Ziftomenib With 7+3 Shows Early Promise in Newly Diagnosed NPM1-Mutated/KMT2A-Rearranged AML

The addition of ziftomenib at 600 mg once daily to cytarabine and daunorubicin (7+3) demonstrated a manageable safety profile and showed early antitumor activity in patients with newly diagnosed NPM1-mutated and KMT2A-rearranged acute myeloid leukemia (AML), according to updated data from the phase 1a/b KOMET-007 trial (NCT05735184).1

Data presented at the 2025 SOHO Annual Meeting demonstrated that 29 patients had grade 3 or higher ziftomenib-related adverse effects (AEs), which included febrile neutropenia (15%), decreased platelet count (15%), anemia (11%), and decreased neutrophil count (11%). Of note, 1 case of grade 3 differentiation syndrome was observed in a patient with KMT2A-rearranged AML and was successfully managed. Two cases of investigator-assessed grade 3 corrected QT prolongation were reported in 2 patients with KMT2A-rearranged AML.

Additionally, efficacy data revealed that ziftomenib plus 7+3 led to an objective response rate (ORR) of 94% in all patients, regardless of mutation or rearrangement status (n = 71); the ORR was 84% and 74% in patients with NPM1-mutated (n = 44) and KMT2A-rearranged (n = 27) AML, respectively.

“In the ongoing KOMET-007 study, ziftomenib 600 mg [daily] combined with 7+3 was well tolerated, with a safety profile consistent with previous reports,” lead study author Amer Zeidan, MBBS, of Yale School of Medicine and Yale Comprehensive Cancer Center, and colleagues, wrote in a poster presentation. “Robust clinical activity with deep responses was demonstrated in newly diagnosed NPM1-mutated and KMT2A-rearranged AML.”

Ziftomenib is a novel, potent, highly selective, oral menin inhibitor that has demonstrated clinical activity as monotherapy and a combination for the treatment of patients with NPM1-mutated and KMT2A-rearranged AML.

A Closer Look at the KOMET-007 Study and Baseline Patient Characteristics

The ongoing phase 1 KOMET-007 study includes the phase 1a dose-escalation portion, and a phase 1b dose-expansion portion evaluating ziftomenib plus venetoclax (Venclexta) and azacitidine (Vidaza), venetoclax monotherapy, or 7+3 for the treatment of patients with NPM1-mutated and KMT2A-rearranged AML.

Notably, patients evaluated on the study are required to be at least 18 years of age, have a documented NPM1 mutation or KMT2A rearrangement, and have either newly diagnosed or relapsed/refractory AML.2 Furthermore, patients must have an ECOG performance status (PS) of 0 to 2, and adequate liver, renal, and cardiac function according to protocol-defined criteria. Specifically, the updated data reflected results from patients with newly diagnosed NPM1-mutated or KMT2A-rearranged AML.1

In the phase 1a portion of the study, patients could receive 1 of 4 dose levels of ziftomenib plus 7+3, which included dose level –1 at 100 mg, dose level 1 at 200 mg, dose level 2 at 400 mg, and dose level 3 at 600 mg. Ziftomenib began on cycle 1, day 8, and was given continuously afterward. Cytarabine was given on cycle 1, days 1 through 7, and daunorubicin on cycle 1, days 1 through 3. Moreover, dose level 3 at 600 mg was established as the recommended phase 2 dose and was given to all patients in the phase 1b portion of the study.

The primary end points of the study are safety, dose-limiting toxicities (phase 1a), and complete remission (CR). Secondary end points include composite CR (CRc), ORR, and duration of response (DOR).

Among all patients on the study (n = 82), the median age is 56 years (range, 18-71), 52% are female, and the majority have an ECOG PS of 0 to 1 (90%). Co-mutations included FLT3 (13%) and IDH1/2 (18%). Additionally, 12% of patients had therapy-related AML, 73% were on treatment, and 93% were on the study. The median follow-up was 18.4 weeks (range, 1.1-47.1).

Additional Efficacy Data

The median duration of CR and the median overall survival (OS) were not reached (NR) among patients with NPM1-mutated AML. Two patients were treated with hematopoietic stem cell transplantation (HSCT), and 3 patients discontinued treatment due to relapse. In a similar trend, patients with KMT2A-rearranged AML had a median duration of CR of 25.6 weeks (95% CI, 8.3-not evaluable) and a median OS that was NR. Six patients received HSCT, with 1 receiving ziftomenib maintenance, and 1 patient discontinued treatment due to an AE.

Of note, the median time to neutrophil and platelet recovery was comparable to that observed with intensive chemotherapy regimens. In particular, an absolute neutrophil count of at least 1.0 x 109/L was 32 days (range, 20-88), and a platelet count of at least 100 x 109/L was 29 days (range, 20-63).

Furthermore, the clinical activity in response-evaluable first-line patients (n = 71) showed that the CRc in all patients was 92%. The 94% ORR was comprised of CRs, CR with partial hematologic recovery, and CR with incomplete hematologic recovery, at 80%, 1%, and 10%, respectively. Regarding minimal residual disease (MRD) negativity, CR MRD negativity was achieved in 76% of patients, and CRc MRD negativity was observed in 73% of patients. The time to CR MRD negativity was a median of 4.5 weeks (range, 2-17), and the time to CRc MRD negativity was a median of 4.3 weeks (range, 2-17).

“Taken together, these data support the phase 3 advancement of this ziftomenib combination in newly diagnosed NMP1-mutated and KMT2A-rearranged AML [in the KOMET-0117 trial (NCT07007312)],” the study authors concluded in the poster presentation.

References

1. Zeidan AM, Wang ES, Fathi AT, et al. Ziftomenib combined with intensive induction chemotherapy (7+3) in newly diagnosed NPM1-M or KMT2A-R acute myeloid leukemia: updated phase 1a/b results from KOMET-007. Presented at: 2025 SOHO Annual Meeting; September 3-6, 2025; Houston, TX. Abstract AML-732.
2. A study to investigate the safety and tolerability of ziftomenib in combination with venetoclax/azacitidine, venetoclax, or 7+3 in patients with AML. ClinicalTrials.gov. Updated June 5, 2025. Accessed September 4, 2025. https://clinicaltrials.gov/study/NCT05735184