Valemetostat

Shows activity

Cancer types include:

breast cancer liver cancer small cell lung cancer

HealthScout AI Analysis

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Overview

Valemetostat (valemetostat tosilate; DS-3201) is an oral, first-in-class dual inhibitor of EZH1 and EZH2 histone methyltransferases being developed for hematologic malignancies and some solid tumors. It received its first regulatory approval in Japan (September 2022) for relapsed/refractory adult T‑cell leukemia/lymphoma (ATL). Clinical development includes monotherapy in ATL and peripheral T‑cell lymphoma (PTCL), as well as early combination studies in solid tumors. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

Target: EZH1 and EZH2 catalytic subunits of Polycomb Repressive Complex 2 (PRC2), which catalyze H3K27 trimethylation (H3K27me3), a repressive chromatin mark. Dual inhibition aims to prevent compensatory activity when only EZH2 is blocked. (pubmed.ncbi.nlm.nih.gov)
Pharmacodynamic effect: Reduces H3K27me3 and de-represses tumor suppressor gene programs; single-cell analyses from clinical samples in ATL describe chromatin decondensation and transcriptional reactivation as on‑mechanism effects. (pubmed.ncbi.nlm.nih.gov)

Efficacy

Adult T‑cell leukemia/lymphoma (ATL) - Open-label, single‑arm phase 2 (Japan; N=25; heavily pretreated): Valemetostat 200 mg once daily achieved an overall response rate (ORR) of 48.0% (90% CI, 30.5–65.9), including 20% complete responses (CRs). Median duration of response (DoR) was not reached at the time of reporting. Responses were observed even after prior mogamulizumab. (pubmed.ncbi.nlm.nih.gov)

Peripheral T‑cell lymphoma (PTCL) - VALENTINE‑PTCL01, multicenter, open‑label phase 2 (12 countries): Among 119 efficacy‑evaluable patients with relapsed/refractory PTCL receiving valemetostat 200 mg daily, ORR was 44% (95% CI, 35–53%) by blinded central review; grade 3–4 cytopenias were the most common severe AEs. Median follow‑up was 12.3 months. Published results support durable responses (median DoR 11.9 months reported in study summaries). (pubmed.ncbi.nlm.nih.gov)

Exploratory in solid tumors (example) - Recurrent small‑cell lung cancer (SCLC), phase I/II combination with irinotecan (N=21 evaluable): Recommended dose selected was 100 mg daily; ORR was 21% (4/19), median PFS 2.2 months, and the combination was not well tolerated, triggering an early stopping rule in phase II. (pubmed.ncbi.nlm.nih.gov)

Safety

Across ATL and PTCL monotherapy trials, the most frequent treatment‑emergent adverse events (TEAEs) include hematologic and low‑grade non‑hematologic toxicities: - Common TEAEs (≥20%): thrombocytopenia, anemia, neutropenia/lymphopenia, alopecia, dysgeusia, decreased appetite, pyrexia. In the ATL phase 2, grade ≥3 events most often were thrombocytopenia, anemia, and leukopenia/neutropenia. (pubmed.ncbi.nlm.nih.gov) - In VALENTINE‑PTCL01, grade 3–4 AEs in PTCL patients included thrombocytopenia (23%), anemia (19%), and neutropenia (17%); serious treatment‑emergent AEs occurred in 40% of PTCL patients, with no treatment‑related deaths reported. (pubmed.ncbi.nlm.nih.gov) - In the SCLC irinotecan combination study, gastrointestinal and constitutional AEs (diarrhea, fatigue, nausea, rash) were frequent; tolerability issues limited further development of that specific combination. (pubmed.ncbi.nlm.nih.gov)

Active trials using Valemetostat

Found 3 active trials using this drug:

A Phase Ib/II, Dose Escalation and Dose Expansion Study of Valemetostat Tosylate (DS-3201b) With Atezolizumab and Bevacizumab in Advanced Hepatocellular Carcinoma (HCC)

Sponsor: University of Alabama at Birmingham (other) Phase: 1/2 Start date: July 29, 2025

HealthScout AI summary: Previously untreated adults with unresectable/advanced HCC (Child-Pugh A, BCLC B not eligible for liver-directed therapy or C, ECOG 0–1) receive valemetostat (oral dual EZH1/EZH2 inhibitor) combined with atezolizumab and bevacizumab on 21-day cycles. Excludes high bleeding risk (e.g., untreated/high-risk varices), active autoimmune disease requiring systemic therapy, uncontrolled HBV/HCV, and prior EZH inhibitor exposure.

ClinicalTrials.gov ID: NCT06294548

Phase I Study of Valemetostat and Atezolizumab as Maintenance Therapy for Patients With Extensive-Stage Small Cell Lung Cancer

Sponsor: Memorial Sloan Kettering Cancer Center (other) Phase: 1 Start date: Jan. 29, 2025

HealthScout AI summary: Adults with newly diagnosed extensive-stage SCLC who have SD/PR/CR after 4 cycles of platinum doublet plus atezolizumab start maintenance atezolizumab (standard dosing) combined with oral valemetostat, an investigational dual EZH1/EZH2 inhibitor targeting H3K27me3 to suppress tumor proliferation. Key allowances include treated, controlled brain mets; key exclusions include recent consolidative chest RT, significant cardiac comorbidities/QTc prolongation, active infections, strong CYP3A modulators, and prior EZH inhibitor use.

ClinicalTrials.gov ID: NCT06807632

Phase 1b Study of EZH1/2 Inhibitor Valemetostat in Combination With Trastuzumab Deruxtecan in Subjects With HER2 Low/Ultra-low/Null Metastatic Breast Cancer

Sponsor: M.D. Anderson Cancer Center (other) Phase: 1 Start date: Feb. 9, 2023

HealthScout AI summary: Adults with metastatic or locally advanced HER2 low, ultra-low, or null breast cancer (IHC 1+/2+/0, ISH-) who have progressed on prior endocrine therapy (if HR+) and at least one line of chemotherapy receive valemetostat, an oral dual EZH1/2 histone methyltransferase inhibitor, in combination with trastuzumab deruxtecan. Prior anti-HER2 therapy (including T-DXd and EZH inhibitors) is not allowed.

ClinicalTrials.gov ID: NCT05633979