Ezharmia (valemetostat) / Daiichi Sankyo - LARVOL DELTA

Rinzimetostat, an allosteric EED inhibitor with best-in-class properties for the treatment of prostate cancer, is effective in PRC2 methyltransferase-resistant settings in preclinical studies (AACR 2026) - P1 | "As predicted from drug binding sites, EZH2 Y666N mutant-expressing prostate cancer cells were impervious to H3K27me3 reduction by EZH2 inhibitors mevrometostat or tazemetostat; however, rinzimetostat inhibited H3K27me3 in EZH2 Y666N mutant cells.Cells engineered with an EZH1/2 inhibitor acquired resistance mutant, EED H213R, demonstrated loss of effectiveness upon treatment with EZH1/2 inhibitor valemetostat, whereas rinzimetostat equally inhibited H3K27me3 in the EED mutant and wildtype settings. Together, these data suggest that rinzimetostat, as an EED inhibitor, has the potential for superiority in EZH2 and EZH1/2 inhibitor-acquired resistance contexts.In summary, preclinical results demonstrate potential best-in-class drug properties of rinzimetostat, as well as the potential superiority of targeting EED to address paralog compensation and avoid acquired resistance mechanisms that may be liabilities for EZH2 or EZH1/2 inhibitors. Rinzimetostat is under clinical..."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • EZH2 • SUZ12

Histone-modifying enzymes in androgen-deprived prostate cancer: EZH1 as a synergistic therapeutic target (AACR 2026) - "ADT induces EZH1 upregulation, which promotes prostate cancer cell persistence potentially through regulation of cancer 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 • EZH2 • KDM6B • MECOM • SIRT1

Combining PRC2 inhibitors with metronomic chemotherapy: A promising therapeutic strategy for diffuse large B-cell lymphoma (AACR 2026) - "In vitro proliferation assays were performed on both EZH2Y641F mutant (SU-DHL10) and EZH2 wild-type (OCI-LY3, Toledo) DLBCL cell lines exposed to thrice-weekly vinorelbine (mVNR) and daily PRC2 inhibitors (PRC2i: tazemetostat, valemetostat, ORIC-944), alone and in concomitant combination, for 144h. These findings offer a solid rationale for combining PRC2i and mCHEMO as an encouraging therapeutic approach for DLBCL, particularly in elderly or fragile patients, due to their low toxicity profiles. Overall, these results warrant additional in vitro investigations to elucidate the mechanisms underlying the reported effects and in vivo experiments in DLBCL models to validate our new therapeutic strategy, which holds potential for rapid translation into future clinical trials."

IO biomarker • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • EZH2

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."

Checkpoint inhibition • Journal • Dermatology • Follicular Lymphoma • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Immunology • Lymphoma • Oncology • CD8 • EZH2

Safety of valemetostat and pembrolizumab in advanced or metastatic 1L NSCLC without actionable genomic alterations expressing PD-L1 with TPS = 50%: Interim results from the phase Ib trial (ELCC 2026) - P1/2 | "There were no dose-limiting toxicities, AESIs (combined elevations of aminotransferases and bilirubin, and secondary malignancy), or TEAEs that led to Tx discontinuation.Conclusions The combination of Vale 150–300 mg/day and fixed-dose Pembro 200 mg Q3W was well-tolerated in pts with advanced/metastatic 1L NSCLC expressing PD-L1 with TPS ≥50% and no AGAs. The RP2D of the phase Ib part is yet to be determined."

Clinical • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • CD4 • CD8 • PD-L1

DS3201-330: A Study of Valemetostat Tosylate Plus Pembrolizumab versus Pembrolizumab Alone in First-Line NSCLC Without Actionable Genomic Alterations (clinicaltrialsregister.eu) - P1/2 | N=21 | Completed | Sponsor: Daiichi Sankyo Inc.

