Ziftomenib Meets CR/CRh End Point in R/R NPM1+ AML

Topline data from the phase 2 KOMET-001 trial (NCT04067336) evaluating the investigational once-daily oral menin inhibitor ziftomenib in patients with relapsed/refractory (R/R) NPM1-mutant acute myeloid leukemia (AML) met its primary end point of complete remission (CR) plus CR with partial hematological recovery (CRh) rate.1

Data for the primary end point was statistically significant. The risk:benefit profile for ziftomenib was encouraging, and the safety and tolerability of ziftomenib were consistent with previous reports.

Findings from the trial have been submitted for presentation at an upcoming medical conference. Kura Oncology intends to submit a new drug application (NDA) to the FDA in the second quarter of 2025 seeking the approval of ziftomenib for the treatment of patients with relapsed/refractory AML harboring NPM1 mutations.

“We are excited to report positive topline results in [patients with] relapsed/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 a news release. “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/refractory NPM1-mutant AML next quarter. Furthermore, we believe the positive FDA interactions for the [phase 3] 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 was designed to assess evidence of clinical activity, safety, and tolerability of ziftomenib. In April 2024, the FDA granted breakthrough therapy designation to ziftomenib for the treatment of heavily pretreated patients with relapsed/refractory NPM1-mutant AML, which marked ziftomenib as the first investigational agent to be granted breakthrough therapy designation for this patient population.2

Eligibility criteria included patients at least 18 years of age; an ECOG performance status of 0 to 2; a life expectancy of at least 2 months; adequate liver and kidney function; and peripheral white blood cell counts of 30000/μL or fewer.3 However, hydroxyurea was permitted to control and maintain white blood cell count before trial enrollment. Trial exclusion criteria included those with a diagnosis of acute promyelocytic leukemia, chronic myelogenous leukemia in blast crisis, and clinically active central nervous system leukemia.

All patients received ziftomenib monotherapy during the single-arm trial. Along with the CR/CRh primary end point in phase 2, secondary end points included CR rate with and without minimal residual disease negativity; duration of response; transfusion independence; event-free survival; and overall survival.

In the phase 1a/1b portion of the KOMET-001 study, 60% (n = 83/139) of screened patients received at least 1 dose of ziftomenib (phase 1a, n = 30; phase 1b, n = 53).4 In phase 1a (dose escalation), patients were treated with ziftomenib at 50 mg (n = 1), 100 mg (n = 1), 200 mg (n = 6), 400 mg (n = 5), 600 mg (n = 5), 800 mg (n = 11), and 1000 mg (n = 1). In phase 1b (dose validation and dose expansion), patients were either randomly assigned to 1:1 to dose validation (n = 34) or allocated to dose expansion (n = 19) to receive 600 mg of ziftomenib as the recommended phase 2 dose. Patients in the dose-validation group were treated with ziftomenib at 200 mg (n = 17) or 600 mg (n = 17).

The KOMET-017 protocol will include the phase 3 KOMET-017-IC trial evaluating ziftomenib or placebo in combination with 7+3 induction chemotherapy in patients with newly diagnosed NPM1-mutant or KMT2A-rearranged AML.1 KOMET-017-NIC will examine ziftomenib or placebo plus venetoclax (Venclexta) and azacitidine in patients with newly diagnosed NPM1-mutant AML who are unable receive intensive chemotherapy. Both trials are expected to initiate in the second half of 2025.

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. February 5, 2025. Accessed February 6, 2025. https://ir.kuraoncology.com/news-releases/news-release-details/kura-oncology-and-kyowa-kirin-announce-positive-ziftomenib
2. Kura Oncology receives breakthrough therapy designation for ziftomenib in NPM1-mutant AML. News release. Kura Oncology. April 22, 2024. Accessed February 6, 2025. https://ir.kuraoncology.com/news-releases/news-release-details/kura-oncology-receives-breakthrough-therapy-designation
3. First in human study of ziftomenib in relapsed or refractory acute myeloid leukemia. ClinicalTrials.gov. Updated March 15, 2024. Accessed February 6, 2025. https://clinicaltrials.gov/study/NCT04067336
4. 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 Nov;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