Ezharmia (valemetostat) / Daiichi Sankyo - LARVOL DELTA

Dissecting the whole trajectory of aid-induced genomic instability from mutational activity to chromosomal translocation formation (ASH 2025) - "EZH2 inhibitors, such as tazemetostat and valemetostat, areepigenetic regulators approved by the FDA for the treatment of follicular lymphoma and adult T-cell leukemia/lymphoma, respectively. Overall, to our knowledge this work represents the most comprehensive mapping of AID-inducedmutational and genotoxic activity, shedding light on the whole trajectory of AID activity from thevery early initiation steps of cytidine deamination to the formation of DSB intermediates up tothe final outcome of chromosomal translocations. The described approach can be exploited tofunctionally dissect the impact of novel drugs on AID-mediated genomic instability in B celllymphoma."

Adult T-Cell Leukemia-Lymphoma • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Gene Therapies • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Solid Tumor • PIK3CD

Epigenetic reprogramming via EZH1/2 inhibition enhances T cell-mediated immunotherapies against multiple myeloma (ASH 2025) - "Introduction:Although BCMA-targeted CAR-T therapies and CD3×BCMA bispecifics (e.g., teclistamab) have shownclinical promise, most r/r MM patients eventually relapse due to tumor-intrinsic resistance and T-celldysfunction...We, therefore, hypothesized that inhibition of EZH1 and EZH2 could enhance T cell–basedimmunotherapy for MM by both directly impairing tumor growth and survival, and by boosting T cell–mediated cytotoxicity.Methods and We first demonstrated a strong tumor-intrinsic anti-clonogenic effect of the EZH2 inhibitor (tazemetostat)and the dual EZH1/2 inhibitor (valemetostat) on the MM cell line RPMI-8226... These findings support a dual mechanism of action EZH1/2 inhibitors directly suppress MMclonogenicity and immune evasion, while concurrently enhancing the function and cytotoxicity of T cell–based immunotherapies. By preserving T-cell activity and reprogramming tumor cells, EZH1/2 inhibitionrepresents a promising strategy to improve the durability and..."

IO biomarker • B Cell Lymphoma • Graft versus Host Disease • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • CD31 • CD70 • CXCL10 • CXCL14 • CXCL9 • EZH2 • IFNG • IL2 • LAMA1 • LAMA2 • PECAM1 • SDC2

Valemetostat monotherapy in patients with relapsed or refractory B-cell lymphoma: Final results of the Phase 2 valym study from the lysa (ASH 2025) - P2 | "In this phase 2 study of valemetostat in B-cell lymhoma, modest activity was observed inMCL, MZL and HL while an encouraging ORR of 62% was observed in FL. Interestingly, ORR and CRR were33% and 25% in 12 patients with EZB LBCL molecular subtype, pointing out potential selective activity.Importantly, a manageable safety profile was observed in heavily pretreated and elderly patientpopulation supporting further development in combination."

Clinical • Monotherapy • P2 data • B Cell Lymphoma • Basal Cell Carcinoma • Bladder Cancer • Follicular Lymphoma • Genito-urinary Cancer • Hematological Malignancies • Infectious Disease • Large B Cell Lymphoma • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Melanoma • Neutropenia • Non-Hodgkin’s Lymphoma • Non-melanoma Skin Cancer • Solid Tumor • Thrombocytopenia • EZH2

Combined FLT3 and EZH1/2 inhibition reduces LSCs and promotes myeloid differentiation in PDX models of AML (ASH 2025) - "EZH1, a close homolog of EZH2, was stableor increased with FLT3i, suggesting a potential compensatory effect that could contribute to resistance.Combined FLT3 and EZH1/2 inhibition using gilteritinib and valemetostat increased the anti-leukemiceffect in vitro in primary FLT3-ITD AML and in vivo in genetically engineered mouse models (GEMMs).Mice treated with the combination exhibited increased myeloid differentiation and reduced leukemicburden. Our findings validate the FLT3i and EZH1/2 combination as a novel approach to therapy inFLT3-ITD AML and suggest a potential effect of this combination through inhibition of wild-type FLT3.Early assessment suggests that valmetostat decreases LSC frequency and that combination therapy withFLT3i may improve responses. Additional studies in FLT3 wild-type AML are planned."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • DNMT3A • EZH2 • FLT3 • NF1 • NPM1 • PRKDC

