Ziftomenib (KO-539), an innovative oral selective menin inhibitor, has shown encouraging results in clinical trials, offering renewed hope for patients with treatment-resistant acute myeloid leukemia (AML). The drug targets the interaction between the menin protein and the KMT2A protein complex, crucial in leukemogenesis, particularly in AML cases with NPM1 mutations or KMT2A rearrangements.
Mechanism of Action
Eunice S. Wang, Chief of the Leukemia/Benign Hematology Service at Roswell Park Comprehensive Cancer Center, explained that ziftomenib blocks the binding and activation of menin, which is imperative for the activation of transcription factors like HOXA9 and MEIS1. These factors promote leukemia stem cell self-renewal and block differentiation. The NPM1 mutant protein acts similarly, driving comparable biology in NPM1 mutant AML.
KOMET-001 Trial
The KOMET-001 trial, a Phase Ia/Ib study conducted across 22 hospitals in France, Italy, Spain, and the U.S., enrolled adults with relapsed or refractory AML. Phase Ia involved dose escalation (50 to 1,000 mg), while Phase Ib focused on patients with NPM1 mutations or KMT2A rearrangements, randomly assigned to 200 mg and 600 mg ziftomenib dose cohorts. The pharmacokinetic data supported the dosing strategy, with nearly linear increases in plasma concentration from 50 mg to 1,000 mg. Maximum plasma concentration was reached at 3 hours for 200 mg doses and 6 hours for 600 mg doses.
Key Findings from KOMET-001
Results from the trial, which ran from September 2019 to August 2022 and included 83 patients, were particularly significant for patients with NPM1 mutations. At the 600 mg recommended Phase II dose, 9 out of 36 patients (25%) with KMT2A rearrangement or NPM1 mutations achieved complete remission (CR) or complete remission with partial hematologic recovery (CRh). Specifically, 7 out of 20 patients (35%) with NPM1 mutation reached CR at this dose level. Response rates varied based on specific co-mutations, with NPM1-mutant patients with FLT3 co-mutations showing a 33% CR rate. Patients with IDH1 or IDH2 co-mutations achieved 50% remission rates, while those with both FLT3 and IDH co-mutations showed a 50% remission rate, and NRAS mutation carriers achieved a 60% composite complete remission rate.
The median time-to-first response was 51 days. For NPM1-mutant patients on the 600 mg dose, responses lasted a median of 6.6 months. Two NPM1-mutant patients who underwent stem cell transplants maintained remission through the study's end, with one continuing ziftomenib as post-transplant maintenance therapy.
The drug's safety profile proved manageable. The most common severe adverse events included anemia (24%), febrile neutropenia (22%), and pneumonia (19%). Differentiation syndrome, an expected effect of menin inhibition, occurred in 15% of patients, leading to suspending enrollment for patients with KMT2A rearrangements.
Notably, only 3% of patients developed a MEN1 mutation after 4 treatment cycles, indicating remarkable resistance characteristics compared to other menin inhibitors.
Ziftomenib in Newly Diagnosed AML
In a phase I KOMET-007 trial, ziftomenib combined with 7+3 chemotherapy in newly diagnosed AML patients with NPM1 mutations or KMT2A rearrangements demonstrated robust clinical activity. In 46 patients evaluable for response, 100% of the NPM1 mutated cohort achieved complete clinical remission, with about 75% achieving measurable residual disease (MRD) negativity. Complete remission was achieved by 83% of the KMT2A-rearranged cohort, with similar MRD negativity rates. At 31 weeks of median follow-up, the median duration of response and overall survival had not been reached in either mutational subtype.
Combination Studies and Future Directions
Research continues to explore combinations with other therapies to enhance effectiveness. Ziftomenib is currently in clinical studies in combination with 7+3 induction chemotherapy and azacytidine and venetoclax. Additional studies are examining it in combination with other intensive regimens and FLT3 inhibition (gilteritinib). The FDA's Breakthrough Therapy designation for ziftomenib is designed to expedite its development and review process, potentially leading to FDA submission as early as 2025.
