It’s my pleasure to give you a short overview on the APHINITY study, a trial that explores the role of pertuzumab, an antibody directed against HER2, that inhibits the heterodimerization of HER2 with other HER family members like HER3 and HER4 in patients with early HER2 positive breast cancer.

We randomised over a two year period 4,800 patients that have confirmed HER2 positive status to be treated with adjuvant treatment composed of chemotherapy trastuzumab and pertuzumab in the experimental arm and chemo trastuzumab and placebo in the control arm. The anti-HER2 antibodies were given for a total of one year and we allowed several anthracycline taxane sequence regimens or non-anthracycline containing docetaxel, carboplatin, trastuzumab regimens as a backbone. Based on the result of a previous trastuzumab study, BCRG006, we expected a three year disease free survival rate in the placebo arm of 89.2% and aiming for a hazard ratio of 0.75 we expected a three year IDFS rate of 91.8% for the pertuzumab arm.

Here you can see the results. At three years we see an absolute difference of around 1% between the two treatment arms in favour of pertuzumab but you can also see that after four years the curves are separating even larger. Even at this early point of time the stratified hazard ratio is 0.1, that means that there is a relative risk reduction with the introduction of pertuzumab of 90% in these patients. This result was statistically significant at a p-value of 0.045. The number needed to treat in this overall population was 112 to avoid one relapse of disease.

Subgroup analysis showed that the effect of pertuzumab is very homogeneous, all over the subgroups. None of the interaction tests were significant. I want to highlight two of these subgroups according to nodal status and hormone receptor status. In the node positive subgroup, which was about two-thirds of the patients, the difference at three years is 1.8% and the unstratified hazard ratio is 0.77. So here the relative risk reduction is 23% and that was statistically significant. The number needed to treat in this subgroup is 56. In the hormone receptor negative subgroup, about one-third of all patients, the difference at three years is 1.6%, the unstratified hazard ratio is 0.76 and the number needed to treat 63.

Using a dual anti-HER2 blockade requires always a certain attention to cardiac toxicity therefore we defined a specific primary cardiac endpoint of severe heart failures and cardiac deaths. These were observed in the pertuzumab in 17 patients, in the placebo arm in 8 patients. The treatment difference of 0.4 was not statistically significant. Looking into more asymptomatic or mild symptomatic LVF drops there was no difference between the two treatment arms at all. Most of the grade 3 or higher adverse events were hematologic but I want to highlight that the adverse event that was most different between the two treatment arms was diarrhoea. 9.8% of patients in the pertuzumab arm had grade 3 or higher diarrhoea, 3.7% in the placebo arm. This was mainly confined to the chemotherapy period and was more pronounced in patients receiving the TCH regimen.

In conclusion, the APHINITY study met its primary objective. Pertuzumab reduced the risks of IDFS events in 19% compared to placebo at a medium follow-up of 45 months. The treatment effect was homogeneous throughout all subgroups, however the node positive and hormone receptor negative cohorts appeared to derive most benefit at the current point of time and, of course, this might change with longer follow-up. Cardiac toxicity was low and not different between the two arms. The incidence of diarrhoea was increased in the pertuzumab arm and it occurred predominantly during chemotherapy and with TCH.

Continued follow-up of up to ten years is planned and is important to assess overall survival, longer term IDFS and safety analysis. Thank you very much.