Ziftomenib Plus 7+3 Yields High Response Rates in Newly Diagnosed AML

Adding the oral menin inhibitor ziftomenib (Komzifti) to standard 7+3 intensive induction chemotherapy produced high rates of complete remission and measurable residual disease (MRD) negativity in patients with newly diagnosed NPM1-mutated or KMT2A-rearranged acute myeloid leukemia (AML), according to updated results from the phase 1 KOMET-007 trial (NCT05735184). The data were presented by Amer M. Zeidan, MD, of Yale University and Yale Comprehensive Cancer Center, during an oral session at the 2026 European Hematology Association (EHA) Congress.¹

Ziftomenib is a potent, selective, once-daily oral menin inhibitor that became the first targeted therapy approved by the FDA for adults with relapsed or refractory NPM1-mutated AML in November 2025.² NPM1 mutations and KMT2A rearrangements drive leukemogenesis in approximately 35% to 40% of patients with AML, and preclinical data have suggested synergy between menin inhibition and standard cytotoxic chemotherapy. KOMET-007 is an ongoing, global, multicohort, open-label trial evaluating ziftomenib in combination with standard therapies in newly diagnosed or relapsed/refractory AML.

In the intensive-chemotherapy cohorts, ziftomenib was initiated on day 8 of cycle 1 and continued thereafter, with cytarabine administered on days 1 through 7 and daunorubicin on days 1 through 3. Patients could proceed to ziftomenib maintenance monotherapy for up to 2 years following consolidation or transplant.

A dose-escalation phase evaluated ziftomenib at 200, 400, and 600 mg once daily, and the 600-mg dose—the approved monotherapy dose—was selected as the recommended phase 2 dose. The analysis included 99 patients treated at 600 mg: 49 with NPM1-mutated AML and 50 with KMT2A-rearranged AML. The primary end points were safety and response, and the data cutoff was April 10, 2026.

All patients had newly diagnosed AML and were considered fit for intensive chemotherapy. In the NPM1-mutated cohort, the median age was 60 years (range, 30-71), 51% of patients were female, and 90% had an ECOG performance status of 0 or 1; this cohort was enriched for higher-risk features because the dose-escalation phase required adverse-risk cytogenetics, an age of 60 years or older, or therapy-related disease. In the KMT2A-rearranged cohort, the median age was 43 years (range, 18-70), 62% of patients were female, and 96% had an ECOG performance status of 0 or 1. FLT3 co-mutations were present in 14% of patients in each cohort, and therapy-related AML was reported in 4% of the NPM1-mutated cohort and 20% of the KMT2A-rearranged cohort.

Among patients with NPM1-mutated AML, the composite complete remission (CRc) rate was 96%, including a 94% complete remission (CR) rate, and the overall response rate (ORR) was 98%. In the KMT2A-rearranged cohort, the CRc rate was 90%, with an 82% CR rate and a 92% ORR. Local minimal residual disease (MRD) negativity among CRc responders was 85% in the NPM1-mutated cohort and 82% in the KMT2A-rearranged cohort. By central next-generation sequencing among responders with NPM1-mutated disease, MRD negativity was achieved in 79% of patients at a threshold of less than 0.1% and 56% at a threshold of less than 0.01%, with all such responses occurring within 2 treatment cycles.

After a median follow-up of 17.6 months in the NPM1-mutated cohort and 11.0 months in the KMT2A-rearranged cohort, the median duration of CR was not reached for NPM1-mutated AML and was 12.0 months (95% CI, 6.0-not evaluable [NE]) for KMT2A-rearranged AML. Median overall survival (OS) was not reached in either cohort. The 12-month OS rate was 94% in the NPM1-mutated cohort and 71% in the KMT2A-rearranged cohort, and 60-day mortality was 2% (n = 1/49) and 4% (n = 2/50), respectively. Ten patients in the NPM1-mutated cohort and 32 in the KMT2A-rearranged cohort proceeded to hematopoietic stem cell transplantation.

The addition of ziftomenib to 7+3 did not appear to increase the risk of complications relative to historical controls, and no new safety signals were identified. The most common grade 3 or higher treatment-emergent adverse events across all 99 patients were febrile neutropenia (63%), thrombocytopenia (60%), and anemia (37%), consistent with the known profile of 7+3. Time to neutrophil and platelet recovery, at a median of approximately 28 days, was comparable to that observed with intensive chemotherapy alone, suggesting no additive myelosuppression.

Adverse events of special interest for menin inhibitors were limited and manageable. Grade 3 differentiation syndrome occurred in 4 patients (4%; 1 NPM1-mutated, 3 KMT2A-rearranged), with no grade 4 events or related deaths; all cases resolved with protocol-specified mitigation, and 3 patients continued ziftomenib. Grade 3 QTc prolongation was reported in 3 patients (3%), none considered ziftomenib-related, with no grade 4 events; all events resolved and patients continued treatment.

Zeidan concluded that ziftomenib at 600 mg daily combined with 7+3 was well tolerated and associated with high response rates in newly diagnosed NPM1-mutated and KMT2A-rearranged AML. The findings support the ongoing phase 3 KOMET-017 program (NCT07007312), which comprises 2 independently powered, registration-enabling trials enrolling approximately 1300 patients—one evaluating ziftomenib with 7+3 in patients fit for intensive chemotherapy and the other evaluating ziftomenib with venetoclax (Venclexta) and azacitidine (Vidaza) in patients unfit for intensive chemotherapy.

Disclosures: Zeidan noted serving as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; Akesobio; Agios; Amgen; AstraZeneca/Alexion, Astellas; BioCryst; Beigene; Boehringer Ingelheim; Celgene/BMS; Chiesi/Cornerstone biopharma; Daiichi Sankyo; Dr Reddy; Epizyme; Faron; Fibrogen/Kyntro Bio; GSK; Glycomimetics; Genentech/Roche; Gilead; Geron; Innocare, Janssen/J&J; Jasper; Karyopharm; Kyowa Kirin; Keros; Kura; Novartis; Notable; Orum; Otsuka; Oncoverity, Pfizer; Puretech/Gallop Oncology, Regeneron; Rigel; Seattle Genetics; Shattuck labs; Schrodinger; Syros; Syndax; Servier; Takeda; Treadwell; Taiho; Vincerx; and Zentalis.

He also received clinical research support (institutional) from: AbbVie; Agios, AkesoBio, Astex/Taiho; Bristol-Meyers Squibb/Celgene; Daiichi Sankyo; Faron, Geron; GSK, Genentech/Roche, Kura; Innocare, Novartis; Orum; Oncoverity, Shattuck Labs; Syros, Systimmune, Sillajen, and Takeda.

He also received travel support from Fibrogen/Kyntra Bio, Kura.

References

1. Zeidan AM, Wang E, Erba HP, et al. Ziftomenib combined with intensive induction (7+3) for newly diagnosed NPM1-m or KMT2A-r acute myeloid leukemia (AML): long-term results from the KOMET-007 trial. Presented at: 2026 European Hematology Association Congress; June 11-14, 2026; Stockholm, Sweden. Abstract S130.
2. FDA approves ziftomenib for relapsed or refractory acute myeloid leukemia with an NPM1 mutation. FDA. November 13, 2025. Accessed June 14, 2026. https://tinyurl.com/bdh2raan