Compound Name:Ado-trastuzumabMolecular Target:HER-2Molecular Structure:humanized IgG1k mAbLicensed Indication:HER-2 positive metastatic breast cancerManufacturer and/or Distributor:Genentech/ ImmunogenInitial FDA Approval:2013Summary:

Ado-trastuzumab emtansine is the novel formulation of the anti-HER2 monoclonal antibody trastuzumab (Herceptin®) covalently linked by a thioether to the microtubule inhibitory drug DM1, which is a maytansine derivative. After binding to HER2 on the surface of tumor cells, ado-trastuzumab emtansine is internalized into lysosomes, where the toxic moiety is released. DM1 then binds to tubulin to disrupt microtubule networks, which causes cell cycle arrest and mitotic death. Ado-trastuzumab emtansine also has some of the same in vitro activities as trastuzumab, including inhibition of HER-2 mediated signaling and shedding, and cytotoxicity by ADCC.


Ado-trastuzumab emtansine is approved for treatment of patients with HER2-positive metastatic breast cancer who have previously been treated with trastuzumab and a taxane, separately or in combination. Subsequent to several phase II trials, approval was based on a single phase III randomized open-label trial comparing ado-trastuzumab emtansine to treatment with lapatinib plus capecitabine. Ado-trastuzumab emtansine provided improved overall survival and progression-free survival, as well as favorable responses by several other parameters.


Clinical trials in other cancers, including gastric cancer, are ongoing. Gastric cancers overexpress HER2 15-20% of the time. The ToGA trial demonstrated that patients who where HER2-positive with advanced gastric and gastroesophageal junction adenocarcinoma had a statistically significant improvement in overall survival when given trastuzumab in combination with 5-FU/capecitabine and cisplatin compared to those not given trastuzumab. Work with cell lines also shows potential for use in HER-2 positive bladder cancer. 


Safety concerns include hepatotoxicity, left ventricular dysfunction, embryo-fetal toxicity, infusion reactions, thrombocytopenia, and pulmonary or neurotoxicity.


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