T-DM1 Effective Prior to Surgery in Early Breast Cancer

June 24, 2015

Neoadjuvant ado-trastuzumab emtansine demonstrated promising complete pathological response in patients with hormone receptor-positive and HER2-positive early stage breast cancer

Nadia Harbeck, MD, PhD

Neoadjuvant ado-trastuzumab emtansine (T-DM1; Kadcyla) demonstrated promising pathological complete response (pCR) rates in patients with hormone receptor (HR)-positive and HER2-positive early stage breast cancer, according to findings from the phase II ADAPT trial.

In the 3-arm trial, patients were randomized to receive T-DM1 with or without endocrine therapy or trastuzumab plus endocrine therapy. The pCR rate was found to be substantially higher in the T-DM1 arms compared with trastuzumab plus endocrine therapy (P<.001). In the T-DM1 alone arm (n = 37) the pCR rate was 40.5%. In the T-DM1 plus endocrine therapy arm (n = 48) the pCR rate was 45.8%. In the trastuzumab plus endocrine therapy arm (n = 45) the pCR rate was just 6.7%.

Findings from the phase II study were presented by Nadia Harbeck, MD, PhD, head of the Breast Center, Oncological Therapy and Clinical Trials Unit, University of Munich, Germany, at the 2015 ASCO Annual Meeting. In January 2015, an independent data and safety monitoring board analyzed results from an interim analysis of 130 patients. As a result of the high-level of efficacy seen in the T-DM1 arms, the board recommended that the study should be stopped.

Of the 130 patients analyzed at the interim analysis, more than half were premenopausal (range, 45.8%-60%). The majority of tumors were larger than 2 centimeters (range, 45.9%-57.8%) and a third of patients were node positive (range, 27.1%-37.8%). Three-fourths of patients across all three arms had G3 disease.

In an exploratory analysis it was found that pCR rates differed substantially between pre- and post-menopausal patients treated with T-DM1. In premenopausal patients (n = 22), single-agent T-DM1 demonstrated a 27% pCR rate versus 60% in those who were postmenopausal. A substantial difference between was not observed between the two groups in the combination arm (45.5% vs 46.2%).

"In the premenopausal patients, adding endocrine therapy increased pCR from 27% to about 46%, whereas this was not the case in the postmenopsaul patients," Harbeck said. "This is an interim analysis and these are low numbers, but these need to be followed-up because in the postmenopausal patients we did see a slight decrease when endocrine therapy was added."

Across all arms of the ADAPT trial there were only 16 serious adverse events in 13 patients. The most common all-grade adverse events with single-agent T-DM1 were thrombocytopenia (30%), aspartate aminotransferase increase (19%), alanine aminotransferase increase (22%), and infections and infestations (11%).

In the T-DM1 combination arm, some of the adverse events seen with single-agent T-DM1 were less frequent. The most common all-grade adverse events in this arm were thrombocytopenia (15%), infections and infestations (15%), aspartate aminotransferase increase (10%), and alanine aminotransferase increase (6%).

"In our study, there was a lower frequency of higher grade events associated with T-DM1," Harbeck explained. "These were all treatment-naive patients, before they started T-DM1. In all other trials reported so far, patients had extensive pretreatment, including chemotherapy."

The pCR rates experienced by patients with single-agent T-DM1 were comparable to those seen in other clinical trials for patients with HER2+/HR+ early breast cancer. These findings suggest that T-DM1 should be explored further as a potential neoadjuvant treatment in this setting, Harbeck concluded.

Harbeck N, Gluz O, Christgen M, et al. Efficacy of 12-weeks of neoadjuvant TDM1 with or without endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer: WSG-ADAPT HER2+/HR+ phase II trial.J Clin Oncol.2015;33 (suppl; abstr 506).