Safety data from revealed that 98% of patients treated in the trial (n = 83) experienced treatment-emergent adverse effects (TEAEs), including 96% of NPM1-mutated group (n = 51) and 100% of KMT2A-rearranged population (n = 32). The most common TEAEs across all patients included nausea (41%), fatigue (37%), thrombocytopenia (36%), febrile neutropenia (33%), and diarrhea, leukopenia, and neutropenia (31% each). The most common TEAEs related to treatment with ziftomenib included nausea (16%), fatigue and pruitus (15% each), as well as thrombocytopenia, febrile neutropenia, neutropenia, and anemia (10% each).
Moreover, the incidence of grade 3 or higher TEAEs among all patients was 92%, including 90% and 94% of the NPM1-mutated and KMT2A-rearranged groups, the most common of which included thrombocytopenia (34%), febrile neutropenia, leukopenia, neutropenia (31% each), and anemia (21%). Additionally, the most common ziftomenib-related TEAEs included febrile neutropenia and neutropenia (10% each), thrombocytopenia and leukopenia (8% each), and anemia (7%). No ziftomenib-related QTc prolongation was observed in these groups, and 2% of patients discontinued therapy due to ziftomenib-related AEs: a grade 4 instance of sepsis and a grade 3 instance of stomatitis both in the KMT2A-rearranged group.
“In the ongoing KOMET-007 study, ziftomenib [at] 600 mg once daily combined with [venetoclax/azacitidine] was well tolerated in patients with relapsed/refractory NPM1-mutated or KMT2A-rearranged [AML],” Amir T. Fathi, MD, program director of the Center for Leukemia at Massachusetts General Hospital and associate professor of Medicine at Harvard Medical School in Boston, said in the presentation. “There were low rates of ziftomenib-related myelosuppression, there was no ziftomenib-related QTc prolongation, [and] there was 1 case of differentiation syndrome…it was a grade 3 event in a [patient with NPM1 mutations] that was successfully managed per protocol-mandated measures, and the patient thereafter was able to resume ziftomenib.”
What were the efficacy data?
In the NPM1-mutated and KMT2A-rearranged groups, respectively, the objective response rate (ORR) was 65% and 41%. The composite complete remission (CRc) rate was 48% and 28%, respectively, with 27%, 13%, and 8% of the former group achieving a CR with full, partial (CRh), and incomplete hematologic recovery (CRi), vs 41%, 6%, and 16% achieving each in the latter group. The minimal residual disease (MRD) negativity rate was 60% vs 43% in the respective groups, with a median time to first MRD negativity of 8.8 weeks (range, 2.9-21.4) and 8.1 weeks (range, 7.7-18.9).
When stratified by receipt of prior venetoclax, treatment-naive patients generally experienced more pronounced clinical activity. In the NPM1-mutated group, between those who did not receive venetoclax vs those who did, the respective CRc rate and ORR was 70% vs 28% and 83% vs 48%, and the MRD negativity rates were 54% vs 71%. For patients in the KMT2A-rearranged group, the CRc, ORR, and MRD-negativity rates were 60% vs 14%, 70% vs 27%, and 25% vs 67%, respectively.
For patients with NPM1-mutated disease, the median duration of CRc was 39.9 weeks (95% CI, 16.1-not estimable [NE]), including 39.9 weeks (95% CI, 12.9-NE) among patients who had no prior venetoclax. In those with KMT2A-rearranged disease, the median duration of CRc was 12.4 weeks (95% CI, 0.9-NE), including 10.0 weeks (95% CI, 0.9-NE) among those with no prior venetoclax. The median overall survival (OS) in the respective groups was 54.9 weeks (95% CI, 32.0-NE) vs 21.1 weeks (95% CI, 12.4-64.9).
What were the key design characteristics?
In the ongoing phase 1 KOMET-007 trial, patients received escalating doses of ziftomenib plus venetoclax and azacitidine starting at 200 mg up to 600 mg in the dose-escalation phase of the trial. In the phase 1b dose-escalation/recommended phase 2 dose confirmation portion of the trial, patients received 600 mg of ziftomenib plus venetoclax and azacitidine. Azacitidine was given on cycle 1 at days 1 to 7, with additional cycles based on bone marrow biopsy results; venetoclax was given per label in 28-day cycles, with adjustments to cycles length based on bone marrow biopsy results.
Among all patients treated with 600 mg of ziftomenib, the median age was 62 years (range, 19-85), and 48% were female. Most patients were White (71%) with an ECOG performance status of 1 (51%). The median number of prior therapies was 1 (range, 1-4), the most common of which included venetoclax (58%), hematopoietic stem cell transplantation (HSCT; 19%), and menin inhibitors (10%).
The primary end points of the trial included CR rates and AEs. Secondary end points included duration of response, ORR, CRc rates, and MRD negativity.
Based on results from the phase 1b/2 KOMET-001 trial (NCT04067336), ziftomenib received FDA approval as a treatment for patients with relapsed/refractory NPM1-mutated AML in November 2025.2,3
References
- Issa GC, Fathi A, Zeidan A, et al. Ziftomenib in combination with venetoclax and azacitidine in relapsed/refractory NPM1-m or KMT2A-r acute myeloid leukemia: updated phase 1a/b safety and clinical activity results from KOMET-007. Blood. 2025;146(suppl 1):764. doi:10.1182/blood-2025-764
- Wang ES, Montesinos P, Issa GC, et al. Ziftomenib in relapsed/refractory (R/R) NPM1-mutant acute myeloid leukemia (AML): phase 1b/2 clinical activity and safety results from the pivotal KOMET-001 study. J Clin Oncol. 2025;43(suppl_16):6506. doi:10.1200/JCO.2025.43.16_suppl.6506
- FDA approves ziftomenib for relapsed or refractory acute myeloid leukemia with a NPM1 mutation. News release. FDA. November 13, 2025. Accessed December 8, 2025. https://tinyurl.com/2mcsxzuv
