Dr Pollyea on the Mechanism of Revumenib in KMT2A-Rearranged R/R AML

Dan Pollyea, MD, MS, clinical director, Leukemia Services; Robert H. Allen Endowed Chair in Hematology Research; associate professor, medicine, Division of Hematology, the University of Colorado School of Medicine, discusses the mechanism of action for the menin inhibitor revumenib (SNDX-5613) in KMT2A-rearranged relapsed/refractory acute myeloid leukemia (AML).

Revumenib is a potent, oral, selective inhibitor of the menin-KMT2A interaction, which represents a potential therapeutic strategy derived from foundational research, Pollyea begins. The genetic rearrangements of KMT2A lead to the aberrant expression of homeobox (HOX) genes and their DNA-binding cofactor, MEIS1. This abnormal gene expression program, typically found in stem cells, results in a hematopoietic differentiation block and subsequent leukemic transformation, he explains. In leukemias driven by KMT2A rearrangements, menin functions as a critical oncogenic cofactor, making it a meaningful target for future therapeutic intervention, Pollyea emphasizes.

The development of menin inhibitors has been a key focus for several years, and the current generation of these agents is now reaching clinical fruition, Pollyea continues. These agents are particularly significant in the context of several other AML subtypes, including NMP1-mutant leukemias, he adds. However, KMT2A-rearrangements are distinctive due to their specific upregulation of HOX and MEIS1, setting them apart as a unique subset of leukemias, Pollyea says. Consequently, this subgroup has been among the first to benefit from exposure to menin inhibitors, he explains. Early clinical data with these inhibitors have been encouraging, suggesting that they could be highly effective therapeutic options.

On March 26, 2024, the FDA granted priority review to a new drug application (NDA) seeking the approval of revumenib for the treatment of adult and pediatric patients with relapsed/refractory KMT2A-rearranged acute leukemia. The FDA recently extended the Prescription Drug User Fee Act target action date to December 26, 2024.

The NDA is supported by findings from the phase 1/2 AUGMENT-101 trial (NCT04065399), which showed that adult and pediatric patients with KMT2A-rearranged AML or acute lymphocytic leukemia who received revumenib monotherapy (n = 57) achieved a complete response (CR)/CR with a partial hematologic recovery (CRh) rate of 23% (95% CI, 12.7%-35.8%; 1-sided P = .0036) with a median time to CR/CRh of 1.9 months (95% CI, 0.9-4.5).