Positive results continue to be reported for trastuzumab emtansine (T‑DM1), the antibody-drug conjugate linking trastuzumab (Herceptin) to a cytotoxic agent. Early results of the international phase III EMILIA study, presented at the 2012 ASCO Annual Meeting, showed a 35% reduction in risk of progression among patients with advanced HER2-overexpressing breast cancer who received T-DM1, compared to standard treatment with capecitabine (Xeloda) and lapatinib (Tykerb).¹

‘Breakthrough’ Results

“For patients facing metastatic breast cancer, this is a breakthrough,” said lead author Kimberly L. Blackwell, MD, of Duke Cancer Institute at Duke University, Durham, North Carolina.

Dr. Blackwell was referring not only to the 3.2-month improvement in progression-free survival, but to the tolerability of the novel agent, which disrupts HER2 signaling and delivers the cytotoxic DM1 component intracellularly. 

Co-investigator David Miles, MD, of Mount Vernon Hospital in London, United Kingdom, emphasized the favorable toxicity profile of T-DM1 in an interview with The ASCO Post.

“The issue with capacitabine/lapatinib is toxicity. You have a 20% incidence of very difficult-to-manage diarrhea, whereas with T-DM1 this was a negligible issue in the trial. From a patient point of view, in terms of side effects and quality of life, the outcomes are greatly superior with T-DM1,” Dr. Miles said. 

EMILIA Trial Details

EMILIA investigators randomly assigned 991 patients with HER2-positive locally advanced or metastatic breast cancer who had previously received a taxane and trastuzumab. Patients received T-DM1 (3.6 mg/kg IV every 3 weeks) or a combination regimen dubbed XL (capecitabine, 1,000 mg/m² twice daily on days 1–14 every 3 weeks, plus lapatinib, 1,250 mg daily) every 3 weeks until progression. Patients progressing on standard therapy were allowed to cross over to T-DM1.

By independent review after a median follow-up of approximately 1 year, T-DM1 delayed disease progression by 9.6 months in contrast to 6.4 months with capecitabine/lapatinib. This represented a 35% reduction in the risk of progression (P < .0001), which was also seen by investigator review, Dr. Blackwell reported at the ASCO Plenary Session.

“There was a consistency of effect,” she added. “Essentially no subgroup favored capecitabine/lapatinib treatment.” Only in women ≥ 65 years old was T-DM1 not superior to standard treatment.

Median overall survival was not reached with T-DM1, and was 23.3 months with capecitabine/lapatinib, for a 38% reduction in mortality risk (P = .0005). “However, the interim statistical stopping boundary based on number of deaths was not met,” she pointed out. Therefore, the difference is not yet statistically significant.

Despite lacking statistical significance, Dr. Blackwell maintained, “there is an apparent survival benefit with T-DM1.” More than 65% of the T-DM1 recipients were alive at the time of analysis, compared with 47.5% of the capecitabine/lapatinib group.

Objective response rates were 44% with T-DM1 and 31% with capecitabine/lapatinib, and median response duration was almost doubled with the antibody-drug conjugate: 12.6 vs 6.5 months. Patient-reported outcomes according to the FACT-Breast Trial Outcome Index and symptom progression were also significantly better with T-DM1, Dr. Blackwell reported.

Additional Data

An equally striking difference between the arms was observed in tolerability. Dose reductions were required for only 16.3% of the T-DM1 arm, compared to 53.4% with capecitabine and 27.3% with lapatinib. Median dose intensity was 99.9% with T-DM1, compared with 77.2% for capecitabine and 93.4% with lapatinib.

The most common adverse events of at least grade 3 for T-DM1 included thrombocytopenia (12.8% vs 0.2%) and transient elevations in alanine aminotransferase (2.9% vs 1.4%) and aspartate aminotransferase (4.3% vs 0.8%). As expected, capecitabine/lapatinib was associated with significantly more diarrhea, hand-foot syndrome, and vomiting. ■

Disclosure: Drs. Blackwell and Miles reported no potential conflicts of interest.

Reference

1. Blackwell KL, Miles D, Gianni L, et al: Primary results from EMILIA, a phase 3 study of trastuzumab emtansine (T-DM1) vs capecitabine and lapatinib in HER2-positive locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane. 2012 ASCO Annual Meeting. Abstract LBA1. Presented June 3, 2012.