The U.S. Food and Drug Administration (FDA) has approved Revuforj (revumenib) for the treatment of adult and pediatric patients (one year and older) with relapsed or refractory acute leukemia harboring a lysine methyltransferase 2A (KMT2A) translocation. This marks a significant advancement as Revuforj becomes the first and only menin inhibitor available for this aggressive form of leukemia.
The approval was based on data from the Phase 1/2 AUGMENT-101 trial, which evaluated Revuforj in patients with relapsed or refractory acute leukemia with a KMT2A translocation. The trial demonstrated clinically meaningful remission rates and durability, offering a potential new treatment option for patients with limited alternatives.
Efficacy and Safety Data
The efficacy evaluation was based on an FDA analysis of 104 patients treated with Revuforj in the AUGMENT-101 trial. The rate of complete remission (CR) plus complete remission with partial hematological recovery (CRh) was 21% (22/104 patients; 95% CI: 13.8%, 30.3%). The median duration of CR+CRh was 6.4 months (95% CI: 2.7, not estimable), and the median time to CR or CRh was 1.9 months (range: 0.9, 5.6 months). Notably, 23% (24/104 patients) underwent hematopoietic stem cell transplantation (HSCT) following Revuforj treatment.
The safety profile of Revuforj was assessed in 135 patients. Common adverse reactions (≥20%) included hemorrhage (53%), nausea (51%), increased phosphate (50%), musculoskeletal pain (42%), and infection (41%). Serious adverse reactions (≥5%) included infection (24%), febrile neutropenia (19%), and differentiation syndrome (12%).
Mechanism of Action
Revuforj (revumenib) is an oral menin inhibitor. In KMT2Ar acute leukemias, the binding of KMT2A fusion proteins with menin drives the activation of a leukemogenic transcriptional pathway. Revumenib inhibits the menin-KMT2A interaction, altering the transcription of multiple genes, including differentiation markers.
Clinical Significance
Rearrangements of the KMT2A gene are associated with a poor prognosis and high relapse rates. More than half of patients with KMT2Ar acute leukemia relapse after conventional frontline therapies, with a median overall survival of less than one year. In later lines of treatment, only 5% of patients achieve complete remission, and the median overall survival is less than three months. The approval of Revuforj addresses a critical unmet need in this patient population.
Warnings and Precautions
Revuforj carries a boxed warning for differentiation syndrome (DS), which can be fatal. Symptoms of DS include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and renal dysfunction. The drug also carries warnings for QTc interval prolongation and embryo-fetal toxicity.
Dosing and Availability
Syndax expects Revuforj to be available in 110 mg and 160 mg tablets through specialty distributors and pharmacies in November 2024. A 25 mg tablet formulation and an oral solution are anticipated to be available in late Q1 or early Q2 2025 for patients weighing less than 40 kg.
Expert Commentary
"The FDA approval of the first menin inhibitor is a major breakthrough for patients with R/R acute leukemia with a KMT2A translocation, a genetic alteration associated with a very poor prognosis," said Ghayas C. Issa, M.D., Associate Professor of Leukemia at The University of Texas MD Anderson Cancer Center. "The significant clinical benefit and robust efficacy seen with Revuforj represents a substantial improvement over what has been historically observed in these patients with previously available therapies and has the potential to be an important new treatment option for patients."
