Dr Fathi on the Efficacy and Safety of Ziftomenib in R/R NPM1-Mutant AML

“Overall, the study did meet its primary end point in terms of the composite CR/CRh rate. Ziftomenib currently has a Prescription Drug User Fee Act date in November [2025]. We’re hoping that it will become a potential option for patients with NPM1-mutated AML.”

Amir Fathi, MD, program director of the Center for Leukemia at Massachusetts General Hospital; as well as an associate professor of medicine at Harvard Medical School, discussed findings from the phase 1b/2 KOMET-001 trial (NCT04067336)investigating ziftomenib (KO-539) in patients with relapsed/refractory, NPM1-mutant acute myeloid leukemia (AML).

The registrational phase 2 portion of KOMET-001 enrolled adult patients with relapsed/refractory NPM1-mutant AML. Patients received ziftomenib at 600 mg once daily.

This oral therapeutic regimen demonstrated encouraging efficacy in a heavily pretreated, relapsed/refractory population of patients with NPM1-mutated AML, according to Fathi. The study reported a complete remission (CR)/CR with partial hematologic recovery (CRh) rate of 23% in the phase 2 population (n = 92). Furthermore, the overall response rate—including CR, CRh, CR with incomplete hematologic recovery, CR with incomplete platelet recovery, morphologic leukemia-free state, and partial response—was 33%. Importantly, the efficacy of ziftomenib appeared consistent across subgroups, including patients with prior exposure to hematopoietic stem cell transplantation or prior treatment with venetoclax (Venclexta), which is an encouraging finding, he reported.

Treatment with ziftomenib was generally well tolerated, Fathi said. Notably, the agent did not exhibit a significant signal for QT interval prolongation—a concerning adverse effect (AE) observed with other menin inhibitors, he explained. Additionally, minimal clinically significant drug-drug interactions were reported, he stated.

Differentiation syndrome, which promotes the differentiation of leukemic blasts into mature hematopoietic cells, is a known class effect associated with menin inhibitors due to their mechanism of action, Fathi emphasized. In KOMET-001, grade 3 instances of this AE occurred in 13% of patients; no grade 4 or 5 differentiation syndrome was reported. Although differentiation syndrome can be associated with significant inflammation and systemic symptoms, all cases observed in the study were managed effectively using standard supportive interventions, including corticosteroids and cytoreductive therapy when clinically indicated, he noted.

Overall, the study successfully met its primary end point of composite CR/CRh rate, Fathi highlighted. Ziftomenib for the treatment of adult patients with relapsed/refractory NPM1-mutant AML is currently under FDA priority review and holds a Prescription Drug User Fee Act decision date of November 30, 2025. If approved, ziftomenib may be a valuable treatment option for patients with NPM1-mutated AML, he concluded.