TUXEDO-4: phase II study of trastuzumab-deruxtecan in HER2-low breast cancer with new or progressing brain metastases

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. NCT06048718 (clinicaltrials.gov); 2023 -506,702-39–00 (EudraCT number). Breast cancer cells often spread to the brain (brain metastases) or the membranes surrounding the brain and spinal cord (leptomeningeal disease). Therapies to treat these serious conditions are limited. Trastuzumab deruxtecan (T-DXd), which targets a protein called HER2 (found on the surface of breast cells to control their growth) and includes a powerful anti-cancer component to kill the tumor cells, has shown clinically meaningful results in both HER2-positive (high concentration of HER2 proteins) and HER2-low (low concentration of HER2 proteins) breast cancers. Interestingly, T-DXd has successfully worked in HER2-positive breast cancer patients with brain metastases and/or leptomeningeal disease, but results in their HER2-low counterparts are limited. TUXEDO-4 is a medical study to evaluate the effectiveness of T-DXd in HER2-low breast cancer patients with recently diagnosed or worsening brain metastases, with or without aggressive leptomeningeal disease. The study is taking place in Austria and Spain, and will recruit 27 adult patients. TUXEDO-4 trial TUXEDO-4 is an international, multicenter, single-arm, two-stage optimal Simon’s design, phase II clinical trial evaluating the efficacy of trastuzumab-deruxtecan (T-DXd) in human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC) patients presenting with newly diagnosed or progressing brain metastases (BMs), with or without type II leptomeningeal disease (LMD). TUXEDO-4 is an international, multicenter, single-arm, two-stage optimal Simon’s design, phase II clinical trial evaluating the efficacy of trastuzumab-deruxtecan (T-DXd) in human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC) patients presenting with newly diagnosed or progressing brain metastases (BMs), with or without type II leptomeningeal disease (LMD).