Humanized PDX models reveal Lymphoma–Host interactions and enhanced T-cell therapies via epigenetic modulation (ASH 2025) - "To explore this complex ecosystem,we analyzed DLBCL biopsies from patients receiving chemotherapy (R-CHOP) or immunotherapy(chimeric antigen receptor CAR T cells) using integrated omics and functional assays, together with fullyhumanized mouse models (HuMice). We analyzed 68 DLBCL cases (48 post R-CHOP and 20 post CAR T-cell–treated) and 48 matchedpatient-derived xenografts (PDX) by bulk RNA-seq, single-cell RNA/TCR-seq, and WES/CAPP-seq...However, splenic T-cells from IR-DLBCL-HuPDX exhibited strong proliferation, clonal expansion, and cytotoxicity against matched tumors.To enhance responses in ID-DLBCL-HuPDX, we performed dose-response screens of single- and dual-drug combinations using clinical phase compounds shown to improve immune responses (e.g.,valemetostat, DNMT1i, GSK-3685032, azacytidine, belinostat, romidepsin, and lenalidomide) and identifysynergistic associations (Vale+GSK, Vale+ Lena: Synergy Score >20)... Epigenetic therapies reprogram the..."

IO biomarker • IO Companion diagnostic • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Gene Therapies • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • CD34 • CD8 • DNMT1 • IFNG • TNFA

A phase Ib/II, dose escalation and dose expansion study of valemetostat tosylate (DS-3201b) with atezolizumab and bevacizumab in advanced hepatocellular carcinoma (HCC). (ASCO-GI 2026) - P1/2 | "Clinical Trial Registration Number: NCT06294548 The full, final text of this abstract will be available on Jan 05 at 05:00 PM EST."

Metastases • P1/2 data • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Phase 1b study of EZH1/2 inhibitor valemetostat in combination with trastuzumab deruxtecan in subjects with HER2 low/ultra-low/null metastatic breast cancer (SABCS 2025) - P2 | "If 11 or more responses are observed among 26 patients, the treatment will be considered promising. This two-stage design yields 78% power under the alternative hypothesis of ORR=50% (null ORR = 30%) while controlling the one-sided type I error at 10%."

Clinical • Combination therapy • Metastases • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • EZH2 • HER-2 • SLFN11

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 | Sponsor: Daiichi Sankyo | Trial completion date: Sep 2025 ➔ Feb 2027

Monotherapy • Trial completion date • Adult T-Cell Leukemia-Lymphoma • Follicular Lymphoma • Hematological Malignancies • Hepatosplenic T-cell Lymphoma • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • ALK • CD8

Adult T-cell leukemia/lymphoma treated with mogamulizumab followed by allogeneic stem cell transplantation after bridging therapy with valemetostat (PubMed, Rinsho Ketsueki) - "Although valemetostat bridging therapy controlled ATLL and allowed for a treatment-free interval after mogamulizumab therapy, it delayed regulatory T cell (Treg) recovery and caused severe aGVHD. Further improvements are needed in the management of severe GVHD after mogamulizumab administration, such as monitoring of Tregs and residual mogamulizumab concentrations."

Journal • Acute Graft versus Host Disease • Adult T-Cell Leukemia-Lymphoma • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation

Treatment and Outcome of ATL Diagnosed in 2021 to 2023 By the Kagoshima ATL Registry (ASH 2024) - "Among them, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), VCAP-AMP-VECP (VCAP : vincristine, cyclophosphamide, doxorubicin, and prednisolone, AMP : doxorubicin, ranimustine, and prednisolone, and VECP : vindesine, etoposide, carboplatin, and prednisolone), any chemotherapy by cytotoxic agents combined with mogamulizumab (Moga+CTx), and CHP therapy combined with brentuximab vedotin (BV-CHP) were performed in 30.0 %, 28.3 %, 28.3 %, and 13.4% of patients, respectively. BV or Moga with or without CTx were most frequently used in the second-line treatment (n=81). This registration is expected to provide real-world data of ATL by regional registry in one of the world's most endemic area in HTLV-1 under the circumstances of the decreasing of HTLV-1 infected individuals in younger people and recent Introduction of novel therapeutic agents including tucidinostat and valemetostat in Japan."

Adult T-Cell Leukemia-Lymphoma • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Study of Valemetostat (DS-3201b) in Combination With Darolutamide in Metastatic Castration Resistant Prostate Cancer (mCRPC) (clinicaltrials.gov) - P1 | N=60 | Not yet recruiting | Sponsor: Daiichi Sankyo

New P1 trial • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Concentration-QTc Analysis of Valemetostat in Patients With Hematologic Malignancies. (PubMed, Clin Transl Sci) - P1 | "At the steady-state geometric mean maximum concentrations in the dose range of 100-700 mg tested in the DS3201-A-J101 and DS3201-A-U102 studies, the 90% CI upper bounds for model-predicted ΔQTcF and ΔQTcP were 1.52-8.38 ms, all of which were below the clinically significant threshold of 10 ms. The analysis supports a lack of a clinically meaningful effect on the QTc interval for valemetostat."

