Roche Holding AG, and its subsidiaries Genentech Inc and Chugai Pharmaceutical Co Ltd, are developing trastuzumab emtansine (trastuzumab-DM1) for the treatment of HER2+ metastatic breast cancer. Trastuzumab emtansine is a tumor-activated prodrug resulting from the conjugation of the humanized anti-HER2 mAb trastuzumab, which has been used in the treatment of breast cancer for over 10 years, with ImmunoGen Inc's cytotoxic and antimitotic maytansine derivative DM1. The maytansinoids bind microtubules in a manner similar to the vinca alkaloids; however, maytansinoids have been recognized to be 20- to 100-fold more potent at blocking mitosis. Nevertheless, the use of these compounds as single agents is limited by toxicity. By conjugating DM1 with trastuzumab, the delivery of the cytotoxic agent to target cells is more specific and reduces the safety concerns. In preclinical studies, the conjugation was effective in breast cancer cell lines resistant to trastuzumab, and demonstrated complete tumor regression in SCID mice bearing KPL4 breast cancer xenografts. Clinically, trastuzumab emtansine exhibited efficacy in patients with HER2+ metastatic breast cancer who had progressed on previous chemotherapy regimens or with trastuzumab therapy. Furthermore, preclinical studies have reported that trastuzumab emtansine potentiates the effect of a number of chemotherapeutic agents (including carboplatin, 5-fluorouracil and docetaxel), other antibodies, receptor tyrosine kinase inhibitors and PI3K inhibitors, and many of these combinations are set to be tested in humans. Trastuzumab emtansine offers an exciting new option for the treatment of patients with refractory, metastatic breast cancer.