Updated Data Show T-DM1 Improves Overall Survival in HER2-Positive Breast Cancer

Sunil Verma, MD

An updated analysis of the phase III EMILIA trial showed that the antibody-drug conjugate T-DM1 significantly extended survival compared with the combination of lapatinib/capecitabine in women with HER2-positive, unresectable, locally advanced or metastatic breast cancer. The data were presented at the European Society for Medical Oncology (ESMO) 2012 Congress.

At a median follow-up of about 20 months, T-DM1 reduced the mortality risk by 32% (hazard ratio [HR] = 0.68; 95% CI, 0.55-0.85; P <.001), with a 6-month difference favoring T-DM1. Median overall survival (OS; death from any cause) was 30.9 months for T-DM1 versus 25.1 months for lapatinib/capecitabine, which experts called “unprecedented” in metastatic breast cancer.

“The significant improvement in progression-free survival and overall survival as well as the favorable safety suggest that T-DM1 should be an important therapeutic option in the treatment of metastatic HER2-positive breast cancer,” said lead author Sunil Verma, MD, Sunnybrook Odette Cancer Center, Toronto, Ontario, Canada. The results of the EMILIA trial were simultaneously published online in the New England Journal of Medicine to coincide with Verma’s presentation (http://www.nejm.org).

The OS data presented at ESMO were from the second EMILIA interim analysis, with a data cutoff of July 31, 2012, when more than 50% of targeted survival events had occurred. Final OS data are expected in 2014.

T-DM1 is an antibody-drug conjugate linking trastuzumab to the potent chemotherapy (DM1), allowing intracellular delivery of chemotherapy that is said to be 500 times more cytotoxic than paclitaxel.

The EMILIA trial was conducted at 213 sites in 26 countries. Investigators randomized 991 patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane in a 1:1 ratio to T-DM1 or lapatinib/capecitabine. Pre-specified stratification factors included world region, number of prior chemotherapy regimens for metastatic breast cancer or unresectable locally advanced breast cancer, and presence of visceral disease.

Final progression-free survival (PFS) data, presented earlier at the 2012 ASCO Annual Meeting, showed a median PFS of 9.6 months with T-DM1 versus 6.4 months with lapatinib/capecitabine, a 35% reduction in the risk of progression favoring T-DM1 (HR = 0.65; 95% CI, 0.55-0.77; P <.001)

Objective response rates were 43.6% for T-DM1 versus 30.8% for lapatinib/capecitabine (P <.001).

Subgroup analysis showed favorable results for T-DM1 in most subgroups. Verma said that regional differences were probably due to different post-progression treatment in various countries.

Grade 3 or higher adverse events occurred more frequently with lapatinib/capecitabine: 57% versus 41% for T-DM1. Patients in the T-DM1 arm had a higher incidence of thrombocytopenia and increased serum aminotransferase levels, whereas those treated with lapatinib/capecitabine had higher rates of diarrhea, nausea, vomiting, and hand-foot syndrome. The rates of cardiac dysfunction were very low and similar in both treatment arms.

Formal discussant of this trial, Javier Cortes, MD, Vall d’Hebron University Hospital and Institute of Oncology, Barcelona, Spain, was quite impressed with the nearly 6-month improvement in survival. “I do not remember any paper in metastatic breast cancer with an improvement of 6 months. T-DM1 is clearly better than previous drugs for survival. This will benefit thousands of women.”

He also said that the cardiac safety data suggest that T-DM1 may be a good option for patients who cannot receive trastuzumab due to cardiac problems.

Genentech announced in August that it had submitted an application to the FDA for T-DM1 in HER2-positive metastatic breast cancer.

Verma S, Miles D, Gianni L. Updated overall survival results from EMILIA, a phase 3 study of trastuzumab emtansine (T-DM1) vs capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC). Paper presented at: 37th European Society for Medical Oncology Congress; September 28-October 2, 2012; Vienna, Austria. Abstract LBA12.

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