A Phase II, Randomized, Open-label Study of Lapatinib Plus Chemotherapy Versus Trastuzumab Plus Chemotherapy in HER2-positive and p95HER2-positive Metastatic Breast Cancer

Inclusion Criteria: * Female ≥ 18 years of age * Histologically or cytologically confirmed invasive breast cancer with distant metastasis(ses) (designated as Stage IV or metastatic breast cancer) * Diagnosis with Stage IV or metastatic disease at either primary diagnosis or recurrence * Not received prior systemic or local treatment (e.g., chemotherapy, endocrine or radiotherapy) for Stage IV/metastatic breast cancer * Prior adjuvant and/or neo-adjuvant therapy is permitted * Documentation of HER2 overexpression or gene amplification, in the invasive component of either a metastatic disease site or primary tumor, defined as: 3+ by IHC and/or HER2/neu gene amplification by fluorescence, chromogenic or silver in situ hybridization \[FISH, CISH or SISH; \>6 HER2/neu gene copies per nucleus or a FISH, CISH or SISH test ratio (HER2 gene copies to chromosome 17 signals) of ≥2.0\] * Documentation by the central laboratory of positive p95HER2 expression in the invasive component of either a metastatic disease site (preferred) or primary tumor * No history of CNS metastases (including leptomeningeal involvement) or stable CNS metastases (defined as asymptomatic and off steroids for ≥ 3 months) * Baseline Left Ventricular Ejection Fraction (LVEF) ≥50% measured by echocardiography (ECHO) or multi-gated acquisition scan (MUGA) * Recovered or stabilized from all adverse events associated with prior anti-cancer therapies, including radiotherapy, at the time of screening * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 * Have adequate marrow and organ function as defined as: SYSTEM LABORATORY VALUES Hematologic ANC ≥1.5 x 109/L Hemoglobin ≥9 g/dL (after transfusion if needed) Platelets ≥100 x 109/L Hepatic Albumin ≥ 2.5 g/dL Serum bilirubin ≤1.5 x ULN unless due to Gilbert's syndrome AST and ALT ≤3 x ULN Renal Calculated creatinine clearance ≥ 40 mL/min Serum Creatinine ≤1.5 mg/dL or 132.6µmol/L (Abbreviations: ANC, absolute neutrophil count; ULN, upper limit of normal; AST, aspartate aminotransferase; ALT, alanine aminotransferase) * Women of childbearing potential, including women whose last menstrual period was \<12 months ago (unless surgically sterile) must have a negative serum pregnancy test and agree to use effective contraception, as defined in protocol * Signed Informed Consent Form Exclusion Criteria: * History of other malignancy. Exception: Subjects who have been disease-free for 5 years or subjects with a history of completely resected non-melanoma skin cancer (basal or squamous) are eligible * Concurrent anti-cancer treatment or concurrent treatment with an investigational drug * Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment * Prior treatment with anti-HER2 therapy, except trastuzumab or lapatinib (time from last dose of trastuzumab or lapatinib to randomization must be ≥3 months) * Serious cardiac illness or medical condition including but not confined to: * Uncontrolled arrhythmias * Uncontrolled or symptomatic angina * History of congestive heart failure (CHF) * Documented myocardial infarction \<6 months from study entry * Current active hepatic or biliary disease (with exception of Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment) * Concurrent disease or condition, or any pre-existing medical disorder that in the opinion of the investigator may interfere with the subject's safety, obtaining informed consent or compliance to the study procedures * Pregnant or lactating female * Any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels (consult with GSK Medical Monitor if uncertain about eligibility) * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the study drugs or their excipients that, in the opinion of the investigator contra-indicates participation