The antibody-drug conjugate trastuzumab deruxtecan has been shown to lead to a high intracranial response rate in patients with HER2+ breast cancer and active brain metastases in the phase 2 TUXEDO-1 trial, recently published on Nature Medicine.
Bain metastases are a major burden in solid malignancies and of special concern in HER2-positive breast cancer: up to 15% of all patients with metastatic breast cancer will eventually develop brain metastases during their respective course of disease. The prospective, open-label, single-arm TUXEDO-1 trial enrolled 15 patients with HER2-positive breast cancer and newly diagnosed untreated brain metastases or brain metastases progressing after previous local therapy, previous exposure to trastuzumab and pertuzumab and no indication for immediate local therapy. Patients received trastuzumab deruxtecan intravenously at the standard dose (5.4 mg per kg bodyweight) once every 3 weeks. The primary endpoint was intracranial response rate and results show that 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, with a best overall intracranial response rate of 73.3%. No new safety signals were observed and global quality of life and cognitive functioning were maintained over the treatment duration. «TUXEDO-1 is a prospective study indicating clinically relevant activity of the antibody-drug conjugate trastuzumab deruxtecan in active brain metastases from HER2-positive breast cancer with comparable intra- and extracranial response rates in a pretreated population. In addition, the progression-free survival results indicate prolonged disease control despite the presence of brain metastases. The results therefore suggest that trastuzumab deruxtecan could be safely used for the treatment of patients with active brain metastases from HER2-positive breast cancer, in case immediate local intervention is not indicated, and more generally support the notion that antibody-drug conjugates may be of interest in central nervous system malignancies and, thus, further clinical exploration in this context is warranted».