Breast cancer (BC) is the most common cause of leptomeningeal disease (LMD) and the second most common cause of brain metastases (BMs) among all solid malignancies. Both BMs and LMD are associated with high morbidity and mortality and treatment options are limited. Trastuzumab deruxtecan (T-DXd), an antibody drug conjugate combining a HER2-targeting antibody with a topoisomerase I inhibitor, has shown activity in HER2-positive (HER2[+]) and HER2-low tumors in both preclinical and clinical settings. Similarly, T-DXd has shown efficacy in HER2[+] BC patients with central nervous system (CNS) involvement. However, data on activity in HER2-low BC patients with BMs and/or LMD using T-DXd are limited. TUXEDO-4 is an international, multicenter, single-arm, two-stage optimal Simon's design, phase II trial (NCT06048718) that will recruit a total of 27 adult patients (13 in the first stage, and 14 in second stage depending on responses in the first stage) to evaluate T-DXd in the HER2-low metastatic BC population presenting with newly diagnosed or progressing BM with or without type II LMD.