Pertuzumab and Trastuzumab or Trastuzumab Emtansine with Tucatinib for the Treatment of Locally Advanced, Unresectable, or Metastatic HER2 Positive Breast Cancer with Brain Metastasis Progression, BRIDGET Study

Inclusion Criteria

• Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately
• Age >= 18 years at the time of consent
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
• Locally advanced/unresectable or metastatic breast cancer with presence of brain metastases
• Histologically confirmed HER2+ breast carcinoma by The American Society of Clinical Oncology (ASCO)-College of American Pathologists (CAP) guidelines, with HER2+ defined by in situ hybridization (ISH), immunohistochemistry (IHC), or fluorescence in situ hybridization (FISH) methodology on most recent biopsy
• Currently receiving: (1) first-line trastuzumab/pertuzumab OR (2) second-line T-DM1 in the metastatic setting OR (3) adjuvant trastuzumab-based therapy or T-DM1 with isolated intracranial recurrence. Patients with de novo metastatic disease and brain metastases or isolated intracranial recurrence can enter upon initiation of maintenance trastuzumab/pertuzumab after chemotherapy if deemed necessary by treating oncologist and meeting other inclusion criteria
• Systemic disease otherwise stable per RECIST 1.1 or no evidence of extracranial disease
• Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
• Platelets >= 100 x 10^9/L
• Hemoglobin >= 9 g/dL
• Total serum bilirubin =< 1.5 times upper limit of normal (ULN)
• Aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (or =< 5 x ULN if liver metastases are present)
• Serum creatinine =< 1.5 x ULN or estimated creatinine clearance >= 50 mL/min as calculated using the Cockcroft-Gault (CG) equation
• Left ventricular ejection fraction (LVEF) >= 50%
• Central nervous system inclusion - Based on screening brain magnetic resonance imaging (MRI), patients must have ALL of the following: * Adequate local therapy to existing brain lesions >= 5mm including surgical resection and/or stereotactic radiosurgery * Limited to first or second intracranial progression * Time since stereotactic radiosurgery (SRS) is >= 7 days prior to first dose of study treatment * Time since surgical resection is >= 14 days prior to first dose of study treatment * Time since local therapy < 8 weeks. Patients with de novo metastatic breast cancer presenting with brain metastases may enter following cessation of chemotherapy if within 12 weeks of local therapy to the brain NOTE: Relevant records of any CNS treatment including radiation must be available to allow for classification of target and non-target lesions
• Females of childbearing potential must have a negative serum pregnancy test at screening. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
• Females of childbearing potential and males must be willing to abstain from heterosexual intercourse or to use contraception

Exclusion Criteria

• Previously been treated with: Lapatinib, neratinib, afatinib, tucatinib or other investigational HER2/epidermal growth factor receptor (EGFR) or HER2 tyrosine kinase inhibitor (TKI) at any time previously (patients treated with adjuvant neratinib allowed if relapse > 12 months after last dose)
• Clinically significant cardiopulmonary disease
• Clinically significant acute infection requiring systemic antibacterial, antifungal, or antiviral therapy including: * Tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings, and tuberculosis [TB] testing in line with local practice), * Hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), * Hepatitis C, or * Human immunodeficiency virus (positive human immunodeficiency virus [HIV] 1/2 antibodies) NOTE: Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of hepatitis B surface antigen [HBsAg]) are eligible. Patients positive for hepatitis C (hepatitis C virus [HCV]) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Subjects with HIV/acquired immunodeficiency syndrome (AIDS) with adequate antiviral therapy to control viral load would be allowed if they are stable and have been on treatment for >= 4 weeks prior to first dose of study drug(s). Subjects with viral hepatitis with controlled viral load would be allowed while on suppressive antiviral therapy. Testing not required
• Unable for any reason to undergo MRI of the brain
• Use of a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the inhibitor, or a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment
• Central nervous system exclusion - Based on screening brain MRI, patients must not have any of the following: * Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent) * Diffuse leptomeningeal disease or positive CSF cytology; however, discreet dural-based metastases are allowed * Poorly controlled seizures. Defined as seizures that continue to occur despite optimal anticonvulsant medications based on investigator discretion. * History of whole brain radiation therapy * Any untreated brain lesions >= 5 mm
• Active infection requiring intravenous systemic therapy
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study)
• Patients with a prior or concurrent malignancy within last 3 years whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen, per treating physician discretion, are not eligible for this trial
• Treatment with any investigational drug within 30 days prior to registration