Promising Intracranial Activity With Trastuzumab Deruxtecan Among Patients With HER2-Positive/Low Metastatic Breast Cancer With Active Brain Metastases
According to a real-world analysis, there was promising intracranial activity seen with trastuzumab deruxtecan (T-DXd) among patients with HER2-positive or HER2-low, metastatic breast cancer with active brain metastases.
Study authors commented that T-DXd “theoretically could cross the blood-brain barrier and yield significant activity in [brain metastases],” though, as patients with active brain metastases are often excluded from clinical trials, “the activity of T-DXd in [metastatic breast cancer with brain metastases] remains lacking solid evidence.” There were 2 prospective phase 2 trials, TUXEDO and DEBBRAH, which evaluated the activity of T-DXd among patients with HER2-positive breast cancer with active brain metastases. These studies showed high intracranial objective response rates (73.3% and 44.4%, respectively), but their sample sizes were limited (n = 15 and n = 9) and the study designs were unrandomized phase 2. Because of this lack of strong prospective data, “real-world data for T-DXd would be particularly valuable.”
This multicenter, retrospective real-world study included 38 patients with HER2-positive/-low metastatic breast cancer with active brain metastases who received T-DXd between June 2022 and May 2024. The primary end point was rate of best intracranial response (iORR) at any radiological assessment following administration of at least 1 cycle of T-DXd. Secondary end points included intracranial progression-free survival (iPFS), PFS, overall survival (OS), and safety.
At the data cutoff date, there were 21 patients (55.3%) who remained on-treatment with T-DXd. The iORR among patients with HER2-positive disease with active brain metastases (n = 29) was 65.5%, with 1 patient in complete remission and 18 patients in partial remission (via RANO-BM). The iORR among patients with HER2-low disease (n = 9) was 66.7%, with 1 patient in complete remission and 5 in partial remission. With a median follow-up duration of 10.3 months, the time to intracranial progression and overall survival data were not mature. Therefore, the median iPFS and OS were not calculated. The 12-month iPFS rate was 79.8% for patients with HER2-positive disease and 51.9% for HER2-low disease. Among patients with HER2-low disease, the median PFS was 12.8 months and the 12-month OS rate was 86.5%. Among patients with HER2-low disease, median PFS was 6.33 months and the 12-month OS rate was 85.7%.
The most common adverse events were fatigue and nausea. The main grade 1 to 2 hematological toxicities were anemia and neutropenia. The grade 3 adverse events included anemia, neutropenia, depression, interstitial lung disease, and fatigue. There was 1 HER2-positive patient who experienced grade 4 interstitial lung disease. There were no treatment-related deaths.
Study authors concluded that this data “further solidified T-DXd as a potential therapeutic option for patients with active brain involvement from HER-positive and HER2-low [metastatic breast cancer].” They added that “further long-term monitoring and larger cohort are necessary to confirm and expand upon these findings.”
Source:
Duan F, Hua X, Lu W, et al. Trastuzumab deruxtecan in patients with active brain metastases from HER2-positive/low metastatic breast cancer: A retrospective multicenter real-world study. Breast Cancer Res. Published online: July 21, 2025. doi:10.1186/s13058-025-02088-5.
