^
    9d
    Enhancer of Zeste Homolog 1 and 2 Inhibitor-Induced Colitis Mimicking Immune Checkpoint Inhibitor-Induced Colitis. (PubMed, Intern Med)
    An 80-year-old woman with relapsed nodal T-follicular helper cell lymphoma, not otherwise specified, developed severe watery diarrhea during valemetostat therapy...To the best of our knowledge, this is the first reported case of enhancer of zeste homolog 1 and 2 (EZH1/2) inhibitor-induced colitis. EZH1/2 inhibition may lead to T cell-mediated intestinal injury through epigenetic dysregulation; therefore, patients receiving EZH1/2 inhibitors who develop persistent diarrhea should undergo early endoscopic and histological evaluations.
    Journal • Checkpoint inhibition
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    CD8 (cluster of differentiation 8) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)
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    Ezharmia (valemetostat)
    11d
    DS3201-343: Phase 1 trial of valemetostat and darolutamide in mCRPC (2025-522512-16-00)
    P1, N=4, Not yet recruiting, Daiichi Sankyo Inc.
    New P1 trial
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    Nubeqa (darolutamide) • Ezharmia (valemetostat)
    12d
    Valemetostat Therapy for Relapsed Adult T-Cell Leukemia/Lymphoma After Allogeneic Hematopoietic Stem Cell Transplantation. (PubMed, Hematol Oncol)
    At the last follow-up, four patients were alive without disease, four were alive with disease, and three died due to progressive disease. Hence, valemetostat is a promising salvage therapy for relapsed adult T-cell leukemia/lymphoma after allo-HCT.
    Retrospective data • Journal
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    IL2 (Interleukin 2)
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    Ezharmia (valemetostat)
    21d
    EZHiSWITCH: Efficacy and Safety of the Valemetostat in Patients With Selected Solid Tumors. (clinicaltrials.gov)
    P2, N=900, Recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Not yet recruiting --> Recruiting
    Enrollment open
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    ARID1A (AT-rich interaction domain 1A) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • PBRM1 (Polybromo 1) • BAP1 (BRCA1 Associated Protein 1) • SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2)
    |
    Ezharmia (valemetostat)
    1m
    DS3201-330: A Study of Valemetostat Tosylate Plus Pembrolizumab versus Pembrolizumab Alone in First-Line NSCLC Without Actionable Genomic Alterations (2024-519671-26-00)
    P1/2, N=21, Completed, Daiichi Sankyo Inc.
    New P1/2 trial
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    EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK (Neurotrophic receptor tyrosine kinase)
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    PD-L1 expression • KRAS mutation
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    PD-L1 IHC 22C3 pharmDx
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    Keytruda (pembrolizumab) • Ezharmia (valemetostat)
    1m
    2024/3993 EZHiSWITCH: An open label phase II platform modular study exploring the efficacy and safety of the Valemetostat (EZH1/2 inhibitor) in patients with selected solid tumors. (2024-519788-16-00)
    P1/2, N=600, Not yet recruiting, Institut Gustave Roussy
    New P1/2 trial
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    ARID1A (AT-rich interaction domain 1A) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • PBRM1 (Polybromo 1) • BAP1 (BRCA1 Associated Protein 1) • SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2)
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    Ezharmia (valemetostat)
    2ms
    EZH2 Inhibition Reshapes 3D Chromatin Architecture to Induce Immunogenic Phenotype in Small Cell Lung Cancer. (PubMed, bioRxiv)
    Employing Micro-C, a micrococcal nuclease-based 3D genome mapping technique, we show that EZH1/2 inhibition with Valemetostat induced significant changes at multiple genome organizational levels (compartment, topological associated domain, and chromatin loop) without incurring cell death in NE SCLC...Notably, EZH1/2 inhibition reactivated Class I MHC expression by facilitating enhancer-promoter looping. Our results demonstrate that repression of a subset of EZH2 targets including Class I MHC genes is affected through modulation of 3D genome structure to the level of chromatin looping and further support clinical investigation of EZH2 inhibition in boosting therapeutic efficacy of ICI in SCLC patients.
    Journal • IO biomarker
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    EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • SLFN11 (Schlafen Family Member 11) • HLA-B (Major Histocompatibility Complex, Class I, B)
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    Ezharmia (valemetostat)
    2ms
    Phase 1b Study of EZH1/2 Inhibitor Valemetostat in Combination With Trastuzumab Deruxtecan in Subjects With HER2 Low/Ultra-low/Null Metastatic Breast Cancer (clinicaltrials.gov)
    P1, N=17, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=37 --> 17
    Enrollment closed • Enrollment change
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    HER-2 (Human epidermal growth factor receptor 2) • UGT1A1 (UDP glucuronosyltransferase family 1 member A1)
    |
    PATHWAY antiHer2/neu (4B5) Rabbit Monoclonal Primary Antibody
    |
    Enhertu (fam-trastuzumab deruxtecan-nxki) • Ezharmia (valemetostat)
    3ms
    EZHiSWITCH: Efficacy and Safety of the Valemetostat in Patients With Selected Solid Tumors. (clinicaltrials.gov)
    P2, N=900, Not yet recruiting, Gustave Roussy, Cancer Campus, Grand Paris
    New P2 trial
    |
    Ezharmia (valemetostat)
    3ms
    Polycomb Repressive Complexes as Therapeutic Targets in Hematologic Malignancies. (PubMed, Exp Hematol)
    Therapeutic targeting of H3K27me3 with EZH2-selective inhibitors such as tazemetostat has shown clinical benefit in lymphoma; however, their efficacy is limited by functional redundancy with EZH1. The dual EZH1/2 inhibitor valemetostat overcomes this limitation by reactivating tumor suppressor genes, achieving durable responses in ATL and peripheral T-cell lymphoma (PTCL). Nonetheless, therapeutic resistance can emerge through PRC2 gatekeeper mutations and compensatory DNA methylation. These findings underscore the value of targeting the dysregulated epigenome and support the continued clinical development of dual EZH1/2 inhibitors.
    Review • Journal
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    EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • KMT2D (Lysine Methyltransferase 2D) • CREBBP (CREB binding protein) • BCOR (BCL6 Corepressor) • BMI1 (BMI1 proto-oncogene, polycomb ring finger) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)
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    EZH2 mutation
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    Tazverik (tazemetostat) • Ezharmia (valemetostat)
    3ms
    A Study of Valemetostat (DS-3201b) in Combination With Darolutamide in Metastatic Castration Resistant Prostate Cancer (mCRPC) (clinicaltrials.gov)
    P1, N=60, Recruiting, Daiichi Sankyo | Not yet recruiting --> Recruiting
    Enrollment open
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    Nubeqa (darolutamide) • Ezharmia (valemetostat)
    4ms
    Valemetostat Tosylate (DS-3201b), an Enhancer of Zeste Homolog (EZH) 1/2 Dual Inhibitor, for Relapsed/Refractory Peripheral T-Cell Lymphoma (VALENTINE-PTCL01) (clinicaltrials.gov)
    P2, N=155, Active, not recruiting, Daiichi Sankyo | Trial completion date: Sep 2025 --> Feb 2027
    Trial completion date
    |
    ALK (Anaplastic lymphoma kinase) • CD8 (cluster of differentiation 8)
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    ALK positive • ALK negative
    |
    Ezharmia (valemetostat)