Phase 2 Randomized, Double-Blinded, Controlled Study of Tucatinib vs Placebo in Combination With Capecitabine and Trastuzumab in Patients With Pretreated Unresectable Locally Advanced or Metastatic HER2+ Breast Carcinoma

• Histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ hybridization (ISH), immunohistochemistry (IHC), or fluorescence in situ hybridization (FISH) methodology

• Received previous treatment with trastuzumab, pertuzumab, and T-DM1

• Progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy

• Have measurable or non-measurable disease assessable by RECIST 1.1

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

• Adequate hepatic and renal function and hematologic parameters

• Left ventricular ejection fraction (LVEF) ≥ 50%

• CNS Inclusion - Based on screening 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

⁃ Previously treated brain metastases not needing immediate local therapy

• Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy

∙ 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 the following criteria are met:

‣ i. Time since whole brain radiation therapy (WBRT) is ≥ 21 days prior to first dose of study treatment, time since stereotactic radiosurgery (SRS) is ≥ 7 days prior to first dose of study treatment, or time since surgical resection is ≥ 28 days.

‣ ii. Other sites of disease assessable by RECIST 1.1 are present

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