Background: HER2+ breast cancer (BC) is an aggressive subset of BC with high rates of brain metastases (BM) and poor survival. A recent study illustrates activation of the PI3K/mTOR pathway in approximately two-thirds of BCBM across all subtypes. Everolimus, a novel oral derivative of rapamycin that selectively inhibits mTOR, is clinically-active in combination with trastuzumab (with or without chemotherapy) in advanced HER2+ BC. Everolimus penetrates the blood brain barrier. We are evaluating the efficacy and safety of everolimus plus trastuzumab and vinorelbine in patients (pts) with HER2+ BCBM. Methods: Pts with HER2+ BCBM progressing following cranial radiation and measuring > 0.5cm are eligible for enrollment. Treatment with prior vinorelbine or mTOR inhibition is prohibited. Steroid treatment is allowed if stable or decreasing doses ≥7 days prior to study entry. Pts with leptomeningeal disease are excluded. Pts receive everolimus (5mg orally daily), trastuzumab 2mg/kg and vinorelbine 25mg/m² (both IV days 1, 8, 15) of a 21 day cycle. Intra- and extracranial disease is assessed every 9 weeks by gadolinium-enhanced brain MRI and CT chest/abdomen/pelvis, respectively. The primary endpoint is intracranial response rate (RR) assessed by modified RECIST. Secondary objectives include extracranial RR (assessed by RECIST 1.1), intra- and extracranial time to progression, progression free survival, overall survival, quality of life, and correlative science endpoints. Statistical considerations: In this two stage design, a sample size of 28 evaluable pts (n=11 in Stage 1) has 80% power to detect a difference between the null (≤5% intracranial RR) and alternative hypothesis (>5%) at a 0.05 significance level. If 1 pt has a CR, PR or SD for ≥ 3 months in the 1st stage, 17 additional pts will be enrolled. Assuming a 20% drop-out rate, 35 total pts will be enrolled. Correlative studies: Archival primary and/or metastatic tissues are required from all pts to evaluate intrinsic BC subtype, protein (p-AKT, pS6, PTEN) and gene expression to identify biomarkers that may be predictive of response or resistance to this novel combination (NCT01305941).