Dr Daver on the Potential Role for Menin Inhibitors in Frontline AML

“The battleground where [menin inhibitors] are going to be used with the most [efficacy], in terms of curing patients rather than improving median survival by a few months, is going to be in the frontline [setting].”

Naval G. Daver, MD, professor, director, Division of Leukemia Research Alliance Program, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the potential role for menin inhibitors in the frontline treatment of patients with acute myeloid leukemia (AML).

The primary focus of ongoing research into menin inhibitors is to secure regulatory approval, a critical step before these agents can be broadly explored in combination regimens—including with minimal residual disease (MRD)–directed therapies—or in maintenance settings, Daver begins. Establishing the safety profile, drug-drug interactions, and cardiac effects, such as QTc prolongation, in single-agent trials is essential to ensure their subsequent safe and effective use in combination with other agents, he explains.

Currently, most menin inhibitors are progressing through phase 2 single-arm studies, Daver continues. Revumenib (Revuforj), the first menin inhibitor to enter clinical trials, is leading the development pipeline, he states. Following closely are ziftomenib (KO-539), enzomenib (DSP-5336), and bleximenib (JNJ-75276617), according to Daver. Each of these agents is also being evaluated in frontline combinations, where they are expected to have the most significant effect, Daver says.

Preliminary data from a cohort of the phase 1/2 Beat AML trial (NCT03013998) evaluating the combination of azacitidine (Vidaza), venetoclax (Venclexta), and revumenib in patients with newly diagnosed, treatment-naive AML were presented at the 2024 EHA Congress, Daver reports. As of the data cutoff date of May 1, 2024, patients in the efficacy-evaluable population (n = 24) achieved a composite complete remission rate of 96%, and 92% of patients also attained MRD-negative status. Although the durability of these responses is not yet fully understood, the high response rates indicate potential improvements in MRD clearance and depth of response with this combination, ultimately translating into better overall survival, Daver explains.

Other triplet combinations with ziftomenib, enzomenib, or bleximenib are under investigation and are expected to yield data by late 2025, he continues. These findings will provide further clarity on the role of menin inhibitors in improving outcomes for patients with AML, particularly when incorporated into standard or novel therapeutic regimens, Daver concludes.