By Cecilia Brown - March 20, 2023
The menin inhibitor revumenib was associated with “promising antileukemic activity leading to deep and sustained remission” in patients with relapsed or refractory acute leukemia, according to results from a first-in-human phase I clinical trial.
Ghayas C. Issa, MD, of the MD Anderson Cancer Center, and colleagues conducted the research and published its results in Nature.
Revumenib is a potent, selective oral inhibitor of interaction between menin and lysine methyltransferase 2A (KMT2A). Dr. Issa and colleagues evaluated the drug in acute leukemia because the interaction between menin and KMT2A, an epigenetic regulator, is a “dependence” in acute leukemia caused by rearrangement of KMT2A or a mutation in the nucleophosmin 1 gene (NPM1).
“KMT2A rearrangements occur in up to 10% of acute leukemias and have an adverse prognosis, whereas NPM1 mutations occur in up to 30%, forming the most common genetic alteration in acute myeloid leukemia,” Dr. Issa and colleagues wrote.
The phase I trial tested revumenib in 68 patients with relapsed or refractory acute leukemia. Most patients (82%) had acute myeloid leukemia (AML), 16% had acute lymphoblastic leukemia (ALL), and 2% had mixed-phenotype acute leukemia. Around two-thirds (68%) of patients had KMT2A rearrangements, 21% had mutated NPM1, and 12% had neither KMT2A rearrangements nor NPM1 mutations.
Complete remission (CR) or CR with partial hematologic recovery occurred in 30% of the 60 patients who were evaluable. Of those patients, 78% had undetectable measurable residual disease (MRD), as assessed by multiparameter flow cytometry. The median time to CR or CR with partial hematologic recovery was 1.9 months.
“Although imaging assessment was not mandated on study, responses were notably seen in both bone marrow and extramedullary sites in two of six evaluable patients with extramedullary leukemia at enrollment,” Dr. Issa and colleagues wrote.
In patients who achieved CR or CR with partial hematologic recovery, the median duration of response was 9.1 months (95% CI, 2.7 to not reached) at a median follow-up of 11.9 months. The median overall survival was seven months in the efficacy population, regardless of remission status, at median follow-up of 14.3 months.
No responses occurred in the eight patients who did not have a KMT2A rearrangement or NPM1 mutation, which was “consistent with the preclinical hypothesis regarding the efficacy of menin inhibition in patients with NPM1 mutations or KMT2A [rearrangement],” Dr. Issa and colleagues wrote.
Dr. Issa and colleagues also conducted an exploratory descriptive analysis to evaluate responses by leukemia lineage and age. They identified morphologic remissions in 27 of 49 patients (55%) with AML, in four of ten patients (40%) with ALL, and in the one patient who had a mixed-phenotype acute leukemia. When evaluating responses by age group, they found morphologic remission occurred in four of the eight (50%) pediatric patients and in 28 of 52 (54%) adults.
The therapy was associated with a “low frequency” of grade 3 or higher treatment-related adverse events, Dr. Issa and colleagues wrote, noting that asymptomatic prolongation of the QT interval on electrocardiography was the only dose-limiting toxicity.
Overall, these data “establish menin inhibition as a therapeutic strategy for susceptible acute leukemia subtypes,” according to the study’s authors.
“In conclusion, in children and adults with highly refractory acute leukemia with KMT2A [rearrangement] or NPM1 mutation, menin inhibition with revumenib monotherapy was associated with promising antileukemic activity leading to deep and sustained remission,” Dr. Issa and colleagues wrote.
Reference
Issa GC, Aldoss I, DiPersio J, et al. The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. Nature. 2023. doi:10.1038/s41586-023-05812-3
Original Source: First-in-Human Study of Revumenib Shows ‘Promising’ Activity in Acute Leukemias | Blood Cancers Today