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 ofClinical Oncologists (ASCO) College of American Pathologists (CAP) guidelines priorto randomization (defined as a 3+ score on immunohistochemistry (IHC) and/or 2+ IHCand concurrent positive by ISH).

• Have unresectable locally advanced or metastatic disease.

• If recurrent (after [neo]adjuvant therapy), must be at least 6 month treatmentfree from any trastuzumab and pertuzumab received in the early breast cancersetting 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 breastcancer prior to study enrollment. Participants are eligible provided they arewithout evidence of disease progression following completion of induction therapy.

• Known hormone receptor status (per local guidelines; may be hormone receptorpositive [HR+] or negative [HR-])

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

• CNS Inclusion - Based on screening contrast-enhanced brain magnetic resonanceimaging (MRI), participants may have any of the following:

• No evidence of brain metastases

• Untreated brain metastases which are asymptomatic not needing immediate localtreatment and, if identified on prior brain imaging, without evidence ofprogression 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 haveprogressed since treatment

Exclusion Criteria:

• Prior treatment with any tyrosine kinase inhibitor targeting HER2 and/or epidermalgrowth factor receptor (EGFR) including pyrotinib, lapatinib, tucatinib, neratinib,and afatinib (except neratinib if given in extended adjuvant setting and ≥ 12 monthshave 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 ofdexamethasone (or equivalent)

• Any untreated brain lesion in an anatomic site which may pose risk toparticipant

• Known or suspected leptomeningeal disease (LMD)

• Poorly controlled (>1/week) seizures, or other persistent neurologic symptoms