Trastuzumab deruxtecan in HER2-positive breast cancer with brain metastases: a single-arm, phase 2 trial

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.

Antibody drug conjugates targeting HER2: Clinical development in metastatic breast cancer

“…The DESTINY-Breast04 trials did not report on the outcomes of patients with BM [ 59 ]. The phase II TUXEDO-1 trial included 15 patients with HER2+ BC and BM that were either newly diagnosed and untreated (6 patients) or had progressed after local therapy (9 patients) [ 80 ]. All patients were previously exposed to an anti-HER2–directed therapy including 9 patients having received T-DM1.…”

“…The extra-and intracranial response rates were comparable (62.2% and 73.3%). Importantly, the quality of life and cognitive function were maintained and the safety profile did not report central nervous system-related adverse events [ 80 ]. The ongoing phase II DEBBRAH trial, is evaluating the efficacy of T-DXd in pretreated patients with HER2+ and HER2-low BC with stable, untreated, or progressing BMs and/or leptomeningeal carcinomatosis [ 81 ].…”

Management of Brain Metastases from Human Epidermal Growth Factor Receptor 2 Positive (HER2+) Breast Cancer

“…Similarly, the prospective single arm phase 2 TUXEDO-1 trial evaluated T-DXd activity in HER2+ patients with active brain metastases. The first 15 patients have been reported with an intracranial response rate of 73.3% and a mPFS of 14 months [ 12 ].…”

Anti-Hormonal Therapy in Breast Cancer and Its Effect on the Blood-Brain Barrier

“…Another study was published in August 2022 on T-DXd and BM. The TUXEDO-1 trial is a prospective study reporting the activity of T-DXd in patients with active BM, in which 15 patients were included [ 113 ]. A response rate of 73.3% and a progression free survival of 14 months could be demonstrated.…”

“…A response rate of 73.3% and a progression free survival of 14 months could be demonstrated. These data appear very promising as these data are probably the longest reported period of any prospective study related to PFS, but they are limited to a small population [ 113 ].…”