Ezharmia (valemetostat) / Daiichi Sankyo - LARVOL DELTA

Valemetostat for patients with relapsed or refractory peripheral T-cell lymphoma (VALENTINE-PTCL01): a multicentre, open-label, single-arm, phase 2 study. (PubMed, Lancet Oncol) - P2 | "These data show that treatment with valemetostat leads to durable responses in patients with relapsed or refractory peripheral T-cell lymphoma, with a manageable safety profile."

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

A Phase 1 Trial of Valemetostat Plus Darolutamide in Metastatic Castration-Resistant Prostate Cancer (ESMO 2026) - No abstract available

Metastases • P1 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Precision diagnostics in prostate cancer treatment (PREDICT): A phase 2 multi-arm biomarker-based study (Alliance A032102). (ASCO-GU 2025) - "Patients with Rb loss (DNA), Rb functional loss signature (RNA), NEPC signature (RNA) will be allocated to treatment with the EZH1/2 inhibitor valemetostat. Patients with at least 2 of 3 tumor suppressor gene DNA alterations (TP53, RB1, PTEN), FANC alteration (DNA), or SLFN11 overexpression (RNA) will be allocated to cabazitaxel plus carboplatin. Patients without any study-defined alterations will be allocated to physician choice treatment with either cabazitaxel, ARPI, or 177Lu-PSMA-617...A maximum of 64 patients with measurable disease and 94 patients with non-measurable disease for a total of 158 patients, will be accrued to each treatment arm. This Simon two-stage minimax design has a type 1 error equal to 0.05 when the probability response is 0.20 and has power of 0.90 if the probability of response is 0.37."

Biomarker • P2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • EZH2 • PTEN • RB1 • SLFN11 • TP53

Precision diagnostics in prostate cancer treatment (PREDICT): A phase 2 multi-arm biomarker based study (Alliance A032102). (ASCO 2025) - P2 | "Patients with Rb loss (DNA), Rb functional loss signature (RNA), NEPC signature (RNA) will be allocated to treatment with the EZH1/2 inhibitor valemetostat. Patients with at least 2 of 3 tumor suppressor gene DNA alterations (TP53, RB1, PTEN), FANC alteration (DNA), or SLFN11 overexpression (RNA) will be allocated to cabazitaxel plus carboplatin. Patients without any study-defined alterations will be allocated to physician choice treatment with either cabazitaxel, ARPI, or 177Lu-PSMA-617...A Simon two-stage minimax design per arm was used to determine whether the response rate for measurable disease patients was greater than 0.20. This design has a type 1 error equal to 0.05 and has power equal to 0.90 if the probability of response is 0.37."

Biomarker • P2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • EZH2 • PTEN • RB1 • SLFN11 • TP53

Phase 1b study of EZH1/2 inhibitor valemetostat in combination with trastuzumab deruxtecan in patients with HER2 low/ultra-low/null metastatic breast cancer. (ASCO 2024) - P1, P2 | "If 11 or more responses are observed among 26 patients, the treatment will be regarded as 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 Positive Breast Cancer • Interstitial Lung Disease • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • EZH2 • HER-2 • SLFN11

DS3201-324: A Study of Valemetostat Tosylate in Combination With DXd ADCs in Subjects With Solid Tumors (clinicaltrials.gov) - P1 | N=210 | Active, not recruiting | Sponsor: Daiichi Sankyo | N=98 ➔ 210

Enrollment change • Breast Cancer • Gastric Cancer • HER2 Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2

