Confirmed survival benefit of trastuzumab emtansine (T-DM1) over capecitabine plus lapatinib: updated results from the EMILIA trial

One of the highlights at the 2012 annual meeting of the American Society of Medical Oncology (ASCO) was the presentation of the EMILIA study. During this year’s annual symposium of the European Society of Medical Oncology (ESMO) the EMILIA investigators confirmed the impressive increase in overall survival (OS) of women with HER2-positive advanced breast cancer that are treated with trastuzumab emtansine (T-DM1) compared to capecitabine plus lapatinib. Moreover, the safety profile of T-DM1 was shown to be favourable to that of lapatinib plus capecitabine.

In the phase III EMILIA study, a total of 991 women with HER2-positive locally advanced or metastatic breast cancer, who were previously treated with taxane and trastuzumab and who had disease progression on metastatic therapy or within six months of adjuvant treatment, were randomly assigned to receive T-DM1 (3.6mg/kg q3w IV) or capecitabine (1000mg/m2PO bid days 1-14, q3w) plus lapatinib (1250mg/day PO q4d). The primary endpoints of the study were progression-free survival (PFS) by independent review, overall survival (OS) and safety, while secondary objectives included PFS by investigator assessment, objective response rate (ORR) and duration of response (DR).

Both arms in this study were well balanced for patient and disease characteristics. Twelve percent of the patients in both study arms did not receive prior therapy for metastatic breast cancer. The median dose intensity in the study was 77.2% for capecitabine, 93.4% for lapatinib and 99.9% for T-DM1. During ASCO 2012, T-DM1 was shown to be associated with a 3.2 increase in PFS compared to capecitabine-lapatinib (9.6 vs. 6.4 months; HR[95%CI]: 0.65[0.55-0.77]; p 0.0001). This PFS advantage was maintained across all investigated subgroups. The first interim analysis of OS demonstrated a significant survival benefit of T-DM1 over lapatinib-capecitabine (not reached vs. 23.3 months; HR[95%CI]: 0.621[0.48-0.81]; p=0.0005). The confirmatory OS analysis, presented during ESMO 2012, demonstrated that T-DM1 is associated with an increase of 5.8 in OS compared to capecitabine plus lapatinib (30.9 vs. 25.1 months; HR[95%CI]: 0682[0.55-0.85]; p=0.0006). In this confirmatory analysis, the OS rates at 12 and 24 months were 85.2% and 78.4% and 64.7% and 51.8% for T-DMA and lapatinib-capecitabine respectively. In addition to this, T-DM1 was associated with a significantly better ORR (p=0.0002) and DR (12.6 months with T-DM1 vs. 6.5 months with capecitabine plus lapatinib). In general, the incidence of grade 3/4 undesirable effects was lower with T-DM1 compared to capecitabine plus lapatinib (40.8% vs. 57.0%). This was also the case for the rate of undesirable effects leading to treatment discontinuation (5.9% and. 10.7% respectively). The most commonly observed grade 3/4 undesirable effects with lapatinib plus capecitabine were diarrhoea (20.7%), hand-foot syndrome (16.4%), vomiting (4.5%), neutropenia (4.3%) and hypokalmia (4.1%). For T-DM1 the most common grade 3/4 undesirable effects were thrombocytopenia (12.9%) and increased levels of AST (4.3%) and ALT (2.9%).

In summary, the EMILIA study demonstrates that T-DM1 is associated with a significant improvement in PFS and OS compared to combination therapy with capecitabine and lapatinib. Moreover, all secondary endpoints including ORR and DR were also better with T-DM1. Interestingly, this impressive efficacy does not come at the cost of increased toxicity with the safety profile of T-DM1 comparing favourable to that of lapatinib plus capecitabine. As such, T-DM1 should form an important therapeutic option in the management of HER2-positive metastatic breast cancer.

Reference

Verma S, Miles D, Gianni L et al. Updated overall survival 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. Presented at ESMO 2012, Abstract LBA12.