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FDA approves ziftomenib for NPM1-mutated R/R AML

On November 13, 2025, the US Food and Drug Administration (FDA) approved the menin inhibitor ziftomenib for adult patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) harboring a susceptible NPM1 mutation who have no satisfactory alternative treatment options.1

NPM1-mutated AML and the unmet need in relapse

NPM1 mutations are among the most common genomic lesions in AML, occurring in around 30% of adult cases and defining a biologically distinct subset of disease. Although many patients with NPM1-mutated (NPM1-m) AML respond well to frontline intensive chemotherapy or venetoclax-based regimens, relapse is frequent and outcomes in the R/R setting are poor, particularly after failure of venetoclax.2

Until very recently, there were no therapies specifically approved for R/R NPM1-m AML. The approval of the first menin inhibitor revumenib for this population in October 2025,3 followed closely by ziftomenib, marks a rapid evolution of the treatment landscape.

Pivotal clinical trial: KO-MEN-001

The approval was supported by the Phase I/II KO-MEN-001 (KOMET-001; NCT04067336) trial, an open-label, single-arm trial evaluating the safety and efficacy of ziftomenib in 112 adults with R/R NPM1-m AML. Patients treated with ziftomenib achieved a complete remission (CR) plus CR with partial hematological recovery (CR+CRh) rate of 21.4% (95% CI: 14.2, 30.2) with a median duration of five months. Improvements in transfusion needs were also observed: 21.2% of patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline became independent of RBC and platelet transfusions during any 56-day post-baseline period.1

The most frequent grade ≥3 treatment-emergent adverse events included febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%). Differentiation syndrome was reported in 25% of patients, 15% at grade 3 and no grade 4-5 events. 3% of patients discontinued therapy due to adverse events attributed to ziftomenib.4

Amir Fathi, MD, MPH, Massachusetts General Hospital, Boston, MA, recently discussed the trial at this year’s SOHO Annual Meeting. He stated, “The drug is well tolerated. There is no signal for QT  prolongation. It seems to have activity in patients who are traditionally more resistant, such as those who have progressed on venetoclax or have relapsed following transplant…There is a signal for differentiation syndrome, which is also seen with other menin inhibitors and is thought to be a class effect, which is important because we need to monitor for that particular entity very closely.”

Future directions

The approval of ziftomenib consolidates menin inhibition as a key targeted strategy in NPM1-m AML but also raises important questions: optimal sequencing with other menin inhibitors, the role of ziftomenib as a bridge to transplant, and mechanisms of resistance within this molecular subgroup.

The planned KOMET-017 trial (NCT07007312) will evaluate ziftomenib in combination with intensive chemotherapy or venetoclax/azacitidine in newly diagnosed NPM1-m or KMT2A-rearranged AML, exploring the role of this agent in earlier treatment lines.

References

  1. U.S. Food and Drug Administration. FDA approves ziftomenib for relapsed or refractory acute myeloid leukemia with a NPM1 mutation. Available here. (Last accessed 14/11/2025).
  2. Ranieri R, Pianigiani G, Sciabolacci S, et al. Current status and future perspectives in targeted therapy of NPM1-mutated AML. Leukemia. 2022;36(10):2351–2367. Available here. (Last accessed 14/11/2025).
  3. U.S. Food and Drug Administration. FDA approves revumenib for relapsed or refractory acute myeloid leukemia with a susceptible NPM1 mutation. Available here. (Last accessed 14/11/2025).
  4. Wang ES, Montesinos P, Foran J, et al. Ziftomenib in Relapsed or Refractory NPM1-Mutated AML. Lancet Oncol. 2025;43(31):3381–3390. Available here. (Last accessed 14/11/2025).

Written by Hannah Elkheir

Reviewed by Anya Dragojlovic Kerkache