EHA 2025 | Updated results of KOMET-007: exploring ziftomenib with 7+3 in newly diagnosed NPM1m or KMT2Ar AML

The KOMET-007 study is an ongoing study looking at the combination of ziftomenib with either Azacitidine-venetoclax, venetoclax alone, or Cytarabine and Daunorubicin in a 7+3 combination. At the congress here today, I’m going to be presenting the data from the Phase Ia/Ib portion from the study where we combined ziftomenib 600 milligrams once daily with intensive chemotherapy 7+3 for patients with newly diagnosed NPM1-mutated AML or KMT2A-rearranged AML. 

Both NPM1 mutation and the KMT2A fusion proteins drive leukemogenesis through their interactions with the chromatin scaffolding protein known as menin. These mutations are found in 35% to 40% of patients with acute myeloid leukemia. Ziftomenib is an orally bioavailable selective potent menin inhibitor that has already shown activity as monotherapy and in combination with other therapies in KMT2A-rearranged and in NPM1-mutated AML. 

So I am presenting data here at EHA regarding the patients that we have now treated at the dose of 600 milligrams daily with 7+3. These patients were all newly diagnosed with acute myeloid leukemia. They were independently put in cohorts for either NPM1-mutated or KMT2A-rearranged. In the Phase Ia portion, we only took high-risk patients, so that was all KMT2A-rearranged patients, but in the NPM1-mutated, it was only patients age 60 and older, those with therapy-related AML, and or those with adverse risk karyotype. In the Phase Ib, any patient that was eligible for intensive chemotherapy could be included in the study. 

In the study, patients would start 7+3 chemotherapy on day 8. They would then start ziftomenib, 600 milligrams, once daily. If they achieved a remission, they could get up to four cycles of high-dose Cytarabine with continuous ziftomenib and then go on to get ziftomenib as a monotherapy maintenance. Patients were allowed to undergo allogeneic transplant at any time during the course of the study, and they could actually go back on ziftomenib maintenance after allogeneic transplant. So far, we only have one patient on ziftomenib maintenance after allotransplant, but we do have 15 patients total on ziftomenib maintenance. 

As far as the safety that we saw, there were no new safety signals. The safety was, as we have seen, with ziftomenib as a monotherapy, but also the safety of 7+3 and high-dose Ara-C chemotherapy. Importantly, we saw only one case of grade 3 differentiation syndrome in a patient with a KMT2A rearrangement, and this was successfully managed with our typical mitigating strategies. We saw two patients with ziftomenib-related, potentially related, I should say, QT prolongation. Both patients actually were on other drugs at the same time that could cause QT prolongation. So really didn’t see a signal for anything different than what we would see with 7+3. And importantly, in terms of myelosuppression, there were reports of decreased neutrophils, decreased platelets, anemia, febrile neutropenia. And in terms of the cytopenias, all but one of those cytopenias occurred in patients receiving ziftomenib with chemotherapy, and all of them were also attributed to potentially to the chemotherapy as well as the ziftomenib, so hard to parse out. 

I think a better indicator of the potential for myelosuppression is the median time to neutrophil and platelet recovery. And what we saw in the study was a time to neutrophil and platelet recovery that was similar to what has been reported in the control arm of the QuANTUM-First study, in the control arm of the Lancet publication of CPX-351 with 7+3 chemotherapy. So no new safety signals there. 

In terms of efficacy, most patients responded. The CRc rate, so that’s CR or CRi-CRH, was 89% in the NPM1-mutated group and 78% in the KMT2A-mutated group. Just looking at CR alone, it was 84% with NPM1, and it was 74% in the NPM1-mutated group. Furthermore, the majority of these CRc patients achieved MRD negativity by a local assay for MRD. The median survival has not been reached in either group, the follow-up is very short. 

So in summary, we’re very encouraged by the safety data, by the preliminary efficacy data, the depth of these remissions occurring very quickly within four to five weeks. And so this provides a basis for going forward with a large randomized Phase III study known as KOMET-017. This is a registration-enabling study of ziftomenib versus placebo with 7+3 followed by HIDAC and maintenance, and in patients who are unfit for intensive chemotherapy, ziftomenib versus placebo in those patients with newly diagnosed NPM1, KMT2A-rearranged, who are unfit for intensive chemotherapy combination with ven-aza in that case. That data with the combination of ven-aza is still maturing and probably will be presented later this year, but we’ll see.

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