ASH 2020 | Phase I trial of the KMT2A inhibitor KO-539 in R/R AML
Amir Fathi, MD, MPH, Massachusetts General Hospital Cancer Center, Boston, MA, shares the preliminary results of a Phase I/IIa study (NCT04067336 ) of KO-539 in relapsed/refractory acute myeloid leukemia (AML) patients. KO-539 is a novel inhibitor of the menin-KMT2A protein-protein interaction. The KMT2A complex is involved in epigenetic dysregulation in AML, and known KMT2A aberrations cause an aggressive form of AML with poor prognosis; this provides the rationale behind the development of this candidate drug. This interview took place during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, 2020.
Transcript (edited for clarity)
For what I can say is based on the abstract that was presented and published online, so menin is a key protein that interacts with MLL, also known as KMT2A. These epigenetic modulators are very important and alterations in these proteins and their interactions can impact the differentiation of myeloid progenitors and trigger the development of various hematologic malignancies, including myeloid malignancies...
For what I can say is based on the abstract that was presented and published online, so menin is a key protein that interacts with MLL, also known as KMT2A. These epigenetic modulators are very important and alterations in these proteins and their interactions can impact the differentiation of myeloid progenitors and trigger the development of various hematologic malignancies, including myeloid malignancies.
Drugs that help sort of interfere with the interaction between menin and MLL seem to at least pre-clinically suggest activity as therapeutics for myeloid malignancies. Among these is KO-539, a menin inhibitor with initial interest in looking at patients who had MLL alterations, either translocations or mutations, or those who have NPM1 mutations. NPM1 downstream also acts on the complex involving MLL and menin.
This study was a dose-escalation Phase I study, and there’s going to be Phase II portion of it. Dose escalation was actually agnostic of alterations, meaning any patient, regardless of the type of mutations or alterations, could go on. Today, a handful or more of patients have been enrolled.
When we’ve looked at several dose levels, intriguingly as was presented in the abstract, several patients have had responses, including a CR, and I think additional data is going to be presented on the day of the presentation.
I think it’s exciting. It’s intriguing. It’s an oral regimen so far, appears to be well tolerated with encouraging PKs. This class of drug, I think, potentially has a lot of promise in myeloid malignancies, as we learned more and more about it and see if it has single-agent efficacy and then, ultimately, whether it will have even more utility in combination with conventional regimens.
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