Oncology Frontier: What do you think of the data of dual HER2 blockade comes from APHINITY？

 

Dr von Minckwitz: Many of my colleagues are a bit with the magnitude of the effect that was observed especially when they consider what the NeoSphere and ADVANCE studies showed， almost doubling the PCR rate. We have to be aware that in NeoSphere， patients only received docetaxel for four cycles and trastuzumab for 12 weeks， so the additional effect of pertuzumab was much easier to determine. In APHINITY， there was robust full chemotherapy and one year of trastuzumab given. We also need to be aware that for a favorable group of HER2-positive patients nowadays providing data for only less than four years in median of follow-up is very early. The prognosis for these patients was very good， much better than expected. As the control arm showed a 3-year disease-free survival of 93%， an absolute improvement of 1% by pertuzumab is probably not so bad and I would always refer to the relative risk reduction of 19%， which is OK. We have to wait to see how this will develop over time.

 

Oncology Frontier: According to the APHINITY study，what changes will happen to clinical practice in early breast cancer(EBC)？

 

Dr Wang: In my opinion， the results from APHINITY are fantastic. It is the first time that we have proved that dual blockade is effective in metastatic and adjuvant settings. Before today， I think a lot of the doctors had been frustrated that the beneficial NeoALTTO trial results had not translated into the ALTTO trials， but now we have the APHINITY results， we can feel confident we are heading the right way. As far as translating these results into clinical practice， it is still too early to make predictions， as Professor von Minckwitz said. The difference is not that dramatic and we will have to wait and see. For some high-risk patients (hormone receptor-negative， node-positive) it may be a better choice of therapy.

 

Oncology Frontier: Could you tell us about the main characters of patents enrolled in the trial?

 

Dr von Minckwitz: First of all of course， they had to have HER2-positive tumors. They had to have node-positive disease， or if they were node-negative， they had to have other risk factors including tumor size >1cm， hormone receptor-negative， grade 3 disease or of a young age. All patients needed to have sufficient cardiac function.

 

Oncology Frontier: In the clinical setting， how to choose the appropriate patient for Trastuzumab (T) plus pertuzumab (P) treatment？

 

Dr von Minckwitz: In Germany， we have approval to use pertuzumab for two years now in the neoadjuvant setting. We are treating in general many patients neoadjuvantly， probably much more than in other countries. The majority of these patients have certain risk features. They have a high probability of being node-positive， they are receptor-negative or they have large tumors， for example. So we use pertuzumab already， and the APHINITY study is very helpful now because it shows that were right in doing that. We now have the proof that disease-free survival is improved. Even in the neoadjuvant setting though， there are patients who are not at that high a risk where we would not necessarily use pertuzumab. APHINITY would support that approach. In a country where there is less use of neoadjuvant treatment and surgery is done first， there is now an open window to use dual blockade in the adjuvant setting.

 

Oncology Frontier: what can chinese doctors learn from APHINITY on the treatment conception and practice？

 

Dr Wang: It is a somewhat embarrassing question to answer because we don’t have pertuzumab in China in clinical use. We have trials ongoing in the metastatic setting and neoadjuvant setting， so maybe in the future we can keep up with the rest of the world. As a concept， we all agree with our international colleagues. HER2 is a driver gene， so dual blockade may provide more opportunity for complete blockade and result in better survival. In APHINITY we have not seen that much difference， but it is still too early to confirm future outcomes.

 

Oncology Frontier: Could you please introduce to us about the common treatment modalities of early HER2-positive breast cancer in Europe.

 

Dr von Minckwitz: There are many countries in Europe， so I better refer to what we do in Germany. It is different from the UK， for example. With small node-negative tumors， we use paclitaxel/trastuzumab. For larger T1 tumors where we operate first， we use an anthracycline/taxane sequence and we start trastuzumab together with the taxane in most centers. The treatment of choice tends towards neoadjuvant treatment in HER2-positive disease， and the majority of these patients will get dual blockade. As neoadjuvant treatment is of shorter duration and NeoSphere was not conducted with continuing trastuzumab after surgery， it is more affordable to use pertuzumab in the neoadjuvant setting. NeoSphere reported this tendency towards a better disease-free survival， and in conjunction with APHINITY， at least some of the efficacy of pertuzumab can be reached with three months treatment， which is one-quarter of the cost of one-year treatment， so it is sensible to do this.

