(ChemotherapyAdvisor) – Women with metastatic, HER2-positive breast cancer with tumors that express high levels of HER2 derived the greatest survival benefit from treatment with trastuzumab emtansine (T-DM1), according to biomarker subgroup analysis of the phase 3 EMILIA trial reported at the American Association for Cancer Research (AACR) Annual Meeting 2013, in Washington, DC.

“EMILIA was a landmark phase 3 clinical trial,” said José Baselga, MD, PhD, physician-in-chief at Memorial Sloan-Kettering Cancer Center, New York, NY. “It showed that T-DM1 prolonged progression-free and overall survival for patients with HER2-positive metastatic breast cancer that had been previously treated with trastuzumab and a taxane chemotherapy compared with lapatinib plus capecitabine. Also, it provided proof-of-concept that a new class of drugs called antibody-drug conjugates can benefit patients.”

Compared with capecitabine plus lapatinib, patients in all biomarker subgroups had longer progression-free survival (9.6 vs. 6.4 months) and overall survival (OS; 30.9 vs. 25.1 months) with T-DM1, reported Dr. Baselga and colleagues.

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Tumor tissue collected for HER2 testing from patients enrolled in EMILIA was also used for HER2 mRNA analysis by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and for PIK3CA assessment. Patients with tumor samples that expressed greater than the median amount of tumor HER2 mRNA were considered to have high levels of HER2; those with low levels of HER2 had tumor samples expressing the median amount of tumor HER2 mRNA or less.

Patients with tumors expressing higher levels of HER2 derived greater benefit from treatment with T-DM1 compared with patients with tumors expressing lower levels of HER2; OS was 34.1 versus 26.5 months (hazard ratio, 0.53; 95% CI: 0.37-0.76).

For women with tumors expressing higher levels of HER2, those receiving T-DM1 had a 47% decreased risk for death compared with those receiving lapatinib and capecitabine.

Patients treated with capecitabine plus lapatinib with PIK3CA mutations were found to have worse outcomes than those with wild type PIK3CA. “T-DM1-treated patients with PIK3CA mutations had a similar treatment benefit as those without, suggesting that the unique mechanism of action of T-DM1 may overcome PIK3CA mutation resistance,” he added.

“Even though everyone enrolled in the clinical trial had breast cancer expressing elevated levels of HER2, we know that each person’s tumor has different molecular features,” said Dr. Baselga. “Even the degree to which HER2 expression is elevated differs from patient to patient.

“Our findings are an important step toward identifying the best therapy for individual patients with HER2-positive breast cancer,” he added. “HER2-positive breast cancer is not a uniform disease; each patient is different. These data help us as we look to identify a panel of molecular features that we can use to make informed treatment decisions.”

Based on the EMILIA trial results, the U.S. Food and Drug Administration approved Kadcyla (ado-trastuzumab emtansine, or T-DM1) a trademark of Genentech, a member of the Roche Group, on February 22, 2013.

Abstract LB-63