Background: HER2 gene product is overexpressed in ~20% of breast cancer and is associated with an aggressive phenotype and poor prognosis. Finding suitable patients with HER2+ MBC who adhere to strict protocol criteria, coupled with various competitive clinical trials presents recruitment challenges. A 3-trial approach that enrolls patients in different HER2+ MBC settings with nonoverlapping inclusion criteria may boost recruitment at each center. Methods: Three ongoing global phase III trials are examining the clinical profile of lapatinib (Table). COMPLETE (EGF108919; NCT00667251) is a study of taxane-based chemotherapy with lapatinib or trastuzumab, followed by lapatinib or trastuzumab monotherapy, as first-line therapy for HER2+ MBC patients. The primary endpoint is progression-free survival (PFS); secondary endpoints include overall survival (OS), time to CNS metastases at first progression, and incidence of CNS metastases at progression. EGF114299 (NCT01160211) tests an aromatase inhibitor (AI) in combination with lapatinib, trastuzumab, or both in HR+, HER2+ postmenopausal MBC patients. The primary endpoint compares OS in the lapatinib/trastuzumab/AI arm vs trastuzumab/AI arm. Secondary endpoints include OS in the lapatinib/AI vs trastuzumab/AI arms and lapatinib/trastuzumab/AI vs lapatinib/AI arms, PFS, and biomarker evaluation. CEREBEL (EGF111438; NCT00820222) examines the incidence of CNS metastasis as site of first relapse on lapatinib+capecitabine vs trastuzumab+capecitabine in HER2+ MBC patients previously treated with anthracyclines or taxanes and with an independently reviewed baseline MRI scan confirming no CNS metastases. Secondary endpoints include PFS, time to first CNS metastasis, and OS. Each study is open to accrual and will further elucidate the role of lapatinib in multiple settings of HER2+ MBC.