T-DM1 Superior to Capecitabine plus Lapatinib in Advanced Breast Cancer

Chicago—The first phase 3 study to evaluate trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer found that the investigational antibody drug conjugate had superior efficacy and safety compared with an established regimen of capecitabine and lapatinib. Patients who took T-DM1 had significantly improved progression-free survival compared with the other group.

An interim analysis of overall survival (the coprimary end point) also favored T-DM1, although it did not meet the prespecified efficacy-stopping boundary. Kimberly L. Blackwell, MD, the study’s lead author and professor of medicine and assistant professor of radiation oncology at Duke University, said a final overall survival analysis is targeted at 632 events and is expected to occur in early 2014.

Dr. Blackwell noted that trastuzumab was introduced at the ASCO meeting in 1998 as an effective and innovative way of targeting cancer cells. Trastuzumab, a humanized monoclonal antibody, in combination with chemotherapy has been shown to improve survival in metastatic and early-stage breast cancer.

“Today, 14 years later, this same antibody has been improved in a way that we expect to benefit patients and lessen the toxicity of traditional chemotherapy through the use of an antibody drug conjugate,” said Dr. Blackwell, who presented the results in a plenary session at the ASCO meeting. “Targeted therapy for cancer has progressed another step forward with [this] study, and T-DM1 should offer an important therapeutic option in the treatment of HER2-positive breast cancer.”

In 2 previous phase 2, single-arm trials, patients taking T-DM1, who had been previously treated with trastuzumab, had objective response rates of 25.9% and 34.5%, respectively. Based on those results, the researchers designed the current study.

Patients were randomized at 213 sites in 26 countries in a 1:1 ratio to receive 3.6 mg/kg of T-DM1 intravenously every 3 weeks or 1000 mg/m² of capecitabine orally twice daily on days 1 through 14 and then every 3 weeks plus 1250 mg per day of oral lapatinib. They took the regimen until experiencing disease progression or unmanageable toxicity.

All of the 978 patients had received prior taxane therapy and trastuzumab. The first patient was treated on February 23, 2009, and the last patient was treated on October 13, 2011. The clinical data cut off for this analysis was January 14, 2012.

As assessed by an independent review board, patients in the T-DM1 group had a median progression-free survival of 9.6 months compared with 6.4 months in the capecitabine plus lapatinib group (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.55-0.77; P<.0001). Investigator-assessed progression-free survival (a secondary end point) found similar results (HR, 0.658; 95% CI, 0.56-0.77; P<.0001).

Dr. Blackwell said there was a “consistent treatment effect favoring T-DM1 in most subgroups,” and no subgroup efficacy analysis favored capecitabine plus lapatinib.

At the interim analysis, the median overall survival in the capecitabine plus lapatinib group was 23.3 months, which Dr. Blackwell called “quite good” and better than in many other phase 3 trials. The median overall survival had not been reached in the T-DM1 group. The absolute difference in overall survival was 7.7% at 1 year and 17.9% at 2 years in favor of T-DM1. After 2 years, 65.4% of patients in the T-DM1 group survived compared with 47.5% in the other group.

All-grade adverse events were similar between the groups, but there were more grade ≥3 adverse events (AEs) in patients treated with capecitabine and lapatinib (57.0% vs 40.8% in the T-DM1 arm). In addition, a higher percentage of patients in the capecitabine plus lapatinib group discontinued treatment because of an AE (10.7% vs 5.9%).

“I think [T-DM1] is the first of many antibody drug conjugates to follow that will link a potent anticancer agent to a targeted delivery system of an antibody,” Dr. Blackwell said. “I think this will offer a very important therapeutic option for patients faced with HER2-positive metastatic breast cancer.”