Menin inhibitors for AML: Current status and insights from ASH 2024

Alterations in nucleophosmin 1 (NPM1) and lysine methyltransferase 2A (KMT2A) genes drive leukemogenesis in approximately 35–40% of acute myeloid leukemia (AML) cases.¹ Menin inhibitors have emerged as a promising therapeutic approach for KMT2A-rearranged (KMT2Ar) and NPM1-mutated (NPM1m) acute leukemias. Revumenib is the first menin inhibitor to be approved by the U.S. Food and Drug Administration (FDA) for relapsed/refractory (R/R) KMT2Ar acute leukemias.² Several other menin inhibitors, with distinct safety and activity profiles, are currently in development.^1-7

Below, we summarize presentations by Recher,³ Searle,⁴ Aldoss,⁵ Isaa,⁶ Zeidner,² Zeidan,⁷ and Fathi,¹ from the 66th American Society of Hematology (ASH) Annual Meeting and Exposition 2024, discussing the latest developments in menin inhibitors for the treatment of AML.

Bleximenib

Bleximenib in combination with intensive chemotherapy in newly diagnosed AML: Results from the ALE1002 trial³

Findings from Arm A of the ongoing phase Ib ALE1002 trial (NCT05453903) of bleximenib in combination with venetoclax and azacitidine in KMT2Ar or NPM1m R/R AML were previously reported.⁸ Here, we summarize findings from Arm C of the trial, evaluating safety and preliminary efficacy of bleximenib in combination with 7+3 intensive chemotherapy (IC) in patients with newly diagnosed (ND) AML who were fit for IC. At the data cut-off of October 9, 2024, 28 patients were included in the safety population; the median age was 58 years, and 54% were female.

Key findings

• In the 21 patients included in the efficacy set, the overall response rate (ORR) was 95%, with 86% achieving composite complete remission (CRc: CR/CR with partial hematologic recovery [CRh]/CR with incomplete hematologic recovery [CRi]).
  • Patients with KMT2Ar and NPM1m AML had similar response rates.
  • Among ORR responders, 13 patients were active on treatment, with 9 continuing bleximenib monotherapy; 3 proceeded to allograft, and 4 discontinued.
  • No cases of relapse or mortality were reported.
• The safety profile of bleximenib was consistent with the known adverse events (AEs) of IC.
  • Grade ≥3 treatment-emergent AEs (TEAEs) were observed in 93% of patients; most common (occurring in ≥10% of patients) were thrombocytopenia (68%), febrile neutropenia (61%), neutropenia (54%), anemia (54%), leukopenia (32%), pneumonia (21%), sepsis (14%), elevated gamma-glutamyl transferase (GGT; 14%), nausea (10%), stomatitis (10%), and hypotension (10%).
  • Median times to platelet and neutrophil count recovery were 32 and 33 days, respectively.
  • There were no reports of differentiation syndrome (DS), dose-limiting toxicities (DLTs), corrected QT interval (QTc) prolongation, or clinically significant myelosuppression in induction; rates of DS were lower in bleximenib combination therapy compared with monotherapy.
• Further exploration of bleximenib combination therapies in the ALE1002 trial is ongoing to inform future phase III trials.

Bleximenib monotherapy in R/R acute leukemia: Results from the cAMeLot-1 trial⁴

The cAMeLot-1 trial (NCT04811560) is an ongoing phase I/II, multicenter, dose-finding study of bleximenib monotherapy (evaluating 45 mg, 90/100 mg, and 150 mg twice-daily dose levels) in patients with KMT2Ar or NPM1m R/R acute leukemia. As of October 2024, 146 patients with R/R acute leukemia were included (AML, n = 132; ALL, n = 7; other acute leukemia, n = 7). Median age was 60 years; 54.8% were female; 56.8% had KMT2Ar, and 39.7% had NPM1m acute leukemia.

Key findings

• In the efficacy population (n = 52), ORRs with 45 mg, 90/100 mg, and 150 mg were 36.4%, 47.6%, and 55.0%, respectively, with CR/CRh rates of 18.2%, 33.3%, and 40.0%, respectively.
  • Median times to first response were 1.5 months, 1.4 months, and 1.0 months, respectively.
• The safety profile was tolerable across doses.
  • The most common Grade ≥3 TEAEs (occurring in ≥15% patients) were thrombocytopenia (31.5%), anemia (26.7%), neutropenia (25.3%), and febrile neutropenia (18.5%).
  • No QTc prolongation was noted.
  • DS was observed in 14.4% of patients; the majority of cases were low grade.
  • Bleximenib 150 mg twice-daily dosing was associated with more AE-induced dose modifications/discontinuations and increased Grade ≥3 neutropenia.
• Based on safety, efficacy, and pharmacodynamics findings, bleximenib 100 mg twice daily was selected as the recommended phase II dose (RP2D). The phase II portion of the cAMeLot-1 trial is ongoing to further evaluate bleximenib RP2D in R/R KMT2Ar and NPM1m AML.

