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The interaction between menin and KMT2A plays an important role in aberrant transcription and leukemogenesis in acute myeloid leukemia (AML), as previously covered on the AML Hub. Therefore, menin inhibitors represent an important class of therapeutic agents for patients with AML, particularly those with mutated NPM1 (NPM1m) or KMT2Arearrangements (KMT2Ar) leading to overexpression of HOXA9 and MEIS1 genes.1-4
Below, we summarize six presentations from the European Hematology Association (EHA) 2024 Hybrid Congress, by Issa,1 Zeidner,2 Wei,3 Daver,4 Hertlein,5 and Mitra,6 on menin inhibitors that are currently in development for the treatment of AML.
Revumenib, a selective, small-molecule inhibitor of the menin-KMT2A interaction (Figure 1), is in development for the treatment of AML with KMT2Ar and NPM1m.
Figure 1. Mechanism of action of revumenib*
A Rearrangements in KMT2A result in overexpression of HOX and MEIS genes, which blocks hematopoietic differentiation and leads to promotion of leukemia cells. Menin is crucial for the KMT2A protein complex to bind to the HOX gene. B Revumenib, a potent, selective, small-molecule inhibitor of the menin-KMT2A interaction, downregulates HOX and MEIS transcription, leading to hematopoietic differentiation and an antileukemic effect.
AML, acute myeloid leukemia; KMT2Ar, histone-lysine-N-methyltransferase 2A rearrangement; NPM1m, mutated NPM1.
*Adapted from Issa1 and data from Issa et al.7
In the AUGMENT-101 phase II trial (NCT04065399; Figure 2), 94 heavily pre-treated patients were included in the safety population (median age, 37 years; female, 56%) and 57 in the efficacy population (median age, 34 years; female, 58%) at the data cut-off of July 24, 2023.
Figure 2. AUGMENT-101 study design*
AML, acute myeloid leukemia; BW, body weight; CR, complete remission; CRc, composite CR (CR/CRh/CRp/CRi); CRh, CR with partial hematologic recovery; CRi, CR with incomplete hematologic recovery; CRp, CR with incomplete platelet recovery; KMT2Ar, KMT2A rearrangement; NPM1m, mutated NPM1; ORR, overall response rate; PO, oral administration; R/R relapsed/refractory; RP2D, recommended phase II dose.
*Adapted from Issa.1 Data cut-off: July 24, 2023.
Figure 3. Response rates observed with revumenib A in the overall efficacy population and B stratified by subgroups and KMT2A rearrangement*
CR, complete remission; CRc, composite CR (CR/CRh/CRp/CRi); CRh, CR with partial hematologic recovery; CRi, CR with incomplete hematological recovery; CRp, CR with incomplete platelet recovery; HSCT, hematopoietic stem cell transplantation; ORR, overall response rate.
*Data from Issa.1
Venetoclax plus azacitidine is an important combination therapy for older patients with AML; however, it is still limited by poor long-term outcomes and relapse rates in patients with NPM1m or poor risk cytogenetics. Hence, the combination of venetoclax and azacitidine with revumenib is currently under investigation in patients with newly diagnosed (ND) AML with NPM1m or KMT2Ar.
One substudy of the Beat AML master trial is an open-label phase Ib dose escalation and expansion trial (NCT03013998) evaluating the safety and recommended dose of revumenib in combination with azacitidine and venetoclax in patients with ND AML with NPM1m or MLL rearrangement (MLLr), who are unable to undergo intensive induction therapy (Figure 4).2,8
Two dose levels (DLs) of revumenib were assessed:
Figure 4. Beat AML substudy design of revumenib + venetoclax + azacitidine in ND NPM1m or KMT2Ar AML*
ANC, absolute neutrophil count; AML, acute myeloid leukemia; Aza, azacitidine; DLT, dose-limiting toxicity; DoR, duration of response; IV, intravenous; KMT2Ar, KMT2A rearrangement; MRD, minimal residual disease; ND, newly diagnosed; NPM1m, mutated NPM1; ORR, overall response rate; OS, overall survival; PLT, platelets; PO, oral administration; QD, once a day; SQ, subcutaneous; Ven, venetoclax.
