icovamenib (BMF-219)

Next-generation agents (ziftomenib, bleximenib, enzomenib, BMF-219) have displayed similar composite complete remission rates (20-35%) and overall response rates (45-65%) in heavily pretreated KMT2Ar and NPM1m acute myeloid leukemia (AML) with measurable residual disease (MRD) negativity and prolonged overall survival (5-7 months)...Acquired mutations in the menin gene described in 39% of post-revumenib relapses have not been identified following other inhibitors (ziftomenib, bleximenib), prompting new questions about resistance mechanisms. These promising results swiftly led to the launch of multiple trials of menin inhibitors combined with intensive (cytarabine and anthracycline) and nonintensive (venetoclax and hypomethylating) chemotherapy backbones...Ongoing/pending phase 3 trials will clarify whether menin blockade should be incorporated into frontline and maintenance regimens for all patients with KMT2A rearranged or NPM1 mutant disease. In the current era, menin inhibition remains a key pillar of the success of precision medicine for AML therapy.

P1, N=60, Recruiting, Biomea Fusion Inc.

P2, N=37, Terminated, Biomea Fusion Inc. | Active, not recruiting --> Terminated; Sponsor made a business decision to terminate the study based on prioritization of portfolio.

P1/2, N=443, Completed, Biomea Fusion Inc. | Active, not recruiting --> Completed

Currently, six menin inhibitors are in clinical evaluation as monotherapy or in combination regimens: revumenib, ziftomenib, bleximenib (previously JNJ-75276617), enzomenib (previously DSP-5336), DS-1594, and BMF-219. We discuss their efficacy, safety profiles, and potential roles within the current treatment algorithm. The continued clinical evaluation of menin inhibitors may redefine treatment paradigms for NPM1m and KMT2Ar AML and other acute leukemia with the aberrant MEIS1-HOXA axis, offering new hope for patients with limited therapeutic options.

P2, N=37, Active, not recruiting, Biomea Fusion Inc. | N=190 --> 37 | Trial primary completion date: Aug 2025 --> May 2025

P1, N=55, Terminated, Biomea Fusion Inc. | Active, not recruiting --> Terminated; Biomea Fusion, Inc., is no longer pursuing oncology indications for BMF-219. No safety concerns or efficacy observations led to this study closure.

Menin inhibitors demonstrate promising clinical activity in molecularly defined leukemias, with Revumenib establishing proof-of-concept for this therapeutic approach. However, challenges remain, including resistance development, optimal timing of therapy initiation, and determination of effective combination strategies. Larger randomized trials with extended follow-up are needed to establish long-term efficacy and safety profiles. The rapid clinical development of multiple agents in this class suggests an expanding role for Menin inhibitors in leukemia treatment paradigms.

P1, N=55, Active, not recruiting, Biomea Fusion Inc. | Recruiting --> Active, not recruiting | N=177 --> 55

P1, N=13, Terminated, Biomea Fusion Inc. | N=90 --> 13 | Trial completion date: Oct 2026 --> Jan 2025 | Recruiting --> Terminated | Trial primary completion date: Jun 2025 --> Jan 2025; Biomea Fusion, Inc., is no longer pursuing oncology indications for BMF-219. No safety concerns or efficacy observations led to this study closure.

Not available.

P1/2, N=414, Active, not recruiting, Biomea Fusion Inc. | Suspended --> Active, not recruiting | Trial primary completion date: Jul 2024 --> Nov 2024