PS5-09-22: Phase 1b study of EZH1/2 inhibitor valemetostat in combination with trastuzumab deruxtecan in subjects with HER2 low/ultra-low/null metastatic breast cancer

Abstract Background: Low HER2-expressing breast cancers have traditionally been classified as HER2-negative and treated as TNBC or hormone receptor (HR)-positive. Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate composed of an anti-HER2 antibody conjugated to topoisomerase I payload, is approved for clinical use in HER2-low (IHC 1+ or IHC 2+/ ISH negative) metastatic breast cancer (MBC). In the DAISY study (NCT04132960), meaningful clinical response was observed with T-DXd in HER2 IHC 0 MBC. Valemetostat is an oral, selective dual inhibitor of enhancer of zeste homolog 1 and 2 (EZH1/2, methyltransferases that specifically methylate histone H3 lysine 27. It is approved for patients with relapsed or refractory adult T-cell leukemia/lymphoma in Japan. EZH2-mediated PP2A inactivation has been shown to confer resistance to HER2-targeted therapy. Additionally, valemetostat has been shown to upregulate Schlafen11 (SLFN11), a putative DNA/RNA helicase that regulates the sensitivity to DNA-damaging agents such as topoisomerase I inhibitors. Accordingly, this study examines the safety and anti-tumor activity of valemetostat in combination with T-DXd in subjects with HER2 low/ultra-low/null MBC. Trial Design: This is a single-arm, phase-1b study to evaluate the safety and clinical activity of T-DXd in combination with valemetostat in patients with HER2 low/ultra-low/null MBC. The dosing for T-DXd is 5.4 mg/kg Q3W administered intravenously as indicated for current clinical use. Valemetostat will be evaluated in up to five doses (50mg, 75mg, 100 mg, 150 mg, and 200 mg) with a starting dose (level 1) at 100 mg QD. The dose-limiting toxicity (DLT) evaluation period will be the first 2 treatment cycles (42 days). Eligibility criteria: Pathologically confirmed HER2 low/ultra-low/null breast cancer• ECOG performance status ≤1• Measurable disease (for expansion)• Received at least one line of chemo in the metastatic setting• Progressed and would no longer benefit from endocrine therapy (HR-positive).• Normal organ and marrow function• Exclusion: symptomatic brain metastases, interstitial lung disease, cord compression, prior treatment with any anti-HER2 therapy. Specific aims: To evaluate the safety and determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of valemetostat in combination with T-DXd.• To evaluate the objective response rate (ORR) of valemetostat at the RDE in combination with T-DXd• To determine the duration of response, clinical benefit rate, progression-free survival, and overall survival of valemetostat at the RDE in combination with T-DXd.• To evaluate the pharmacokinetics and pharmacodynamic markers of valemetostat and T-DXd combination• To evaluate the immunogenicity of T-DXd when co-administered with valemetostat. Statistical methods: Approximately 15 evaluable patients will be enrolled for the dose-escalation portion based on the Bayesian optimal interval design with a target DLT rate of 25%. Patients enrolled and treated in cohorts of 3. The expansion will be performed at the RDE using the 2-stage Bayesian optimal dose-expansion design. In the first stage, 13 evaluable patients (including those treated at the RDE in the dose-escalation part) will be enrolled. If 5 patients respond in the first stage, the study will be stopped for futility. If ≥ 5 responses are observed, 13 additional evaluable patients will be enrolled. If 11 or more responses are observed among 26 patients, the treatment will be considered 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%. Citation Format: S. Damodaran, A. N. Marx, T. Iwase, Y. Yuan, M. Kai, J. Lee, C. H. Barcenas, N. T. Ueno. Phase 1b study of EZH1/2 inhibitor valemetostat in combination with trastuzumab deruxtecan in subjects with HER2 low/ultra-low/null metastatic breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-09-22.