Menin Inhibitors Have Potential to Become the Next Class of Targeted Therapy in AML

Eunice S. Wang, MD

The acute myeloid leukemia (AML) treatment landscape has a novel class of agents coming down the pipeline. Menin inhibitors that target NMP1 mutations and KMT2A and KMT2Ar rearrangements have been showing early promise in terms of efficacy and safety in multiple clinical trials.

Success with menin inhibition was first shown in preclinical models. NMP1 and KMT2A/KMT2Ar alterations cause the complex and upregulation of transcription factors that are essential for leukemogenesis to activate, and menin inhibitors can block this activation.

“We think when those processes are active. Myeloid cells become stuck in a dedifferentiated state, and that promotes leukemia growth. In preclinical studies, use of these menin inhibitors against acute leukemia cells with NMP1 mutations, as well as those characterized by KMT2A rearrangements, leading to apoptosis and cell death via induction of what we thought was similar to a clinical differentiation syndrome, said Eunice S. Wang, MD, in an interview with Targeted Oncology™.

Early findings have now been reported from first-in-human studies of menin inhibitors in patients with AML, showing encouraging efficacy and safety. First, in the COMET-001 study (NCT04067336), KO-539 showed early biologic activity in patients with relapsed AML. The agent also demonstrated unique pharmacokinetic characteristics that could lead to clinical benefit. Notably, some patients in the study had KMT2Ar mutations.¹

In the AUGMENT-101 (NCT04065399) study, SNDX-5613 achieved promising antileukemia activity in patients with heavily-pretreated KMT2A and NMP1-mutated acute leukemia, along with acceptable safety.²

In the interview, Wang, chief of the Leukemia Service at Roswell Park Comprehensive Cancer Center, discussed the growing use of menin inhibitors in AML and clinical trial research further supporting the treatment strategy.

TARGETED ONCOLOGY: Can you talk about NPM1 mutations, KMT2A/KMT2Ar rearrangements in AML?

Wang: In acute myeloid leukemia, NMP1-mutated disease comprises about one-third of all newly diagnosed cases, particularly in patients under the age of 60. Patients who have rearrangements in the MLL gene, now known as the KMT2Ar gene have a prevalence of about 5% to 10%. Those patients are associated with an intermediate adverse prognosis and have translocation of 2 genes;1 that is located on the 11th chromosome, and 1that's located on a different chromosome. These rearrangements can occur with about 80 different chromosome partners and can occur not only in patients with AML, but in a small percentage of patients that have pediatric acute leukemias as well as acute lymphocytic leukemia.

Before the in-human trials that are happening, what was shown preclinically with the use of menin inhibitors in AML?

Menin inhibitors are targeted agents that block the binding of the protein menin to a complex epigenetic entity, which is based on the MLL or KMT2A gene. The interaction between menin and this KMT2A complex leads to activation of the complex and upregulation of transcription factors that are essential for leukemogenesis. Blocking that activation with a targeted protein inhibitor of menin allows that complex to be inactive, thereby downregulating some of the transcriptional processes that lead to the underlying leukemia.

We think when those processes are active, myeloid cells become stuck in a dedifferentiated state, and that promotes leukemia growth. In preclinical studies, use of these menin inhibitors against acute leukemia cells with NMP1 mutations as well as those characterized by KMT2A rearrangements lead to apoptosis and cell death via induction of what we thought was similar to a clinical differentiation syndrome.

Can you discuss the AUGMENT-101 study?

The AUGMENT study was the first-in-human evaluation of a menin inhibitor in patients with relapsed and refractory acute leukemias characterized by NMP1 mutations and KMT2A gene rearrangements.This study enrolled dozens of patients with very refractory disease that had failed multiple lines of therapy including allogeneic stem cell transplantation.

The menin inhibitor SNDX-5613 was given twice a day at both escalating dose characterizations and then also at fixed doses based on the initial dose-finding cohort results of the AUGMENT-101 study. Findings presented at the American Society of Hematology Annual Meeting 2021 demonstrated in the 50 evaluable patients with an NMP1 mutation or KMT2A rearrangement, an overall response rate of approximately 50%. The complete remission and incomplete account recovery rate was about 24%,and in patients who did achieve a response of which they were 9, the duration of response in those patients lasted over a year.

The major side effects of the AUGMENT-101 study and the dose-limiting toxicity of the drug were found to be QTC prolongation, which occurred in about 10% or 12% of individuals. Few individuals had evidence of serious differentiation syndrome. This first-in-human study of the first-in-class menin inhibitor demonstrated impressive efficacy as monotherapy in the select biological subgroups of patients, particularly in patients who had failed multiple lines of prior therapy.

The COMET-001 study of a novel menin inhibitor is ongoing in relapsed or refractory AML. Can you discuss this study?

The COMET-001 study is a first-in-human study of a different menin inhibitor, KO-539. This agent was initially evaluated in a dose escalation phase and then an expansion phase. The expansion phase has evolved 2 doses of the drug and is evaluating the agent specifically in patients who had NMP1 mutation, as well as KMT2A rearrangements.

To date, the early data on that trial presented in 2020 at the ASH meeting demonstrated tolerability and efficacy in patients both with KMT2A mutation or NMP1 rearrangement. There have been incidences of differentiation syndrome which have been observed, and further results of this agent will be updated in the ASH 2022 meeting, for which we're eagerly awaiting the outcomes.

The fact that these 2 menin inhibitors have demonstrated evidence of clinical activity to date has spurred active interest in vetted inhibitors as a class of agents. There currently are at least 3 or 4 other menin inhibitors that have shown promising efficacy in preclinical models, which are now moving forward in the early-phase testing in patients with these 2 biological alterations.

What are some other agents that are coming down the pipeline in AML?

I think that the menin inhibitors as a class have the promise to be the next class of targeted therapies for acute myeloid leukemia. We've seen since 2017, the advent of multiple mutations specific agents for this disease, including FLT3 inhibitors and IDH1/IDH2 inhibitors. We're now moving towards more mutational-directed therapy with agents that are showing efficacy, not only in NMP1- and KMT2A-altered patients, but also potentially in patients that have the dreaded p53 mutation.

We're looking forward to having agents that are already established in the field and for novel combinations of targeted therapy with chemotherapy backbones, whether they be intensive, 7 + 3, or non-intensive venetoclax-based/hypomethylating regimens. Looking into the future, we see combined therapy moving into the upfront setting for some of these mutational subsets. We also see the advent of additional targeted therapy moving forward for additional subsets of this disease. More and more, we are moving towards better drugs, better targeting, and improved personalization or individualization of therapy for both the patient as well as the patient's disease.

_REFERENCES:

_{1. Wang ES, Altman JK, Pettit K, et al. Preliminary data on a phase 1/2A first in human study of the menin-KMT2A (MLL) Inhibitor KO-539 in patients with relapsed or refractory acute myeloid leukemia. Blood. 2020;136(suppl 1:7-8. doi:10.1182/blood-2020-134942}

_{2. Stein EM, Aldoos I, DiPersio JF, et al. Safety and efficacy of menin inhibition in patients (pts) with MLL-rearranged and NPM1 mutant acute leukemia: A phase (Ph) 1, first-in-human study of SNDX-5613 (AUGMENT 101). Blood. 2021;138(suppl 1):699. doi:10.1182/blood-2021-146944}