Results of a patient-level pooled analysis of three studies of trastuzumab deruxtecan in HER2-positive breast cancer with active brain metastasis

Background: Brain metastases (BMs) are common in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer, increasing morbidity and mortality. Systemic therapy for BMs can be effective, with the triple combination of trastuzumab, capecitabine, and tucatinib being a potential standard. More recently, intracranial activity of antibodyedrug conjugates has been reported, but the size of individual studies has been small. Therefore, this patient-level pooled analysis was conducted. Patients and methods: This is a patient-level pooled analysis of the prospective phase II DEBBRAH and TUXEDO-1 trials and the retrospective DFCI/Duke/MDACC cohort. Patients with evaluable active BMs (defined as newly diagnosed and untreated or progressing with measurable tumor-related size after previous local therapy) from HER2-positive breast cancer (BC) and treated with trastuzumab deruxtecan (T-DXd) included in these studies were eligible. The primary endpoint was intracranial objective response rate (ORR-IC) by Response Assessment in Neuro-Oncology (RANO)-BM criteria. Results: Overall, 37 patients were assessable for intracranial response assessment. BMs progressing after prior local therapy were present in 64.9% of patients. The median patient age was 49.1 years. All patients had received prior trastuzumab and the median number of prior systemic treatment lines was 3 (0-13). The pooled ORR-IC by RANOBM criteria was 64.9% [95% confidence interval (CI) 47.5% to 79.8%] with low heterogeneity observed between the studies included. The clinical benefit rate by RANO-BM was 81.1% (95% CI 64.8% to 92.0%). The median progression-free survival was 13.3 months (95% CI 8.4-22.6 months) and the median overall survival was 22.5 months (95% CI 14.9 months-not achieved) with high heterogeneity between studies and numerically longer in patients with few prior treatment lines. Quality of life remained stable throughout treatment, with no new safety concerns. Conclusions: This patient-level pooled analysis of DEBBRAH, TUXEDO-1, and the DFCI/Duke/MDACC cohort indicates clinically relevant intracranial activity of T-DXd in patients with active HER2-positive BC, BMs, and extensive systemic pretreatment. The results therefore support the use of T-DXd when clinically indicated irrespective of BMs.