Intracranial activity of trastuzumab deruxtecan in HER2-low breast cancer with brain metastases: A systematic review and meta-analysis.

Abstract

e13082 Background: Human epidermal growth factor receptor 2 (HER2)–low breast cancer, defined as HER2 immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization–negative, represents a newly targetable subtype comprising nearly half of all breast cancers. Brain metastases are a common and morbid complication of metastatic breast cancer, yet patients with active central nervous system (CNS) disease are frequently excluded from clinical trials. Trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate with a cleavable linker and potent topoisomerase I inhibitor payload, has demonstrated substantial intracranial activity in HER2-positive disease. However, the intracranial efficacy of T-DXd in patients with HER2-low breast cancer remains incompletely characterized. Methods: A systematic literature search was conducted across PubMed/MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and Web of Science from database inception through January 1, 2025. A total of 2,275 records were identified and screened. Eligible studies included randomized controlled trials and prospective or retrospective clinical studies evaluating trastuzumab deruxtecan in patients with HER2-low metastatic breast cancer and measurable brain metastases. Studies were required to report intracranial objective response rate (IC-ORR), defined as complete or partial intracranial response among CNS-evaluable patients, assessed by study-defined criteria (RECIST 1.1 or RANO-BM). Results: Five studies comprising 62 patients with HER2-low metastatic breast cancer and brain metastases were included. Using a random-effects proportional meta-analysis with Freeman–Tukey double arcsine transformation, the pooled intracranial objective response rate (IC-ORR) was 46% (95% CI, 27–65%). Between-study heterogeneity was moderate (I² = 47.7%, p = 0.11), with consistent directionality of intracranial activity observed across included cohorts. Conclusions: Across five studies, T-DXd demonstrated clinically meaningful intracranial activity in HER2-low metastatic breast cancer with brain metastases, yielding a pooled IC-ORR of 46%. This provides one of the first quantitative benchmarks of CNS response in HER2-low disease, where evidence has been limited to small, heterogeneous cohorts. These findings support dedicated prospective trials in HER2-low patients with active CNS disease and standardized intracranial endpoints to refine patient selection and expected benefit. Summary of outcomes. Study Year CNS-Evaluable Patients (N) Intracranial Responders (CR+PR) IC-ORR (%) Zhou et al. 2025 15 7 46.7 (21.0–73.0) Batista et al. 2024 6 3 50.0 (12.0–88.0) Lazaratos et al. 2024 6 4 66.7 (22.0–96.0) Duan et al. 2025 9 6 66.7 (30.0–93.0) Burnside et al. 2024 26 6 23.1 (9.0–44.0) Pooled estimate (random effects) — 62 26 46.0 (27.0–65.0)*