Abstract
Trastuzumab deruxtecan is an antibody–drug conjugate with high extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. We conducted the prospective, open-label, single-arm, phase 2 TUXEDO-1 trial. We enrolled patients aged ≥18 years 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 of 5.4 mg per kg bodyweight once every 3 weeks. The primary endpoint was intracranial response rate measured according to the response assessment in neuro-oncology brain metastases criteria. A Simon two-stage design was used to compare a null hypothesis of <26% response rate against an alternative of 61%. Fifteen patients were enrolled in the intention-to-treat population of patients who 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, with a best overall intracranial response rate of 73.3% (95% confidential interval 48.1–89.1%), thus meeting the predefined primary outcome. No new safety signals were observed and global quality-of-life and cognitive functioning were maintained over the treatment duration. In the TUXEDO-1 trial (NCT04752059, EudraCT 2020-000981-41), trastuzumab deruxtecan showed a high intracranial response rate in patients with active brain metastases from HER2-positive breast cancer and should be considered as a treatment option in this setting.
Main
Brain metastases are a major burden in solid malignancies and of special concern in human epidermal growth factor receptor 2 (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, making metastatic breast cancer the second most common cause of brain metastases among all solid tumors after lung cancer1, with the highest incidences reported in triple-negative and HER2-positive disease2. Overall, incidence of brain metastases has been rising over the last two decades, commonly attributed to improved overall survival due to the progress in systemic therapy options3 and a hypothetical shift to a more aggressive phenotype in patients recurring after primary adjuvant treatment4. Screening of asymptomatic patients and the ensuing diagnosis of asymptomatic brain metastases might further contribute to this observation.
Local therapy such as whole-brain radiotherapy (WBRT), stereotactic radiotherapy (SRT), stereotactic radiosurgery (SRS) and neurosurgery has been the mainstay of brain metastases treatment5,6, but patients’ prognosis remains generally poor with median overall survival times ranging from 2 months to 16 months, with outcomes differing by metastatic breast cancer subtype1. Overall survival in excess of 24 months was reported in patients with HER2-positive metastatic breast cancer brain metastases7. For these patients, systemic treatment has become an attractive alternative approach to WBRT when SRT or SRS is not possible or indicated, aiming at the prevention of WBRT-associated neurocognitive decline. Research in the field of systemic treatment has initially focused on small-molecule tyrosine-kinase inhibitors (TKIs) due to their low molecular mass. In contrast, larger molecules such as antibodies and antibody–drug conjugates (ADCs) were considered ineffective because of the blood–brain barrier (BBB). As the BBB is, however, disrupted at the site of metastases and replaced by a blood–tumor barrier with higher endothelial fenestration, larger molecules may also penetrate the brain parenchyma8,9. Indeed, 64Cu-tagged trastuzumab visualized brain metastases10 and several case series reported on the potential activity of the ADC T-DM1 (ado-trastuzumab emtansine) in breast cancer brain metastases11,12.
Trastuzumab deruxtecan (DS-8201a) is a new HER2-directed ADC consisting of a humanized HER2-directed monoclonal antibody (MAAL-9001) with the same amino acid sequence as trastuzumab, a cleavable molecular linker stable in plasma and deruxtecan, a topoisomerase-I inhibitor with high inhibitory potency and high membrane permeability13,14. The drug:antibody ratio in trastuzumab deruxtecan is 8:1 and therefore higher compared with earlier generation ADCs including T-DM1 (ref. 14). Trastuzumab deruxtecan was found to harbor clinically relevant activity in HER2-positive metastatic breast cancer progressing on previous T-DM1 (ref. 15) and prolonged progression-free survival (PFS) when directly compared with T-DM1 in the prospective randomized DESTINY-Breast03 study (hazard ratio (HR) 0.28, 95% confidence interval (CI) 0.22–0.37)16. Although outcomes were comparable in patients with stable brain metastases at baseline (HR = 0.25)17, data regarding the potential activity of trastuzumab deruxtecan in active brain metastases are limited. Therefore, the prospective, single-arm, single-center, phase 2 TUXEDO-1 trial was initiated. The study was specifically designed to evaluate efficacy and safety of trastuzumab deruxtecan in a population of HER2-positive breast cancer patients with active brain metastases (that is, newly diagnosed brain metastases or brain metastases progressing after previous local therapy) and more broadly as proof of principle for the intracranial activity of ADCs.