Revumenib

Revumenib in patients with R/R KMT2Ar AML: Updated results from the AUGMENT-101 trial⁵

Results from an interim analysis of the phase II AUGMENT-101 trial (NCT04065399) of revumenib in patients with KMT2Ar AML have been reported previously.⁹ Below, we summarize findings from an updated analysis of the trial. A total of 116 patients were included in the safety population (median age, 35.5 years; female, 57.8%; AML, 82%) and 97 in the efficacy population (median age, 37 years; female, 56.7%; AML, 80.4%) at the data cut-off of Feb 29, 2024.

Key findings

• Consistent with results from the interim analysis, ORR was 63.9%.
  • Among 18 of 22 patients achieving CR/CRh, minimal residual disease (MRD) negativity was attained in 61.1%.
  • Median time to achieve first ORR was 1.0 month and first CR/CRh was 2.0 months.
  • Median duration of CR/CRh was 6.4 months.
• Among patients achieving ORR, 33.9% proceeded to hematopoietic stem cell transplantation (HSCT). Of those, 42.9% restarted revumenib post-HSCT.
  • Eight of those who proceeded to HSCT were in CR/CRh; of six with available MRD status, 66.7% were MRD-negative.

• The safety profile was manageable and consistent with interim findings.
  • Grade ≥3 TEAEs were observed in 91.4%; most common (occurring in ≥10% patients) were febrile neutropenia (38.8%), anemia (19.8%), platelet count reduction (16.4%), DS (14.7%), neutrophil count reduction (14.7%), white blood cell count reduction (14.7%), sepsis (13.8%), and QTc prolongation (12.9%).
  • Any-grade DS and QTc prolongation were observed in 26.7% and 29.3% of patients.
  • There were no treatment discontinuations due to cytopenias, DS, or QTc prolongation.
• Revumenib demonstrated clinically meaningful responses in the largest cohort of R/R KMT2Ar acute leukemia, including the largest pediatric population to date. The analysis of the NPM1m AML cohort is underway.

All-oral combination of revumenib with decitabine/cedazuridine and venetoclax: Results from the SAVE trial⁶

In the phase I/II SAVE trial (NCT05360160), the all-oral combination of revumenib, venetoclax, and the hypomethylating agent decitabine/cedazuridine (ASTX727) was investigated in children aged ≥12 years and adults with R/R AML. As of November 18, 2024, 33 patients with AML were enrolled; median age was 35 years, 58% were female, and 49% had KMT2Ar and 36% NMP1m AML.

Key findings

• In the phase I dose-escalation portion, revumenib dose level 1 (163 mg orally every 12 h from Day 1–28) was chosen as the RP2D.
• ORR was 82% and CR/CRh was 48%.
  • Among CR/CRh responders, MRD negativity was 88%.
  • 39% underwent HSCT, and seven patients proceeded to revumenib maintenance.
  • At a median follow-up of 9.3 months, duration of CR/CRh was not reached.
• The safety profile of the combination was acceptable.
  • The most common Grade ≥3 TEAEs occurring in ≥15% of patients were febrile neutropenia (33%), lung infection (33%), increased aspartate aminotransferase/alanine aminotransferase (18%), reduced platelet count (18%), respiratory failure (18%), sepsis (18%), and sinusitis (15%).
  • Grade ≥3 TEAE QTc prolongation and DS were observed in 9% and 3% of patients, respectively.
• The trial is now enrolling patients with ND KMT2Ar, NPM1m, or NUP98-rearranged AML who are ineligible for IC.

Enzomenib

Enzomenib (DSP-5336) in patients with R/R acute leukemia²

Interim findings from the ongoing phase I/II DSP-5336-101 trial (NCT04988555) of enzomenib (DSP-5336, designed to have low lipophilicity and basicity to minimize off-target toxicity) in patients with KMT2Ar or NPM1m acute leukemia were reported previously.¹⁰ Here, we summarize updated results from the phase I portion of the trial. At the data cut-off of October 22, 2024, 84 patients with acute leukemia (48.8% with KMT2Ar and 27.4% with NPM1m) were included; median age was 61.5 years, 57.1% were female, 52.4% were White, and 79.8% had received prior venetoclax treatment.

