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

Inclusion Criteria

• Centrally confirmed HER2+ breast carcinoma according to the 2018 American Society of Clinical Oncologists (ASCO) College of American Pathologists (CAP) guidelines prior to randomization (defined as a 3+ score on immunohistochemistry (IHC) and/or 2+ IHC and concurrent positive by ISH).

• Have unresectable locally advanced or metastatic disease.

  • If recurrent (after [neo]adjuvant therapy), must be at least 6 month treatment free from any trastuzumab and pertuzumab received in the early breast cancer setting for advanced HER2+ disease.

• Have received 4-8 cycles of pre-study induction therapy including only trastuzumab, pertuzumab, and taxane as first-line of therapy for the treatment of advanced breast cancer prior to study enrollment. Participants are eligible provided they are without evidence of disease progression following completion of induction therapy.

• 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-enhanced brain magnetic resonance imaging (MRI), participants may have any of the following:

  • No evidence of brain metastases

  • Untreated brain metastases which are asymptomatic not needing immediate local treatment 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 tyrosine kinase inhibitor targeting HER2 and/or epidermal growth factor receptor (EGFR) 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-enhanced MRI of the brain

• CNS Exclusion - Based on screening brain MRI and clinical assessment

  • Symptomatic brain metastasis after CNS-directed local therapy
  • 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