Ezharmia (valemetostat)

P1/2, N=22, Terminated, Memorial Sloan Kettering Cancer Center | Completed --> Terminated; Due to DLTs

P1, N=140, Recruiting, Daiichi Sankyo | Trial completion date: Feb 2029 --> Nov 2028 | Trial primary completion date: Feb 2029 --> Nov 2028

In a recent publication, Yamagishi et al. explore how responses of a patient with adult T-cell leukemia/lymphoma to valemetostat, an EZH1/2 inhibitor, are associated with changes in H3K27me3, chromatin accessibility and gene expression, and how these changes can be circumvented in relapsed disease.

P2, N=148, Active, not recruiting, Daiichi Sankyo | Trial completion date: Sep 2025 --> Apr 2028

P1, N=140, Recruiting, Daiichi Sankyo | Not yet recruiting --> Recruiting

In this study, we used DNA or histone demethylating agents, 5-Azacytidine (5-AZA) or DS-3201 (valemetostat), respectively, to treat primary effusion lymphoma (PEL) cells, alone or in combination with AG490, a Signal transducer and activator of transcription 3 (STAT3) inhibitor. Differently from 5-AZA, the inhibition of the EZH1/2 histone methyltransferase by DS-3201, reported to contribute to STAT3 activation in other cancers, slightly affected STAT3 phosphorylation or survival in PEL cells, either alone or in combination with AG490. This study suggests that 5-AZA, by upregulating the expression level of SOCS3 and PTPN6/SHP1, reduced STAT3 activation and improved the outcome of treatment targeting this transcription factor in PEL cells.

P2, N=141, Active, not recruiting, The Lymphoma Academic Research Organisation | Recruiting --> Active, not recruiting | Trial completion date: Jun 2024 --> Oct 2024 | Trial primary completion date: Jun 2024 --> Oct 2024

P1/2, N=45, Not yet recruiting, University of Alabama at Birmingham

Here we show the potency and mechanisms of action and resistance of the EZH1-EZH2 dual inhibitor valemetostat in clinical trials of patients with adult T cell leukaemia/lymphoma...We identified subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. Targeting epigenetic drivers and chromatin homeostasis may provide opportunities for further sustained epigenetic cancer therapies.

P1, N=140, Not yet recruiting, Daiichi Sankyo, Inc.

Focusing on mutated SMARCA4 as the therapeutic target, growth inhibition assays showed a strong response to the CDK4/6 inhibitor palbociclib, but much less to the EZH1/2 inhibitor valemetostat. In conclusion, cell line TCS627 carries both histologic and genetic features characteristic of TCS and is a valuable model for both basic research and preclinical testing of new therapeutic options for treatment of TCS patients.

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.

P1; Phase classification: P1b --> P1

No treatment-related or grade ≥3 adverse events were reported. Appropriate valemetostat dose reductions are warranted when used concomitantly with strong CYP3A and P-gp dual inhibitors.

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%. Contact information for people with a specific interest in the trial sdamodaran@mdanderson.org (NCT05633979)

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.

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.

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.

One patient with TP63-rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.

Recently, novel agents, including mogamulizumab, lenalidomide, brentuximab vedotin, tucidinostat and valemetostat, have been approved for patients with relapsed or refractory aggressive adult T-cell leukemia-lymphoma, and the combination of mogamulizumab with multi-agent chemotherapy or brentuximab vedotin with cyclophosphamide, doxorubicin and prednisone has been approved for patients with untreated aggressive adult T-cell leukemia-lymphoma in Japan. Importantly, the aging of patients with adult T-cell leukemia-lymphoma has recently been reported, and no standard of care for elderly patients with adult T-cell leukemia-lymphoma has been established. New evidence must be obtained from prospective clinical trials to improve the prognosis of patients with adult T-cell leukemia-lymphoma.

Valemetostat was well tolerated in healthy subjects; treatment-emergent adverse events were mild (grade 1) in severity. Based on these trials, the tablet formulation of valemetostat is suitable for use in subsequent clinical trials and should be administered under fasted conditions to avoid a negative food effect.

