Komzifti (ziftomenib)

P2, N=6, Recruiting, Kyowa Kirin Co., Ltd.

The combination of ziftomenib 600 mg with venetoclax/azacitidine was well tolerated with deep and durable clinical activity in R/R NPM1-m AML. This trial was registered at www.ClinicalTrials.gov as #NCT05735184.

Currently, several small-molecule menin inhibitors are being tested in combination with conventional therapies. This publication reviews the recent progress in investigating the clinical evidence of menin inhibitors (revumenib, ziftomenib, bleximenib, enzomenib, BMF-219, emilumenib) toward aggressive leukemias, guides future study and optimal treatment for patients with this type of leukemia.

P1/2, N=263, Active, not recruiting, Kura Oncology, Inc. | Recruiting --> Active, not recruiting

P3, N=1300, Recruiting, Kura Oncology, Inc.

The modeling results demonstrated a wide therapeutic margin for ziftomenib in adult R/R NPM1-m AML patients and supported a dose of 600 mg once daily in this patient population. Additionally, ER analyses demonstrated that antifungal azoles had no clinically meaningful impact on efficacy or safety profiles and thus could be co-administered with ziftomenib.

In this preclinical study, we demonstrate that the MI ziftomenib, in combination with the XPO1 inhibitor selinexor, synergistically inhibited the growth of multiple KMT2A- r and NPM1 -m AML cell lines (CI<1). In vivo , combination therapy improved survival in both MV4;11 and OCI-AML3 cell line and primary patient-derived KMT2A - r and NPM1 -m AML xenograft models in NSG mice, effective even at reduced drug doses. These preclinical findings demonstrate that simultaneous inhibition of the menin-KMT2A interaction and XPO1 can be a more effective translational strategy for treating KMT2A- r and NPM1 -m AML than MI monotherapy to deepen responses and delay/prevent relapses.

We critically evaluate the preclinical and clinical development of menin inhibitors, including revumenib, ziftomenib, bleximinib, and icovamenib, summarizing efficacy signals in relapsed/refractory disease, safety profiles, and emerging resistance mechanisms. Special attention is given to combination strategies with venetoclax, FLT3 inhibitors, chemotherapy, and epigenetic agents, which aim to enhance response durability and mitigate resistance. Finally, we discuss ongoing clinical trials, unresolved challenges in patient selection and sequencing, and future directions for integrating menin inhibition into precision-based treatment paradigms for acute leukemia.

Here, we detail the current targeted therapies available for AML: specifically, those targeting the BCL2 family (venetoclax), FLT3 (midostaurin, gilteritinib, quizartinib), IDH1/2 (enasidenib, ivosidenib), and MENIN (revumenib, ziftomenib). In addition, we outline potential mechanisms of resistance against these therapies, as well as efforts being taken to prevent or bypass them.

We next assessed ziftomenib against four MEN1 (gene encoding menin) mutants (T349M, M327I, G331R, G331D) associated with clinical resistance to another menin inhibitor revumenib. The crystal structures of ziftomenib in complex with menin wild-type, T349M or G331R mutants revealed a similar binding mode of ziftomenib to these menin variants, rationalizing potent inhibitory activity towards these mutants. Ziftomenib has recently received FDA approval for adult patients with NPM1-mutated acute myeloid leukemia and continues to be evaluated clinically in leukemias with NPM1 or KMT2A alterations, both as monotherapy and in combinations.

P3, N=1300, Recruiting, Kura Oncology, Inc. | N=719 --> 1300

P2, N=70, Not yet recruiting, Uma Borate | Initiation date: Jan 2026 --> Apr 2026