Evaluating Single-Agent Ziftomenib’s Performance in NPM1+ R/R AML

Ziftomenib yielded a median overall survival of 16.4 months in responders with NPM1-mutant AML who received ziftomenib in the phase 1b/2 KOMET-001 trial.

At the Society of Hematological Oncology 2025 Annual Meeting, Ghayas C. Issa, MD, MS, presented results on ziftomenib in relapsed/refractory acute myeloid leukemia (AML) harboring NPM1 mutations from the phase 1b/2 KOMET-001 trial (NCT04067336).¹

Ziftomenib achieved an overall response rate (ORR) of 35% in the pooled analysis, with a complete remission (CR) and complete remission with partial hematologic recovery (CRh) rate of 25%. Notably, after a median follow-up of 4.1 months (range, 0.1-19.7), the median time to CR/CRh was 2.8 months (range, 1.0-15.0) and the median time to ORR was 1.9 months (range, 0.8-3.7). The rate of measurable residual disease (MRD) among CR and CRh responders evaluated for MRD was 65%.

The median overall survival (OS) was 6.1 months (95% CI, 3.8-8.4); in responders vs non-responders, the median OS was 16.4 months (95% CI, 9.6-20.4) vs 3.5 months (95% CI, 2.5-4.0), respectively.

Regarding safety, any adverse effects of grade 3 or higher occurred in 94% of patients, with the most common being febrile neutropenia (22%), anemia (21%), and thrombocytopenia (20%); differentiation syndrome events occurred in 13% of patients, none of which were grade 4 or 5.

Following his presentation, Issa, 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® about the results.

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 relapsed, they’re as bad as any other leukemia. That’s why we need new targeted therapies to improve outcomes for our patients.

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.

What were the most significant findings?

Excitingly, we saw single-agent activity with ziftomenib, which is what we’ve also seen in the phase 1 study of this drug. We found a complete remission or a complete remission with partial hematologic recovery rate of about 25% in the pooled phase 1b/2 cohort. This met the primary end point of the phase 2 study, which was to compare it with a historical control. In other words, with this drug, we are doing better than we would have expected if those patients [received] any other therapy. The duration of the response was about 4 months. Those patients, in general, have very resistant disease. This is an advancement because this therapy could be used in combination in the future and [may] improve outcomes for patients.

How did patients tolerate the therapy?

There were no new findings that we didn’t know of from the phase 1 study. The main on-target effect was differentiation syndrome, which was controlled with the protocol strategies that we’ve used with ziftomenib. All patients who got steroids had their differentiation syndrome resolved; there were no grade 4 [events] or death from differentiation syndrome. Otherwise, compared with other targeted therapies for AML or chemotherapy, this drug didn’t have significant severe adverse effects, so it was well tolerated.

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 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 are the potential clinical implications of these results?

Based on these results, there was a submission to the FDA for approval of ziftomenib for this indication, which is NPM1-mutant relapsed/refractory [AML].² We hope that, soon, this drug will be available as a standard of care for patients. Even more importantly, we’re trying to test it to improve outcomes for all patients, including newly diagnosed patients with NPM1. There are ongoing studies that will test the addition of ziftomenib to standard induction chemotherapy, either high-intensity chemotherapy, such as “7 + 3”, or in older, unfit patients, which is azacitidine and venetoclax. In the future, we hope that the addition of ziftomenib would improve the chances of cure for patients by adding them to these therapies.

What other research is currently building off these results?

This is the randomized control study that is meant to be registrational, meaning if we meet the primary end point, this would be the new standard of care for induction treatment of NPM1-mutant [AML]. There are multiple other combination studies going on in the relapsed/refractory setting, such as combinations with [hypomethylating agents] and venetoclax—the KOMET-007 study [NCT05735184]—combinations with low-dose cytarabine, combinations with gilteritinib [Xospata], or combinations with high-intensity chemotherapy in the KOMET-008 study [NCT06001788]. All these [studies] are ongoing, and we’ll be presenting results soon.

References

1. 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.
2. Kura Oncology and Kyowa Kirin report positive pivotal ziftomenib monotherapy data at 2025 ASCO Annual Meeting. News release. Kura Oncology and Kyowa Kirin. June 2 and 3, 2025. Accessed September 9, 2025. https://tinyurl.com/376xycme