In a phase 1 clinical trial of 68 people with advanced leukemia more than half of those enrolled responded to the novel precision medicine Revumenib. The study results, published in the journal Nature also revealed that 18 people with refractory leukemia achieved a complete or near-complete remission.
About Revumenib
Revumenib is an orally administered precision cancer medicine know as a “menin inhibitor.” Revumenib was granted Orphan Drug Designation by the FDA and the European Commission for the treatment of people with AML. It has also received Fast Track designation by the FDA for the treatment of adult and pediatric patients with advanced acute leukemias harboring a KMT2A rearrangement or NPM1 mutation. Revumenib is thought to inhibit the menin-KMT2A interaction in patients with advanced KMT2A-rearranged or NPM1-mutant acute myeloid or lymphoid leukemias.
What is Menin?
Menin is a nuclear protein encoded by the MEN1 gene, which is mutated in patients with multiple endocrine neoplasia type 1 (MEN1) syndrome. Menin is known to act as a tumor suppressor in endocrine organs, but it is also required for leukemic transformation in mouse models. Although primarily a nuclear protein, lesser amounts of menin are also detectable in the cytoplasm and even the cell membrane where it is likely involved in several important cell functions.
Acute leukemias with KMT2A gene rearrangements are difficult to treat and NPM1 mutations are the most common genetic alteration in acute myeloid leukemia. The interaction of the menin protein with KMT2A is critical in driving expression of leukemia-promoting genes.
In the Phase I AUGMENT-101 clinical trial the overall response rate among 60 patients treated with Revumenib was 53%, and the rate of complete remission was 30%, with 78% of patients achieving clearance of measurable residual leukemia.
Overall the trial enrolled 68 patients with acute myeloid leukemia (82%), acute lymphocytic leukemia (16%) and mixed phenotype acute leukemia (2%). Patients were heavily pretreated and 46% had a prior allogeneic stem cell transplant. Among enrolled patients, 67.6% had KMT2A rearrangements, 20.6% had NPM1 mutations and 11.8% had other genotypes.
The median duration of response was 9.1 months and median overall survival was seven months. Twelve patients proceeded to allogeneic stem cell transplant following response to Revumenib.
The majority of the participants in the trial experienced side effects that included low blood counts, fatigue, diarrhea and asymptomatic prolongation of the QT interval on electrocardiography. None of which required discontinuation of treatment.
Trials for the Revumenib are ongoing at the University of Texas MD Anderson Cancer Center, the City of Hope in California, and other leading cancer centers.
References:
