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The 600-mg RP2D of Ziftomenib in combination with venetoclax/azacitidine displayed high response rates in NPM1-mutated AML.
High durable morphologic and minimal residual disease (MRD)–negative complete remission rates were shown in patients newly diagnosed with NPM1-mutated acute myeloid leukemia (AML) who received 600 mg of ziftomenib (Komzifti) in combination with azacitidine (Vidaza) and venetoclax (Venclexta), according to data from the phase 1b KOMET-007 trial (NCT05735184) presented at the 2025 ASH Annual Meeting and Exposition.1
Composite complete remissions (CRc) occurred in 86% of patients, with a median time to first CRc of 3.4 weeks (range, 2,4-9,6). The objective response rate was 89%, the CR rate was 73%, the CR with hematologic recovery (CRh) rate was 5%, the CR with incomplete hematologic recovery (CRi) rate was 8%, the morphologic leukemia-free state rate was 3%, and the partial response rate was 0%. Of note, 3% of patients had no response, and 8% were not evaluable. The CR/CRh rate was 77% for FLT3 and 89% for IDH1/2 mutations.
Central MRD negativity was assessed using next-generation sequencing. The MRD negativity rate, with a threshold of 0.1% or less, was 68% compared with 44% for the 0.01% or less threshold; the median time to first MRD negativity was 9.4 weeks vs 9.6 weeks, respectively. The timing of MRD negativity was by cycle 1 for 6% vs 0%, by cycle 2 for 71% vs 64%, by cycle 3 for 94% vs 91%, and by cycle 4 for 100% vs 100%.
At the median follow-up of 26.1 weeks, the median duration of CR was not reached, and the median overall survival was not reached either. There were 5 patients with NPM1 mutations who underwent hematopoietic stem cell transplant, and 3 who underwent ziftomenib maintenance. Additionally, 68% of patients remained alive and continued on the study.
For CRc responders, the median days to an absolute neutrophil count (ANC) of ≥ 0.5 x 109/L was 36 (range, 1-69), the median days to ANC recovery of ≥ 1.0 x 109/L was 37 (range, 1-69), the median days to platelet count recovery of ≥ 50 x 109/L was 24 (range, 0-84), and the median days to platelet count recovery of ≥ 100 x 109/L was 30 (range, 20-77). The study highlighted comparable times to neutrophil and platelet count recovery when compared with venetoclax and azacitidine alone.
“In the ongoing KOMET-007 study, ziftomenib 600 mg QD combined with venetoclax/azacitidine showed high rates of durable morphologic and MRD-negative CR in newly diagnosed NPM1-mutated AML,” Gail J. Roboz, MD, professor of medicine and director of the Clinical and Translational Leukemia Program at the Weill Medical College of Cornell University and the NewYork-Presbyterian Hospital, said during the presentation.
A total of 40 patients were assessed for the recommended phase 2 dose of ziftomenib plus venetoclax/azacitidine in the first-line setting. Ziftomenib began on cycle 1 day 8 and continued thereafter; venetoclax was given per label in 28-day cycles, and azacitidine was given on cycle 1 days 1 to 7. When venetoclax was administered, adjustments were made to dosing and cycle length based on blast clearance in the cycle 1 bone marrow biopsy, which was conducted between days 14 and 28.
The primary end points were CR and adverse effects (AEs). Secondary end points were CRc, ORR, duration of response, and MRD.
The response-evaluable population included 37 patients. The median follow-up was 26.1 weeks. As of the presentation, 70% of patients were still on the study, and 55% were still receiving ziftomenib.
The median patient age was 75 years, 78% of patients were White, and 58% of patients had an ECOG performance status of 2. Additionally, 35% of patients had FLT3 mutations, and 23% had IDH1/2.
All treatment-emergent adverse effects (TEAEs) that occurred in 25% or more of patients included nausea (40%), vomiting (40%), diarrhea (40%), fatigue (40%), and thrombocytopenia (38%). TEAEs related to ziftomenib included nausea (23%), neutropenia (23%), fatigue (20%), thrombocytopenia (20%), aspartate aminotransferase increase (18%), and decreased appetite (15%).
All grade 3 or higher TEAEs and grade 3 or higher TEAEs relating to ziftomenib were neutropenia (38% vs 20%, respectively), thrombocytopenia (28% vs 18%), leukopenia (25% vs 10%), and anemia (20% vs 13%). AEs of interest related to ziftomenib were grade 2 differentiation syndrome (3%) and were successfully resolved with protocol-specified mitigation. Additionally, there was grade 3 investigator-assessed QTc prolongation (3%), but it was resolved with electrolyte repletion. Both patients resumed ziftomenib treatment.
“The addition of ziftomenib to venetoclax/azacitidine did not result in increased toxicity. Myelosuppression was as expected for venetoclax/azacitidine, and the times to neutrophil and platelet count recovery were comparable to those for venetoclax/azacitidine alone,” Roboz concluded.
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