Inclusion Criteria:

• Centrally confirmed HER2+ breast carcinoma per 2018 American Society of Clinical Oncologists (ASCO) College of American Pathologists (CAP) guidelines.
• Have unresectable locally advanced or metastatic disease.
• If recurrent (after [neo]adjuvant therapy), must be at least 6 month treatment free from any trastuzumab or pertuzumab received for advanced HER2+ disease.
• Have received 4-8 cycles (21 day cycles) of previous treatment with trastuzumab, pertuzumab, and taxane as first-line therapy for advanced HER2+ breast cancer with no evidence of disease progression.
• Known hormone receptor status (per local guidelines; may be hormone receptor positive [HR+] or negative [HR-]).
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 -CNS Inclusion.
• Based on screening contrast brain magnetic resonance imaging (MRI), participants may have any of the following:
  • No evidence of brain metastases;
  • Untreated brain metastases which are asymptomatic and, if identified on prior brain imaging, without evidence of progression since starting first-line induction therapy with trastuzumab, pertuzumab, and taxane;
  • Previously treated brain metastases which are asymptomatic;
  • Brain metastases previously treated with local therapy must not have progressed since treatment.

Exclusion Criteria:

• Prior treatment with any anti-HER2 and/or anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor including pyrotinib, lapatinib, tucatinib, neratinib, and afatinib (except neratinib if given in extended adjuvant setting and ≥ 12 months have elapsed since last neratinib dose prior to start of study drug).
• Unable to undergo contrast MRI of the brain -

CNS Exclusion:

• Based on screening brain MRI and clinical assessment.
• Symptomatic brain metastasis.
• Progression of brain metastases since starting first line trastuzumab, pertuzumab, and taxane.
• Ongoing use of systemic corticosteroids at a total daily dose of > 2 mg of dexamethasone (or equivalent).
• Any untreated brain lesion in an anatomic site which may pose risk to participant.
• Known or suspected leptomeningeal disease (LMD).
• Poorly controlled (> 1/week) seizures, or other persistent neurologic symptoms.

Eligibility last updated 2/28/22. Questions regarding updates should be directed to the study team contact.