Efficacy and Safety of T-DXd in HER2+ and Low/Zero Metastatic BCBM: A Retrospective Multicenter Real-World Study

Accumulating data demonstrate the robust overall and intracranial activity of trastuzumab deruxtecan (T-DXd) in HER2-positive breast cancer brain metastasis (BCBM). Limited data are available on HER2-low/zero BCBM, as well as patients with symptomatic active BM, leptomeningeal disease (LMD), and poor performance status. This multicenter, retrospective, real-world study enrolled patients diagnosed with HER2-positive or low/zero BCBM receiving T-DXd. Progression-free survival (PFS), intracranial progression-free survival (IC-PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), IC-ORR, IC-DCR, and adverse events (AEs) were evaluated. From January 2020 to July 2024, 58 HER2-positive and 30 HER2-low/zero patients were enrolled. In the HER2-positive cohort, the median PFS, IC-PFS, and OS were 11, 13, and 46 months, respectively. ORR and DCR were 65.2% and 91.3% systemically, with IC-ORR and IC-DCR of 61.0%/90.2% (RECIST 1.1) and 59.5%/88.1% (RANO-BM). In the HER2-low/zero cohort, median PFS, IC-PFS, and OS were 4, 5, and 26 months. ORR and DCR were 33.3% and 66.7%. IC-ORR and IC-DCR were 44.4% and 88.9% by RECIST 1.1 and RANO-BM. HR+/HER2-low patients had significantly longer PFS than HR-/HER2-low (10 vs. 3 months, p < 0.001). In the LMD cohort, the 12-month IC-PFS rates were 67.7% and 60.0% in HER2-positive and low/zero cohorts. The most common AEs included fatigue (45.9%) and appetite loss (25.2%). Seven (8.0%) patients suffered interstitial lung disease (ILD), including 2 (2.3%) grade 3. T-DXd showed substantial and durable overall and intracranial efficacy in HER2-positive and low/zero BCBM, including challenging subgroups with active BM or LMD.