• Written informed consent, according to local guidelines, signed and dated by the patient or by a legal guardian prior to the performance of any study-specific procedures, sampling, or analyses

• At least 18 years-of-age at the time of signature of the informed consent form (ICF)

• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1

• Have a confirmed diagnosis of locally advanced/metastatic HER2+ breast cancer (based on local laboratory testing per American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines immunohistochemistry 3+ (IHC3+) or fluorescence in situ hybridization + (FISH+))

• Have had prior treatment with at least 1 line of anti-HER2 therapy for locally advanced/metastatic disease or relapsed within 6 months of completion of adjuvant anti-HER2 therapy. Prior treatment with tucatinib in the metastatic setting is allowed

• Measurable disease as measured by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

• Females of child-bearing potential should be using adequate contraceptive measures from the time of screening until 6 months following the last dose of study drug(s), should not be breast feeding and must have a negative pregnancy test prior to start of dosing, or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:

‣ Post-menopausal: defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments

⁃ Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, but not tubal ligation

⁃ Women under 50 years-of-age will be considered postmenopausal if they have been amenorrheic for at least 12 months following the cessation of exogenous hormonal treatments, and have serum follicle-stimulating hormone and luteinizing hormone levels in the postmenopausal range for the institution.

• Male patients with female partners of childbearing potential and female patients of childbearing potential are required to use two forms of acceptable contraception, including one barrier method, during their participation in the study and for 6 months following last dose. Male patients must also refrain from donating sperm during their participation in the study.

• Adequate hematologic function

‣ Absolute neutrophil count (ANC) ≥1500/µL

⁃ Platelet count ≥100,000/µL (no transfusions allowed to meet this requirement)

⁃ Hemoglobin ≥9 g/dL (at least 2-week washout from any transfusion)

• Adequate hepatic function

‣ Total bilirubin ≤1.5 × upper limit of normal (ULN). Exception: participants with known history of Gilbert's Syndrome who have a direct bilirubin ≤1.5 × ULN in addition to a normal aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are eligible.

⁃ AST and ALT ≤2.5 × ULN (≤5 × ULN if liver metastases are present)

• Estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73 m2

• Left ventricular ejection fraction (LVEF) ≥50% based on screening echocardiogram (ECHO)/multigated acquisition (MUGA)

• Central nervous system (CNS) Inclusion - Based on screening contrast brain magnetic resonance imaging (MRI), patients must have one of the following:

‣ No evidence of brain metastases

⁃ Untreated brain metastases not needing immediate local therapy. For patients with untreated CNS lesions \>2.0 cm on screening contrast brain MRI, discussion with and approval from the Medical Monitor is required prior to enrollment.

⁃ Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions.

⁃ Previously treated brain metastases:

• Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy, provided that there is no clinical indication for immediate re-treatment with local therapy in the opinion of the Investigator.

• Patients treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during screening for this study may be eligible to enroll if all of the following criteria are met:

• Time since whole brain radiotherapy (WBRT) is ≥14 days prior to first dose of treatment, time since stereotactic radiosurgery (SRS) is ≥7 days prior to first dose of treatment, or time since surgical resection is ≥28 days

• Other sites of disease assessable by RECIST 1.1 are present