EHA 2021 | KOMET-001: targeting menin-KMT2A in AML
Eunice Wang, MD, Roswell Park Comprehensive Cancer Center, Buffalo, NY, gives an overview of the Phase I/II first-in-human KOMET-001 dose-escalation trial-in-progress (NCT04067336) of KO-539, a menin-KMT2A inhibitor, in patients with relapsed or refractory acute myeloid leukemia (AML). Dr Wang discusses the rationale for the trial, highlighting the poor prognosis of patients with KMT2A mutations with standard chemotherapy, and the lack of therapies targeting NPM1-mutant AML. Dr Wang also comments on the mechanism of action of KO-539 and the potential identification of predictive biomarkers. Preliminary data from eight evaluable patients has indicated clinical activity. This interview took place at the virtual European Hematology Association (EHA) Congress 2021.
Transcript (edited for clarity)
Patients that have AML characterized by MLL or KMT2A mutations have a poor prognosis with standard chemotherapy. We also know that for patients who have NPM1-mutant disease in the relapsed/refractory setting, that there are no currently targeted therapies that address NPM1-mutant AML. To address both of these poor prognostic subsets, there has been an emerging body of data suggesting that menin-inhibitors targeting the menin-MLL or KMT2A gene complex, can be effective in the laboratory in eradicating these disease subsets...
Patients that have AML characterized by MLL or KMT2A mutations have a poor prognosis with standard chemotherapy. We also know that for patients who have NPM1-mutant disease in the relapsed/refractory setting, that there are no currently targeted therapies that address NPM1-mutant AML. To address both of these poor prognostic subsets, there has been an emerging body of data suggesting that menin-inhibitors targeting the menin-MLL or KMT2A gene complex, can be effective in the laboratory in eradicating these disease subsets.
So, for that reason, we have initiated a Phase I/Ib trial of a novel menin-inhibitor, KO-539, which is being sponsored by Kura Oncology. This particular trial is a dose escalation trial examining KO-539, an oral menin-inhibitor at escalating doses, starting at 50 milligrams all the way up to the current dose of 800 milligrams for safety tolerability, and a recommended Phase II dose.
We are actively accruing patients independent of their mutational status for the dose escalation phase. Following this, the plan is to expand to specific mutational subsets, specifically patients with relapsed or refractory NPM1 or KMT2A-mutant disease to evaluate the preliminary efficacy of at least one to two doses of this agent moving forward. For efficacy assessment, we will be looking at CR rates as well as CR/CRi rates, disease-free survival, as well as overall survival and transfusion independence.
Exploratory biomarkers are being examined on the study to see whether there is a particular predictor of response or specific genetic subtypes or mutational profile, which would predict for improved efficacy or response.
In preliminary data presented at the ASH 2020 meeting, we did note that out of eight evaluable patients, there were some evidence of clinical activity in six out of the eight patients, including CR in two patients, one of which had a target NPM1 mutation and the other one who did not. This trial is being presented at EHA as a trial-in-progress and we anticipate having more updates for the escalation and hopefully the recommended Phase II dosing at the upcoming ASH meeting in 2021.
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