Abstract 3790: Preclinical assessment of valemetostat, a dual inhibitor of EZH2 and EZH1, combined with trastuzumab deruxtecan and datopotamab deruxtecan for multiple solid tumors
Authors: Daisuke Honma, Akiko Toyota, Yasuhiro Hama, Yasuki Kamai, Daisuke Okajima, Yoshiyuki Hizukuri, Maiko Narahara, Yuka Yamamoto, Emi Nosaka, Katsuki Usami, Kazumi Sato, Hiroki Goto, Ayumi Tezuka, Ayako Kato, Chisa Wada, Naoya Wada, Megumi Minami, Hideki Kobayashi, Mayumi Kitagawa
Journal: Cancer Research (2025)

Abstract Epigenetic dysregulation contributes to the development and progression of various cancers. Enhancer of zeste homolog (EZH)2 and EZH1 are enzymes that promote trimethylation of histone H3 at lysine 27 (H3K27me3), a repressive transcriptional mark associated with gene silencing. Valemetostat tosylate (valemetostat; DS-3201) is a first-in-class, oral, dual inhibitor of EZH2 and EZH1 that has demonstrated a greater potential to reduce H3K27me3 than EZH2-selective inhibitors and has strong antitumor activity in in vitro and in vivo studies. Dual inhibition of EZH2 and EZH1 could potentially alter the expression of genes involved in drug sensitivity and resistance in cancer cells, making valemetostat a candidate for combination therapies with established agents. This study assessed the preclinical activity of valemetostat combined with trastuzumab deruxtecan (T-DXd; DS-8201), a human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate (ADC), and with datopotamab deruxtecan (Dato-DXd; DS-1062), a trophoblast cell surface antigen 2 (TROP2)-directed ADC. Both T-DXd and Dato-DXd include a plasma-stable, selectively cleavable tetrapeptide-based linker and a topoisomerase I inhibitor payload (DXd, an exatecan derivative). The combined effects of valemetostat with DXd was tested in vitro in breast cancer (BC) and gastric cancer (GC) cell lines. Changes in the expression of various proteins and gene signatures were assessed by Western blot and RNA-sequencing analysis. The combined effects of valemetostat with each DXd-ADC were examined in in vivo mouse models bearing BC, GC, and non-small-cell lung cancer (NSCLC) tumors. In vitro, valemetostat enhanced cell-killing activities of the DXd payload in BC and GC cells in a concentration-dependent manner. Valemetostat upregulated the expression of Schlafen 11 (SLFN11) and HER2, in multiple HER2-low BC cell lines, and increased phosphorylation of H2AX, a marker of DNA damage, in a GC cell line. Gene signature analysis revealed that valemetostat reduced DNA damage response (DDR) signatures and increased major histocompatibility complex (MHC) signatures in BC, GC, and NSCLC in vitro models. Furthermore, valemetostat enhanced in vivo antitumor activities of T-DXd and Dato-DXd in human tumor xenografted models. 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). Citation Format: Daisuke Honma, Akiko Toyota, Yasuhiro Hama, Yasuki Kamai, Daisuke Okajima, Yoshiyuki Hizukuri, Maiko Narahara, Yuka Yamamoto, Emi Nosaka, Katsuki Usami, Kazumi Sato, Hiroki Goto, Ayumi Tezuka, Ayako Kato, Chisa Wada, Naoya Wada, Megumi Minami, Hideki Kobayashi, Mayumi Kitagawa. Preclinical assessment of valemetostat, a dual inhibitor of EZH2 and EZH1, combined with trastuzumab deruxtecan and datopotamab deruxtecan for multiple solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3790.