Journal • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma

EZH1/2 Inhibition Improves the Anti-Tumor Efficacy of CAR and TCR T-Cell Based Therapies Against Multiple Liquid and Solid Tumors (ASH 2024) - "We observed that CART22 and CART79b co-cultured with tazemetostat showed enhanced cytotoxicity (72 hs, CART22-taz vs -DMSO p<0.001; CART79b-taz vs -DMSO p<0.01)...Pretreating an array of MM (e.g. RPMI-8226) and AML (e.g. THP-1, KG-1) cell lines with tazemetostat before exposure to anti-BCMA (CARTBCMA) or anti-CD33 CART (CART33) significantly increased killing efficacy at multiple E : T ratio and even with ineffective single-agent CART doses (72 hs; CARTBCMA-taz vs -DMSO p<0.01; CART33-taz vs -DMSO p<0.001)...Furthermore, we show that the novel EZH2/1 inhibitor valemetostat lead to an increased improvement of tumor killing as compared to EZH2i alone. Mechanistically, we demonstrate that EZH1/EZH2 modulation can unlock the full potential of adoptive T-cell immunotherapy."

Clinical • IO biomarker • Acute Myelogenous Leukemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Ewing Sarcoma • Hematological Malignancies • Large B Cell Lymphoma • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Prostate Adenocarcinoma • Prostate Cancer • Sarcoma • Solid Tumor • CD79B • EZH2 • HER-2

Valemetostat Monotherapy in Patients with Relapsed or Refractory Large B-Cell Lymphoma: Primary Results of the Phase 2 Valym Study from the Lysa (ASH 2024) - P2 | "TEAEs were manageable and safety profile was similar to that of the phase I first-in-human study. This suggests valemetostat could be used in combination for future development."

Clinical • Monotherapy • P2 data • Adult T-Cell Leukemia-Lymphoma • Alopecia • Anemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Fatigue • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Large B Cell Lymphoma • Leukemia • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Respiratory Diseases • Septic Shock • Thrombocytopenia • EZH2

Valemetostat for Relapsed or Refractory B-Cell Lymphomas: Primary Results from a Phase 1 Trial (ASH 2023) - P1, P1/2, P2 | "Valemetostat demonstrated encouraging clinical activity in pts with R/R B-NHLs. The safety profile of valemetostat was acceptable; cytopenias were common but manageable and did not require Tx discontinuation between 150–300 mg/d. Clinical responses were durable, with a median DOR of > 1.5 y. Results for pts in this trial with R/R T-NHLs are presented in another abstract (Jacobsen et al.) at this congress."

P1 data • Alopecia • Anemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Immunology • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • EZH2

Efficacy and Safety of Valemetostat Monotherapy in Patients with Relapsed or Refractory Peripheral T-Cell Lymphomas: Primary Results of the Phase 2 VALENTINE-PTCL01 Study (ASH 2023) - P2 | " Pts were ≥ 18 years of age, had a confirmed diagnosis of PTCL, had R/R disease after ≥ 1 prior line of systemic therapy, and pts with anaplastic large cell lymphoma (ALCL) had received prior brentuximab vedotin treatment. Valemetostat demonstrated a high ORR of 43.7% with durable responses (median DOR of 11.9 months) in pts with R/R PTCL, and responses were observed across all PTCL subtypes. A valemetostat dose of 200 mg/day was tolerable; safety analysis showed that the most common TEAEs were cytopenias. These primary results from the VALENTINE-PTCL01 study suggest that valemetostat provides a clinically meaningful benefit for pts with R/R PTCL."

Clinical • Monotherapy • P2 data • Adult T-Cell Leukemia-Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • Thrombocytopenia • ALK • EZH2

Prediction of Clinical Response By Phased Variants in Circulating Tumor DNA (ctDNA) in the VALENTINE-PTCL01 Trial of Patients with Relapsed or Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL) (ASH 2024) - P2 | "Declines in ctDNA-MRD at C2D1 and C5D1 correlated with response to therapy and PFS. These data suggest that ctDNA-MRD monitoring could serve as a noninvasive biomarker assessment to help predict response and survival in patients with R/R PTCL and during valemetostat treatment."

Circulating tumor DNA • Clinical • Adult T-Cell Leukemia-Lymphoma • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • ALK • EZH2

PRC2-Mediated Apoptosis Evasion Is a Therapeutic Target of MDS/AML Harboring Inv(3)/t(3; 3) and -7 (ASH 2023) - "Hemasphere 2020), as well as OCI-AML20, another AML cell line with inv(3) and -7, and found that both YCU-AML1 and OCI-AML20 showed high response to EZH2 inhibitors valemetostat and tazemetostat. Moreover, primary MDS/AML patient bone marrow (BM) sample harboring inv(3) and -7 exhibited preferential sensitivity to valemetostat compared to BM samples derived from healthy control or MDS/AML patients with or without -7 in vitro. Taken together, our study unraveled PRC2-mediated inactivation of GADD45γ-p38α-TP53 axis as a molecular basis for evasion of apoptosis in MDS/AML with inv(3)/t(3; 3) and -7, which can be preferentially abrogated by EZH2 inhibition leading to efficient induction of apoptosis in this high-risk MDS/AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lung Cancer • Myelodysplastic Syndrome • Oncology • Solid Tumor • PTEN

