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.

Fig. 1

CONSORT flow diagram of the TUXEDO-1 trial. BM, brain metastases.

Fig. 2

Waterfall plot of responses in patients evaluable for response by RANO-BM criteria in the TUXEDO-1 trial. Blue bars illustrate the radiographic change of maximum brain metastasis size after start of trastuzumab deruxtecan therapy compared to the baseline measurement. Red dotted lines denote thresholds for response and progression by RANO-BM criteria.

Fig. 3

Kaplan–Meier plot showing progression-free survival times (months) in the TUXEDO-1 trial.

Extended Data Fig. 1. Health-related quality-of-life.

Health-related quality-of-life. Data are presented as mean values +/- SEM. At each cycle data are based on (n/N) participants where n denotes the number of participants completing a section of the questionnaire at a specific cycle and N the total number of participants reaching that cycle.

Extended Data Fig. 2. Neuron specific enolase levels.

Neuron specific enolase levels (ng/ml) in patients with and without response to trastuzumab deruxtecan.