Ezharmia (valemetostat) / Daiichi Sankyo - LARVOL DELTA

Reduced EZH1/2 expression in imipridone-treated cells correlates with synergy following combinations with EZH1/2 or HDAC inhibitors in diffuse glioma and other tumors. (PubMed, Am J Cancer Res) - "Small molecule imipridones including ONC201, ONC206 and ONC212 have anti-cancer activity mediated in part through the integrated stress response, induction of TRAIL and its receptor DR5, and activation of mitochondrial caseinolytic protease ClpP with impaired oxidative phosphorylation...RNA-seq showed ONC201 and EHZ2i tazemetostat-treated cells have similar transcriptional profiles and share overlap of top regulated genes...ONC201 and EZH2i share similar targets and actions on tumors. Synergistic combinations of imipridones plus EZH1/2i or imipridones, EZH2i and HDACi merit further investigation."

Journal • Brain Cancer • Breast Cancer • CNS Tumor • Gastric Cancer • Gene Therapies • Genito-urinary Cancer • Glioma • Lung Cancer • Oncology • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • EZH2

Safety and efficacy of the EZH1/2 inhibitor valemetostat tosylate (DS-3201b) in pediatric patients with malignant solid tumors (NCCH1904): A multicenter phase I trial. (ASCO 2025) - "Clinical Trial Registration Number: jRCT2031190268 The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • P1 data • Oncology • Pediatrics • Solid Tumor • EZH2

Enhancing TIL efficacy in NSCLC through epigenetic reprogramming and computational modeling (AACR 2025) - "Thus, we further hypothesize that modern sequencing data and mathematical biology can discover alternative mechanisms of T cell suppression that will suggest novel targets for TIL-combination treatment.To test these hypotheses, we have tested the EZH2 inhibitor valemetostat with anti-PD1 in a murine model of non-small cell lung cancer...Our blending of classic bench science with bio-informatics has the potential to deepen our understanding of TIL therapy and to identify new way to improve therapeutic responses. Funding: T32 CA165990 (DRP), R01 CA237643 (CFB), R01 HL170193 (CFB), P30 CA177558 (Markey Shared Resources)."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IFNG • IL2

Targeting heterogeneity to improve non-small cell lung cancer treatments (AACR 2025) - "Using a syngeneic lung cancer model, we observed that the EZH2 inhibitor valemetostat combined with anti-PD1 immunotherapy drives tumor regression, increased activated T cells and increased antigen expression on the tumor cells...Our previous studies showed that dietary MR improved carboplatin response and slowed tumor progression in an aggressive KRAS/Lkb1 mouse model1...Together these studies show that modulating EZH2 or methionine levels in NSCLC are effective ways to increase treatment efficacy. We also demonstrate use of cutting edge "multi-culture" experiments that can successfully model in vivo environments to better predict cancer response to treatment."

Heterogeneity • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD8 • KRAS • STK11

Drug screens identify new therapeutic targets that synergize with EZH1/2 inhibition in adult T-cell leukemia/lymphoma (AACR 2025) - "In light of these mechanisms, a phase II clinical trial evaluated the efficacy of Valemetostat (VAL), a dual EZH1/2 inhibitor, in ATLL patients...Finally, we tested these nine hits in 6x6 combination matrices to precisely determine the optimal dosing with VAL.Currently, we are expanding our validation across additional ATLL cell lines and optimizing dosage schedules for in vivo testing on our established ATLL models to ensure synergistic effective.This research aims to identify novel targets that will sensitize resistant ATLL to epigenetic therapies. These findings may contribute to developing strategies to address drug resistance and offer additional treatment opportunities for this difficult-to-treat disease."

Clinical • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • EZH2

Targeting mesenchymal cells with epigenetic therapy in lung cancer and lung disease (AACR 2025) - "Several EZH2 inhibitors (tazemetostat and valemetostat) provide a reliable and therapeutically tolerable treatment option for diseased patients...In vivo, we have observed that EZH2 inhibition attenuates the fibrosis that occurs after exposure to bleomycin...Our preliminary results suggest that EZH2 inhibition can alter cells to be more susceptible to anti-PD1, and we are now examining the contributions of mesenchymal cells to these phenotypes. Together our results suggest that targeting EZH2 may improve aspects of both pulmonary fibrosis and lung cancer, and be a way to target these co-occurring diseases to improve patient outcomes."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • TGFB1

Exploring epigenetic control of immunogenicity in small cell lung cancer through multi-omics analyses (AACR 2025) - "In SCLC cell lines treated with EZH1/2 dual inhibitor valemetostat, we examine changes in chromatin accessibility (ATAC-seq), three-dimensional chromatin organization (micro-C profile), and gene expression (RNA-seq).Key Findings: Gene set enrichment analysis of RNA-seq data revealed upregulation of genes involved in antigen processing, presentation, and inflammatory response pathways following EZH1/2 dual inhibition in SCLC cell line H146... Our integrative multi-omics approach reveals a comprehensive model of EZH1/2 contribution to SCLC pathogenesis, highlighting its role in chromatin reorganization and gene expression regulation. Future work will focus on identifying additional therapeutically relevant genes within the EZH1/2-regulated network for potential intervention strategies."

