Phase 1b study of EZH1/2 inhibitor valemetostat in combination with trastuzumab deruxtecan in patients with HER2 low/ultra-low/null metastatic breast cancer.

TPS1120 Background: In the DAISY study (NCT04132960), meaningful clinical response was observed with Trastuzumab deruxtecan (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. EZH2-mediated PP2A inactivation confers resistance to HER2-targeted therapy. Additionally, valemetostat upregulates Schlafen11 (SLFN11), a putative DNA/RNA helicase, that regulates the sensitivity to DNA damaging agents such as topoisomerase I inhibitors. Based on these preclinical studies, 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. Methods: 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 (NCT05633979). The dosing for T-DXd is 5.4 mg/kg Q3W administered intravenously as indicated for current clinical use by FDA approval. Valemetostat will be evaluated at three dose levels (100 mg, 150 mg, and 200 mg orally), 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). Major eligibility criteria: Pathologically confirmed HER2 low/ultra-low/null breast cancer; ECOG performance status ≤1; Measurable disease; Received at least one line of chemo in the metastatic setting; Progressed and would no longer benefit from endocrine therapy; Normal organ and marrow function. Exclusion criteria: symptomatic brain metastases, interstitial lung disease, cord compression, prior treatment with any anti-HER2 therapy. Objectives: To evaluate the safety and determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE); To evaluate the objective response rate (ORR); To determine the duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS); To evaluate the pharmacokinetics and pharmacodynamic markers. Statistical methods: Approximately 12 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 will be enrolled 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 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 regarded as 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%. Clinical trial information: NCT05633979 .