 

Oncology Frontier: After the APHINITY results were released，which Trastuzumab (T) plus pertuzumab (P) treatment modality do you prefer: Neoadjuvent only？Adjuvent only？Or from neoadjuvent to adjuvent？

 

Dr von Minckwitz: Well I am biased having done so much research in the neoadjuvant field. In our Guideline， it clearly says that for HER2 patients and triple-negative patients， neoadjuvant treatment is the first choice. I believe in this concept. Regarding NeoALTTO/ALTTO， if we did a meta-analysis of all lapatinib neoadjuvant studies， I think there would be a moderate (but not necessarily significant) improvement in PCR. ALTTO saw a moderate (but not significant) effect with lapatinib and one of the main reasons why it was just not positive was because there was a third arm. If the third arm wasn’t there， then the p-value would have been significant. So it is a borderline thing. To me， there is not too much difference from APHINITY. The hazard ratios are not that different. It is in terms of the toxicity profile where I would say there is an advantage with pertuzumab.

 

Dr Wang: Dual blockade is really important for anti-HER2 therapy. In both APHINITY and the ALTTO trial， the trend is clearly consistent. Even though in the ALTTO trial there was not a significant difference， the trend is clear that dual blockade shows clear efficacy. I have a question regarding neoadjuvant therapy. If a patient uses trastuzumab and pertuzumab in the neoadjuvant setting and achieves PCR， should they stop or continue for a year on dual blockade?

 

Dr von Minckwitz: We still recommend continuing on trastuzumab for a year. There is no trial evidence for pertuzumab continuation and currently we wouldn’t， plus we don’t have a label for one year anyway. There are trials on the way looking at that. It is definitely one of the big questions currently and we have a lot of discussion related to the costs involved. If we want to distribute resources to as many patients as possible， it might be better not to continue.

 

Dr Wang: We have two clinical trials in the adjuvant setting with dual blockade. One is sequential neratinib followed by trastuzumab for two years， and the other is the APHINITY combination for one year. If both of those drugs were approved in Europe， which would you prefer?

 

Dr von Minckwitz: Neratinib is not an easy drug. Diarrhea is a real issue over such a long period. We had to be careful with the incidence of diarrhea in the APHINITY study. We have not released those data yet， but there was a meta-analysis of the metastatic NeoSphere study looking at when this diarrhea occurs and how long does it last. It is much more pronounced for the first couple of cycles and then it reduces， so the annoyance to patients is less. The quality of life assessment was no different between the two groups. In the ExteNET study with neratinib， the quality of life is worse. It is a burden for the patient， so we have to be careful with how we approach treatment.

 

Oncology Frontier: Could you please analyze the treatment pattern of HER2-positive breast cancer between the East and the West? And what is the major challenge of anti-HER2 therapies we are facing today in china?

 

Dr Wang: In China， the only anti-HER2 therapy we have is trastuzumab and lapatinib. Pertuzumab， TDM1 and others are still only in clinical trials. We have to change the government policy for new drug approval to keep pace with the rest of the world， otherwise we will always be behind. The other issue in China is the insurance system. Trastuzumab is now covered by insurance so it is getting better and in some areas， the government pays part of the expense of trastuzumab. But in most areas of China， most HER2-positive patients pay for their treatment on their own. This is a big issue that has to change， so that more patients can get maximum benefit from these drugs. Each coin has two sides. The current situation gives the domestic pharmaceutical industry opportunities to develop similar or new drugs and some of these are in clinical trials and some of those look promising. That is good for Chinese patients. But we have to wait for these drugs to be approved – that is the biggest issue.