Epigenetic controller • Endocrine Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • EZH2 • HLA-B • HLA-C

Preclinical assessment of valemetostat, a dual inhibitor of EZH2 and EZH1, combined with trastuzumab deruxtecan and datopotamab deruxtecan for multiple solid tumors (AACR 2025) - P1 | "Results from in vitro and in vivo analyses suggest that valemetostat potentiates the antitumor effect of DXd-ADCs via multiple cellular mechanisms, including increased expression of SLFN11, neoantigen presenting molecules (eg, MHC), ADC targets (eg, HER2), and reduced expression of genes involved in the DDR. A phase 1b, open-label, Master Protocol trial is currently investigating the clinical safety, tolerability, and preliminary efficacy of valemetostat in combination with T-DXd and Dato-DXd in patients with various solid tumors (NCT06244485)."

Preclinical • Breast Cancer • Gastric Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EZH2 • SLFN11

Pharmacokinetics, metabolism, and excretion of [14C]-valemetostat in healthy male participants, and in vitro plasma protein binding. (PubMed, Cancer Chemother Pharmacol) - "Valemetostat was rapidly absorbed into the systemic circulation, mainly excreted via the biliary/fecal route, primarily metabolized by CYP3A enzymes to CALZ-1809a, and highly bound to plasma proteins, with a greater affinity to AAG than HSA in vitro."

Journal • PK/PD data • Preclinical • EZH2

Targeted Treatment for Metastatic Prostate Cancer, The PREDICT Trial (clinicaltrials.gov) - P2 | N=474 | Recruiting | Sponsor: Alliance for Clinical Trials in Oncology | Not yet recruiting ➔ Recruiting

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

Clinical and therapeutic significance of genetic profiling in adult T-cell leukemia/lymphoma. (PubMed, Leuk Res) - "Furthermore, genetic and epigenetic events influencing response to molecularly targeted therapies, such as mogamulizumab and valemetostat, have also been identified. Collectively, these insights underscore the clinical importance of assessing genetic alterations. This review highlights the latest insights into the genetic landscape of ATLL and their clinical implications, which will facilitate the development of future strategies for targeted and personalized therapy."

IO biomarker • Journal • Review • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • PD-L1 • PRKCB

TOLLIP downregulation by cigarette smoke exposure impairs human lung defense against Influenza A virus infection. (PubMed, Am J Pathol) - "EZH1/2 siRNA or their pharmacological inhibitor valemetostat tosylate in part restored TOLLIP and reduced IAV levels in CS-exposed airway epithelial cells and PCLS. Our findings suggest that repeated CS exposure during viral infection reduced TOLLIP levels and increased viral load in part through EZH1/EZH2-H3K27me3-mediated epigenetic mechanisms. Targeting EZH1 and EZH2 may serve as one of the potential therapeutic strategies to restore TOLLIP expression and host defense against viral infections in COPD patients."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Infectious Disease • Influenza • Pulmonary Disease • Respiratory Diseases • EZH2

Polycomb repressive complex 2 (PRC2) pathway's role in cancer cell plasticity and drug resistance. (PubMed, Funct Integr Genomics) - "Inhibitors like MAK683 and EED226 disrupt EED's ability to maintain PRC2 activity, thereby reducing H3K27me3 levels and reactivating tumor suppressor genes. Valemetostat, a dual inhibitor of both EZH2 and EED, has shown promising results in aggressive cancers like diffuse large B-cell lymphoma and small-cell lung cancer, underlining the therapeutic potential of targeting multiple PRC2 components...Tazemetostat, a selective EZH2 inhibitor, has demonstrated significant clinical efficacy in EZH2-mutant cancers, such as non-Hodgkin lymphomas and epithelioid sarcoma. However, the compensatory function of enhancer of zeste homolog 1 (EZH1) in some cancers requires dual inhibition strategies, as seen with agents like UNC1999 and Tulmimetostat, which target both EZH1 and EZH2. Given PRC2's multifaceted role in cancer biology, its inhibition represents a promising avenue for therapeutic intervention. The continued development of PRC2 inhibitors and exploration of their..."

