The prospective, open-label, single-arm, phase 2 TUXEDO-1 trial enrolled patients with HER2-positive breast cancer and newly diagnosed untreated brain metastases or brain metastases progressing after previous local therapy. Patients received trastuzumab deruxtecan intravenously at the standard dose of 5.4 mg per kg bodyweight once every 3 weeks. Fifteen patients received at least one dose of study drug. Two patients (13.3%) had a complete intracranial response, nine (60%) had a partial intracranial response and three (20%) had stable disease as the best intracranial response. There were no new safety signals.