I’m happy to present to you the overall survival results from the TH3RESA study which is a randomised phase III trial comparing T-DM1 versus a treatment of physician’s choice in patients with HER2 positive metastatic breast cancer previously treated with a taxane, trastuzumab and lapatinib.

T-DM1 is an antibody drug conjugate composed of trastuzumab which is linked to DM1, a cytotoxic microtubule inhibitor. T-DM1 is approved as a single agent for the treatment of patients with HER2 positive metastatic breast cancer previously treated with trastuzumab and a taxane. T-DM1 is approved based on the phase III EMILIA study which compared T-DM1 versus capecitabine and lapatinib where it prolonged progression free survival by 3 months and overall survival by nearly 6 months.

The goal of the TH3RESA study was to investigate T-DM1 in a more advanced population compared to the EMILIA study. The main inclusion criteria were HER2 positive advanced breast cancer and two or more prior HER2 directed therapies for advanced breast cancer, including trastuzumab, lapatinib and a taxane. Patients were randomised to T-DM1 at the registered dose or to a treatment of physician’s choice in a two to one randomisation. Importantly, the study was amended in September 2012 when the EMILIA study showed overall survival benefit. From that moment patients in the treatment of physician’s choice arm were allowed to cross over to T-DM1 at progression.  Progression free survival by investigator and overall survival were co-primary endpoints for the TH3RESA study.

Concerning statistical analysis, the overall type 1 error rate of 5% was split asymmetrically between the two co-primary endpoints, progression free survival and overall survival. The primary progression free survival analysis was already presented before and showed that progression free survival increased from 3.3 months with treatment of physician’s choice, to 6.2 months with T-DM1. At that moment the first interim overall survival analysis was performed with only 21% of targeted events reached resulting in a trend for improved overall survival but at that point not yet crossing the stopping boundary.

So here we present the second interim overall survival analysis with 69% of events reached and the median follow-up of 30.5 months. If this second interim overall survival analysis would cross the pre-specified stopping boundary of 0.012 this would also be the final overall survival analysis for TH3RESA.

The main baseline characteristics are shown here. You can see that about half of the patients had ER positive disease and three-quarters had visceral involvement in both groups. More than half of the patients received four or more prior regimens for advanced breast cancer in both groups and brain metastases were present at baseline in around 10% of patients and needed to be treated and stabilised before inclusion.

The treatment of physician’s choice consisted in 80% of cases of trastuzumab-containing combinations, mostly with chemotherapy but also with lapatinib or hormonal therapy. Chemotherapy as a single agent was chosen in 16.8% as the treatment of physician’s choice.

At the cut-off date 79% and 67% discontinued the study, mostly because of death in both arms. Post progression therapy was recorded in 62% and 46% respectively. Importantly, 44.9% of the patients in the treatment of physician’s choice arm crossed over to T-DM1 at progression within the study and another 6.6% in that arm crossed over to T-DM1 as a non-study treatment. So at least 50% of patients in the control arm received T-DM1 after progression on their treatment of physician’s choice.

This slide shows the overall survival analysis. Median overall survival improved by 6.9 months from 15.8 months in the treatment of physician’s choice arm to 22.7 months in the T-DM1 arm with a stratified hazard ratio of 0.68 and a corresponding p-value of 0.0007. Since this clearly crossed the pre-specified crossing boundary this analysis is also the final overall survival analysis for TH3RESA. Subgroup analysis showed no clear differences in different subgroups, as you can read, only for world region we noticed some trends for improved benefits outside of the US versus the US but we should be cautious because these are small numbers and the confidence intervals are wide.

Non-haematological grade 3 or higher toxicity was more frequent in the control arm for all the registered side effects and the most important difference was seen for diarrhoea. For haematological grade 3 or higher adverse events thrombocytopenia was more frequent in the T-DM1 arm while neutropenia and febrile neutropenia were more frequent in the treatment of physician’s choice arm.

So, in conclusion, T-DM1 demonstrated a clinically meaningful and statistically significant improvement in overall survival compared to a treatment of physician’s choice in patients with HER2 positive metastatic breast cancer previously treated with a taxane, trastuzumab and lapatinib. Median overall survival improved by 6.9 months which was highly significant and this result was reached despite at least 50% crossover and about 80% of patients in the control arm receiving trastuzumab-containing regimens.

Despite longer treatment duration relative to control, T-DM1 had a favourable safety profile consistent with previous studies and the TH3RESA results, together with the EMILIA overall survival benefit which was updated and presented this morning as a poster by Veronique Diéras, they both solidify the role of T-DM1 in the treatment of patients with previously treated HER2 positive advanced breast cancer. Thank you.