Impact of trastuzumab deruxtecan (T-DXd) and brain stereotactic radiosurgery on intracranial control and radionecrosis risk in HER2-positive or -low breast cancer brain metastases

Background: While trastuzumab deruxtecan (T-DXd) demonstrates intracranial efficacy, the potential for radionecrosis (RN) when combined with stereotactic radiosurgery (SRS) remains a concern, given the established risk with other antibody-drug conjugates like T-DM1. This study evaluated the safety and efficacy of T-DXd and SRS in patients with HER2-positive or -low breast cancer brain metastases (BCBM). Methods: We conducted a multi-center retrospective analysis of 113 patients (461 SRS treatments) treated with SRS and anti-HER2 agents. Patients were stratified into T-DXd(+) (n = 29 patients, 61 treatments) and T-DXd(−) (n = 84 patients, 400 treatments) groups. Endpoints included RN, radionecrosis-free survival (RNFS), and intracranial control outcomes (any intracranial progression, local failure, and distant intracranial metastasis). Results: No cases of RN were observed in the T-DXd(+) group, compared with 11 cases in the T-DXd(−) group (p = 0.028). On multivariate analysis, T-DXd(+) status remained significantly associated with improved RNFS (HR 0.31, p = 0.009). In the treatment-level analysis, the 1-year cumulative incidence of RN was 0% for T-DXd(+) versus 4.3% for T-DXd(−) (p = 0.009). Additionally, T-DXd(+) was associated with significantly better 1-year outcomes for any intracranial progression (40% vs. 76%, p < 0.001), local failure (6.6% vs. 29%, p = 0.002), and distant intracranial metastasis (40% vs. 66%, p = 0.009). All efficacy endpoints remained significant on multivariate analysis. Conclusion: Combining T-DXd with SRS demonstrated a favorable safety profile without increasing the risk of radionecrosis. Furthermore, this combination was associated with superior intracranial control, encompassing both local and distant outcomes, supporting the potential of T-DXd combined with SRS as an effective and well-tolerated approach for HER2-positive or -low BCBM.