IO biomarker • Journal • Review • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Genito-urinary Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Sarcoma • Small Cell Lung Cancer • Soft Tissue Sarcoma • Solid Tumor • EZH2

Valemetostat Plus Trastuzumab Deruxtecan (T-DXd) or Datopotamab Deruxtecan (Dato-DXd) in Patients With Solid Tumors (JSMO 2025) - No abstract available

Clinical • Oncology • Solid Tumor

Valemetostat Plus Pembrolizumab in Advanced or Metastatic Non-Small-Cell Lung Cancer Expressing PD-L1 With TPS ≧50% (JSMO 2025) - No abstract available

Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

EZH1/EZH2 inhibition enhances adoptive T cell immunotherapy against multiple cancer models. (PubMed, Cancer Cell) - "In human B cell lymphoma, EZH2 inhibition (tazemetostat) improved the efficacy of anti-CD19 CAR-T by enhancing activation, expansion, and tumor infiltration. Lastly, combined EZH1/EZH2 inhibition (valemetostat) further boosted CAR-T efficacy and expansion in multiple cancers. This study shows that EZH1/2 inhibition reprograms tumors to a more immunogenic state and potentiates ACT in preclinical models of both liquid and solid cancers."

Journal • Preclinical • Acute Myelogenous Leukemia • B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Prostate Cancer • Sarcoma • Solid Tumor • 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

DS3201-A-J201: Valemetostat Tosylate (DS-3201b) Phase 2 Study in Relapsed or Refractory Adult T-cell Leukemia/Lymphoma (clinicaltrials.gov) - P2 | N=25 | Completed | Sponsor: Daiichi Sankyo Co., Ltd. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2025 ➔ Oct 2024

Trial completion • Trial completion date • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

DS3201-A-J101: DS-3201b in Participants With Lymphomas (clinicaltrials.gov) - P1 | N=100 | Active, not recruiting | Sponsor: Daiichi Sankyo Co., Ltd. | Trial completion date: Dec 2024 ➔ Dec 2026

Trial completion date • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Study of Valemetostat in Combination With Atezolizumab in People With Lung Cancer (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center

New P1 trial • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

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

VALYM: Study of Valemetostat Tosylate as a Single Agent in Patients With Relapse/Refractory B-cell Lymphoma (clinicaltrials.gov) - P2 | N=141 | Active, not recruiting | Sponsor: The Lymphoma Academic Research Organisation | Trial completion date: Oct 2024 ➔ Oct 2026

Trial completion date • B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • SLC1A5

Evaluating Valemetostat and Dato-DXd for NSCLC: An Upcoming Trial (YouTube) - "Valemetostat is a novel therapy that's demonstrated clinical efficacy and safety across multiple hematologic malignancies, but what role might it have in treating patients with advanced, unresectable, or metastatic non-squamous non-small cell lung cancer (NSCLC)? To find out, an upcoming trial is examining the efficacy and safety of combining valemetostat and datopotamab deruxtecan (Dato-DXd). Here with Dr. Jacob Sands to talk about the study's design and next steps is Dr. Alex Spira..."

Video

Valemetostat and Trastuzumab Deruxtecan in Patients With HER2-Low, Previously Treated, Unresectable or Metastatic Breast Cancer (SABCS 2024) - P1 | "Preclinical data suggest synergistic effects of valemetostat in combination with T-DXd and datopotamab deruxtecan. The relationship between HER2 expression and clinical response will also be explored. If you have a patient who could potentially be eligible for this trial, please contact Daiichi Sankyo for clinical trial information at DS3201-324SiteCommunications@dsi.com."

Clinical • Metastases • 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 • EZH2 • HER-2 • SLFN11

Continued Progress in Breast Cancer at SABCS (Businesswire) - "...two spotlight poster presentations highlighting the first exploratory biomarker analysis assessing the impact of genomic alterations on the efficacy of ENHERTU compared to ado-trastuzumab emtansine (T-DM1) in patients with HER2 positive metastatic breast cancer from the DESTINY-Breast03 phase 3 trial, and the effects of ENHERTU on health-related quality of life and neurological function from the DESTINY-Breast12 phase 3b/4 trial in patients with previously treated HER2 positive metastatic breast cancer...Final results from the dose expansion portion of the DESTINY-Breast08 phase 1b trial evaluating ENHERTU in combination with capecitabine or capivasertib in patients with HER2 low metastatic breast cancer also will be presented as a poster presentation...Trial-in-progress posters will feature the trial designs from a sub-protocol of a phase 1b master protocol trial evaluating ENHERTU in combination with valemetostat...in patients with....HER2 positive metastatic breast cancer..."

Clinical data • Clinical protocol • HER2 Positive Breast Cancer