EHA 2025 | Findings from the KOMET-001 study of ziftomenib in patients with NPM1-mutated AML

So at this year’s meeting at the European Hematology Association, we’re presenting data on KOMET-001, which was a Phase I/Phase II study of a menin inhibitor, ziftomenib, in relapsed or refractory acute myeloid leukemia. Menin inhibitors are a class of drug that interfere with the interaction of menin and KMT2A, two proteins that are important for leukemogenic potential in terms of upregulating certain leukemia-inducing factors, including MEIS1. The drug interferes with the interaction of menin and KMT2A, and in that way, downregulates expression of these leukemogenic pathways, leading to normal differentiation, normal maturation of leukemic cells into normal hematopoiesis. And that is thought to be the mechanism of action of the drug. So this monotherapy study in relapsed/refractory patients with AML was a Phase I/Phase II study that focused on individuals that had mutations or molecular subsets that would be susceptible, which included KMT2A rearranged AML as well as NPM1 mutated AML. However, it is important to say that the Phase Ib/Phase II portion of the study which we’re presenting today is focused on NPM1 mutated AML patients with the hope of this being a registrational study potentially having this drug be available for NPM1 mutated patients. And in fact, the Phase II study did meet its primary endpoint. And the CR-CRh composite remission was 23%, therefore meeting the endpoint. And the overall response rate, which included MLFS and partial remissions and CRis, which are sort of lesser responses, was 33%. There was also an improvement in terms of transfusional independence in about 20% of patients, which is interesting and exciting. As far as tolerability, the drug was pretty well tolerated. There was not a clinically significant incidence of any QT prolongation, which was seen with other menin inhibitors that have been understudied. Differentiation syndrome, which is actually the mechanism of action, but if the differentiation is too profound, it can cause an inflammatory reaction. It’s a class effect seen with all menin inhibitors. Occurred in about 13% in terms of grade three differentiation syndrome in patients treated on this study, but it was well-managed, generally speaking, with sort of standard approaches for differentiation syndrome. The response rates that we saw were preserved, whether patients had prior exposure to venetoclax and prior transplant, which is also encouraging. So overall, I think this data is promising, and we have a PDUFA date in November, so our hope is that this drug will, in terms of regulatory approval, become potentially an option for patients depending on further review by regulatory authorities.

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