A “Revu” of Initial Phase 1 Clinical Trial Results of Menin Inhibition in Patients with Relapsed/Refractory Acute Leukemias

Acute leukemias with KMT2A rearrangements are associated with leukocytosis at initial clinical presentation, resistance to standard chemotherapies, and higher relapse rates.^1-5  To date, more than 130 5’ fusion partners for KMT2A have been identified in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).^4,6  While KMT2A rearrangements in adults are generally associated with poor prognosis, the success of treatment in children depends on leukemia subtype, age at diagnosis, and specific KMT2A fusion partner.^7,8  Detailed genetic and biologic characterization studies over the past two decades have highlighted the potential for precision medicine-based therapies that target the unique Achilles’ heels of KMT2A-rearranged acute leukemias.^3,8,9 

KMT2A-rearranged leukemias overexpress HOX family genes and their co-factor MEIS1, which leads to an arrest in lymphoid or myeloid cell differentiation and ensuing leukemogenesis.¹⁰  Disruption of KMT2A binding to its essential co-factor menin downregulates aberrant HOX and MEIS1 expression and leads to release of the differentiation halt.¹¹  Recently developed menin inhibitors that target the critical KMT2A-menin interaction have demonstrated remarkable anti-leukemia activity in preclinical studies of KMT2A-rearranged ALL and AML. Importantly, menin inhibitors also appear to have potent activity in other leukemias with high HOX gene and MEIS1 expression, including NUP98-rearranged AML and NPM1-mutant AML, and possibly in other AML subtypes harboring partial tandem duplication of KMT2A or mutations in SET2D, RUNX1, or DNMT3A.¹² 

Dr. Ghayas Issa and colleagues recently reported initial findings of the multi-site AUGMENT-101, a first-in-human phase 1 trial (NCT04065399) that explored the safety and dosing of the menin inhibitor revumenib (SNDX-5613), primarily in adults with relapsed/refractory KMT2A-rearranged or NPM1-mutant acute leukemias.¹³  Revumenib was administered orally every 12 hours as monotherapy for 28 days per cycle in two parallel dose-finding cohorts depending on concomitant use of azole antifungal prophylaxis, given the CYP3A4 metabolism of revumenib and the potential for drug interactions.

Sixty-eight patients (including eight children) were enrolled from November 2019 to March 2022 (37 in Arm A without CYP3A4 inhibitors, 37 in Arm B with CYP3A4 inhibitors). The median number of previous lines of therapy was four (range, 1-12), and nearly half of participants (31 of 68, 46%) had received prior allogeneic hematopoietic stem cell transplants. In this trial, revumenib therapy appeared to be well-tolerated overall in both cohorts of patients. Treatment-emergent adverse events included QT interval prolongation >500 ms (one adult participant with dose-limiting toxicity), nausea, febrile neutropenia, and thrombocytopenia. Consistent with the biologic mechanism of menin inhibition, eight patients (14%) experienced grade 1 or 2 differentiation syndrome, which was successfully treated with steroids or hydroxyurea. The reported overall response rate (ORR) was 55%, including a complete remission (CR)/CR with partial hematologic recovery (CRh) rate of 24%. However, somatic mutations in MEN1 (encoding the menin protein) occurred in 12 of 31 patients (38.7%) treated with revumenib, most often within two cycles, highlighting a need for additional therapeutic approaches to decrease the potential for development of rapid resistance to menin inhibition.¹⁴  Following these initial results with revumenib monotherapy, the successor AUGMENT-102 phase 1 trial (NCT05326516) is now investigating the ability of revumenib in combination with multi-agent chemotherapy in adult and pediatric patients with relapsed/refractory KMT2A-rearranged, NPM1-mutant, or NUP98-rearranged acute ALL or AML to enhance anti-leukemia activity and/or reduce differentiation syndrome complications.