Revumenib safe, effective in AML related to NPM1 mutations
Almost half of patients in Phase 2 trial see clinical response
Oral therapy revumenib showed positive results in patients with relapsed or refractory acute myeloid leukemia (AML) driven by NPM1 mutations, with nearly half of participants achieving a clinical response in a pivotal Phase 2 trial.
Syndax, revumenib’s developer, announced positive safety and efficacy results from the Phase 1/2 AUGMENT-101 trial (NCT04065399) in participants with this difficult to treat form of blood cancer. The study, “Menin inhibition with revumenib for NPM1-mutated relapsed or refractory acute myeloid leukemia: the AUGMENT-101 study,” was published in Blood.
“We are thrilled to publish the first positive pivotal dataset in patients with an NPM1 mutation, the most common genetic alteration observed in AML,” Neil Gallagher, MD, PhD, head of research and development at Syndax, said in a company press release.
In 2024, the U.S. Food and Drug Administration (FDA) approved revumenib, under the brand name Revuforj, as an oral therapy for patients ages 1 and older with hard-to-treat acute leukemias caused by a KMT2A gene translocation, a type of DNA rearrangement. Results from a subset of AUGMENT-101 participants with KMT2A mutations supported the therapy’s approval.
With the new data from participants with NPM1 mutations, Syndax submitted a supplemental new drug application (sNDA) to the FDA. If approved, this would expand the medication’s availability to AML patients with this genetic signature. There are no FDA approved treatments specifically for AML with NPM1 mutations.
Treatment aims to slow disease progression
The NPM1 gene encodes a protein of the same name. Mutations in this gene, found in approximately 28% of newly diagnosed adult AML cases, are linked to disruptions in genetic stability within cells. When mutated, the NPM1 protein may play a role in the cellular interactions between two other proteins, KMT2A and menin. KMT2A-menin interactions can disrupt gene expression and drive the development of AML, a fast-growing cancer of the blood and bone marrow that affects immature white blood cells.
This type of leukemia often responds well at first to strong chemotherapy, but if the cancer comes back or doesn’t respond, there is no standard treatment. When it returns, it’s particularly hard to treat, especially if it comes back quickly.
People with NPM1-mutated AML usually do better after the first treatment than those without the mutation, but about half of adult patients still experience disease progression or death.
Revumenib aims to block interactions between KMT2A and menin, slowing the disease progression. AUGMENT-101 is testing the therapy in various types of leukemias, including those associated with aberrant KMT2A or NPM1.
The newly published results concern data from 64 adult patients with relapsed or refractory NPM1 AML who were dosed twice daily with capsules, tablets, or liquid formulations of revumenib. Many of these participants had received multiple other treatments, with 35.9% having three or more previous therapies.
The study’s primary goals were to measure how often patients achieved complete remission, meaning no detectable signs of leukemia following treatment, or complete remission with partial recovery, when some but not all leukemia signs were reduced, and to assess the safety and how well people tolerated revumenib.
In this group, 47% of participants achieved a clinically meaningful response, with 23% of them achieving a complete response or a complete response with partial recovery, whereby blood cell counts haven’t fully returned to normal levels.
“In the older, heavily pretreated population enrolled in this trial, it is very encouraging to observe that nearly 50% of patients achieved an overall response and that revumenib was generally well-tolerated,” said Martha L. Arellano, MD, a professor at Emory University and principal investigator of AUGMENT-101.
Of these responders, 16.7% had hematopoietic stem cell transplant (HSCT), a procedure intended to replace bone marrow damaged during the disease, while in remission. Overall, participants survived for a median of four months, but among responders, the median survival was 23.3 months.
”Responses were seen across subgroups regardless of co-mutations [mutations occurring together with those in NPM1], prior HSCT, or number of prior lines of therapy,” the researchers wrote.
As well as examining efficacy, the team assessed safety in 84 participants, both adults and children. Their findings were consistent with previous safety reports on revumenib. Ten participants reduced their dosage after an adverse event related to treatment, and 25 discontinued the therapy. The most common serious adverse event was low white blood cell counts accompanied by a fever, called febrile neutropenia, which occurred in 21.4% of participants.
The researchers said 13.1% of participants developed serious differentiation syndrome, a group of severe side effects associated with some AML medications. Revumenib carries a boxed warning for differentiation syndrome under its indication for KMT2A mutation-related leukemia.
“These findings add to the growing body of evidence supporting revumenib’s paradigm-changing potential as treatment for a significant subset of acute leukemias,” Arellano said.
The results supported Syndax’s sNDA application, which asks the FDA to approve revumenib to treat AML associated with NPM1 mutations.
Trials testing the medication in combination with standard-of-care treatments and as a therapy for newly diagnosed patients are also ongoing.
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