This study focuses on recent topics on the development of innovative therapies and the identification of prognostic indicators, considering the recent elucidation of the pathogenesisof ATL. Specifically, this study also delineates the advancements in developing novel EZH1/2 inhibitors and comprehensive genetic analysis; the molecular pathogenesis determined through comprehensive gene knockdown and knockout techniques, with its potential as a therapeutic target; the latest discoveries from the analysis of super-enhancer regions; and the prognostic factors extracted from comprehensive genetic analysis.

Next, using an assay system that utilizes the spontaneous proliferation characteristic of peripheral blood mononuclear cells derived from patients with HAM (HAM-PBMCs), we investigated the effects of EZH2 selective inhibitors (GSK126 and tazemetostat) and EZH1/2 dual inhibitors (OR-S1 and valemetostat, also known as DS-3201), particularly on cell proliferation rate, cytokine production, and HTLV-1 proviral load. This study showed that EZH1/2 inhibitors suppress HTLV-1-infected cell proliferation through apoptosis and the hyperimmune response in HAM. This indicates that EZH1/2 inhibitors may be effective in treating HAM.

Do we require an autologous stem cell transplantation in all patients? Is there room for improvement in the setting of relapsed and refractory disease?

P1/2; N=40; Not yet recruiting; Sponsor:National Cancer Institute (NCI)

P2, N=148, Active, not recruiting, Daiichi Sankyo, Inc. | Trial completion date: Mar 2026 --> Sep 2025 | Trial primary completion date: Dec 2023 --> May 2023

P1/2, N=60, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

P1/2, N=22, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Mar 2024 --> May 2023 | Trial primary completion date: Mar 2024 --> May 2023

P1, N=80, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Jan 2023 --> Apr 2024 | Trial primary completion date: Jan 2023 --> Apr 2024

P1/2, N=22, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Mar 2023 --> Mar 2024 | Trial primary completion date: Mar 2023 --> Mar 2024

The effective CI of ONC206 plus tazemetostat and panobinostat ranges 0.27-0.77 in U251 GBM and 0.11-0.71 in SU-DIPG-13 DMG cells...The effective CI of ONC212 plus valemetostat ranges 0.33-0.83 in 22Rv1...The synergies between ONC201 and EZH1/2 or HDAC inhibitors provide clues for developing novel therapy for the mentioned tumors. Overexpression of EZH2 is in process to elucidate the role of EZH2 in the mechanism of the anti-cancer effect of ONC201.

P1b; Not yet recruiting --> Recruiting | Initiation date: May 2023 --> Feb 2023

P1/2, N=60, Not yet recruiting, M.D. Anderson Cancer Center

Here, we investigated the effect of combination treatment with DNA demethylating agents (azacytidine (AZA), decitabine (DAC), and OR-2100 (OR21), which is silylated derivative of decitabine) and inhibitors of enhancer of zeste homolog 2 (EZH2) (EPZ-6438 and DS-3201b) which catalyze trimethylation of H3K27, in ATL. DUSP5 was downregulated by DNA methylation and H3K27me3 accumulation in the promoter region in HTLV-1-infected cells from ATL patients during ATL leukemogenesis. The present results demonstrate that dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth by restoring DUSP5, and the dual targeting of aberrant DNA and histone methylation is a feasible therapeutic approach for ATL.

P1b; N=37; Not yet recruiting; Sponsor:M.D. Anderson Cancer Center

Valemetostat was approved in Japan in September 2022 for the treatment of patients with relapsed or refractory adult T-cell leukaemia/lymphoma (R/R ATL), a subtype of NHL. This article summarizes the milestones in the development of valemetostat leading to this first approval for R/R ATL.

Current therapy for aggressive type ATL is still unsatisfactory and prognosis of relapsed and refractory (r/r) ATL after lenalidomide or mogamulizumab treatment is poor. Valemetostat significantly reduced markers of ATL progression. Ably and sIL-2R to very low levels in all patients. In contrast, PVL assay did not exhibit complete %PVL reduction.