Background: Treatment options for patients with leptomeningeal metastasis (LM) are limited and prognosis is poor. Tucatinib is a potent, highly selective HER2-targeted tyrosine kinase inhibitor. The combination of tucatinib-trastuzumab-capecitabine is approved for patients with metastatic HER2+ breast cancer, with or without brain metastases, who have received ≥ 1 prior HER2-based regimens in the metastatic setting. Patients with LM were excluded from HER2CLIMB (NCT02614794). The aim of this study was to determine the benefit of this regimen in patients with HER2+ breast cancer and LM. We previously reported preliminary efficacy data, with a median OS of 10 months and a median time to CNS progression of 6.9 months. Here, we present additional data on LM objective response, provider-rated neurologic clinical exam, and patient-reported outcomes (PRO). Methods: TBCRC049 (NCT03501979) is an investigator-initiated phase 2 study evaluating a tucatinib-trastuzumab-capecitabine regimen in adults with HER2+ breast cancer and newly diagnosed LM. Eligible patients had a Karnofsky performance status > 50 and untreated LM (defined as positive CSF cytology and/or radiographic evidence of LM plus clinical signs/symptoms). In 21-day cycles, patients received PO tucatinib, PO capecitabine, and IV trastuzumab. The primary endpoint was OS. LM objective response was assessed using a composite of neuroaxis imaging, neurologic clinical exam, and CSF cytology, derived from RANO-LM. The clinical exam incorporated the NANO scoring tool and symptom evaluation using MDASI-BT. Up to 4 provider-rated baseline target neuro deficits were monitored. An imaging scorecard was used. PROs were assessed using the LASA and MDASI-BT tools. Results: Enrollment was planned for 30 patients but closed at 17 patients following FDA approval of tucatinib (April 2020). All patients (median age 53 years) had MRI evidence of LM, 15 (88%) were symptomatic, and 8 (47%) had abnormal CSF cytology. At data cutoff (7/20/21), 5 (38%) of 13 response-eligible patients achieved LM objective response per the composite criteria at first response assessment, and all 13 (100%) achieved clinical benefit (SD, PR, or CR). Notably, 7 (58%) of 12 evaluable patients with target neurologic deficits at baseline experienced improvement of deficits. All 17 completed ≥ 75% of LASA and MDASI-BT PRO questionnaires at pre-specified timepoints. The mean improvement in LASA score was 13.5, indicating improved QOL and the mean improvement in MDASI-BT score was 32, indicating improved symptom burden. Conclusions: This is the first prospective evidence of clinically meaningful benefit including objective responses, symptom improvement, and quality of life, along with extended survival, with a systemic regimen for LM from HER2+ BC. These data support the trend toward using systemic therapy as an initial approach in CNS metastases. Clinical trial information: NCT03501979.