The APHINITY trial addressed the question of how far a dual HER2 blockade can improve disease free survival in early breast cancer. There was a good rationale for doing that as pertuzumab has a different way of working; opposite to trastuzumab it binds not on the transmembrane region it binds on the dimerization region where it inhibits the dimerization of the HER2 receptor with HER3 and HER4. Therefore it appeared reasonable to combine those two approaches and this was already very successful in the metastatic field where pertuzumab added to docetaxel and trastuzumab improved disease progression free survival and even overall survival. It also almost doubled the pathologic complete response rate in the neoadjuvant setting of HER2 positive breast cancer.
But still we know that despite the introduction of trastuzumab a significant proportion of patients with HER2 positive breast cancer relapse in the long term and that was the motivation to conduct the APHINITY study. In this study we randomised 4,805 patients to either chemotherapy, trastuzumab and placebo or chemotherapy, trastuzumab and pertuzumab. Patients received this antibody treatment for a total of one year and radiotherapy or endocrine treatment was conducted only after the end of chemotherapy. There were a number of chemotherapy regimens allowed: either several sequences of anthracycline and taxane based regimens or a non-anthracycline TCH regimen. The trial finally met its primary objective, it could demonstrate that the addition of pertuzumab can increase the invasive disease free survival in these patients. There was an absolute increase of 1% at the three year time interval which appears to be a small number but this is an early outread of the study and we can observe already that the relative risk reduction is 19% which is quite good and is an outlook of what could be the case later on when these patients have been observed for a longer time.
We could also see that at this early analysis that so far this effect is predominantly deriving from patients with node positive breast cancer as well as from patients with hormone receptor negative tumours. So whereas in the total population we have a number to treat of 112 this is reduced to 52 and 63 patients in the node positive and in the hormone receptor negative patients.
We also looked at safety, there was a major impact on the cardiac safety of this dual HER2 blockade and we could see that severe cardiac events or cardiac deaths occurred in 17 patients in the pertuzumab arm and in 8 patients in the placebo arm. This absolute difference of 0.4% was not statistically significant and as well mild symptomatic or asymptomatic drops of the left ventricular ejection fraction were similarly distributed between the two arms. Another safety signal was regarding diarrhoea, higher grade diarrhoea, we observed around 10% of grade 3 or higher diarrhoea in the pertuzumab arm and 4% in the placebo arm. This was confined mainly to the chemotherapy period and was more prominent in patients receiving the TCH chemotherapy backbone.
So in total this trial gives now a support and makes us more confident that the use of pertuzumab as it has been already approved for the neoadjuvant setting is reasonable. We can continue in doing that, as in the neoadjuvant setting we are treating anyhow more higher risk patients. This is supported by this first analysis of the APHINITY study and also patients that were operated up front and have a higher clinical stage have now a new option available how they can be treated to improve their further outcome.
The big story from last year was the trastuzumab biosimilar, do you think that might work alongside pertuzumab or could there be a pertuzumab biosimilar in the near future?
There will be some and I expect that there also will be a pertuzumab biosimilar. The development of a biosimilar is not as easy as a usual generic, you have to perform proper phase III studies. So far what we know from trastuzumab it appears to be possible to do that so these biosimilars will, at least in many health systems, allow that these antibodies become cheaper and that the then available money can be used for new agents like pertuzumab. But in the long term also pertuzumab will become cheaper because of that.
Do you think that substituting trastuzumab for a biosimilar in this case would have any effect on the success or limiting the adverse events?
I believe this is not very likely. What we know from these biosimilars, they are quite well investigated right now, they have at least similar efficacy, they don’t induce antibodies. So a very similar profile as trastuzumab and, as I mentioned at the beginning, it’s more about using two drugs with a different mechanism of action. I would imagine that this is also the case by using a trastuzumab biosimilar.