The investigational menin–MLL inhibitor KO-539 may be active in patients with acute myeloid leukemia: In a phase I trial, the agent induced complete remissions in two patients with relapsed/refractory disease and showed signs of activity in several others.

The investigational menin–MLL (KMT2A) complex inhibitor KO-539 (Kura Oncology) may be active in patients with acute myeloid leukemia (AML): In the phase I/IIa KOMET-001 trial, the agent induced complete remissions in two patients with relapsed/refractory disease and showed signs of activity in several others. Preliminary results were presented at the 2020 American Society of Hematology Annual Meeting, held virtually December 5–8.


The interaction between menin and MLL plays an essential role in regulating expression of HOXA9 and MEIS1, genes involved in the development of AML. This interaction “is most prominent in patients that have MLL-rearranged AML, as well in patients that have NPM1-mutant AML,” said Eunice Wang, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, NY, who presented the results. MLL rearrangements, she added, occur in about 5% to 10% of patients with AML and are associated with a particularly poor prognosis. The menin–MLL complex is also involved in AML with IDH1/2, EZH2, DNMT3A, and FLT3 mutations.

KO-539 is designed to block menin from binding to MLL—which, in the context of MLL-rearranged or NPM1-mutant AML, “is hypothesized to reduce transcription of HOXA9 and MEIS promoters and result in terminal differentiation of AML blasts,” Wang explained.

Researchers are assessing KO-539 in patients with relapsed/refractory AML regardless of mutation type. Wang reported on 12 patients treated daily with doses ranging from 50 mg to 400 mg. Six patients are still undergoing treatment; six discontinued treatment due to confirmed disease progression, worsening of symptoms, or withdrawal of consent.

Of the six patients still being treated, one achieved complete remission with no evidence of minimal residual disease (MRD), and one achieved complete remission with evidence of MRD. In addition, one patient experienced stable disease, another had decreased peripheral blasts, and a third achieved a morphologic leukemia-free state.

Seven patients experienced grade 1 or 2 side effects—namely nausea, rash, and diarrhea—and five patients experienced side effects classified as grade 3 or higher. Side effects were generally manageable, Wang said, and did not cause anyone to discontinue treatment.

“The early biological activity of KO-539 in relapsed and refractory AML is encouraging,” Wang said, pointing to activity in patients with varied genomic alterations. Enrollment in phase I of the trial is continuing; phase II will include expansion cohorts of patients with KMT2A rearrangements and NPM1 mutations.

“The fact that in the first handful of patients they saw two complete remissions in patients who were heavily pretreated is a very promising signal,” said Gabriel Mannis, MD, of Stanford University in California, who is not involved in KOMET-001. He noted that although one patient in remission had an NPM1 mutation, the other did not have NPM1-mutated or MLL-rearranged disease. “The results that they presented raise the questions, ‘Should we be studying this in all comers? Could this drug be more broadly applied to other types of AML?’”

Mannis will be an investigator on the AUGMENT-101 trial evaluating another menin–MLL inhibitor, SNDX-5613 (Syndax). Early in 2020, researchers reported that in phase I of the trial, the agent induced a complete remission and a partial remission in patients with MLL rearrangements. Phase II will focus on MLL-rearranged and NPM1-mutated AML, as well as MLL-rearranged acute lymphoblastic leukemia.

“The early signs of efficacy that we're seeing—along with what I think is really very elegant preclinical data—gives me a lot of hope that this class of drugs will soon be part of our arsenal against what have been historically very difficult-to-treat leukemias,” Mannis said. –Catherine Caruso

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