Tucatinib With Brain and/or Spinal XRT in Patients With HER2+ Metastatic Breast Cancer and LMD

Inclusion Criteria: Phase 1 Men or women with HER2+ metastatic breast cancer. Evidence of LMD in the brain and/or spine Age 18+ at time of consent; ECOG ≤ 2; If applicable, the last dose of prior chemotherapy, immunotherapy, endocrine therapy therapy must have been completed 14 days prior to study enrollment. More than 14 days or 5 half-lives from the last dose of any experimental agent is required, whichever is greater; All toxicity related to prior cancer therapies must have resolved to ≤ Grade 1 prior to enrollment, except for alopecia; neuropathy, must have resolved to ≤ Grade 2. Phase 2: Inclusion Criteria Left ventricular ejection fraction (LVEF) must be within institutional limits of normal as assessed by ECHO or MUGA documented within 2 weeks prior to starting systemic therapy on the study; Adequate hematologic, liver, and renal function within 2 weeks prior to phase 2 enrollment, as follows: Hemoglobin ≥ 9 g/dL ANC ≥ 1 x109/L Platelets ≥ 100 x109/L Total bilirubin ≤ 1.5 X upper limit of normal (ULN) AST and ALT ≤ 2.5X ULN International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN Creatinine clearance (CrCL) ≥ 50 mL/min Exclusion Criteria: Phase 1 Prior WBRT for brain metastases Prior therapy specifically directed at LMD Inability to comply with MRI-based surveillance of CNS disease. Inability to swallow pills or any significant gastrointestinal diseases such as inflammatory bowel disease. Presently known dihydropyrimidine dehydrogenase deficiency; Diagnosed with Hereditary fructose intolerance; Diagnosed with Gilbert's disease; Prior history of other cancer with evidence of disease within the last 5 years; Prior use of tucatinib at any time prior to enrollment. Phase 2: Currently pregnant or breastfeeding; Use of a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the inhibitor or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to the first dose of systemic therapy Myocardial infarction or unstable angina within 6 months prior to the first dose of systemic therapy. Blood product transfusions in order to meet eligibility criteria