Inclusion Criteria:

• Patients (men or women) must have histologically or cytologically confirmed invasive breast cancer, with metastatic disease. Patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis by physical exam or radiologic study.
• Invasive primary tumor or metastatic tissue confirmation of HER2-positive status, defined as presence of one or more of the following criteria:
  • Over-expression by immunohistochemistry (IHC) with score of 3+ (in > 30% of invasive tumor cells) AND/OR HER2 gene amplification (average of > 6 HER2 gene copies per nucleus or a FISH ratio [HER2 gene copies to chromosome 17 signals] of ≥ 2.0), according to guidelines and in keeping with past eligibility for ratio of ≥ 2.0 rather than the ratio of > 2.2 required by new guidelines:
    • http://www.asco.org/quality-guidelines/recommendations-human-epidermal-growth-factor-receptor-2-testing-breast-cancer
  • Note: Patients with a negative or equivocal overall result (FISH ratio of < 2.0 or ≤ 6.0 HER2 gene copies per nucleus) and IHC staining scores of 0, 1+, 2+ are not eligible for enrollment.
• No increase in corticosteroid dose in the week prior to baseline brain imaging.
• Age ≥ 18 years old.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Patients must have normal organ and marrow function as described below:
  • Absolute neutrophil count > 1,000/uL;
  • Platelets > 100,000/uL;
  • Total bilirubin ≤ 1.5 X upper limit of normal (ULN) ;
  • AST(SGOT)/ALT(SGPT) ≤3 X institutional ULN without liver metastases, or ≤ 5X institutional ULN with liver metastases;
  • Creatinine ≤ 2.0 mg/dL or creatinine clearance ≥ 50 mL/min.
• Left ventricular ejection fraction ≥ 50%, as determined by RVG (MUGA) or echocardiogram within 60 days prior to initiation of protocol therapy.
• Prior therapy (see specifics by each cohort below):
  • Prior trastuzumab is allowed for all cohorts;
  • Prior capecitabine is NOT allowed for participants enrolled to Cohorts 3A/3B ONLY;
  • Prior lapatinib is allowed for Cohorts 1, 2, and 3B, but NOT Cohort 3A;
  • Prior T-DM1 is NOT allowed for Cohorts 4A and 4B but is required for Cohort 4C. Dose reductions on prior T-DM1 for Cohort 4C do not preclude enrollment on Cohort 4C. Patients on 4C may have progressed on prior T-DM1 in the CNS or non-CNS sites and had to have tolerated therapy without significant toxicity that would preclude retreatment;
  • No prior therapy with neratinib is allowed on any cohort;
  • There is no limit to the number of previous lines of therapy (including chemotherapy, trastuzumab, and endocrine therapies). At least 2 weeks washout period post chemotherapy, any prior protocol therapy, lapatinib, other targeted or biologic or immunotherapy, or radiation therapy is required prior to study entry;
  • No washout is required for hormonal therapy, but concurrent hormonal therapy is not allowed for patients on study. The only exception to this is longstanding ovarian suppression in pre-menopausal patients, if this has been started ≥ 6 months prior to study enrollment. Other hormonal therapies are not allowed while patients are on study.
• The effects of neratinib, capecitabine, and T-DM1 on the developing human fetus are not known. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• HIV-positive individuals on combination antiretroviral therapy are eligible for enrollment and will be monitored closely for potential pharmacokinetic interactions with neratinib.
• Concomitant medications listed in Appendix J should be avoided (when possible) while on study.
• Ability to understand and willingness to sign a written informed consent document.
• For Cohorts 1, 3A/3B, 4B and 4C patients must have new or progressive measurable CNS lesions, as assessed by the patient’s treating physician. This includes patients who have progressed after at least one line of standard local treatment for CNS disease (WBRT, SRS, or surgical resection as below).
• In Cohort 2, eligible patients will include those who have CNS disease that is amenable for surgery (typically < 3 brain metastases and with planned resection by neurosurgery). These patients may include those who have received or not received previous treatment(s) for their CNS.
• Further eligibility details for patients with progressive disease (Cohorts 1, 3A/3B, 4A, 4B, 4C):
  • Patients must have measurable CNS disease, defined as at least one parenchymal brain lesion that can be accurately measured in at least one dimension with longest dimension ≥10 mm by local radiology review. Note: measurable non-CNS disease is NOT required for study participation;
  • It is anticipated that some patients may have multiple progressive CNS lesions, one or several of which are treated with SRS or surgery with residual untreated lesions remaining. Such patients are eligible for enrollment on this study providing that at least one residual (i.e., non-SRS-treated or non-resected) lesion is measurable (≥10 mm). The location of the measurable lesion should be documented in the patient chart and case report form;
  • Patients who have had prior cranial surgery are eligible, provided that there is evidence of measurable residual or progressive lesions, and at least 2 weeks have passed since surgery. If a patient has surgical resection followed by WBRT, then there must be evidence of progressive CNS disease after the completion of WBRT;
  • Except for those in Cohort 4A where prior local CNS therapy is not allowed, patients who have had prior WBRT and/or SRS and then whose prior treated lesions have progressed thereafter are also eligible for all other cohorts. In this case, lesions which have been treated with SRS may be considered as target lesions if there is unequivocal evidence, in the opinion of the treating physician, of progression.
• Further eligibility details for patients with operable disease (Cohort 2):
  • It is anticipated that that patients who have intracranial disease amenable to surgery will have measurable CNS disease prior to study entry and to resection. However, this is not an eligibility requirement. Measurable disease is also not required to continue on protocol subsequent to surgical resection;
  • For patients who undergo surgery, postoperative whole brain radiation therapy will not be allowed while patients are on study (concurrent neratinib and radiation therapy has not been studied and toxicity of this is unknown). Patients will require discontinuation of neratinib if WBRT will be administered. However, if the treated provider feels that targeted radiosurgery (SRS, gamma knife, etc.) would be of benefit postoperatively, patients may proceed with this and then begin neratinib AFTER radiation completes.
• Further eligibility details for patients on Cohort 4A: All patients on Cohort 4A will not have received prior radiation or surgery to their brain. Prior systemic therapy aimed to treat disease in the brain is allowed (i.e., prior systemic standard therapy or protocol systemic therapy for brain mets).
  • Note: Laboratory tests required for eligibility must be completed within 4 weeks prior to study entry. Baseline measurements in the CNS must be documented from tests up to 21 days prior to planned start of protocol therapy unless not covered by insurance. If insurance coverage is an issue, a case by case approval of testing beyond this window may be approved by the overall study PI. Other non-laboratory tests must be performed as indicated.

