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Chicago, IL—The experimental antibody-drug conjugate trastuzumab emtansine (T-DM1) demonstrated a significant improvement in progression-free survival (PFS) compared with capecitabine plus lapatinib among patients with HER2+ locally advanced or metastatic breast cancer (MBC) previously treated with a taxane and trastuzumab, primary results from the randomized phase 3 EMILIA trial1 reported here at the 2012 Annual Meeting of American Society of Clinical Oncology.

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T-DM1 comprises trastuzumab, a stable linker, and the potent microtubule-disrupting drug, DM1, a maytansine derivative.2 Joining trastuzumab directly to DM1 incorporates the antitumor activities of trastuzumab and the HER2-targeted delivery of DM1, noted Kimberly L. Blackwell, MD, professor of medicine and assistant professor of radiation oncology at Duke University Medical Center, Durham, NC.

The clinical rationale for EMILIA was based on two single-arm phase 2 trials of T-DM1 in patients who had received more than one HER2-directed therapies for MBC with objective response rates (ORR) of 25.9%3 and 34.5%4, respectively; a randomized phase 2 trial in patients without prior HER2-directed therapy for MBC in which median PFS was longer with T-DMI vs trastuzumab + docetaxel, 14.2 vs 9.2 months (HR 0.59; P=0.035);5 and a randomized, phase 3 study that demonstrated the superiority of capecitabine plus lapatinib vs capecitabine alone in women with HER2+ MBC that progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab.6

The study randomized patients with confirmed HER2+ MBC (IHC3+ and/or FISH+) who had prior treatment with taxane and trastuzumab and disease progression on metastatic therapy or within 6 months of adjuvant therapy to either T-DM1 3.6mg/kg IV every 3 weeks or capecitabine 1,000mg/m2 orally twice daily on days 1-14 every three weeks + lapatinib 1,250mg orally daily until disease progression.

Patients were stratified by world region, number of prior chemotherapy regimens for MBC or unresectable locally advanced breast cancer, and presence of visceral disease. Primary end points were PFS by independent review, OS, and safety. Key secondary end points were PFS by investigator, ORR, duration of response, and time to symptom progression. An interim OS analysis (efficacy boundary: HR=0.617; P=0.0003) was planned at the time of the final PFS analysis.

From February 2009 to October 2011, 991 patients were enrolled; 490 were treated in the T-DM1 arm and 488 in the capecitabine plus lapatinib arm. Clinical data cutoff was January 14, 2012.

Baseline demographics, prior therapy, and disease characteristics were balanced between the two arms. Median age was 53 years in both treatment arms. The majority of patients in each arm were white (72% and 75%, respectively) and 100% had ECOG PS 0 or 1. Duration of prior trastuzumab treatment was <1 year in 43% and 42% of patients and ≥1 year in 58% and 57% of those in the T-DM1 and capecitabine + lapatinib arm, respectively, with a median time since last trastuzumab therapy of 1.5 months in both arms. A total of 12% of patients in each arm had not received prior therapy for MBC.