and unable to tolerate intensive chemotherapy or transplant,” Eunice Wang, MD, chief of the leukemia service and professor of oncology at Roswell Park Comprehensive Cancer Center, said in a statement.2 “The clinical data demonstrate deep and durable responses with a manageable safety profile, including no drug-drug interactions and no boxed warnings for QTc prolongation or Torsades de Pointes—key advantages for patients on multiple concurrent medications. This approval equips physicians with a new oral therapy to integrate into care and improve outcomes for this vulnerable patient population.”

Efficacy Data From KOMET-001

The trial included patients who had received a median of 2 prior lines of therapy, with approximately 59% who had prior venetoclax exposure.5 There was a confirmed CR/CRh rate of 21.4% (95% CI, 14.2-30.2), and the median duration of CR/CRh was 5 months (95% CI, 1.9-8.1). In addition, 61% of patients achieved measurable residual disease negativity, suggesting deep molecular remission.

Although the median overall survival (OS) for all R/R patients was 6.6 months, patients who achieved a CR/CRh saw a notably extended median OS of 18.4 months.

Prespecified subgroup analyses indicated comparable CR/CRh rates regardless of prior therapeutic exposure, including previous allogeneic hematopoietic stem cell transplantation, prior venetoclax exposure, or the presence of comutations such as FLT3 or IDH1/2.

Safety Results of Ziftomenib

The prescribing information includes warnings and precautions for differentiation syndrome (DS), QTc interval prolongation, and embryo-fetal toxicity, according to the FDA. DS occurred in 25% of patients.

The most common Grade 3 or higher treatment-emergent adverse events (≥ 10%) included febrile neutropenia (26%), anemia (20%), thrombocytopenia (20%), differentiation syndrome (15%), decreased platelet count (15%), neutropenia (14%), pneumonia (14%), and sepsis (14%).

“In AML, where many patients face severe disease progression and limited treatment options, the evolution toward targeted therapies such as Komzifti represents a major step forward and offers potential to transform existing standards of care,” said Takeyoshi Yamashita, PhD, executive vice president and chief medical officer of Kyowa Kirin.2

References

1. FDA approves ziftomenib for relapsed or refractory acute myeloid leukemia with a NPM1 mutation. News release. 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 FDA approval of Komzifti (ziftomenib), the first and only once-daily targeted therapy for adults with relapsed or refractory NPM1-mutated acute myeloid leukemia. News release. Kura Oncology. November 13, 2025. Accessed November 13, 2025. https://ir.kuraoncology.com/news-releases/news-release-details/kura-oncology-and-kyowa-kirin-announce-fda-approval-komziftitm

3. Joszt L. Revumenib granted FDA approval for R/R NPM1-mutated AML. AJMC®. October 24, 2025. Accessed November 13, 2025. https://www.ajmc.com/view/revumenib-granted-fda-approval-for-r-r-npm1-mutated-aml

4. Falini B, Brunetti L, Sportoletti P, Martelli MP. NPM1-mutated acute myeloid leukemia: from bench to bedside. Blood. 2020;136(15):1707-1721. doi:10.1182/blood.2019004226

5. Wang ES, Montesinos P, Foran J, et al; KOMET-001. Ziftomenib in relapsed or refractory NPM1-mutated AML. J Clin Oncol. 2025;43(31):3381-3390. doi:10.1200/JCO-25-01694