Key findings

• Promising clinical activity was observed from two optimized dose cohorts – 200 mg twice daily and 300 mg twice daily.
  • Objective response rate (CR + CRh + CRi + morphologic leukemia-free state) was 65.2% in patients with KMT2Ar (50.0% with 200 mg and 73.3% with 300 mg) and 58.8% in patients with NPM1m (60.0% with 200 mg and 58.8% with 300 mg) acute leukemia.
  • CR/CRh was 30.4% in patients with KMT2Ar (12.5% with 200 mg and 40.0% with 300 mg) and 47.1% in those with NPM1m (50.0% with 200 mg and 42.9% with 300 mg) acute leukemia.
  • Median time to first objective response was 1.0 month and 1.9 months in patients with KMT2Ar and NPM1m acute leukemia, respectively, with median duration of response not reached and 7.0 months, respectively.
• Enzomenib was well tolerated across dose levels (40 mg to 400 mg twice daily).
  • The most common Grade ≥3 TEAEs, occurring in ≥15% patients, were sepsis (25.0%), febrile neutropenia (23.8%), reduced platelet count (21.4%), anemia (16.7%), pneumonia (16.7%), reduced neutrophil count (16.7%), and hemorrhage (11.9%).
  • There were no DLTs, treatment-related deaths or discontinuations.
  • DS was observed in 10.7% of patients, with no associated deaths or treatment discontinuation.
  • QTc prolongation occurred in 1% of patients.
• Additional combination cohorts have been initiated, and dose optimization is ongoing to determine the RP2D for the phase II expansion portion.

Ziftomenib

Ziftomenib in combination with cytarabine and daunorubicin: Results from the KOMET-007 trial⁷

The KOMET‑007 trial (NCT05735184) is an ongoing, open-label, dose-escalation (phase Ia) and expansion (phase 1b) study of ziftomenib once-daily in combination with standard induction chemotherapies in ND and R/R NPM1m or KMT2Ar AML. Here, we summarize interim results from the phase Ia portion in patients with ND adverse-risk AML. As of October 1, 2024, 51 patients with AML (24 with NPM1m and 27 with KMT2Ar) were included in the safety population.

Key findings

• Among 46 patients in the efficacy set (NPM1m; n = 23; KMT2Ar, n = 23), CRc was 100% in patients with NPM1m and 83% in patients with KMT2Ar AML.
  • Among CRc responders tested for MRD, MRD negativity was achieved in 76% and 75% in patients with NMP1m and KMT2Ar AML, respectively.
• The combination was well tolerated across all dose levels in patients with both NPM1m and KMT2Ar AML.
  • Most common TEAEs of any grade (occurring in ≥30% of patients) included febrile neutropenia (67%), diarrhea (53%), reduced platelet count (43%), anemia (37%), nausea (37%), constipation (35%), and reduced neutrophil count (35%).
  • No DLTs or ziftomenib-induced QTc prolongation were reported.
  • One Grade 3 DS was observed, which was managed successfully without treatment discontinuation.
• Given the promising clinical activity and lack of safety issues with higher doses, the phase 1b dose expansion is further evaluating 600 mg ziftomenib-based combinations in patients with ND NMP1m and KMT2Ar AML.
• The registration-enabling phase III KOMET-017 trial of ziftomenib in both fit and unfit patients with KMT2Ar and NPM1m AML is expected to be initiated in 2025.

Ziftomenib in combination with venetoclax and azacitidine: Results from the KOMET-007²

The KOMET‑007 (NCT05735184) trial is also evaluating ziftomenib in combination with venetoclax and azacitidine in patients with R/R KMT2Ar and NPM1m AML. As of October 1, 2024, 54 patients were included in this cohort. Median age was 59 years, 56% were female, and 69% had received prior venetoclax treatment.

Key findings

• Among 22 patients with NPM1m and 27 with KMT2Ar AML, ORR was 68% and 33%, respectively, while CRc was 50% and 15%, respectively.
  • In patients with prior venetoclax exposure, ORR was 50% in those with NPM1m (n = 14) and 30% in those with KMT2Ar AML (n = 20).
  • Six patients with NPM1m and three with KMT2Ar AML underwent HSCT, while one from each group proceeded to ziftomenib maintenance.
• The safety profile across all dose levels aligned with the known AEs of venetoclax and azacitidine in R/R AML.
  • Any-grade TEAEs occurred in 98% of patients; the most common Grade ≥3 TEAEs, occurring in ≥25% of patients, were reduced platelet count (31%), anemia (26%), and febrile neutropenia (26%).
  • Grade 2 or 3 DS was observed in four patients; all the cases were manageable without treatment discontinuation.
  • No DLTs or cases of ziftomenib-associated QTc prolongation were reported.
• Based on the positive initial results, a dose-expansion phase evaluating this triplet combination is underway.

Conclusions

Menin inhibitors are rapidly shaping the treatment paradigm for patients with KMT2Ar or NPM1m AML. The U.S. FDA approval of revumenib in R/R KMT2Ar AML marks a key milestone in this evolving landscape, while ongoing trials with bleximenib, enzomenib, and ziftomenib continue to explore optimized dosing, combination approaches, and efficacy in a range of patient populations, including those who are fit, unfit, newly diagnosed, or R/R. Further trials are ongoing to investigate the full potential of menin inhibitors in KMT2Ar and NPM1m AML.

This educational resource was independently supported by Johnson and Johnson. All content was developed by SES in collaboration with an expert steering committee; funders were allowed no influence on the content of this resource.