Exclusion Criteria:

• Participants who have had chemotherapy or radiotherapy (including investigational agents) within 2 weeks prior to entering the study or those who have not recovered adequately from adverse events due to agents administered more than 4 weeks earlier (excluding alopecia). Washout from trastuzumab or hormonal therapy is not required.
• Participants who are currently receiving any other investigational agents.
• History of severe allergic reactions or intolerability attributed to compounds of similar chemical or biologic composition to neratinib (all cohorts), capecitabine for Cohorts 3A/3B, and T-DM1 for Cohorts 4A-4C.
• Concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs), including phenytoin, carbamazepine, oxcarbazepine, fosphenytoin, phenobarbital, pentobarbital, or primidone.
• Patients who are receiving any cancer-directed concurrent therapy, such as concurrent chemotherapy, radiotherapy, or hormonal therapy while on study. Concurrent treatment with bisphosphonates and denosumab is allowed for bony metastases but should be started before the first dose of neratinib.
• Any prior treatment with capecitabine for patients enrolled to Cohorts 3A/3B, prior lapatinib for participants on Cohort 3A, and T-DM1 for Cohorts 4A-4B.
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• For Cohorts 4A, 4B, and 4C: Patients with myocardial infarction or cardiomyopathy onset within the last 6 months are excluded.
• Active hepatitis B or hepatitis C with abnormal liver function tests (Cohorts 4A-4C):
  • Positive Hepatitis B (Hepatitis B surface antigen and antibody) and/or Hepatitis C (Hepatitis C antibody test) as indicated by serologies conducted ≤ 3 months prior to registration if liver function tests are outside of the normal institutional range.
  • Note: Patients with positive Hepatitis B or C serologies without known active disease are eligible if they meet all laboratory requirements.  Patients with laboratory evidence of vaccination to Hepatitis B (e.g., positive antibodies) are also eligible.
• Active liver disease from autoimmune disorders or sclerosing cholangitis.
• Lung disease from etiology other than metastatic breast cancer resulting in dyspnea at rest (4A-4C).
• More than two seizures over the last 4 weeks prior to study entry.
• Patients with known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign body. However, Head CT with contrast is allowed in place of MRI at baseline and throughout the study if MRI is contraindicated and a participant’s CNS lesions are clearly measurable on the head CT.
• Those with leptomeningeal metastases as the only site of CNS disease.
• Significant malabsorption syndrome or inability to tolerate oral medications.
• Any predisposing chronic condition resulting in baseline grade 2 or higher diarrhea.
• Inability to comply with study and/or follow-up procedures.
• Pregnant women are excluded from this study because neratinib (and other agents on study) is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with neratinib, breastfeeding should be discontinued if the mother is treated with neratinib. Negative urine pregnancy test is required for women of childbearing potential within 4 weeks of planned treatment start.
• Individuals with a history of a different active malignancy are ineligible.