Chemotherapy and Lapatinib or Trastuzumab in Treating Women With HER2/Neu-Positive Metastatic Breast Cancer

Key inclusion criteria:

• Histologically confirmed adenocarcinoma of the breast.

• MBC (stage IV) at primary diagnosis or at relapse after curative intent therapy.

• Local or central laboratory confirmed HER2/neu overexpressing and/or amplifieddisease in the invasive component of the primary or metastatic lesion as defined by:

1. 3+ over expression by immunohistochemistry (IHC) (>30% of invasive tumourcells);

2. 2+ or 3+ (in 30% or less neoplastic cells) overexpression by IHC analysis ANDfluorescence or chromogenic in situ hybridization (FISH/CISH) testdemonstrating HER2/neu gene amplification;

3. HER2/neu gene amplification by FISH/CISH [>6 HER2/neu gene copies per nucleus,or a FISH/CISH ratio (HER2 gene copies to chromosome 17 signals) of >=2.2]

• Subjects must have had evidence of metastatic disease, but measurable disease wasnot mandatory. To be considered evaluable for overall response rate (CR and PR),subjects must have had at least 1 measurable lesion as follows:

1. X-ray, physical exam >=20 mm.

2. Conventional computed tomography (CT) scan, magnetic resonance imaging (MRI) >=20 mm.

3. Spiral CT scan >=10 mm.

Key exclusion criteria:

• Subjects with a history of other malignancies, except: adequately treated ductalcarcinoma in-situ or lobular carcinoma in-situ, adequately treated non-melanoma skincancer, curatively treated in-situ cancer of the cervix, or other solid tumor (non-breast) curatively treated with no evidence of disease for >=5 years.

• Subjects who had received prior chemotherapy, immunotherapy, biologic therapy orHER2/neu targeted therapy for recurrent or MBC.

• Subjects receiving ongoing anti-cancer treatment or other investigationalanti-cancer agents for breast cancer or subjects who had used an investigationaldrug within 30 days or 5 half-lives (if known), whichever was longer, preceding thedate of randomization.

• Subjects with: CNS metastases (including leptomeningeal involvement), seriouscardiac illness, peripheral neuropathy grade 2 or greater, subjects withgastrointestinal tract disease, subjects receiving CYP3A4 inhibitors or inducers,and subjects with history of allergic or hypersensitivity reactions to any studydrug or their excipients.