Combination of Valemetostat and T-DXd in HER2-Low Breast Cancer

In this video, Prof François Duhoux is joined by Prof Sara Tolaney, medical oncologist at the Dana Farber Cancer Institute in Boston (MA, USA). During SABCS 2024, Prof Tolaney presented a poster setting out the design and objectives of a global phase 1b study evaluating the combination of valemetostat and trastuzumab deruxtecan (T-DXd) in patients with previously treated, HER2-low unresectable of metastatic breast cancer. 

Valemetostat is a selective dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1.  EZH2 regulates gene expression, including those involved in the DNA damage response, such as DNA/RNA helicase Schlafen 11 (SLFN11). In response to DNA damage, SLFN11 binds to chromatin, causing a replication block and inducing apoptosis. Inhibition of EZH2 with valemetostat may upregulate SLFN11 and sensitize tumor cells to DNA-damaging agents, including ADCs such as T-DXd. The presented phase 1b, study will enroll patients with unresectable or metastatic breast cancer who received 1–2 prior lines of chemotherapy in the recurrent or metastatic setting. To be eligible for the study, patients need to have HER2-low expression (IHC1+ or IHC2+/ISH-). The study consists of two parts: dose-escalation (Part 1; ~ 30 patients) and dose-expansion (Part 2; ~ 40 patients). In Part 1 of the study (dose-escalation), patients will receive valemetostat doses of 50–200 mg PO QD (continuous) and fixed-dose T-DXd 5.4 mg/kg IV Q3W until disease progression. The dose-limiting toxicity evaluation period will be the first treatment cycle (21 days). In Part 2 (dose-expansion), patients will receive valemetostat and T-DXd at the recommended dose for expansion identified in Part 1. The primary study endpoints are safety and tolerability in Part 1, and overall response rate (ORR), safety, and tolerability in Part 2. The secondary endpoints include ORR in Part 1, and pharmacokinetics, PFS, duration of response and overall survival in Part 1 and 2.