*Adapted from Zeidner.2
A total of 26 patients aged ≥60 years were included (7 in escalation DL1a, 6 in escalation DL2a, and 13 in expansion DL2a).
Findings from a phase I study (NCT04811560) of bleximenib monotherapy in patients with R/R AML with KMT2Ar or NPM1m have previously been published on the AML Hub. Below, we summarize results from Cohort A3 of an ongoing phase Ib trial (NCT05453903) of bleximenib in combination with venetoclax and azacitidine in KMT2Ar or NPM1m R/R AML (Figure 5).
Figure 5. A Study design and B dosing schedule of a phase Ib trial of bleximenib + Ven + Aza in KMT2Ar or NPM1m R/R AML*
Aza, azacitidine, BID, twice a day; C, cycle; D, day; IV, intravenous; ND, newly diagnosed; PD, pharmacodynamic; PK, pharmacokinetic; PO, oral administration; QD, once a day; RP2D, recommended phase II dose; R/R relapsed/refractory; SC, subcutaneous; Ven, venetoclax.
*Adapted from Wei.3 Data cut off: May 7, 2024
A total of 60 patients were included, with a median age of 60 years and 55% female.
Figure 6. Preliminary clinical activity*
CR, complete remission; CRh, CR with partial hematologic recovery; CRi, CR with incomplete hematologic recovery; KMT2Ar, KMT2A rearrangement; NPM1m, mutated NPM1; ORR, overall response rate; Ven, venetoclax.
*Data from Wei.3
A first-in-human phase I/II study (NCT04988555) assessed DSP-5336 in patients with R/R MLL rearrangement (MLLr) or NPM1m AML (Figure 7). Among the 57 patients included, median age was 63 years and 57.9% were female. A total of 87.7% of patients had previously received treatment with venetoclax.
Figure 7. Study design of a phase I/II study assessing DSP-5336 in patients with R/R MLLr or NPM1m AML*
AML, acute myeloid leukemia; BID, twice a day; MLLr, MLL rearrangement; NPM1m, mutated NPM1; RP2D, recommended phase II dose; R/R, relapsed/refractory.
*Adapted from Daver.4 Data cut off: May 7, 2024.
Figure 8. Changes in markers with DSP-5336*
MLLr, MLL rearrangement; NPM1m, mutated NPM1.
*Data from Daver.4
The therapies targeting the menin-KMT2A interaction have several limitations, including drug-related cardiac toxicities (such as QTc prolongation) and hotspot mutations in MEN1 at the drug-binding interface. These resistance mutations (e.g., M327 and G331) hinder the interaction of menin-inhibitors with the target residue W346, resulting in loss of their therapeutic potential. Balomenib, a next-generation menin inhibitor, is designed to form an energetically favorable conformation enabling effective target interaction while avoiding W346, thereby addressing cardiotoxicity and reducing the risk of resistance mutations associated with menin inhibitors.
Ziftomenib is currently being investigated in a phase I/II study (KOMET-001 study; NCT04067336); interim findings have previously been published on the AML Hub. Below, we summarize information on the pharmacology and pharmacokinetic profile of ziftomenib.
These presentations demonstrate the potential of menin inhibitors in the treatment of AML. Revumenib was well tolerated and effective in both pediatric and adult patients with R/R KMT2Ar or NPM1m AML, and was also found to be safe and effective in combination with venetoclax and azacitidine in older patients with AML. Bleximenib, in combination with venetoclax and azacitidine, and DSP-5336 were seen to be well tolerated and effective, although their RP2D is yet to be determined. Balomenib demonstrated efficacy and a manageable safety profile in preclinical models, and showed synergy when combined with BCL2 and FLT3 inhibitors. At the RP2D, ziftomenib had a stable pharmacokinetic profile, with no significant drug interactions with potential combination therapies.
These menin inhibitors in early-stage clinical development, both as monotherapy or in combinations, show promising initial results, although further studies are warranted to determine their full therapeutic potential in patients with AML.
This educational resource is independently supported by Syndax. All content is developed by SES in collaboration with an expert steering committee; funders are allowed no influence on the content of this resource.
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