Rationale for Requested Change: Revumenib is a potent and selective oral menin inhibitor, approved by the FDA for the treatment of relapsed and refractory acute leukemia with a KMT2A translocation.[1] Revumenib disrupts the menin-KMT2A interaction, a key driver in KMT2A-rearranged (KMT2Ar) acute leukemias associated with drug resistance and poor survival outcomes. As a novel, first-in-class targeted therapy, revumenib addresses the high unmet need for effective and well-tolerated treatments in relapsed or refractory pediatric KMT2Ar acute lymphoblastic leukemia (ALL).
AUGMENT-101 is a phase 1/2, multi-center, open-label, dose-escalation and expansion study of revumenib conducted across 22 clinical sites. It is the largest trial to date to evaluate a targeted treatment in patients =30 days of age with relapsed/refractory KMT2Ar acute leukemias.[2-3]
In the phase 1/2 trial, 135 patients, including 31 pediatric patients, with relapsed or refractory acute leukemia with KMT2A translocation were treated with revumenib. The median duration of exposure was 2.3 months (range < 1 to 23 months), and 3% of patients were exposed for more than 6 months.[1]
The most common (= 20%) TEAEs were hemorrhage, nausea, phosphate increased, musculoskeletal pain, infection, aspartate aminotransferase increased, febrile neutropenia, alanine aminotransferase increased, parathyroid hormone intact increased, bacterial infection, diarrhea, differentiation syndrome, electrocardiogram QT prolonged, phosphate decreased, triglycerides increased, potassium decreased, decreased appetite, constipation, edema, viral infection, fatigue, and alkaline phosphatase increased.[1]
Dose reduction due to TEAEs occurred in 10% of patients; those leading to a dose reduction in >1% included electrocardiogram QT prolonged. TEAEs leading to permanent discontinuation occurred in 12% of patients; those leading to discontinuation in >1% included infection and respiratory failure. Fatal adverse reactions occurred in 4 (3%) of patients, including 2 with differentiation syndrome, 1 with hemorrhage, and 1 with sudden death.[1]
Differentiation syndrome occurred in 29% of patients, with Grade 3 or 4 in 13% and Grade 5 in one patient. The median time to onset was 10 days (range 3-41 days). Treatment interruption was required for 7% of patients, and treatment was withdrawn for 1%.[1]
The efficacy-evaluable population from the phase 1/2 trial (N=104) consisted of patients with relapsed or refractory acute myeloid leukemia (83%), ALL (15%), or mixed phenotype acute leukemia (2%). The median age was 37 years (range 1–79), including 79 adult and 25 pediatric patients. The median number of prior regimens was 2 (range 1–11), and 44% of patients had received prior HSCT.[1]
The complete remission or complete remission with partial hematologic recovery (CR+CRh) rate was 21.2% (95% CI 13.8-30.3), with a median duration of CR+CRh of 6.4 months (95% CI 2.7-not evaluable). Of the 22 patients who achieved a CR or CRh, the median time to CR or CRh was 1.9 months (range: 0.9, 5.6 months). On subgroup analysis, CR+CRh was achieved by 18/86 (21%) of patients with AML, 3/16 (19%) of patients with ALL, and 1/2 (50%) of patients with MPAL. Overall, 24 (23%) patients underwent HSCT following treatment with revumenib.[1]
A pre-specified interim analysis of the phase 2 portion of the AUGMENT-101 trial assessed the safety and efficacy of revumenib in 94 patients, including 23 patients (25%) who were <18 years old (median, 4.0 years; range, 1.3-17.0 years). The pediatric patients were heavily pretreated, with 61% of patients receiving 3 or more prior lines of therapy (median, 3; range 1–11). Most patients presented with acute myeloid leukemia (74%) followed by ALL (22%), and acute leukemia of ambiguous lineage (4%). Fifty-two percent of patients had received prior HSCT and 57% of patients were treated with prior venetoclax. Patients with acute leukemia that had a composite complete remission (CRc), morphological leukemia-free state, or partial response to revumenib were eligible for HSCT and revumenib maintenance post-transplant.[3-6]
In pediatric patients, the ORR was 46% (n=6/13), CR+CRh rate was 23% (n=3/13; 95% CI, 5-53.8), and CRc rate was 38.5% (n=5/13; 95% CI, 13.9-68.4). The median time to CR+CRh was 2.27 months (range, 1.0-3.9 months). Furthermore, measurable residual disease (MRD)-negative response was reported in 2 of the 3 evaluable patients with CR+CRh and 3 out of 5 patients with CRc. The median overall survival was 6.9 months (95% CI, 2.3-not reached). Of the 6 patients that responded to treatment with revumenib, 4 (67%) proceeded to HSCT; 2 patients were in CR+CRh and 2 were in MLFS or CRp. Two of the patients had restarted revumenib post-transplant at the time of data cutoff.[5-6]
A subset of patients proceeded to transplant. Revumenib post-HSCT was given as maintenance therapy in 16 patients from the Phase 1/2 study. The duration of treatment ranged from 1 to 701 days with 9 patients continuing revumenib at last data update. CRc was maintained after HSCT in 12 (75%) patients who received revumenib maintenance therapy. MRD-negative remissions were maintained in 6 patients who were tested including one patient with disease that converted from an MRD+ to an MRD- response. Durable responses were observed in the posttransplant setting, with 3 patients continuing revumenib maintenance therapy for more than 1 year.[7-8]
The phase 2 safety profile among all pediatric patients (n=23) was consistent with previously published data. Adverse events (AEs) of special interest were differentiation syndrome Grade =2, occurring in 8 patients (35%), and QTc prolongation Grade =2, occurring in 4 patients (1%). There were no AEs that led to dose reduction. One patient discontinued treatment early due to an AE of febrile neutropenia and was not considered to be treatment-related. Grade =3 TRAEs that occurred in =10% of patients included febrile neutropenia (13%) and decreased neutrophil count (13%).[5-6]
The AUGMENT-101 clinical trial demonstrated clinical benefit and a low rate of discontinuation for adverse events, indicating a predictable safety profile in a heavily pretreated population of patients with acute leukemia with a KMT2A translocation, a group considered to have poor prognosis. Additionally, patients with acute leukemia who responded to revumenib treatment were able to receive HSCT. The use of revumenib for the treatment of acute leukemias with KMT2A translocation in patients as young as 1 year old is supported by evidence from adequate and well-controlled trials in adults and pediatric patients and additional pharmacokinetic and safety data in pediatric patients. The patients included 13 infants (age < 2 years), 41 children (age 2 to < 12 years) and 16 adolescents (age 12 to < 17 years).[1] The recommended dosage in patients weighing less than 40 kg is BSA-based. Based on the clinical data and the recent FDA approval, we respectfully request your consideration of revumenib as a relapsed/refractory therapy for this difficult-to-treat subpopulation of ALL.
Thank you for your consideration of this submission.
Sincerely,
Norman Nagl, PhD
Vice President, Head of Medical Affairs
