Reference Detail

Ref Type

Journal Article

PMID

(36922593)

Authors

Issa GC, Aldoss I, DiPersio J, Cuglievan B, Stone R, Arellano M, Thirman MJ, Patel MR, Dickens DS, Shenoy S, Shukla N, Kantarjian H, Armstrong SA, Perner F, Perry JA, Rosen G, Bagley RG, Meyers ML, Ordentlich P, Gu Y, Kumar V, Smith S, McGeehan GM, Stein EM

Title

The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature			2023 Mar 15	920-924	Nature

URL

Abstract Text

Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function1-3. The interaction of menin with lysine methyltransferase 2A (KMT2A), an epigenetic regulator, is a dependence in acute leukaemia caused by either rearrangement of KMT2A or mutation of the nucleophosmin 1 gene (NPM1)4-6. KMT2A rearrangements occur in up to 10% of acute leukaemias and have an adverse prognosis, whereas NPM1 mutations occur in up to 30%, forming the most common genetic alteration in acute myeloid leukaemia7,8. Here, we describe the results of the first-in-human phase 1 clinical trial investigating revumenib (SNDX-5613), a potent and selective oral inhibitor of the menin-KMT2A interaction, in patients with relapsed or refractory acute leukaemia (ClinicalTrials.gov, NCT04065399). We show that therapy with revumenib was associated with a low frequency of grade 3 or higher treatment-related adverse events and a 30% rate of complete remission or complete remission with partial haematologic recovery (CR/CRh) in the efficacy analysis population. Asymptomatic prolongation of the QT interval on electrocardiography was identified as the only dose-limiting toxicity. Remissions occurred in leukaemias refractory to multiple previous lines of therapy. We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Revumenib	Revumenib	3	10

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Revumenib	Revuforj	SNDX5613\|SNDX 5613\|SNDX-5613	MEN1-KMT2A Inhibitor 8	Revuforj (revumenib) inhibits the interaction between Menin and KMT2A (MLL), potentially resulting in antitumor activity and decreased proliferation of tumor cells with KMT2A (MLL) rearrangements or NPM1 mutations (PMID: 36922593, PMID: 36922589). Revuforj (revumenib) is FDA-approved for use in adult and pediatric patients 1 year and older with relapsed or refractory acute leukemia harboring KMT2A translocation (FDA.gov).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KMT2A rearrange	acute leukemia	predicted - sensitive	Revumenib	FDA approved	Actionable	In a Phase I trial (AUGMENT 101), Revuforj (revumenib) treatment demonstrated acceptable safety and resulted in a complete remission or complete remission with partial hematologic recovery (CR/CRh) rate of 30% (18/60) and median duration of response of 9.1 mo in adult and pediatric patients 1 year or older with acute leukemia harboring KMT2A rearrangements or NPM1 mutations, with a CR/CRh rate of 33% (15/46) and median time to CR/CRh of 2.0 mo in KMT2A rearranged patients (PMID: 36922593; NCT04065399).	36922593 detail...