Revumenib Revises the Treatment Landscape for KMT2A-r Leukemia

Menin inhibitors are a novel class of small molecules that are being developed for leukemias harboring chromosomal rearrangements involving the lysine methyltransferase 2A gene (KMT2A-r), since Menin is a molecular dependency in this genetic subtype of leukemia.¹ Issa et al²⁹ report remarkable results from a phase I/II clinical trial of the Menin inhibitor revumenib (Syndax Pharmaceuticals) in a group of patients with heavily pretreated, relapsed/refractory (R/R) KMT2A-r leukemia. On the basis of the detailed understanding of the mechanisms of action of Menin inhibitors, the potential clinical indications are expanding and include patients with a common form of adult acute myeloid leukemia (AML) driven by mutations in the nucleophosmin (NPM1) gene, in addition to a growing list of leukemias driven by dysregulation of HOX/MEIS gene expression.

The KMT2A-r fuses the KMT2A gene with over 100 different translocation partners, many of which encode epigenetic regulators and components of the transcriptional machinery.² KMT2A-r produce oncogenic KMT2A-fusion proteins, which drive the transcription of stem cell-associated genes whose expression is normally restricted to immature hematopoietic progenitors and hematopoietic stem cells.^3,4 Aberrant expression of potent self-renewal genes such as the homeobox (HOX) cluster genes and their cofactor MEIS1—both direct targets of the KMT2A-fusion protein—are critical for leukemogenesis.^5-8 KMT2A-fusion proteins maintain the expression of HOX/MEIS1 and other developmentally restricted genes through the recruitment of additional chromatin complexes, namely the super elongation complex,⁹ the disruptor of telomeric silencing-like 1 complex,¹⁰ and lens epithelium–derived growth factor¹¹ (Fig 1). Detailed mechanistic studies have revealed that both the C-X-X-C motif on KMT2A and the Menin-KMT2A interaction are essential for maintaining transcription of a stem cell-associated gene expression program.^1,12 Since the Menin-KMT2A interaction is critical for maintaining proleukemogenic gene expression, therapeutically targeting this dependency has been proposed as one way to potentially dismantle oncogenic chromatin complexes that drive aberrant transcription in KMT2A-r leukemia.

FIG 1.

Menin inhibitors destabilize the Menin-KMT2A protein:protein interaction, resulting in eviction of Menin and the KMT2A-fusion protein (or wild-type KMT2A, in the case of NPM1 mutant and NUP98-rearranged leukemia) and downregulation of proleukemogenic gene expression.

Even among many promising new targeted agents for leukemia, Menin inhibitors are fundamentally unique in their mechanism of action. Menin inhibitors like revumenib are protein: protein interaction inhibitors (PPIs) that bind to a pocket on Menin and compete with the binding of KMT2A. Disruption of the Menin-KMT2A interaction by small molecules like revumenib leads to global loss of Menin from chromatin/DNA.¹³ These small molecules also disrupt the activity of the oncogenic KMT2A-fusion protein, which is evicted from chromatin at a subset of transcriptionally sensitive genes whose expression is essential for leukemia maintenance (Fig 1).¹³ By disrupting the Menin-KMT2A-fusion protein complex, treatment with Menin inhibitors results in downregulation of a stem cell-associated gene expression program and upregulation of lineage-specific differentiation markers, leading to leukemia cell differentiation.^13-16 Preclinical studies demonstrated that treatment of KMT2A-r patient-derived xenograft models with a Menin inhibitor can eradicate disease, and these encouraging results laid the foundation for clinical translation of Menin inhibitors for patients with KMT2A-r leukemias.^13-16

