Menin Inhibitors Like KO-539 May Represent Next Forefront of AML Treatment

Eunice Wang, MD

The novel menin inhibitor KO-539 is a targeted option that could impact the treatment of difficult-to-treat subsets of patients with acute myeloid leukemia (AML) such as those with NPM1-mutant and KMT2A-rearranged disease, according to Eunice Wang, MD, who added that combination strategies are also under active exploration and may represent the future of care for these patients.

The ongoing, first-in-human phase 1/2 KOMET-001 trial (NCT04067336) aims to examine KO-539 in patients with relapsed/refractory AML. The phase 1, dose-escalation portion of the trial will assess the safety and tolerability, as well as characterize the pharmacokinetics of the agent, and determine a recommended phase 2 dose. The phase 2 portion will examine the safety, tolerability, and efficacy of KO-539 in the subsets of patients whose tumors harbor NPM1 mutations or KMT2A rearrangements.

“The menin inhibitor promises to offer new hope to patients with KMT2A rearrangements and has the potential to be combined with [other therapies] to further enhance outcomes,” Wang said. “As we learn more about the biology and the molecular underpinnings of AML, our ability to treat, and potentially cure, more of our patients moving forward is extremely promising. We hope that this new class of menin inhibitors opens up new horizons.”

In an interview with OncLive^®, Wang, the chief of the Leukemia Service at Roswell Park Comprehensive Cancer Center, discussed the KOMET-001 trial, the potential for KO-539 to address an unmet need in AML, and the future of menin inhibition in this disease.

OncLive^®: What is the rationale for evaluating menin inhibitors in patients with relapsed/refractory AML?

Wang: AML is characterized by diverse biological subsets. There are multiple mutations, cytogenetic and other abnormalities that make it very challenging for us to design a therapy [that can be used] for [all] our patients. For many years, over 4 to 5 decades, we did have a one-size-fits-all [approach in the form of] 7 + 3 [chemotherapy]. [However], as we move into the current era of precision medicine, with our increasing advances in genomic technology, we would like to target the biological underpinnings of the disease more precisely. Although we do have some targeted therapies [available] for patients whose [tumors harbor] mutations like FLT3, IDH1, and IDH2, we have yet to design a molecularly targeted therapy for patients who have other mutations such as NPM1 or KMT2A rearrangements.

NPM1 [is observed] in up to one-third of [patients with] newly diagnosed AML, and is a mutation which is present both at [the time of] diagnosis and relapse. We also know that patients who have rearrangements in the MLL gene, now known as KMT2A, constitute maybe 5% to 10% of newly diagnosed patients [who] have a poor prognosis. We also see this mutation in those with acute lymphocytic leukemia [ALL] and pediatric patients. Up until now, we have not had a targeted therapy for those specific subtypes.

A menin inhibitor is an inhibitor of a protein that is part of the menin KMT2A epigenetic complex. This complex is particularly active and pivotal for leukemia genesis related to NPM1-mutant and KMT2A-rearranged AML. In preclinical models, inhibitors of menin can affect that transcriptional epigenetic complex and allow cells in a very immature myeloblastic cell to undergo differentiation, like what we see…with IDH inhibitors. Targeting the menin epigenetic complex represents a novel strategy [that is] particularly relevant to those mutational subsets; however, this may also be relevant across broader groups of [patients with] AML.

What is the design of the phase 1/2 KOMET-001 study? What are the key objectives?

KO-539 is a novel, potent, oral menin inhibitor that is designed to differentiate and decrease the leukemogenic potential of patients who have NPM1- and KMT2A-rearranged AML. [The agent] may also have efficacy in other subtypes of ALL.

The phase 1/2, first-in-human study is initially looking at [the agent in] dose-escalation cohorts, [and examining its] safety and tolerability; [it also seeks to establish] a safe phase 2 expansion dose. In the initial phase 1 dose-escalation cohort, patients started treatment at a low dose, which was as low as 50 mg per day; [they] were [then] escalated up to 100 mg, 200 mg, 300 mg, 400 mg, 600, mg, and 800 mg. Toxicity [was examined].

Once preliminary toxicity data have been established using a standard 3 + 3 model, we will expand out into the phase 2 portion of the study. [We will be] restricting eligibility at that point to patients with [just] those 2 target mutations or molecular abnormalities, and [we will test] the efficacy of specific doses of KO-539 in those target populations. The study has components of both a phase 1, as well as a phase 2 trial, and the hope is that this design [will] rapidly establish the safety and efficacy of this drug in this [at-]need population.

Do you foresee potential for novel combinations with these agents?

The preclinical data with menin inhibitors are compelling. [These agents] have shown efficacy [when used] as [monotherapy], and an increasing amount of data [suggest] that they may be relevant in combination strategies. For example, FLT3 mutations can be targeted by specific FLT3 inhibitors. Compelling preclinical data show that patients who have, for example, NPM1 and FLT3 mutations, can derive more benefit from a combinatorial strategy of menin and a FLT3 inhibitor; this has not yet been tested in humans.

Of course, we all know about the success of venetoclax (Venclexta)-based therapy for our older AML population. We are very much looking forward to determining whether the menin inhibitor can be used, potentially on top of a chemotherapy backbone, like 7+3, or a venetoclax-based therapy for patients who do not have some other targetable mutations.

All those combinations are being explored and look very promising. Menin inhibitors are an active area of investigation, and multiple companies are developing these targeted [agents]. For example, Syndax has released a press report detailing the results of a phase 1 study [examining] their menin inhibitor, [which showed] efficacy—particularly in patients with those 2 mutations. These studies are very early. [We have] some questions about the safety and tolerability [of these agents], and adverse effects such as QTc prolongation and differentiation syndrome. [That is] something that we are looking at very closely.

Clearly [there is] a lot more to be learned, but this is a very highly promising area for further development. Even if we do not see a lot of activity in the single-agent setting, combinatorial approaches are likely the way ahead for AML therapy in general. [We will be] combining targeted, non-targeted therapies, and maybe in the future, immunotherapeutic drugs.

Could you expand on the unmet need that this research is aiming to address?

For patients who have KMT2A rearrangements, prognosis is particularly poor. The presence of a KMT2A aberration is enough to confer an intermediate-risk prognosis. [Moreover,] KMT2A rearrangements often occur in patients with a complex karyotype, which is the worst of the worst in terms of risk categories. We also know that KMT2A rearrangements occur very commonly in patients with therapy-related acute leukemias, and these are patients who have had prior exposure to topoisomerase inhibitors, those with prior breast cancer, etc. In the pediatric patient population, the presence of a KMT2A rearrangement in ALL, as well as AML, is associated with refractory disease and the need to go to a potentially curative transplant.

Many different patient populations could benefit [from this therapy]. We have been struggling to find a highly effective therapy for [these patients] beyond allogeneic stem cell transplantation. The ability to treat these individuals successfully up front [with this kind of agent], either alone or in combination, offers new hope for patients; this can range from a young woman with a secondary therapy-related AML, to an infant with KMT2A-rearranged relapsed/refractory ALL, to other individuals who have KMT2A-rearranged disease who may have relapsed, recurred, or not responded to up-front therapy and are trying to get to that allogeneic transplantation.

Reference

1. Wang E, Altman J, Issa G, et al. Phase 1/2 first in human study of the menin-KMT2A (MLL) inhibitor KO-539 in patients with relapsed or refractory acute myeloid leukemia. Presented at European Hematology Association 2021 Virtual Congress; June 9-17, 2021; virtual. Abstract PB1408.