Ziftomenib Monotherapy Shows Positive Topline Results in NPM1-Mutant AML

Ziftomenib elicited positive responses in patients with NPM1-mutant acute myeloid leukemia, meeting the primary end point of the phase 2 KOMET-001 trial.

Ziftomenib, a highly selective, oral investigational menin inhibitor, demonstrated positive topline results in the registration-directed, phase 2 KOMET-001 trial (NCT04067336) for the treatment of patients with relapsed or refractory NPM1-mutant acute myeloid leukemia (AML), according to a press release from the developer, Kura Oncology.¹

The trial reportedly met its primary end point of complete response (CR) and CR with partial hematological recovery (CRh). Results have been submitted to an upcoming medical conference in the second quarter of 2025 for presentation.

In April 2024, the FDA granted breakthrough therapy status to ziftomenib in the described population.² The developer is on track to finalize submission of a new drug application for ziftomenib in patients with relapsed or refractory NPM1-mutant AML in the second quarter of 2025.

“We are excited to report positive topline results in [patients with relapsed or refractory] NPM1-mutant AML, underscoring the strong foundation for our ziftomenib program to potentially transform the treatment landscape for these patients,” Troy Wilson, PhD, JD, president and chief executive officer of Kura Oncology, stated in the press release.¹ “We believe this achievement for our KOMET-001 trial positions Kura and Kyowa Kirin to deliver on its path to commercialization of ziftomenib, beginning with our potential first NDA submission in [relapsed or refractory] NPM1-mutant AML next quarter. Furthermore, we believe the positive FDA interactions for the KOMET-017 protocol, including the opportunity for accelerated approval in both trials, pave the way for us to position ziftomenib as a potential frontline therapy to address up to 50% of patients with AML.”

KOMET-001 is a first-in-human, open-label, dose-escalation and dose-validation/expansion trial designed to evaluate the safety, tolerability, and anti-leukemia activity of ziftomenib in those with NPM1-mutant AML.

In the phase 1a/1b portion of the trial, 83 patients were enrolled.³ In the dose-escalation phase, oral ziftomenib was administered once daily going from 50 mg to 1000 mg in 28-day cycles until progression, unacceptable toxicity, or withdrawal; in the dose-validation phase, patients were randomly assigned to receive 200 mg or 600 mg of once daily oral ziftomenib in 28-day cycles to determine the recommended phase 2 dose (RP2D); and in the expansion phase, all patients received 600 mg, the RP2D, in 28-day cycles.

Eligible patients for the phase 2 portion of the trial were 18 years or older and had relapsed or refractory AML harboring a NPM1 mutation who were also ineligible for or have progressed on approved standard-of-care therapies.⁴ Additional criteria included an ECOG performance status from 0 to 2 and a life expectancy of 2 months or more; adequate liver and kidney function per protocol requirements; 30,000 μL or less peripheral white blood cell counts; and agreement to use highly effective methods of contraception throughout the study.

Exclusion criteria included diagnosis of acute promyelotic leukemia or chronic myelogenous leukemia in blast crisis; clinically active central nervous system leukemia; history of hematopoietic stem cell transplantation without adequate hematologic recovery; receipt of chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational less than 14 days prior to the first dose of ziftomenib; and pre-existing disorders predisposing the patient to serious or life-threatening infection.

Primary trial end points of the phase 2 portion were CR and CRh rate at 12 months and following to the end of treatment. Secondary end points were CR and CRh up to 12 months following discontinuation of treatment, the CR rate with and without minimal residual disease, duration of response, transfusion independence, event-free survival, and overall survival.

For all patients across all dose levels in the phase 1a/1b portion of the trial, treatment-emergent adverse events (TRAEs) of grades 1 to 2, 3, 4, and 5, occurred in 7%, 39%, 25%, and 28% of patients.³

References

1. Kura Oncology and Kyowa Kirin announce positive ziftomenib monotherapy registrational trial and positive FDA feedback for upcoming frontline combination trial designs. News release. Kura Oncology, Inc. February 5, 2025. Accessed February 7, 2025. https://tinyurl.com/yc4pth9a
2. Kura Oncology receives breakthrough therapy designation for ziftomenib in NPM1-mutant AML. News release. Kura Oncology, Inc. April 22, 2024. Accessed February 7, 2025. https://tinyurl.com/muzr3bye
3. Wang ES, Issa GC, Erba HP, et al. Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial [published correction appears in Lancet Oncol. 2024;25(11):e542. doi:10.1016/S1470-2045(24)00584-9. Lancet Oncol. 2024;25(10):1310-1324. doi:10.1016/S1470-2045(24)00386-3
4. First in human study of ziftomenib in relapsed or refractory acute myeloid leukemia. ClincalTrials.gov. Updated March 15, 2024. Accessed February 7, 2025. https://tinyurl.com/y6c97st2