A Study of Tucatinib or Placebo With Trastuzumab and Pertuzumab for Metastatic HER2+ Breast Cancer

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