Therapeutic Effects of Inhibitors to Putative DTP-associated Pathways in EGFR-mutant Lung Cancer PDX Models (IASLC-WCLC 2026) - "Our goal is to assess the efficacy of inhibitors targeting these DTP markers in osimertinib (osi)-induced DTPs of EGFR -mutant PDX models. Methods : DTPs were induced in PDX models with EGFR ex19del (PHLC137) by oral gavage with osi (25 mg/kg QD) and osi combination treatment with bemcentinib (AXL inhibitor, 50 mg/kg BID), BI-847325 (AURK inhibitor, 10 mg/kg QD), valemetostat (EZH1/2 inhibitor, 100 mg/kg QD), tazemetostat (EZH2 inhibitor, 500mg/kg QD), or selinexor (XPO1 inhibitor, 10 mg/kg QD)...Conclusions : In patient-derived models, AXL pathway and epigenetic regulators may represent additional vulnerabilities in osi-induced DTPs. However, despite delay in regrowth, all single agent combination treatments with osi did not achieve complete eradication of the DTP cells, suggesting that multiple combinatorial strategies may be required to overcome DTPs."

IO biomarker • Lung Cancer • Oncology • Solid Tumor • EGFR • EZH2

An Open-Label, Single-Arm, Phase 2 Trial of Valemetostat in Relapsed or Refractory Adult T-Cell Leukemia/Lymphoma. (PubMed, Blood) - P2 | "Twenty-five patients (median age, 69.0) with a median of 3 prior lines of therapy were enrolled; 24 had prior mogamulizumab treatment. Grade ≥3 TEAEs included thrombocytopenia, anemia, lymphopenia, leukopenia, and neutropenia. Valemetostat demonstrated promising efficacy and tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL."

Journal • P2 data • Adult T-Cell Leukemia-Lymphoma • Alopecia • Hematological Disorders • Hematological Malignancies • Leukemia • Leukopenia • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Thrombocytopenia • EZH2

VALEMETOSTAT MONOTHERAPY IN PATIENTS WITH RELAPSED OR REFRACTORY PERIPHERAL T-CELL LYMPHOMAS: EFFICACY BY PRIOR LINES OF TREATMENT AND LAST TREATMENT OUTCOME FROM THE VALENTINE-PTCL01 STUDY (EHA 2024) - P2 | " Pts were ≥ 18 years of age, had a confirmed diagnosis of PTCL, and had R/R disease after ≥ 1 prior line ofsystemic therapy, including prior brentuximab vedotin for pts with anaplastic large cell lymphoma. Valemetostat 200 mg/day demonstrated tolerability and a high and durable response in pts with R/R PTCL. Responses trended higher in pts with fewer prior LOT and in pts that relapsed following their last treatment vspts that were refractory. Overall, results from the VALENTINE-PTCL01 study suggest that valemetostat providesa clinically meaningful benefit for pts with R/R PTCL."

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

Precision diagnostics in prostate cancer treatment (PREDICT): A phase 2 multi-arm biomarker-based study (Alliance A032102). (ASCO-GU 2026) - P2 | "Patients with RB1 loss (DNA), an RB functional loss signature (RNA), or an NEPC signature (RNA) will receive the EZH1/2 inhibitor valemetostat; those with ≥2 of 3 tumor suppressor gene alterations (TP53, RB1, PTEN), FANC alterations (DNA), or SLFN11 overexpression (RNA) will receive cabazitaxel plus carboplatin; and those without study-defined alterations will receive physician's choice of cabazitaxel, ARPI, or 177Lu-PSMA-617. The design permits incorporation of additional biomarker-defined arms, and up to 158 patients per arm (64 with measurable and 94 with non-measurable disease) will be accrued under a Simon two-stage minimax design, providing a one-sided type I error of 0.05 if the true response rate is 0.20 and 90% power if the response rate is 0.37 (Clinical trial information: NCT06632977)"

Biomarker • P2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • EZH2 • PTEN • RB1 • SLFN11 • TP53

Valemetostat and trastuzumab deruxtecan (T-DXd) in previously treated advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive gastric or gastro-esophageal junction (GEJ) adenocarcinoma (ESMO-GI 2024) - P1 | "Secondary endpoints include response duration, progression-free and overall survival, pharmacokinetics, and HER2 expression by IHC and ISH with clinical response. An interim futility analysis will be performed when 20 patients are enrolled with ≥ 6 months of follow-up."

