Abstract PO5-20-02: Secondary BRain metastases prevention after Isolated intracranial progression on trastuzumab/pertuzumab or T-DM1 in pts with aDvanced human epidermal Growth factor receptor 2+ brEast cancer with addition of Tucatinib (BRIDGET)

Abstract Background: Despite treatment with trastuzumab-based therapy, up to half of patients with HER2+ advanced/metastatic breast cancer (MBC) will develop brain metastases (BrM). First-line therapy for advanced HER2+ MBC remains a taxane, trastuzumab, pertuzumab (TP) which demonstrates poor brain permeability. Isolated brain relapse with stable or absent extracranial disease remains a clinical problem in both the adjuvant (Untch et al. , ESMO 2019 Congress) and metastatic settings (Noteware et al. , Breast Cancer Res Treat. 2023). Current guidelines recommend continuing current systemic therapy in the setting of first isolated brain relapse following local therapy. Tucatinib, a brain-penetrable HER2-targeting tyrosine kinase inhibitor, when added to trastuzumab and capecitabine improves intracranial progression free survival (PFS) and overall survival (OS) in patients with stable or active HER2+ BrMs. We hypothesize that adding tucatinib to TP or T-DM1 in patients with HER2+ MBC with isolated brain relapse or progression could delay or prevent the development of further intracranial lesions and improve OS. Methods: BRIDGET (NCT05323955) is a single arm, phase II, multicenter study of tucatinib added to TP or T-DM1 after local therapy in patients with isolated brain relapse or progression. A total of 48 patients at 9 U. S. sites as part of the Hoosier Cancer Research Network (HCRN) with metastatic HER2+ breast cancer will be enrolled after 1st or 2nd BrM relapse or progression within 8 weeks of local therapy. Patients must currently be receiving standard of care treatment with TP or T-DM1 in the metastatic setting, or adjuvant trastuzumab-based or T-DM1 therapy with isolated brain recurrence. Extracranial disease must be stable per RECISTv1. 1 or absent. Patients may not have leptomeningeal disease or untreated brain lesions over 5 mm. Patients will receive continuous tucatinib added to their current therapy (TP or T-DM1). The primary objective is intracranial PFS compared to a historical control (H0: PFS 5 months (mos), HA: PFS 8 mos) of the HER2CLIMB clinical trial where patients could continue on trial with isolated brain progression. In these patients, median time from brain progression to second progression or death was 7. 6 mos (95% CI, 3. 9 to 11. 3 mos) in the tucatinib arm versus 3. 1 mos (95% CI, 1. 2 to 4. 1 mos) in the control arm (Lin et al. , J Clin Onc 2020). Secondary endpoints include PFS by RECISTv1. 1, PFS of extracranial disease, locally treated versus new distant intracranial metastasis PFS, site of first progression (brain versus non-brain), OS, and toxicity in patients with BrM. Collection of correlative specimens including archival tissue, cerebrospinal fluid (optional), whole blood for ctDNA are planned. Patient-reported outcomes surveyed utilizing the FACT-BR and FACIT-Fatigue questionnaires are also included for future analyses. As of 7/06/23, accrual is 5 patients of the anticipated 48 patients overall, across 5 sites (Duke University, Dana Farber Cancer Institute, Ohio State University, Providence Portland Medical Center, and Washington University in St. Louis) currently open. An additional 4 sites are pending opening. Those interested in this trial can reach out to the study Principal Investigators, Carey Anders, MD (carey. anders@duke. edu) or Sarah Sammons, MD (sarahlₛammons@dfci. harvard. edu). Citation Format: Sarah Sammons, Amanda Van Swearingen, Laura Noteware, Nusayba Bagegni, Kelly Moulton, Stevie Threatt, Denise Jaggers, Shannon Shea, Eric Lipp, Erin Riley, Sin-Ho Jung, Gloria Broadwater, Masey Ross, Kimberly Strickland, Sasha Beyer, Alison Conlin, Aki Morikawa, Rashmi Murthy, Carey Anders. Secondary BRain metastases prevention after Isolated intracranial progression on trastuzumab/pertuzumab or T-DM1 in pts with aDvanced human epidermal Growth factor receptor 2+ brEast cancer with addition of Tucatinib (BRIDGET) abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84 (9 Suppl): Abstract nr PO5-20-02.