ADC and Immune Targets in Metastatic Breast Cancer

In this video, Dr Gitte Zels, a pathologist in training at the University Hospitals Leuven and Prof François Duhoux (Cliniques Universitaires St.-Luc, Brussels) discuss the key take-aways from a poster presented at SABCS 2024. For this poster, Zels and colleagues compared the expression of clinically relevant biomarkers and potential therapeutic targets between patients with a hormone-receptor positive (HR+) metastatic invasive breast cancer of no special type (IBS-NST) and patients with metastases from an invasive lobular breast cancer (ILC). This analysis revealed that ILC metastases show less immune infiltration than IBC-NST metastases. In contrast, no significant difference in receptor expression was observed between the two tumour types. Furthermore, all patients with ILC had at least one HER2-low/ultralow metastasis, which is relevant for the approval of anti-HER2 ADCs in this setting. With respect to ADC targets and immune checkpoint markers, no significant difference was observed between the two subtypes. However, the ADC targets FN1 and SCL39A6 and the immune checkpoint markers CD47 and Galectin9 were identified as potential targets for metastatic breast cancer in general.

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.