Ziftomenib Achieves Durable Responses in R/R NPM1-Mutant AML Regardless of Prior Venetoclax Exposure: Pivotal KOMET-001 Results
Ziftomenib demonstrated clinically meaningful and durable responses with a favorable safety profile in patients with relapsed/refractory (R/R) NPM1-mutated (NPM1-m) acute myeloid leukemia (AML), according to results from the pivotal phase 2 KOMET-001 study.
These data were presented by Eunice Wang, MD, Roswell Park Comprehensive Cancer Center, Buffalo, New York, at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.
Nearly half of patients relapse or are refractory (R/R) within 1 year leading to limited responses to salvage chemotherapy and NPM1 mutations drive leukemogenesis in approximately 30% of AML cases. Researchers conducted a phase 1b/2 trial to determine the safety and efficacy of ziftomenib, a potent oral menin inhibitor, at 600 mg once daily (QD).
The primary end point was complete remission with full or partial hematologic recovery (CR/CRh). Secondary end points include composite complete remission (CRc), durations of CR/CRh and CRc, and safety.
Overall, 112 patients were included and treated at the 600 mg QD dose across phase 1b/2. The median age was 69 years (range, 22 to 86). Patients’ median number of prior therapies was 2 (range, 1 to 7), of which 60% had prior venetoclax (VEN) therapy, and 23% had undergone transplant.
The CR/CRh rate in the pooled phase 1b/2 population was 25% (95% confidence interval [CI], 17 to 34) and the overall response rate (ORR) was 35% (95% CI, 26 to 44). In phase 2 alone, 23% of patients (95% CI, 15 to 33) achieved CR/CRh, of which 67% were MRD-negative. Between patients with previous venetoclax exposure and those without, CR/CRh rates were comparable (24% vs 21%).
In terms of safety, grade ≥3 treatment-related adverse events occurred in 40% of patients. The most common included differentiation syndrome (13%), as well as anemia, febrile neutropenia, thrombocytopenia, or QTc prolongation among less than 5% of treated patients. Only 3% of patients discontinued treatment due to treatment-related adverse events.
“Taken together, these data support the potential use of ziftomenib monotherapy as a new treatment option for R/R NPM1-m AML,” Wang and researchers concluded.
Source:
Wang E, Montesinos P, Issa G, 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. Presented at 2025 ASCO Annual Meeting. May 30-June 3, 2025; Chicago, IL. Abstract 6506.
