ASH 2023 | KOMET-008: a Phase I trial of ziftomenib combinations in KMT2A-rearranged or NPM1-mutant AML

The Komet-008 study is a trial-in-progress that we presented here at ASH, looking at the combination of ziftomenib, a menin inhibitor, in combination with a variety of standard of care regimens, including chemotherapy as well as gilteritinib, and this is specifically for patients with either an NPM1 mutation or a KMT2A rearrangement, and either FLT3 wild type or mutant. And we’re very excited about this. It’s, of course, initially a Phase I, you know, safety and tolerability study and looking to find a good recommended Phase II dose. 

So the reason we’re excited about it is because, you know, even as single agents, it’s presented over the last several years, menin inhibitors have shown activity even as monotherapy. And that’s really due to a biologic sensitivity of these particular subtype of leukemia cells, which are dependent upon either NPM1 or KMT2A, or a few other specific genomic subsets of rearrangements that force these Hox genes to remain expressed, and the stem cells, you know, remain in a stem cell state and are not differentiating. So what menin inhibitors do, they disrupt this interaction between this core complex and this protein menin and this histone methyltransferase KMT2A on chromatin and that forces the cells to differentiate. And obviously [this is] not working in every single patient but single agent responses. And while their response rates are, you know, we’re pleased to see are impressive, we don’t think of any of these monotherapies as curative. So ideally we’d like to make this more efficacious, get deeper responses and bridge more patients to potentially curative allogeneic stem cell transplant. 

So that’s where this study comes in. So ziftomenib will be combined either again with FLAG-idarubicin, a standard salvage re-induction chemotherapy regimen, or low dose cytarabine for patients who are unfit for intensive chemotherapy, or, and this is what I’m particularly excited about, an all-oral regimen with ziftomenib plus gilteritinib. So there will be a significant subset of patients who have an NPM1 mutation as well as a co-occurring FLT3 mutation. And so both of these agents have single agent activity in this and there’s really very strong preclinical data to suggest that while one agent, you know, might have some impact on slowing down cell proliferation or inducing differentiation, that the combination can really facilitate and enable maybe more durable responses. So we’re really excited about this. We’ve had now a first site initiation visit, and then at Sloan-Kettering, we’re probably having our first site initiation visit, our SIV, in a couple of weeks, 2 or 3 weeks, and so my hope is to put my first patient on in January.