New P1/2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • EGFR • KRAS • NTRK • PD-L1 • ROS1

DS3201-343: Phase 1 trial of valemetostat and darolutamide in mCRPC (clinicaltrialsregister.eu) - P1 | N=4 | Not yet recruiting | Sponsor: Daiichi Sankyo Inc.

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

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."

Journal • Retrospective data • Adult T-Cell Leukemia-Lymphoma • Bone Marrow Transplantation • Cardiovascular • Cytomegalovirus Infection • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Thrombocytopenia • Transplantation • IL2

Current Practice and Research in T-cell and NK/T-cell Lymphoma in Japan (ICKSH 2026) - "For patients with major subtypes of peripheral T -cell lymphoma (PTCL), including PTCL not otherwise specified, angioimmunoblastic T -cell lymphoma (AITL), and anaplastic large cell lymphoma, the 2024 Japanese Society of Hematology (JSH) guidelines recommend the use of brentuximab vedotin (BV) -CHP for CD30 -positive tumors and CHOP -like regimens for CD30 -negative tumors as the first -line treatment...For patients with relapsed /refractory T-cell and NK/T -cell lymphoma, many therapeutic drugs (mogamulizumab, BV , pralatrexate, forodesine, romidepsin, alectinib, denileukin diftitox, tucidinostat, darinaparsin, and valemetostat) are approved and available in Japan...However, among immune checkpoint inhibitors, only atezolizumab was approved for the treatment of ENKL in 2025, and little experience is available with its use. Patients with ENKL in Japan account for less than 1% of all lymphoma patients, which is as low as in Western countries. To fill these gaps, an..."

Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Natural Killer/T-cell Lymphoma • Non-Hodgkin’s Lymphoma • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • TNFRSF8

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

EZHiSWITCH: Efficacy and Safety of the Valemetostat in Patients With Selected Solid Tumors. (clinicaltrials.gov) - P2 | N=900 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris | Not yet recruiting ➔ Recruiting

Enrollment open • Oncology • Ovarian Cancer • Peripheral T-cell Lymphoma • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • ARID1A • BAP1 • EZH2 • PBRM1 • SMARCA2 • SMARCB1

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. (clinicaltrialsregister.eu) - P1/2 | N=600 | Not yet recruiting | Sponsor: Institut Gustave Roussy

New P1/2 trial • Oncology • Ovarian Cancer • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • ARID1A • BAP1 • EZH2 • PBRM1 • SMARCA2 • SMARCB1

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."

IO biomarker • Journal • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • EZH2 • HLA-B • SLFN11

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 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

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

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

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

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 | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Active, not recruiting | N=37 ➔ 17

Enrollment change • Enrollment closed • Breast Cancer • Oncology • Solid Tumor • HER-2 • UGT1A1

Daiichi Sankyo Receives Prime Minister’s Award for Japan Medical Research and Development Grand Prize (Daiichi Sankyo Press Release) - "This year’s award highlights an important industry, government and academia collaboration in Japan, showcasing Dr. Yamagishi’s pioneering research demonstrating that epigenetic abnormalities, specifically excessive methylation of histones by the histone methyltransferases EZH1 and EZH2 play a critical role in the onset and progression of T‑cell lymphomas, as well as recognizing Daiichi Sankyo for the company’s involvement in the development of EZHARMIA, the first dual EZH1 and EZH2 inhibitor approved worldwide for the treatment of relapsed or refractory adult T‑cell leukemia/lymphoma (ATLL) and peripheral T‑cell lymphoma (PTCL)."

Commercial • Adult T-Cell Leukemia-Lymphoma • Peripheral T-cell Lymphoma

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 | "This study was activated in July 2025. Clinical trial information: NCT06294548."

IO biomarker • Metastases • P1/2 data • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CD8 • EZH2

Response to 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

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

Enrollment open • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

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."

Journal • Review • Acute Myelogenous Leukemia • 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 • Targeted Protein Degradation • BCOR • BMI1 • CREBBP • EZH2 • KMT2D • SUZ12