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

• Type of Material: Article
• Authors: Ghayas C Issa, University of Texas MD Anderson Cancer Center; Ibrahim Aldoss, City of Hope, Duarte, CA USA; John DiPersio, Washington University School of Medicine in St. Louis; Branko Cuglievan, University of Texas MD Anderson Cancer Center; Richard Stone, Dana-Farber Cancer Institute; Martha Arellano, Emory University; Michael J Thirman, The University of Chicago; Manish R Patel, Florida Cancer Specialists/Sarah Cannon Research Institute; David S Dickens, University of Iowa; Shalini Shenoy, Washington University School of Medicine in St. Louis; Neerav Shukla, Memorial Sloan-Kettering Cancer Center; Hagop Kantarjian, University of Texas MD Anderson Cancer Center; Scott A Armstrong, Dana-Farber Cancer Institute; Florian Perner, Dana-Farber Cancer Institute; Jennifer A Perry, Dana-Farber Cancer Institute; Galit Rosen, Syndax Pharmaceuticals; Rebecca G Bagley, Syndax Pharmaceuticals; Michael L Meyers, Syndax Pharmaceuticals; Peter Ordentlich, Syndax Pharmaceuticals; Yu Gu, Syndax Pharmaceuticals; Vinit Kumar, Syndax Pharmaceuticals; Steven Smith, Syndax Pharmaceuticals; Gerard M McGeehan, Syndax Pharmaceuticals; Eytan M Stein, Memorial Sloan-Kettering Cancer Center
• Language: English
• Date: 2023-03-30
• Publisher: Emory University Libraries
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41586-023-05812-3
• Title of Journal or Parent Work: Nature
• Volume: 615
• Issue: 7954
• Start Page: 920
• End Page: 924
• Keywords: Protein Binding; Prognosis; Antineoplastic Agents; Humans; Nucleophosmin; Leukemia, Myeloid, Acute; Histone-Lysine N-Methyltransferase; Proto-Oncogene Proteins; Neoplasm, Residual; Remission Induction
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

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.