Why Evaluate Single-Agent Ziftomenib in NPM1+ R/R Acute Myeloid Leukemia?

The phase 1b/2 KOMET-001 trial (NCT04067336) demonstrated that single-agent ziftomenib, a menin inhibitor, achieved responses in patients with relapsed/refractory acute myeloid leukemia (AML) harboring NPM1 mutations, according to newly shared results at the Society of Hematological Oncology 2025 Annual Meeting.

Ghayas C. Issa, MD, MS, the presenting study author and an associate professor in the Department of Leukemia and in the Department of Genomic Medicine in the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center, spoke with CancerNetwork® at the conference after the presentation.

Issa stated that lab evidence showed that disrupting the interaction between menin and KMT2A should lead to responses in this NPM1-positive patient group, and these results corroborated that.

KOMET-001 was a single-cohort trial that enrolled patients 18 years and older with NPM1-mutated relapsed/refractory AML, all of whom received 600 mg of ziftomenib once daily in the phase 2 portion.

Transcript:

CancerNetwork: What was the rationale for conducting the KOMET-001 study?

Issa: Menin inhibitors form a new class of targeted therapies in AML. They’re epigenetic modifiers, so they work by disrupting the genes that cause leukemia. Ziftomenib is a potent menin inhibitor, and in this case, we are testing it in NPM1-mutant [AML], which depends on the menin and KMT2A interaction. NPM1 leukemias, when they’re newly diagnosed, have a good prognosis, but once they relapse, they’re as bad as any other leukemia. That’s why we need new targeted therapies to improve outcomes for our patients.

How does the selective inhibition of the menin-KMT2A interaction address this patient group’s biology?

In NPM1-mutant [AML], the KMT2A and menin interaction is critical to cause the abnormal expression of genes that are responsible for this leukemia. By disrupting the binding of KMT2A and menin by using a small molecule menin inhibitor, the lab evidence is that we can shut down this gene expression and [that will] lead to responses. That’s what we’re seeing in patients, too. With this drug, by targeting this specific node, we’re getting single-agent responses.

What was this study’s design?

This study was single-cohort [and] phase [1b/2]. Patients received the menin inhibitor ziftomenib once a day. Those patients had [AML] and had relapsed/refractory disease…. The main mutation, or the mutation that we’ve analyzed in this phase 2 cohort, is the NPM1 mutation. This [trial] included patients aged 18 and [older], and a variety of patients [in terms of] other baseline characteristics.

References

Issa GC, Wang ES, Montesinos P, et al. Ziftomenib in relapsed/refractory NPM1-mutant acute myeloid leukemia: phase 1b/2 results from the pivotal KOMET-001 study. Presented at the Society of Hematological Oncology 2025 Annual Meeting; September 2-5, 2025; Houston, TX. Abstract AML-789.