Pertuzumab plus trastuzumab and chemotherapy continues to show benefit in HER2-positive breast cancer

Prof Martine Piccart - Université Libre de Bruxelles, Brussels, Belgium

Thank you, Dr Arteaga. Good morning everybody, it’s a great pleasure for me to present on behalf of my co-investigators the six year results of the APHINITY trial. This slide shows our conflicts of interest.

Let me provide you with some background. The APHINITY trial randomly allocated 4,805 women with node positive, high risk node negative, HER2 positive operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus one year of trastuzumab. Radiotherapy and endocrine therapy, if indicated, were given after completion of adjuvant chemotherapy. The primary endpoint of this trial was invasive disease free survival excluding second non-breast primary cancers. Overall survival was one of the many traditional secondary endpoints.

There were five stratification factors, including nodal status, hormone receptor status, chemotherapy regimen, geographic region and protocol version. Indeed, after recruitment of 3,655 women a protocol amendment prohibited inclusion of patients with node negative disease.

The primary analysis was performed after 381 events and a median follow-up of 45 months. The results, as you know, have been published in The New England Journal of Medicine and they show that pertuzumab significantly improves invasive disease free survival with a hazard ratio of 0.81, a p-value of 0.04 but you can also see from the curves that the magnitude of the treatment effect is modest. However, it was more pronounced at that time in patients at high risk of relapse such as node positive patients, you see their outcome on the left with a hazard ratio of 0.77, and patients with hormone receptor negative disease with a hazard ratio of 0.76. The absolute benefits there at three years were 1.8% and 1.6% respectively.

Today I’m going to present the second overall survival analysis of APHINITY. At the first analysis there was no detectable treatment effect with regard to mortality. This is a pre-planned time-driven analysis. The median follow-up now is 74 months. Please note the very stringent p-value of 0.0012 required for statistical significance at this point. There are now 272 deaths which represent 42.5% of the 640 deaths needed for the definitive overall survival analysis. I’m also going to show you interesting updated descriptive analysis of invasive disease free survival and cardiac safety. We now have 508 patients with an invasive disease free survival event.

Here you see the curves pertaining to the second interim overall survival analysis with 74 months median follow-up and you can note the excellent 94% overall survival rate at six year of this population with a very aggressive breast cancer subtype. 125 patients died in the pertuzumab group, 147 in the placebo group. The hazard ratio is 0.85, the p-value is not statistically significant.

Here is the updated descriptive analysis at 74 months follow-up of invasive disease free survival. You can see a hazard ratio of 0.76 translating into a 2.8% absolute improvement with pertuzumab at six years. Please note that pertuzumab reduces the risk of distant recurrences as well as local regional recurrences. The rate of CNS metastasis, contralateral invasive breast cancers and death without prior event are no different between the two treatment groups.

The node positive cohort, interestingly, continues to derive clear benefit from the addition of pertuzumab. The hazard ratio there is 0.72 and this translates into an estimated absolute improvement of 4.5% at six years favouring pertuzumab addition to the standard treatment. In contrast, no treatment effect is detected in the node negative population as you can see on the right.

In the primary analysis there was a suggestion of an enhanced benefit in patients with hormone receptor negative disease. As you can see from this graph these patients still benefit from pertuzumab with a hazard ratio of 0.83 but interestingly now the curves are diverging in the hormone receptor positive population and there is a benefit there emerging very clearly with a hazard ratio of 0.73 translating into a 3% absolute improvement at six years.

So this table essentially summarises the clinical benefit of adjuvant dual HER2 blockade with chemotherapy. On the left you see the hazard ratios with their 95% confidence intervals for the intent to treat population and the clinically relevant subgroups. As presented today and compared to what was presented three years ago, on the right you see the six year invasive disease free survival rates for the pertuzumab group and the placebo group and the absolute benefit with the 95% confidence interval. These benefits have to be balanced, of course, against potential harm coming from the use of pertuzumab but here the great news are that no new cardiac safety issues have emerged with 2.5 more years of follow-up. One additional primary cardiac event was reported in the pertuzumab arm, one additional patient in each arm had a secondary cardiac event. What is important to remember is that the rate of the severe cardiac events is below 1% in the two groups. There were 18 cases in the pertuzumab group, 8 in the placebo group.

In conclusion, regarding the APHINITY second interim analysis of overall survival, we have seen fewer deaths in the pertuzumab arm compared to the placebo arm. The difference of 0.9% is not statistically significant and further follow-up will be very important to determine whether there is a survival benefit associated with pertuzumab administration in early HER2 positive breast cancer. A third interim overall survival analysis that is also time drive is planned in 2.5 years from now.

As far as the updated descriptive analysis of IDFS and safety are concerned, I think we can say that the clinical benefit of pertuzumab in HER2 positive early breast cancer is strengthened in node positive patients. We have a hazard ratio of 0.72. The absolute difference is estimated to be 4.5% but no benefit can be claimed in the node negative population.

Very importantly, after 74 months of follow-up the benefit of pertuzumab is seen regardless of hormone receptor status and no new cardiac safety issues emerged at this interim analysis with an incidence of severe cardiac events below 1% in each arm.

So let me thank all the people who worked really hard in this trial, the staff at the big headquarters, at the clinical trial supporting unit of my institute, the statisticians at Frontier [?], my co-investigators, the central pathology lab in Milan, the many members of the different trial committees and our Rush [?] colleagues. Thank you very much and I am happy to take questions.