KOMET-001 Trial Reveals Emerging Option for Mutant Acute Myeloid Leukemia

Ziftomenib achieved robust response that were sustained over time in patients with relapsed/refractory (R/R) NPM1-mutant acute myeloid leukemia (AML), according to results from the pivotal KOMET-001 study presented during the EHA 2025 Congress in Milan, Italy.

Results from the KOMET-001 presented by Amir Fath, MD of Massachusetts General Hospital were from 112 R/R NPM1-mutant AML patients (51% from US/Canada, 49% from Europe/UK) received the recommended phase 2 dose of 600 mg ziftomenib daily in 28-day cycles with a median follow-up of 4.2 months.

The KOMET-001 study was a multicenter, open-label, registration-enabling phase 1/2 study of ziftomenib in adults with R/R NPM1-mutant and KMT2A-rearranged AML. The recommended phase 2 dose (RP2D) for R/R NPM1-mutant AML was 600 mg of ziftomenib once-daily (QD) as the monotherapy.

 The median age of the study was 69 years (ranging between 22–86), 56% were female, 83% had an ECOG PS 0–1 and had a median of 2 prior therapies (60% had prior venetoclax and 23% had prior stem cell transplant).

The primary endpoint of the phase 2 study was complete remission with full or partial hematologic recovery. Secondary endpoints included the duration of CR/CRh, composite complete remission (CRc), overall response rate (ORR), and safety.  

The results of the study indicate that the phase 2 primary endpoint was met. In all phase 1b/2 patients, the CR/CRh rate was 25% and the ORR was 35%. Among phase 2 patients (N=92), 23% achieved CR/CRh, with 67% measurable residual disease (MRD) negativity measured among CR/CRh responders tested. CR/CRh responses were observed in both venetoclax-naïve and -exposed patients at a rate of 21-24%.  

Overall, ziftomenib was well tolerated with limited myelosuppression and only 3% of patients discontinuing due to treatment-related adverse events (TRAEs). Forty percent of patients experienced grade 3 TRAEs or higher, including 13% with differentiation syndrome. Less than 5% of patients experienced anemia, febrile neutropenia and thrombocytopenia, and 2% experienced QTc prolongation.

Data from KOMET-001 show that ziftomenib monotherapy is a new treatment option for patients with R/R NPM1-mutant AML.