Metastases • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Oncology • EZH2 • HER-2

Valemetostat and trastuzumab deruxtecan (T-DXd) in previously treated advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive gastric cancer or gastro-esophageal junction (GEJ) adenocarcinoma. (ASCO-GI 2025) - P1 | "Secondary endpoints include response duration, progression-free and overall survival, pharmacokinetics, and HER2 expression by immunohistochemistry and in situ hybridization with clinical response. An interim futility analysis will be performed when 20 patients are enrolled with ≥ 6 months of follow-up."

Metastases • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • EZH2 • HER-2

DS3201, an EZH1/2 inhibitor, with ipilimumab in patients with refractory genitourinary tumors (ESMO 2025) - P1 | "Conclusions DS3201 combined with ipilimumab was well tolerated and showed activity in heavily pretreated patients with refractory genitourinary tumors. Correlative analyses suggest immune activation and remodeling of the tumor microenvironment in those with benefit, supporting further investigation of EZH1/2 blockade in combination immunotherapy."

Clinical • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer • CD8 • EZH2 • PTEN • RB1 • TP53

From design to clinic: Medicinal chemistry and pharmacology of approved epigenetic drugs. (PubMed, Eur J Med Chem) - "This review explores the ten epigenetic drugs that have attained worldwide regulatory approval for human therapy: the DNA methyltransferase inhibitors azacitidine (2004) and decitabine (2006), the histone deacetylase inhibitors vorinostat (2006), romidepsin (2009), belinostat (2014), panobinostat (2015) tucidinostat (2015) and givinostat (2024), and the histone methyltransferase inhibitors tazemetostat (2020) and valemetostat (2022). The history and strategy of their discovery and development, their biological targets and mechanisms of action and their therapeutic use. In addition, current advancements and efforts, as well as future perspectives in the design and clinical approval of new epigenetic drugs are discussed."

Journal • Review • Oncology

KEYNOTE-F85: A Study of Valemetostat Tosylate Plus Pembrolizumab Versus Pembrolizumab Alone in First-Line NSCLC Without Actionable Genomic Alterations (clinicaltrials.gov) - P1/2 | N=137 | Active, not recruiting | Sponsor: Daiichi Sankyo | Recruiting ➔ Active, not recruiting

Enrollment closed • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • EGFR • KRAS • PD-L1 • ROS1

DS3201-324: A Study of Valemetostat Tosylate in Combination With DXd ADCs in Subjects With Solid Tumors (clinicaltrials.gov) - P1 | N=98 | Active, not recruiting | Sponsor: Daiichi Sankyo | Recruiting ➔ Active, not recruiting | N=210 ➔ 98

Enrollment change • Enrollment closed • Breast Cancer • Gastric Cancer • HER2 Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2

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: Feb 2027 ➔ Aug 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

Beyond Romidepsin: Novel Therapeutic Targets and Emerging Strategies for Relapsed and Refractory Peripheral T-Cell Lymphoma. (PubMed, Clin Lymphoma Myeloma Leuk) - "Following romidepsin's withdrawal from the R/R PTCL indication in 2021, the only FDA-approved agents are belinostat and pralatrexate, and Brentuximab Vedotin...EZH2 inhibitors represent a mechanistically novel class: valemetostat produced an ORR of 43.7% with a median duration of response of 11.9 months. JAK/STAT inhibitors, including golidocitinib (ORR 44.3%) and cerdulatinib (ORR 51.9% in AITL/TFH), show subtype-selective activity. Rational combinations yield superior efficacy: duvelisib plus romidepsin achieved ORR of 56% (CR 44%), while azacitidine combined with romidepsin produced ORR of 61% (CR 48%), particularly in TFH-phenotype disease (ORR 80%)...The Ro-CHOP trial's failure in unselected populations, contrasted with efficacy signals in nTFHL subsets, underscores a critical lesson: PTCL is not one disease, and future trial designs must incorporate biomarker-driven enrichment strategies to advance precision therapeutics. Improved outcomes can be expected..."

