Ado-trastuzumab emtansine (Kadcyla®/T-DM1 Genentech/Roche), an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker, has shown clinical activity in HER2+ (human epidermal growth factor receptor 2-positive) metastatic breast cancer patients.

Harukaze Yamamoto and his team of researchers at Department of Breast and Medical Oncology, National Cancer Center Hospital in Tokyo, Japan and the Department of Medical Oncology and Translational Research Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan, evaluated the maximum tolerated dose, toxicity and pharmacokinetics of trastuzumab emtansine in Japanese breast cancer patients. The study results were published in the October 20, 2014 online first edition of the Japanese Journal of Clinical Oncology.

Trial Design
In this study, inoperable advanced or recurrent human epidermal growth factor receptor 2-positive breast cancer patients were administered ado-trastuzumab emtansine intravenously at a dose of 1.8, 2.4 or 3.6 mg/kg every 3 weeks. The maximum tolerated dose was estimated using the continual reassessment method.


A total of 10 patients enrolled in this study were given ado-trastuzumab emtansine for a median of seven cycles. The dose-limiting toxicity was grade 3 elevation of aspartate aminotransferase/alanine aminotransferase at the 2.4 mg/kg dose level. The maximum tolerated dose was estimated to be 3.6 mg/kg because at the point when dose-limiting toxicity was evaluable in 10 patients, the probability of dose-limiting toxicity estimated using the continual reassessment method was closest to 25% at a dose of 3.6 mg/kg and this was unchanged by the results for patients enrolled after that.

Study Results
The researchers noted that ado-trastuzumab emtansine up to 3.6 mg/kg was well tolerated by Japanese breast cancer patients. The most frequent adverse events included nausea, arthralgia, fever, fatigue and decreased appetite. Thrombocytopenia and hepatotoxicity tended to be more severe than was seen in Western patients in previous trastuzumab emtansine trials, those adverse events recovered without special supportive treatment.

In general, the study results showed that most of the observed adverse events were generally tolerable. The maximum concentration and area under the concentration-time curve increased linearly with the dose.

Published in: Japanese Journal of Clinical Oncology