FDA Approves Revumenib for the Treatment of Relapsed or Refractory Acute Leukemia

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Updated November 15, 2024, at 4:56 PM.

The FDA approved revumenib (Revuforj, Syndax Pharmaceuticals Inc) for relapsed or refractory acute leukemia lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients aged 1 year and older. The approval comes after efficacy data from the AUGMENT-101 (NCT04065399) phase 1/2 clinical trial. Additionally, oral presentations at the 2024 American Society of Hematology (ASH) Annual Meeting, which will be in San Diego, California, from December 7 to 10, will showcase the safety and efficacy of revumenib as monotherapy or in combination treatments for patients with acute leukemias.^1,2

Revumenib is an oral, small molecule inhibitor of the menin-KMT2A binding interaction that is currently under development for the treatment of KMT2A-rearranged (KMT2Ar), or mixed lineage leukemia rearranged (MLLr) acute leukemias, including acute lymphoid leukemia and mutant NPM1 AML. It was previously granted an orphan drug designation for the treatment of acute myeloid leukemia (AML), acute lymphocytic leukemia, and acute leukemias of ambiguous lineage (ALAL). Additionally, it was granted a fast track designation for the treatment of adult and pediatric patients with relapsed or refractory acute leukemias with a KMT2A rearrangement or NPM1 mutation.^1,2

The treatment’s efficacy as evaluated in a single-arm cohort of the open-label, multicenter phase 1/2 clinical trial, AUGMENT-101 (NCT04065399). The trial enrolled 104 adult and pediatric patients who were at least 30 days of age with relapsed or refractory acute leukemia with a KMT2A translocation. Revumenib was administered until disease progression, unacceptable toxicity, failure to achieve morphological leukemia-free state by 4 cycles of treatment, or hematopoietic stem cell transplantation.^1-3

In the phase 1 portion, patients are administered oral revumenib of escalating dose levels to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), and patients were enrolled in 1 of 6 dose-escalation arms. After determining the RP2D in the first phase, phase 2 involved 3 indication-specific expansion cohorts that were enrolled based on their disease state. The trial’s main efficacy outcome measures were complete remission (CR) plus CR with partial hematologic recovery (CRh), duration of CR+CRh, and conversion from transfusion dependence to independence.^1,3

According to the trial results, the CR+CRh rate was approximately 21.2% (95% CI: 13.8, 30.3), with a median duration of 6.4 months (95% CI: 2.7, not estimable). Among the 22 patients who achieved a CR or CRh, the median time to CR or CRh was about 1.9 months (range: 0.9, 5.6 months). Additionally, of the 83 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 12 patients (14%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Further, 10 of 21 patients (48%) who were independent of both RBC and platelet transfusions at baseline remained transfusion independent during any 56-day period after baseline.^1,3

According to the investigators, revumenib was generally well tolerated with a consistent safety profile to previously reported data. Additionally, treatment-emergent adverse events (AEs) and treatment-related adverse events that led to treatment discontinuation were generally low and were observed in 14% (n = 16) and 5% (n = 6) of patients, respectively.² The most common AEs included the following: hemorrhage; nausea; increased phosphate, aspartate aminotransferase, alanine aminotransferase, intact parathyroid hormone, triglycerides, and alkaline phosphatase; musculoskeletal pain; febrile neutropenia; bacterial infection; diarrhea; constipation; and decreased appetite, among others.¹

"The data being presented this year at ASH demonstrate [our] commitment to develop revumenib as a practice-changing therapy for adult and pediatric patients with acute leukemias," Neil Gallagher, MD, PhD, president and head of research and development at Syndax, said in a news release. "We look forward to presenting these data and continuing to rapidly advance the development of revumenib for adult and pediatric acute leukemia patients who may respond to menin inhibition, such as patients with KMT2Ar or mNPM1 alterations."²

REFERENCES

1. US Food & Drug Administration. FDA approves revumenib for relapsed or refractory acute leukemia with a KMT2A translocation. News release. November 15, 2024. Accessed November 15, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-leukemia-kmt2a-translocation

2. Syndax. Syndax Announces Revumenib Abstracts to Be Presented at the 66th ASH Annual Meeting. November 5, 2024. Accessed November 15, 2024. https://ir.syndax.com/news-releases/news-release-details/syndax-announces-revumenib-abstracts-be-presented-66th-ash

3. A Study of Revumenib in R/​R Leukemias Including Those With an MLL/​KMT2A Gene Rearrangement or NPM1 Mutation (AUGMENT-101). ClinicalTrials.gov identifier: NCT04065399. Updated October 16, 2024. Accessed November 15, 2024. https://clinicaltrials.gov/study/NCT04065399