Journal • Review • Gene Therapies • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • DNMT3A • KLRD1 • RHOA • TET2

A Phase 1/2, Open-label Study of Valemetostat in Combination With Rituximab and Lenalidomide in Relapsed or Refractory Follicular Lymphoma (clinicaltrials.gov) - P1/2 | N=16 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Active, not recruiting | N=60 ➔ 16

Enrollment change • Enrollment closed • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology

HUMANIZED PDX MODELS REVEAL DRUG-REVERSIBLE EPIGENETIC IMMUNE EXCLUSION GOVERNING THERAPY OUTCOME IN DLBCL, ALLOWING PATIENTS STRATIFICATION. (EHA 2026) - "ID/REPIX-high patients displayed significantly worse outcomes following both R-CHOP-(p<0.0001) and CAR-19 (p=0.002) treatment, compared to IR/REPIX-low patients...Valemetostat and Lenalidomide treatments were associated with improved CAR-T cell killing, both in-vitro and in-vivo...Humanized PDX accurately reflect DLBCL physiopathology and immune-host interactions, providing a platform for validating next- generation immunotherapies. Epigenetic therapies reprogram REPIX-high/ID- into REPIX-low/IR-DLBCL, overcoming immune refractoriness and enhancing T-cell infiltration and tumor immunorecognition."

Clinical • IO biomarker • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Gene Therapies • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • CD34 • IFNG

EZH1/2 inhibition improves immunotherapy response through MHC Class II de-repression and neutrophil reprogramming. (PubMed, bioRxiv) - "MHC Class II blockade lowered the ability of bone marrow to boost tumor growth, and reduced the ability of valemetostat with anti-PD1 to reduce tumoroid growth. Patient samples revealed a strong negative correlation between EZH2 and MHC Class II, suggesting that targeting EZH2 activity could lead to marked increase in MHC Class II and improve treatment responses in lung squamous cell carcinomas."

Journal • Hematological Malignancies • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • CD8 • EZH2 • HLA-DRB1

The Role of EZH2 ın Malıgnant Pleural Mesothelıoma and Beyond: Current Practıce and Future Perspectıves. (PubMed, Curr Oncol Rep) - "For nearly twenty years, platinum-pemetrexed chemotherapy has persisted as the unchanged standard treatment; although recent progress in immunotherapy has modestly disrupted this therapeutic plateau, survival outcomes remain disappointingly limited...Preclinical and early clinical data demonstrate that EZH2 inhibitors-including tazemetostat, valemetostat, GSK126, EPZ011989, tulmimetostat, and novel PROTAC-based degraders such as MS1943-can suppress tumor progression, modulate the tumor immune microenvironment, and restore therapeutic sensitivity...Further understanding the dual canonical and non-canonical roles of EZH2 in tumor biology will be key to optimizing targeted and combinatorial treatment strategies. Future research should focus on translating EZH2 inhibition into clinical benefit, identifying predictive biomarkers of response, and exploring rational combinations with chemotherapy, targeted drugs, or immunotherapy to improve survival outcomes in mesothelioma..."

IO biomarker • Journal • Review • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • Targeted Protein Degradation • BAP1 • EZH2

The role of EZH2 dysregulation in the pathogenesis of B-cell lymphomas and its implications as a target therapy. (PubMed, Front Oncol) - "Valemetostat, which inhibits EZH1/2, as well as tazemetostat in combination with other drugs have been subject of recent research. The purpose of this article is to review the role of EZH2 in normal B cell differentiation and in the pathogenesis of B-Cell lymphomas."

IO biomarker • Journal • Review • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Gene Therapies • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • EZH2

Histone-Modifying Enzymes in Androgen-Deprived Prostate Cancer: EZH1 as a Synergistic Therapeutic Target (AUA 2026) - "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."

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

Valemetostat is efficacious against recurrent adult T-cell leukemia/lymphoma skin lesions and cutaneous GVHD. (PubMed, Transplant Cell Ther) - No abstract available

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