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 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 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 Treatment interruption was required for 7% of patients, and treatment was withdrawn for 1%.[1]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 adult and pediatric patients. The baseline characteristics were consistent with that of the overall phase 1/2 study population. 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.[3-4]
The trial met the primary endpoint, with CR+CRh rate in the efficacy population of 22.8% (n=13/57; 95% CI, 12.7%–35.8%), exceeding the null hypothesis defined per protocol of 10% (one-sided P=0.0036) and surpassing the predefined interim analysis efficacy boundary. Furthermore, measurable residual disease (MRD)-negative response was reported in 7 of the 10 evaluable patients with CR+CRh. Median time to CR+CRh was 1.9 months (range, 0.9–4.6) and the median duration of CR+CRh was 6.4 months (range, 3.4–not reached).[3-4]
Additional secondary endpoints included overall response rate (ORR) and overall survival (OS). There was an ORR of 63.2% (95% CI, 49.3–75.6%) with a median time to first overall response of 0.95 months (range 0.9–2.0). The median OS was 8.0 months (95% CI, 4.1–10.9). Responses were reported across major subgroups, including type and number of prior therapy and age. The CR+CRh for ALL patients (n=7) was 14.3% (95% CI, 0.4-57.9). In an exploratory analysis, efficacy was demonstrated for KMT2A rearrangement across various translocation partners.[3-4]
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.[5-6]
The phase 2 safety profile among all treated patients (N=94) was consistent with that of the overall phase 1/2 safety population. TEAEs were managed with dose modification; dose reduction occurred in 10% of patients, dose interruption in 44% of patients, and drug discontinuation in 13% of patients. QTc prolongation (any grade) occurred in 24 patients (26%), with 14% patients experiencing grade 3, and no grade 4 or fatal events. All Grade 3 QTc prolongation was resolved with dose adjustment. Differentiation syndrome (any grade) occurred in 26 patients (28%); 14 (15%) had grade 3 events and one (1%) had a grade 4 event. Differentiation syndrome was effectively managed with corticosteroids and hydroxyurea for leukocytosis. Neither QTc prolongation nor differentiation syndrome resulted in treatment discontinuation. Adverse events leading to death were reported in 14 of 94 patients while receiving revumenib or within 30 days of the last dose.[3-4]
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. 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
