Abstract
Despite trastuzumab-based therapy, up to half of patients with HER2+ metastatic breast cancer (MBC) will develop brain metastases (BrM). First-line therapy for HER2+ MBC, taxane/trastuzumab/pertuzumab (TP), demonstrates poor brain permeability. Isolated brain relapse with stable/absent extracranial disease remains a clinical problem in both the adjuvant and metastatic settings, and current guidelines recommend continuing current systemic therapy following local therapy. Tucatinib, a brain-penetrable HER2-inhibitor, when added to trastuzumab and capecitabine improves intracranial PFS and OS in patients with stable/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. BRIDGET (NCT05323955) is a single arm, phase II 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 through HCRN with HER2+ MBC will be enrolled after 1(st) or 2(nd) BrM relapse/progression within 8 weeks of local therapy. Patients must currently be receiving 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 will receive tucatinib added to their current therapy. The primary objective is intracranial PFS compared to a historical control (H(0): historical iPFS <5 months (mos), H(A): iPFS >8 mos) of the HER2CLIMB trial. In these patients, median time from brain progression to second progression/death was 7.6 mos with tucatinib versus 3.1 mos in the control arm. Secondary endpoints include PFS by RECISTv1.1, PFS of extracranial disease, locally treated versus new distant intracranial metastasis PFS, site of first progression, OS, and toxicity. Collection of correlative specimens and patient-reported outcomes (FACT-BR, FACIT-Fatigue) are also included.