A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer

This is a randomized, international, multi-center, double-blinded study in patients with
progressive unresectable locally advanced or metastatic HER2+ breast cancer who have had
prior treatment with trastuzumab, pertuzumab and T-DM1. Patients will be randomized in a 2:1
ratio to receive tucatinib or placebo in combination with capecitabine and trastuzumab.

Stratification factors include presence or history of treated or untreated brain metastases
or brain lesions of equivocal significance (yes/no), Eastern Cooperative Oncology Group
(ECOG) Performance Status (0 vs. 1), and region of world (US vs. Canada vs. Rest of World).

No crossover from placebo to tucatinib will be allowed.

Safety assessments will be performed at a minimum of once every three weeks throughout study
treatment and 30 days after the last dose of study drugs. Laboratory assessments will be
performed locally at sites. Left ventricular ejection fraction will be assessed by MUGA or
ECHO at screening and once every 12 weeks thereafter.

Contrast brain MRI will be performed at baseline in all patients. Efficacy assessments (CT of
chest, abdomen and pelvis at a minimum) utilize RECIST 1.1 and include patients with
evaluable tumors defined as measurable target lesions and non-measurable non-target lesions.
RECIST assessment is performed at baseline, every 6 weeks for the first 24 weeks, and then
every 9 weeks thereafter. Repeat MRI of the brain will be required on this same schedule only
in those patients with brain metastases identified at baseline. All treatment decisions are
made based upon investigator assessment. All patients undergo a repeat MRI of the brain
within 30 days of the end of treatment unless previously performed at time of disease
progression. Patients in both arms of the study will be followed for OS after completion of
study treatment.

Inclusion Criteria

- Histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ
hybridization (ISH) 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

- Left ventricular ejection fraction (LVEF) ≥ 50%

- CNS Inclusion - Based on screening brain magnetic resonance imaging (MRI), patients
must have one of the following:

1. No evidence of brain metastases

2. Untreated brain metastases not needing immediate local therapy

3. Previously treated brain metastases not needing immediate local therapy

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

2. 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:

- 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.

- Other sites of disease assessable by RECIST 1.1 are present

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

Exclusion Criteria

- Previously been treated with:

1. lapatinib within 12 months of starting study treatment (except in cases where
lapatinib was given for ≤ 21 days and was discontinued for reasons other than
disease progression or toxicity)

2. neratinib, afatinib, or other investigational HER2/epidermal growth factor
receptor (EGFR) tyrosine kinase inhibitor (TKI) at any time previously

3. capecitabine (or other fluoropyrimidine) for metastatic disease except in cases
where capecitabine was given for < 21 days and was discontinued for reasons other
than disease progression or toxicity. Patients who have received capecitabine for
adjuvant or neoadjuvant treatment at least 12 months prior to starting study
treatment are eligible.

- Clinically significant cardiopulmonary disease

- Carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease

- Positive for human immunodeficiency virus (HIV)

- Unable for any reason to undergo MRI of the brain

- Have used a strong CYP3A4 or CYP2C8 inhibitor within 5 half-lives of the inhibitor, or
a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment

- CNS Exclusion - Based on screening brain MRI, patients must not have any of the
following:

1. Any untreated brain lesions > 2.0 cm in size, unless approved by medical monitor

2. Ongoing use of systemic corticosteroids for control of symptoms of brain
metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent)

3. Any brain lesion thought to require immediate local therapy. Patients who undergo
local treatment for such lesions identified by screening contrast brain MRI may
still be eligible for the study based on criteria described under CNS inclusion
criteria

4. Known or suspected leptomeningeal disease (LMD)

5. Poorly controlled seizures