Ziftomenib Shows Significant Benefit in Relapsed/Refractory NPM1+ AML

Treatment with ziftomenib produced clinically meaningful and deep responses among patients with relapsed/refractory acute myeloid leukemia (AML) harboring NPM1 mutations, according to updated results from the phase 1/2 KOMET-001 trial (NCT04067336) published in the Journal of Clinical Oncology.¹

Data showed a complete remission (CR) or CR with partial hematologic recovery (CRh) rate of 22% (95% CI, 14%-32%), meeting the trial’s primary end point and exceeding a conservative historical standard of care (SOC) response rate of 12% in this population (P = .0058). The median time to CR/CRh was 2.8 months (95% CI, 1.0-15.0), and the median duration of CR/CRh was 3.7 months (95% CI, 1.9-7.4). Additionally, treatment yielded a composite CR (CRc) rate of 26% (95% CI, 18%-36%), with a median time to CRc of 2.8 months (range, 0.8-4.6), and a median duration of CRc of 4.6 months (95% CI, 2.8-11.4).

The overall response rate (ORR) was 33% (95% CI, 23%-43%), with a median time to overall response of 1.9 months (range, 0.8-3.7), and a median duration of response (DOR) of 4.6 months (95% CI, 2.8-7.4). Ziftomenib produced a median overall survival (OS) of 6.6 months (95% CI, 3.6-8.6) among all patients, and 18.4 months (95% CI, 8.6-not estimable [NE]) among those with a response.

Investigators reported transfusion-independence conversion for red blood cells in 23% (n = 17/75; 95% CI, 14%-34%) of evaluable patients, and a maintenance rate of 12% (n = 2/17; 95% CI, 2%-36%). The respective conversion and maintenance rates for platelets were 15% (n = 11/71; 95% CI, 8%-26%) and 38% (n = 8/21; 95% CI, 18%-62%). Overall, the transfusion-independence conversion rate was 20% (n = 16/82; 95% CI, 12%-30%), while the maintenance rate was 20% (n = 2/10; 95% CI, 3%-56%).

“Ziftomenib is a potent menin inhibitor with proven efficacy for the treatment of adult patients with NPM1-mutant [AML] who have [progressed on] multiple lines of therapy,” lead study author Eunice S. Wang, MD, chief of Leukemia in the Department of Medicine at Roswell Park Comprehensive Cancer Center, stated in a press release on these findings.² “I am proud to say that [patients at] Roswell Park were among the first in the world to be treated with ziftomenib, and we are continuing to treat patients with this agent in combination with chemotherapy in the newly diagnosed setting.”

In the phase 2 portion of the multicenter, open-label, registration-enabling KOMET-001 study, 92 patients received ziftomenib at 600 mg once daily. The primary end point of phase 2 was the CR/CRh rate. Secondary end points included duration of CR/CRh, CRc rate, ORR, time to first response, measurable residual disease (MRD) negativity, DOR, OS, transfusion independence, and safety and tolerability.

Patients 18 years and older with relapsed/refractory NPM1-mutated AML; an ECOG performance status of 0 to 2; and adequate hepatic, renal, and cardiac function were eligible for enrollment on the trial. Investigators confirmed NPM1 mutation status via local clinical laboratories.

The median age was 69 years (range, 33-84), and most patients were female (53%) and White (82%). Most of the study population had an ECOG performance status of 1 (53%), FLT3-ITD co-mutations (45%), and prior treatment with venetoclax (Venclexta; 59%). The median bone marrow blast percentage was 39.5% (range, 0.5%-98%), and patients received a median of 2 (range, 1-7) prior lines of treatment.

Prespecified subgroup analyses showed that CR/CRh outcomes with ziftomenib were generally comparable across subgroups, with responses observed regardless of age, prior venetoclax receipt, and prior lines of treatment. Analyzing subgroups from a pooled phase 1b/2 population (n = 112) showed similar results as the phase 2 population.

Treatment-emergent adverse effects (TEAEs) of any grade and grade 3 or higher occurred in 100% and 93% of patients, respectively. The most common grade 3 or higher TEAEs included febrile neutropenia (26%), anemia (20%), thrombocytopenia (20%), platelet count decreased (15%), and differentiation syndrome (15%).

Toxicity resulted in dose interruptions in 33% of patients, and dose reductions in 3%. Additionally, 3% of patients discontinued therapy due to AEs related to ziftomenib. Investigators reported no deaths due to ziftomenib-related toxicity.

Previously, the FDA granted priority review to ziftomenib as a treatment for those with relapsed/refractory NPM1-mutated AML in June 2025 based on findings from the KOMET-001 trial.³

“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,” KOMET-001 study investigator Ghayas C. Issa, MD, MS, stated in an interview with CancerNetwork® regarding findings presented at the Society of Hematological Oncology 2025 Annual Meeting.⁴

References

1. Wang ES, Montesinos P, Foran J, et al. Ziftomenib in relapsed/refractory NPM1-mutated AML. J Clin Oncol. Published online September 25, 2025. doi:10.1200/JCO-25-01694
2. Final landmark clinical trial data demonstrates deep, durable responses to menin inhibition in acute leukemia patients. News release. Roswell Park Comprehensive Cancer Center. September 25, 2025. Accessed September 26, 2025. https://tinyurl.com/49nsmepk
3. Kura Oncology and Kyowa Kirin announce FDA acceptance and priority review of new drug application for ziftomenib in adults with relapsed or refractory NPM1-mutant AML. News release. Kura Oncology Inc, Kyowa Kirin Co. June 2, 2025. Accessed September 26, 2025. https://tinyurl.com/yca5675t
4. 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.