Ziftomenib Achieves Responses and is Safe in NPM1+ R/R AML

In the phase 1b/2 KOMET-001 trial (NCT04067336), ziftomenib elicited an overall response rate (ORR) of 35% in the pooled phase 1b/2 data pool, with a complete remission (CR)/complete remission with partial hematologic recovery (CRh) rate of 25%, a morphological leukemia free state rate of 5%, and a partial response rate of 1%. Minimal residual disease (MRD) negativity was achieved by 65% of patients. 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).

Additionally, the median overall survival (OS) was 6.1 months (95% CI, 3.8-8.4), with a median OS of 16.4 months (95% CI, 9.6-20.4) in responders and 3.5 months (95% CI, 2.5-4.0) in non-responders.

Grade 3 or higher treatment-emergent adverse effects (TEAEs) occurred in 95% of patients, with the most common being febrile neutropenia (22%), anemia (21%), thrombocytopenia (20%), pneumonia (15%), and differentiation syndrome (13%); no grade 4 or 5 events of differentiation syndrome were observed.

These results were shared at the Society of Hematological Oncology 2025 Annual Meeting by Ghayas C. Issa, MD, MS, 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.

Transcript:

CancerNetwork: What were the most significant findings?

Issa: 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 [received] 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.

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.