More Research Needed to Ascertain Ziftomenib’s Mechanism of Action in AML

Results from the pivotal phase 2 KOMET-001 trial (NCT04067336) shared at the European Hematology Association 2025 Congress showed that ziftomenib, a selective menin inhibitor, elicited an overall response rate of 35% in patients with relapsed or refractory NPM1-mutant acute myeloid leukemia (AML). The pooled phase 1b/2 analysis (n = 112) also found that complete remission (CR) was observed in 18% of patients and CR with partial hematologic recovery was observed in 7%.

CancerNetwork® spoke with Amir Fathi, MD, associate professor of medicine at Harvard Medical School, program director of the Center for Leukemia at Massachusetts General Hospital, and presenting study author, about what these results may mean for this patient population.

Fathi stated that because AML is a disease that commonly has numerous alterations and mutations such as KMT2A and NPM1, more work is needed to understand how targeted therapies should be sequenced.

Transcript:

[Ziftomenib is] a targeted drug, so only certain types of mutations or alterations are sensitive or vulnerable to this particular pathway. When you inhibit the interaction of menin and KMT2A, it is thought that patients who have NMP1 mutations and KMT2A rearrangements are more likely to respond because those leukemic cells then turn on their normal maturation and differentiation. The programming [helps them] become mature, normal cells and the leukemic burden goes down, and you get this differentiated response over time. In that sense, it’s a unique mechanism of action that is reserved for patients with these particularly susceptible alterations.

That’s more difficult because AML oftentimes has multiple mutations and alterations. We’re going to have to figure out how we’re going to incorporate these targeted therapies that we now potentially have available in terms of combining them all together, sequencing them, when to use them in the front line, and when to use them in relapsed/refractory lines. That is something that has not worked out yet, and only with additional trials and research will we know the right approach.

Reference

Fathi AT, Montesinos P, Issa GC, et al. Ziftomenib in relapsed/refractory NPM1-mutant acute myeloid leukemia: phase 1b/2 clinical activity and safety results from the pivotal KOMET-001 study. Abstract presented at: European Hematology Association 2025 Congress; June 12-15, 2025; Milan, Italy. Abstract PF473.