ABSTRACT

Summary
Background Patritumab deruxtecan (HER3-DXd) is a novel antibody–drug conjugate targeting HER3, which is overexpressed in CNS metastases of metastatic breast cancer. We aimed to evaluate the activity and safety of HER3-DXd in patients with metastatic breast cancer and brain metastases that are newly diagnosed or progressing after local therapy.

Methods TUXEDO-3 trial is a multicohort, multicentre, open-label, single-arm phase 2 trial, done in six sites in Spain and Austria. In this cohort (1 of 3), we enrolled adults (≥18 years) with histologically documented breast cancer and radiologically documented metastatic disease, newly diagnosed brain metastases or brain metastases progressing after local treatment, at least one measurable brain lesion of ≥10 mm, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients received HER3-DXd 5·6 mg/kg intravenously once every 3 weeks. The threshold for the primary endpoint was at least 15% of patients having intracranial response according to Response Assessment in Neuro-Oncology Brain Metastases criteria. Activity and safety analyses were done in the full analysis  population (ie, all participants who received at least one dose of HER3-DXd). This trial (ClinicalTrials.gov NCT05865990 and European Union Clinical Trials Register 2023-503251-10-00) is ongoing and is no longer enrolling patients.

Findings Between Dec 12, 2023, and July 8, 2024, 21 evaluable female patients (five with luminal breast cancer, nine with HER2-positive breast cancer, and seven with triple-negative breast cancer) were recruited. 15 (71%) were White; race was not reported in the remaining six patients. The median number of previous treatment lines foradvanced disease was 4 (IQR 2–4). Median treatment duration was 3·0 months (IQR 0·7–7·7), and median follow-up was 4·9 months (IQR 3·6–8·5). The primary endpoint was met with five (24%) of 21 patients having intracranial responses irrespective of the breast cancer subtype (overall response rate 23·8%, 95% CI 8·2–47·1). The most common grade 3 or worse treatment-emergent adverse events were neutropenia in three (14%) patients, diarrhoea in two (10%) patients, and asthenia and vomiting in one (5%) patient each. Serious adverse events occurred in
six (29%) patients, with one (5%) patient having grade 2 pneumonitis related to the study treatment. No treatmentrelated deaths were reported.

Interpretation HER3-DXd showed promising clinical activity in patients with metastatic breast cancer and active brain metastases, and could offer a novel therapeutic option in this setting.

Funding Daiichi-Sankyo and Merck Sharp & Dohme.

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