Hello, and welcome to the ecancer round-up at ESMO. We’re talking about melanoma and skin cancers and joining me is Teresa Amaral, nice to have you here.

Thank you for having me.

Among the many things that are being discussed at this year’s conference, first of all the surgical options for skin cancer management, if you could tell us what’s come out of this year’s conference.

We actually have some new data that was already presented in ASCO this year but actually it mostly tells us that probably not all patients need to do a complete lymph node dissection once they get a positive lymph node. This is important because it changes the way we handle these kinds of patients. Of course it comes also the question whether this complete lymph node dissection will give us more information and it will give us an advantage in terms of survival. These two studies, the DeCOG trial and MSLT-II trial, showed that there is no advantage in terms of survival.

The thing is that we get a lot of questions whether if we get more information from the lymph nodes can we better predict the survival for these patients. Actually there was a very interesting publication in The European Journal of Cancer that talks about the combination of the tumour burden in the sentinel lymph node and the ulceration of the primary tumour. With these two informations that we get without the complete lymph node dissection we can actually stratify the patients into three risk groups and without any further information we can somehow predict the survival of these patients. So probably we don’t need more information from the complete lymph node dissection we can, with these two combinations, stratify the patients into these three groups and probably use this information for planning future trials in the adjuvant setting.

That leads on to the news about the new classifications in skin cancer and melanoma.

Exactly. That is also new information or a new classification that we get. We had the previous seventh edition of the AGCC classification and now we have the eighth classification. There is a difference between these two that is mostly in stage 3 patients. Before we just had three groups, stage 3a, b and c, and now we have an extra group and this poses some kinds of challenges because all the previous adjuvant trials were done with the previous classification and the results are based on this previous classification and it might be difficult to translate these results into the new classification with four sub-stages. This is something that needs to be handled, not exactly how we should handle that in the future, but it’s an aspect that needs to be handled.

You mentioned adjuvant trials there, a lot of the data coming out of the trials presented at this year’s ESMO meeting are adjuvant and neoadjuvant.

Exactly.

So what have been some of the highlights that you have seen?

Actually we need to separate these two settings, the neoadjuvant and the adjuvant setting. We have some advantages in the neoadjuvant setting that are the fact that we can monitor the tumour during the therapy. Actually different from other tumours we do not just want to achieve the possibility of operating these tumours, we also want to bring the immune cells and the immune system to the tumour. This is something that is different from the chemotherapy that is done in the neoadjuvant setting and it’s somehow special to the melanoma patients.

In the neoadjuvant setting we already had some data previous from the OPACIN trial where they evaluated the same combination in the adjuvant and neoadjuvant setting and we saw that actually this combination is effective in the neoadjuvant setting, the problem is it was very toxic. It was a toxicity that was not tolerated and was not acceptable in this setting. So the trial changed a little bit and they tested another combination, it’s ipilimumab/nivolumab, the same but with a different dosage and a shorter time duration. What we saw in these other data that were presented today actually this is still effective, we still have a lot of pathological complete responses but with a very lower toxicity and this is very important in this setting.

We also see that these pathological complete responses are very well associated with a relapse free survival. It’s yet to be seen if this translates in terms of overall survival or not but for now it seems to be well correlated. Also from this neoadjuvant trial comes information that might be a genetic signature associated with better responses and these are the tumours that have a high interferon gamma signature.

Then for the adjuvant setting we had today the update from the COMBI-AD trial which is a targeted therapy trial as opposed to this immunotherapy from the OPACIN-neo. Last year in ESMO we saw the first data and this data from today actually confirmed an advantage from combination therapy as opposed to placebo in patients with BRAF mutant melanoma and stage 3 melanoma. What was actually the new part of this presentation, there were actually two new parts, the first one is that they presented a model that is a cure rate model that, besides the information that we have from relapse free survival and distant metastasis free survival, somehow predicts or tries to show us which percentage of patients will be cured if they are now without relapse or if they are disease free patients. In this model what we see is that the patients that are now disease free or relapse free have a 54% chance that they are cured compared to 37% of the patients that received placebo so it’s an important aspect.

The second important aspect is that for the adjuvant therapy, as I said, we do not have quite a genetic signature or a biomarker signature. What they presented was that also patients with a high interferon gamma signature seemed to have a better prognosis compared to the other ones and also important is that the tumour burden, or the tumour molecular burden, a high tumour molecular burden seems to be associated with a worse response to targeted therapy. So maybe these patients will do better with immunotherapy, we do not know, but this is a possibility that might be investigated in the future.

So two questions remain to be answered in the BRAF setting – whether patients should start with BRAF directed therapy or immunotherapy and also for the other ones that are not BRAF mutated whether should we start with immunotherapy up front or should we wait until they relapse and then do immunotherapy afterwards. This will be answered by the one trial that is ongoing with pembrolizumab that allows patients to receive immunotherapy if they relapse and were in the placebo arm or if they received previous immunotherapy and they relapse after six months. So questions need to be addressed.

Maybe one of the answers to these questions could be the triplet therapy then?

Yes. Actually we have also in the neoadjuvant setting, from the institution that I am collaborating with, we have the possibility or we are planning a trial where we test a combination of immunotherapy and targeted therapy in the neoadjuvant setting. We have some data from the metastatic setting that was presented also today; the follow-up was too short so we cannot actually draw conclusions from the combination of pembrolizumab and dabrafenib plus trametinib. We are also waiting for information from two trials that are ongoing, one where we have a combination of targeted therapy up front and then we add immunotherapy, this is the TRILOGY trial, and then the second where we had a combination of targeted therapy and immunotherapy up front in the COMBI trial. It seems to be a difference between the patients that receive up front triple combination or the patients that started with the targeted therapy and then we add immunotherapy. Unfortunately we do not have data from these trials that are still ongoing but probably we’ll have to wait a little bit longer to know if this is actually the path that we need to follow also in the neoadjuvant setting and not just in the metastatic setting.

Also it’s obviously important to see if patients can tolerate that kind of treatment schedule.

Yes, the toxicity is one of the points because actually, as I said, the toxicity seems to be different if you do the triple combination up front or if you do targeted and then immunotherapy. What we saw is that if we try to do it all at the same time we see different patterns of toxicity. The immunotherapy toxicities are not different from those that we are already used to seeing in the other immunotherapies but the combination of therapies has different toxicities from what we are used to. So it’s difficult to see if we actually have survival benefits that out-rate the toxicity of the triple combination. It’s to be known.

Time will tell.

Yes, exactly, time will tell.

Thank you so much for your time and talking with us today and we look forward to catching up with you at another conference sometime soon. For everyone watching at home thank you for joining us and we’ll see you with more from ESMO soon.