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Inclusion Criteria:

* Have histologically confirmed HER2+ breast carcinoma, with HER2+ defined by ISH or FISH or IHC methodology
* For patients WITHOUT presence or history of brain metastases, have received previous treatment with trastuzumab, pertuzumab, and T-DM1
* For patients WITH presence or history of brain metastases, have received previous treatment with trastuzumab
* Have progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy (as confirmed by treating physician), or be intolerant of last systemic therapy
* Have measurable disease or non-measurable disease assessable by standard of care imaging methods
* Have ECOG PS 0 or 1
* Have a life expectancy of at least 6 months, in the opinion of the treating physician

Exclusion Criteria:

* Eligible for a tucatinib clinical trial
* Disease recurrence within 3 months of last capecitabine for metastatic disease
* History of allergic reactions to trastuzumab, capecitabine, or compounds chemically or biologically similar to tucatinib, except for Grade 1 or 2 infusion related reactions to trastuzumab that were successfully managed, or known allergy to one of the excipients in the protocol drugs
* Have received treatment with any systemic anti-cancer therapy (excluding hormonal therapy), non-CNS radiation, or experimental agent ≤ 3 weeks of first dose of protocol treatment or are currently participating in an interventional clinical trial. Have received hormonal therapies \<1 week of the first dose of protocol treatment.
* Have any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:

  * Alopecia and neuropathy, which must have resolved to ≤ Grade 2
  * CHF, which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely
  * Anemia, which must have resolved to ≤ Grade 2
* Have clinically significant cardiopulmonary disease
* Have known myocardial infarction or unstable angina within 6 months prior to first dose of protocol treatment
* Are known carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease with uncontrolled disease
* Are known to be positive for HIV with uncontrolled disease
* Are pregnant, breastfeeding, or planning a pregnancy
* Require therapy with warfarin or other coumarin derivatives (non-coumarin anticoagulants are allowed)
* Have inability to swallow pills or significant gastrointestinal disease which would preclude the adequate oral absorption of medications
* Have used strong CYP2C8 inhibitor within 5 half-lives of the inhibitor, or have used a CYP2C8 or CYP3A4 inducer within 5 day prior to start of tucatinib treatment.
* Have known dihydropyrimidine dehydrogenase deficiency
* Have evidence within 2 years of the start of protocol treatment of another malignancy that required systemic treatment.

CNS Exclusion - patients must not have any of the following:

* Any untreated brain lesions \> 2.0 cm in size, unless discussed with medical monitor and approval for enrollment is given
* Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of \> 2 mg of dexamethasone (or equivalent). However, patients on a chronic stable dose of ≤ 2 mg total daily of dexamethasone (or equivalent) may be eligible with discussion and approval by the medical monitor
* Any brain lesion thought to require immediate local therapy, including (but not limited to) a lesion in an anatomic site where increase in size or possible treatment-related edema may pose risk to patient (e.g. brain stem lesions).
* Known or suspected LMD as documented by the treating physician
* Have poorly controlled (\> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy