SOHO 2023 | Ziftomenib: a menin inhibitor for R/R NPM1-mutated AML

Menin inhibitors are being developed in AML based on the pathogenesis of AML in patients with NPM1 mutations and KMT2A rearrangements. Both of those mutations will signal through the Menin-KMT2A pathway and lead to upregulation of HoxA9 and Meis1, blocking differentiation and causing a leukemogenic profile. Menin inhibitors can overcome that interaction between KMT2A and Menin, leading to differentiation, the proposed mechanism of action of menin inhibitors. There are a number of menin inhibitors in development. At SOHO, we presented our data, an encore presentation from our EHA presentation on ziftomenib, specifically in patients with NPM1-mutated acute myeloid leukemia that had relapsed or were refractory to prior lines of therapy. What we saw with this single agent dose at 600mg a day was that the complete remission rate was 40%. So that’s CR and complete remissions without complete blood count recovery was 40%. The median time to that first response was 51 days, the median duration of response, not censoring at the time of transplant, was eight months. So we think that as a single agent, this provides efficacy. On the other hand, how about safety? What we saw in this Phase I expansion or the Phase II part of the study was the drug was well tolerated. We did not see a signal for QT prolongation, and we did not see significant GI toxicity. We did see differentiation syndrome in four of the 20 patients. Only one of them was Grade 3, and it was managed appropriately. So we think the toxicity profile also supports the use of ziftomenib as a single agent in relapsed/refractory NPM1-mutated AML, especially when you compare the results we’re seeing with the outcomes of NPM1-mutated AML that’s relapsed/refractory, as published by Ghayas Issa from the MD Anderson Group. We also studied this in the KMT2A-rearranged patient population. We saw clear biologic activity, but a very pronounced signal for leukocytosis and differentiation syndrome. We are proceeding with ziftomenib development in KMT2A-rearranged AML and ALL, but in combination with chemotherapy. Finally, there’s much discussion about the mechanisms of resistance to the menin inhibitors, with revumenib, they have seen several mutations develop which confer resistance to menin inhibitors, and this has been shown by in vitro work as well. In our study, we only found one patient who developed a menin mutation. We used a different technology than they did in the revumenib study, the revumenib study used a very sensitive single-cell assay, where they picked up and counted any cell that had a mutation. Ours was based on an RNAseq assay- which was less sensitive- but we hypothesized that if that mutation was leading to resistance, we should really be able to see it. So I think we have a lot to learn still about this mechanism and other mechanisms of resistance to menin inhibitors. We look forward to combination studies of menin inhibitors with both intensive and less intensive chemotherapy, with ziftomenib, revumenib, and a number of other drugs that are in development.