Background: Despite significant advances in targeted therapy, HER2+ MBC remains incurable. Ideal treatment includes pertuzumab (P) and T in combination with a taxane in the first line setting, followed by ado-trastuzumab emtansine (K) on progression. Optimal treatment regimens in the > third line of therapy are not defined, but continued anti-HER2 therapy is recommended. m is a Fc-modified monoclonal antibody (Mab) to HER2 that recognizes the same epitope on HER2 as does T with similar affinity. m demonstrates increased affinity to the activating CD16A Fc-receptor found on NK cells and macrophages and decreased affinity to the inhibitory CD32B receptor compared to T. In vitro studies showed enhanced antibody dependent cell-mediated cytotoxicity compared to T. In a phase I dose expansion trial, m showed single agent clinical activity against HER2+ tumors in patients previously treated with T and other anti-HER2 agents. Methods: SOPHIA is a randomized, prospective study testing the hypothesis that m plus CTX is more effective than T plus CTX in patients previously treated for HER2+ MBC. Sequential primary endpoints are centrally assessed progression free survival (PFS) and overall survival (OS). The study size of 530 patients is based on a hazard ratio for OS of 0.75 with a power of 80%. Secondary endpoints are investigator assessed PFS and central response rate. Eligibility includes prior treatment with T, P, and K, no more than 3 prior lines of therapy for MBC, prior demonstration of HER2+ status at a local reference laboratory, and absence of active brain metastases. Eligible patients are randomized 1:1 to receive CTX (physician’s choice: capecitabine, eribulin, gemcitabine or vinorelbine) plus either m or T until disease progression or toxicity. Antibody may be continued after stopping CTX in patients with responding or stable disease. Progress to date: The trial was initiated July 2015 and is ongoing in the US and Europe with planned expansion to Korea and Israel. ClinicalTrials.gov Identifier NCT02492711; Eudract 2015-000380-13 Clinical trial information: NCT02492711