A Randomized, Multicenter, Phase III Open-label Study of the Efficacy and Safety of Trastuzumab Emtansine vs. Capecitabine + Lapatinib in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer Who Have Received Prior Trastuzumab-based Therapy

Inclusion Criteria:

- (Human epidermal growth factor receptor 2 (HER2) status must be prospectively,
centrally tested and be HER2-positive based on central laboratory assay results.

- Histologically or cytologically confirmed invasive breast cancer.

- Prior treatment for breast cancer in the adjuvant, unresectable, locally advanced, or
metastatic setting must include both a taxane, alone or in combination with another
agent, and trastuzumab, alone or in combination with another agent.

- Documented progression of incurable, unresectable, locally advanced or metastatic
breast cancer, defined by the investigator.

- Measurable and/or nonmeasurable disease; patients with central nervous system
(CNS)-only disease are excluded.

- Cardiac ejection fraction ≥ 50% by either echocardiogram (ECHO) or multi-gated
acquisition (MUGA) scan.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

- For women of childbearing potential and men with partners of childbearing potential,
agreement to use a highly effective, non-hormonal form of contraception;
contraception use should continue for the duration of the study treatment and for at
least 6 months after the last dose of study treatment.

Exclusion Criteria:

- History of treatment with trastuzumab emtansine (T-DM1).

- Prior treatment with lapatinib or capecitabine.

- Peripheral neuropathy of Grade ≥ 3 per National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI-CTCAE), Version 3.0.

- History of other malignancy within the last 5 years, except for appropriately treated
carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 1 uterine cancer,
synchronous or previously diagnosed HER2-positive breast cancer, or cancers with a
similar curative outcome as those mentioned above.

- History of receiving any anti-cancer drug/biologic or investigational treatment
within 21 days prior to randomization except hormone therapy, which could be given up
to 7 days prior to randomization; recovery of treatment-related toxicity consistent
with other eligibility criteria.

- History of radiation therapy within 14 days of randomization.

- Brain metastases that are untreated, symptomatic, or require therapy to control
symptoms, as well as any history of radiation, surgery, or other therapy, including
steroids, to control symptoms from brain metastases within 2 months (60 days) of
randomization.

- History of symptomatic congestive heart failure (CHF) or serious cardiac arrhythmia
requiring treatment.

- History of myocardial infarction or unstable angina within 6 months of randomization.

- Current dyspnea at rest due to complications of advanced malignancy or current
requirement for continuous oxygen therapy.

- Current severe, uncontrolled systemic disease (eg, clinically significant
cardiovascular, pulmonary, or metabolic disease).

- Pregnancy or lactation.

- Current known active infection with human immunodeficiency virus (HIV), hepatitis B
virus, or hepatitis C virus.

- Presence of conditions that could affect gastrointestinal absorption: Malabsorption
syndrome, resection of the small bowel or stomach, and ulcerative colitis.

- History of intolerance (such as Grade 3-4 infusion reaction) to trastuzumab.

- Known hypersensitivity to 5-fluorouracil or known dihydropyrimidine dehydrogenase
deficiency.

- Current treatment with sorivudine or its chemically related analogs, such as
brivudine.