Ziftomenib is a highly selective oral menin inhibitor being developed by Kura Oncology in partnership with Kyowa Kirin. It targets menin-KMT2A and menin-NPM1 interactions, which are critical for leukemogenesis in AML with either KMT2A rearrangements (KMT2A-r) or NPM1 mutations (NPM1-m). These subtypes account for a significant portion of AML cases and are associated with poor outcomes, especially in relapsed/refractory settings.

As presented at the European Hematology Association (EHA) 2025 Congress, Ziftomenib dosed at 600 mg once daily in combination with 7+3 chemotherapy demonstrated robust efficacy in newly diagnosed NPM1-m and KMT2A-r AML. Among 71 response-evaluable patients, the composite complete remission (CRc) rate was 92%, with 93% in the NPM1-m group and 89% in the KMT2A-r group. Complete remission (CR) was achieved in 80% of patients overall—84% in NPM1-m and 74% in KMT2A-r. Importantly, high rates of minimal residual disease (MRD) negativity were also observed: 71% for NPM1-m and 88% for KMT2A-r, with median times to MRD negativity of 4.7 weeks and 4.4 weeks, respectively.

Durability of response and early survival data were promising. In NPM1-m patients, neither median duration of CR nor median overall survival (OS) had been reached at a median follow-up of 24.9 weeks. In the KMT2A-r group, the median CR duration was 25.6 weeks, while median OS was not yet reached, with a median follow-up of 15.7 weeks. At the data cutoff, 96% of NPM1-m patients and 88% of KMT2A-r patients were alive and remained on study. These results support advancing to the pivotal KOMET-017 Phase III trials, expected to begin in the second half of 2025. 

The combination was well tolerated, with a safety profile consistent with expectations for intensive chemotherapy. Among 82 patients in the safety population, the most common Grade ≥3 treatment-related adverse events were febrile neutropenia (15%), thrombocytopenia (15%), anemia (11%), and neutropenia (11%). There was one reported case of differentiation syndrome and two cases of QTc prolongation, all managed successfully. Importantly, there were no dose-limiting toxicities, no evidence of additive myelosuppression, and no clinically meaningful QTc prolongation attributed directly to Ziftomenib. Hematologic recovery was not delayed, indicating compatibility with intensive chemotherapy regimens.

KOL insights

“The findings presented at EHA2025 underscore the potential of Ziftomenib in combination with 7+3 as an early intervention in the frontline setting of AML and could offer a meaningful opportunity to improve patient outcomes. The high rates of complete remission and MRD negativity across the 7+3 cohorts are particularly encouraging. The continued rapid enrollment in the Phase Ib portion of this study underscores the urgency and enthusiasm for further evaluating this combination approach.” – Expert Opinion

“We remain very encouraged by the updated clinical activity, safety, and tolerability data from the KOMET-007 study evaluating Ziftomenib with 7+3 in newly diagnosed AML patients with NPM1 mutations or KMT2A rearrangements, these updated data reinforce the combination potential of Ziftomenib in the frontline setting, strengthening our confidence in its ability to provide a valuable treatment option for a significant portion of the AML population.”-– Expert Opinion

Conclusion

Although numerous treatments exist for AML, patient outcomes remain poor, highlighting a significant unmet medical need. The menin pathway is recognized as a key driver of various genetic alterations in AML, with NPM1 mutations occurring in more than 30% of cases and KMT2A rearrangements in approximately 5–10%. While NPM1-mutated AML patients often respond well to initial therapy, relapse is common, and long-term survival remains low, with only 30% overall survival at 12 months in the relapsed/refractory setting.

Menin inhibitors are quickly transforming the treatment landscape for patients with KMT2A-rearranged or NPM1-mutated AML. The recent US FDA approval of REVUFORJ (revumenib) for relapsed/refractory KMT2Ar AML represents a significant milestone, while ongoing studies of bleximenib, enzomenib, and ziftomenib are actively investigating optimal dosing, combination strategies, and efficacy across diverse patient groups—including newly diagnosed, relapsed/refractory, fit, and unfit individuals.