Updated data from the phase 2 AUGMENT-101 trial demonstrate that revumenib (Revuforj) continues to elicit clinically meaningful responses in patients with relapsed or refractory KMT2Ar acute leukemia. The findings, presented at the 2024 ASH Annual Meeting, highlight sustained minimal residual disease (MRD) negativity and a significant percentage of patients proceeding to hematopoietic stem cell transplant (HSCT).
The study represents the largest evaluation of a targeted therapy for patients with relapsed/refractory KMT2Ar acute leukemias, including the largest pediatric menin inhibitor cohort. According to Ibrahim Aldoss, MD, from City of Hope National Medical Center, revumenib is the first approved menin inhibitor and the first approved treatment for KMT2Ar acute leukemia.
Response to Revumenib
As of the February 29, 2024, data cutoff, the overall response rate (ORR) was 63.9% (95% CI, 54%-73%), including a complete remission (CR) or CR with partial hematologic recovery (CRh) rate of 22.7% (95% CI, 14.8%-32.3%) and composite CR (CRc) of 42.3% (95% CI, 32.3%-52.7%).
Of the responders, 61.1% of CR+CRh responders and 58.3% of CRc responders experienced MRD negativity. The median duration of response (DOR) for the CR+CRh responders was 6.4 months (95% CI, 1.9-not reached). Eight patients remained in follow-up without relapse or death. The updated median DOR of CR+CRh for the 13 patients who responded to revumenib treatment in the interim analysis was 13.0 months (95% CI, 3.4-NR).
The median time to first response in all responders was 1.0 month (95% CI, 0.9-3.1), and was 2.0 months (95% CI, 0.9-4.6) in CR+CRh responders.
Overall, 33.9% of patients in the ORR cohort went on to receive HSCT, with 42.9% of them restarting treatment with revumenib after a median of 70 days (range, 35-182). Of the patients who went on to receive HSCT, a significant proportion achieved MRD negativity.
Safety Profile
The safety profile of revumenib remained manageable. Grade 3 or higher treatment-emergent adverse events (TEAEs) or treatment-related adverse events (TRAEs) occurred in 91.4% and 54.3% of patients, respectively. Serious TEAEs and TRAEs were reported in 77.6% and 36.2% of patients, respectively. TEAEs led to dose reduction in 9.5% of patients and discontinuation in 13.8% of patients, while TRAEs led to reduction and discontinuation in 8.6% and 5.2%, respectively.
The most common grade 3 or higher TEAEs included febrile neutropenia (38.8%), anemia (19.8%), decreased platelet count (16.4%), differentiation syndrome (14.7%), decreased neutrophil count (14.7%), decreased white blood cell count (14.7%), sepsis (13.8%), and QTc prolongation (12.9%). No new safety signals were reported, and no patients discontinued treatment due to cytopenias, differentiation syndrome, or QTc prolongation.
Addressing Unmet Needs in Acute Leukemia
Treatments are needed for KMT2Ar acute leukemia, as many patients relapse after chemotherapy and/or HSCT, with remaining remission rates in both adults and pediatrics remaining low. The AUGMENT-101 trial evaluated the safety and efficacy of revumenib, an oral, small molecule menin inhibitor, in this setting.
In the trial, patients received 163 mg (95 mg/m2 if body weight <40 kg) every 12 hours orally plus a strong CYP3A4 inhibitor in 28-day cycles. The primary endpoints were CR and CRh rates, as well as safety and tolerability. Secondary endpoints included the rate of CRc, ORR, DOR, and time to response.
Eligible patients were aged 30 days or more with relapsed/refractory acute myeloid leukemia, acute lymphoblastic leukemia, or mixed-phenotype acute leukemia with KMT2Ar or NPM1m. Patients had to have primary refractory or relapsed refractory disease and were excluded if they had active central nervous system disease.
The median age of patients in the efficacy and safety analyses was 37 years and 35.5 years, respectively. Most patients were in the age range of 18-65 years, and over half were women and White. Patients had undergone a median of 2 prior therapies, with a significant proportion receiving 3 or more prior lines, prior venetoclax, and prior HSCT.