AUGMENT-101 is the largest trial reported to date where patients with KMT2A-r leukemia were treated with a targeted agent. The results of the phase II portion of this study of the small-molecule Menin inhibitor revumenib are reported in this issue of JCO. Revumenib proved to be an effective therapy for this heavily pretreated group of patients with R/R leukemia, as the authors report an overall response rate of 63.2% and a complete remission (CR) or CR with partial hematologic recovery (CR + CRh) rate of 22.8%. Remarkably, many patients who achieved CR in this study proceeded to potentially curative treatment with hematopoietic stem cell transplant. Commensurate with the mechanism of action of revumenib that reverses leukemogenic gene expression and thus promotes leukemia cell differentiation, the investigators of AUGMENT-101 evaluated gene expression as a pharmacodynamic biomarker of response. Proleukemogenic genes that are direct targets of the KMT2A-fusion protein (MEIS1, HOXA9, FLT3, and PBX3) and myeloid differentiation markers (CD11B, CD13, and CD14) were assessed. Relevant changes in gene expression were observed, but this approach failed to discriminate between responders and nonresponders. Differentiation syndrome was reported in approximately one fourth of patients, with only one patient having a grade 4 event; all cases were successfully treated with corticosteroids with or without hydroxyurea. The authors conclude that revumenib is a safe and well-tolerated drug that provides clinical benefit beyond what is offered by currently available therapies.

On the basis of our understanding of Menin-KMT2A function, significant effort has focused on determining whether these mechanisms are important in other difficult-to-treat leukemias driven by stem cell-associated gene expression programs. Preclinical data have shown that Menin inhibitors can target other oncogenic fusion proteins that associate with wild-type KMT2A and Menin to drive HOX/MEIS gene expression.^17-21 For example, oncogenic fusion proteins produced by chromosomal rearrangements of the Nucleo-porin 98 gene (NUP98-r) associate with Menin-KMT2A, and treatment of NUP98-r leukemia cells with a Menin inhibitor results in eviction of Menin, KMT2A, and the NUP98-fusion protein from chromatin at transcriptionally sensitive, key proleukemogenic genes.^19,22 Similarly, Menin inhibitors can displace mutant NPM1 from chromatin,^17,18,23 and on the basis of this mechanism, early-phase clinical trials have demonstrated activity in patients with NUP98-r and NPM1 mutant leukemia (Fig 1).

The future of this potent class of small-molecule Menin inhibitors holds much promise, yet some challenges remain. As might be expected for any targeted therapy, acquired resistance may develop when used as a single agent. In a previous report from the phase I portion of AUGMENT-101,²⁴ a subset of patients initially responded but subsequently developed therapeutic resistance to revumenib.²⁵ A subset of these leukemias were found to have MEN1-binding pocket mutations.²⁵ The development of resistance via binding pocket mutations indicates that revumenib is working through its intended mechanism but also suggests that either second-generation molecules or combination therapies will be necessary in many cases for long-term cure. We suspect that acquired resistance to single-agent treatment will likely arise with all Menin inhibitors currently being developed. Nonetheless, the clinical impact of such mutations is uncertain at this time since not all patients harboring MEN1 mutations demonstrated clinical evidence of therapeutic resistance, and trials like AUGMENT 101 demonstrate the promise of these therapies for patients with KMT2A-r and likely other leukemias.

Although Menin inhibitor resistance remains an incompletely understood problem, combination therapies likely hold the key to future success. Trials of an all-oral combination of revumenib, a hypomethylating agent, and ven-etoclax are already underway (ClinicalTrials.gov identifiers: NCT05360160, NCT06177067). Preclinical data using CRISPR to uncover novel molecular dependencies have provided insight into combinations which may provide synergistic benefit. For AML, preclinical studies have reported that combining Menin inhibitors with mezigdomide (an Ikaros/Aiolos degrader)²⁶ or FHD-286 (a BRM/BRG inhibitor)²⁷ can synergistically induce lethality in AML cells harboring MLL-r or NPM1 mutations. Preclinical work has also revealed that Menin inhibitors may have broader activity than initially anticipated, including in patients with certain solid tumors.²⁸ Early-phase clinical trials of Menin inhibitors are currently underway for some of these potential indications (ClinicalTrials.gov identifier: NCT05731947).

These exciting results from AUGMENT-101 herald a promising beginning for targeted agents like revumenib that disrupt chromatin complexes, offering a new beacon of hope for patients with KMT2A-r leukemia. The results for patients with NPM1 mutant leukemia are still pending and will be awaited with much anticipation given the relatively common prevalence of this leukemia relative to the rarer KMT2A-r subset. Menin inhibitors and other agents that target chromatin will hopefully change the landscape of targeted therapies for leukemias and perhaps other cancers.