Single-Cell RNA Sequencing Revealed the YY1/EZH2/MLH1 Axis As a Possible Therapeutic Target of Intractable Adult T-Cell Leukemia (ASH 2023) - "The EZH1/2 inhibitor valemetostat down-regulated EZH2 (p = 0... Our findings indicate that down-regulation of MLH1 through YY1/EZH2 inhibition plays a key role in the treatment of aggressive ATL."

Clinical • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CADM1 • CD4 • CD48 • CELF2 • EZH2 • IKZF2 • MLH1 • MSH2 • PTPRC • YY1

Embryonic Ectoderm Development (EED) Inhibitor APG-5918 Demonstrates Robust Antitumor Activity in Preclinical Models of T-Cell Lymphomas (TCLs) (ASH 2024) - "The antiproliferative activity of APG-5918 was superior to that of dual EZH1/2 inhibitor valemetostat and EZH2-selective inhibitor tazemetostat under the same experimental conditions. Mechanistically, APG-5918 likely exerts its antitumor activity by modulating the PRC2 complex, leading to apoptosis induction and cell cycle arrest. These findings provide a strong scientific rationale for the future clinical development of APG-5918 for TCLs."

IO biomarker • Preclinical • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • ANXA5 • BCL2L11 • CASP3 • CDK6 • EZH2

Targeting Epigenetic Resistance Mechanisms to PI3 Kinase Inhibition in Leukemic Stem Cells (ASH 2023) - "We found that dual inhibition with copanlisib and the EZH1/2 inhibitor valemetostat leads to a combinatorial effect to strongly decrease the proliferation of AML cell lines and AML patient samples. Overall, our data suggests that PI3K plays an important role in leukemic stem cells, and that EZH2 downregulation is a non-genetic mechanism of resistance to PI3K inhibition. Additionally, our findings indicate that combining PI3K inhibitors with EZH1/2 dual inhibitors could be a promising therapeutic approach to reduce LSCs, prevent resistance, and prolong survival in AML patients."

Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Transplantation • EZH2 • HOXA9 • KMT2A • MEIS1 • PIK3CA

Valemetostat for Relapsed or Refractory Peripheral T-Cell Lymphomas: Primary Results from a Phase 1 Trial (ASH 2023) - P1 | "Valemetostat was well tolerated and showed encouraging clinical activity in pts with R/R T-NHLs. Cytopenias were common but could usually be managed without Tx discontinuation. Valemetostat induced durable responses, with median DOR of > 1.5 y in both the PTCL and ATLL groups."

P1 data • Acute Kidney Injury • Acute Myelogenous Leukemia • Adult T-Cell Leukemia-Lymphoma • Alopecia • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Myelodysplastic Syndrome • Nephrology • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • Renal Disease • T Cell Non-Hodgkin Lymphoma • EZH2

Comment on "Population Pharmacokinetics of Valemetostat and Exposure-Response Analyses of Efficacy and Safety in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma". (PubMed, J Clin Pharmacol) - No abstract available

Journal • PK/PD data • Hematological Malignancies • Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma

Histone-Modifying Enzymes in Androgen-Deprived Prostate Cancer: EZH1 as a Synergistic Therapeutic Target (PCF 2025) - "EZH1 knockdown reduced survival of ADT-treated cells, and organoid models showed synergistic cell death with combined darolutamide and EZH1 inhibition (valemetostat). ADT induces EZH1 upregulation, which promotes prostate cancer cell persistence through regulation of stemness and epithelial-to-mesenchymal transition. These findings establish EZH1 as a mediator of survival after ADT and a promising target for synergistic therapeutic inhibition. Funding Acknowledgements: This study was supported in part by DoD PC150211, UW Prostate SPORE P50CA269011, and NIH/NCIR01CA76184."

Epigenetic controller • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD44 • EZH2 • MECOM • SIRT1

Phase Ib study of valemetostat in combination with datopotamab deruxtecan (Dato-DXd) in advanced non-squamous non-small cell lung cancer (NSCLC): Initial safety results (ESMO 2025) - P1, P3 | "There were no new safety findings and the overall safety profile was generally similar to that of monotherapy Dato-DXd or Vale. Vale 200 mg PO QD + Dato-DXd 6.0 mg/kg IV Q3W will be further investigated in a dose-expansion phase of this trial."

Clinical • Combination therapy • Metastases • P1 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EZH2 • SLFN11 • TOP1