I would like to start with a trial that was presented looking into local therapy or intralesional therapy versus surgery. This is a trial that investigated TVEC that is an intralesional therapy and the patients were randomised to receive either TVEC followed by surgery or surgery at the very beginning. The results that were presented now with the two year follow-up from a large trial in this setting, one needs to say that, showed that TVEC followed by surgery is better than surgery alone. It looks like for the patients that actually received the therapy and then followed by surgery that they received less therapies afterwards in the adjuvant and in the metastatic setting. So the advantage that was seen in the survival from the patients that received the intralesional therapy doesn’t seem to be totally related to the therapies that they received subsequently. So this favours the therapy, the intralesional therapy, before proceeding to surgery.

Then we had also a presentation and discussion of two other trials in the neoadjuvant setting. These were the trials that investigated the combination of ipilimumab nivolumab, two Dutch trials. What is actually striking is that with a very short course of therapy that is just two cycles of combination immunotherapy we had very good pathological response rates. These patients that actually achieved a pathological response rate they had also a long time of relapse free of disease. So this pathological response predicts if the patients will live longer without disease. This is very interesting because in this case we didn’t really have to give adjuvant therapy so they just received these two cycles of therapy in the neoadjuvant setting then they were operated. For these patients that achieved this complete pathological response the results are really good.

In this congress were also presented the biomarker study analysis. What we see is that the combination of biomarker signatures that involve TMB and interferon gamma signature predicts the response to immunotherapy. So the patients that are in the spectrum of these high biomarkers, they actually have a very good response to immunotherapy. On the other hand if you look into those that are on the other side that have low TMB and low interferon gamma signature they have less response to immunotherapy but it doesn’t mean that they do not respond. So you cannot say that they will not respond to immunotherapy, they will respond less to immunotherapy. These results show, combined with others that were seen in the stage 4, that we probably will not have just one biomarker in this setting, we probably need to combine more than one biomarker.

This was the neoadjuvant setting and then moving to the metastatic setting but also a little bit adjuvant, two trials were presented. The first one was the update of the CheckMate-238 where we evaluated nivolumab versus ipilimumab in patients with stage 3c, 3b and 4, no evidence of disease. What we see with this longer follow-up is that the difference between the two arms is increasing and it’s now 13% favouring the PD-1 therapy. Again in this trial what we saw was also an update in terms of the biomarker or a presentation of the biomarker analysis. Again, what we see is that just one biomarker will probably not be enough in this setting of metastatic disease or no evidence of disease. We need probably just to combine more than one.

Another trial that was also presented and this was really interesting in the stage 4 no evidence of disease was the IMMUNED study that was presented by Dirk Schadendorf. In this case they included patients, although my centre also participated, that were stage 4 no evidence of disease and the patients were receiving combined immunotherapy, PD-1 monotherapy or placebo. We see that the patients that received combined immunotherapy had a high discontinuation rate due to toxicity but they also did much better than the other arms. So the placebo arm did clearly worse than the other therapy arms, followed by the monotherapy with PD-1 and the combination of immunotherapy was the one that performed better. This is quite interesting because we had a very high discontinuation rate of approximately 79% and in approximately 50% of the cases the patients just received two cycles of combined immunotherapy. Nevertheless they did very well. So it’s the question do we really need to give further or longer combined immunotherapy or can we shorten these treatments? Also the question nowadays we probably would not include a placebo arm in this trial but at the time that it was initiated it was the best comparator that we had besides nivolumab monotherapy. But it’s questionable if we would nowadays include a placebo arm. Although in some way it will show us if we really need to treat the patients up front or if the patients that relapsed after being in this placebo arm also have a response if they are treated when they recur. But this is the data that we don’t have yet and what we know from this trial is that the combination with combined immunotherapy of ipilimumab plus nivolumab is better than PD-1 alone.

Then we moved to another trial also in stage 4 that was presented by James Larkin, the update of the CheckMate-067 which also shows very interesting data. With this five year update, although this trial, and this is critical that it’s always done in every presentation, is that in this trial where we analysed ipilimumab plus nivolumab versus nivolumab versus ipilimumab the trial was not powered to see a difference between the PD-1 arms. But still not being powered what we see is that the difference is increasing between these two arms, combined immunotherapy and monotherapy with PD-1 alone and now it’s 8% in the five year overall survival. We cannot disconsider this aspect.

Also what was interesting in this trial was that two new concepts were presented. The first one was the time free of following therapies or further therapies and the number of patients that are alive without further therapies after five years. This is really interesting data; we see that the patients that received combined immunotherapy do much better considering these two parameters compared to the nivolumab and to the ipilimumab arm. This is really important because in daily life we need to consider how long can we keep these patients without receiving further therapies, without adding further toxicities. Again, the combination of immunotherapy seems to do better than the other ones.

Another point that is interesting also in this trial is that for the patients that have BRAF mutation they do much better in the combination with immunotherapy than with monotherapy alone. Although this cannot be compared to other trials, we should not compare trials between themselves, but we cannot help to compare the results that we see in the BRAF population in this trial. Another analysis with five years for patients that received combined targeted therapy because they have a BRAF mutation. What we see is that the patients that received combined immunotherapy and have a BRAF mutation in this CheckMate-067 trial have better outcomes compared to the ones that received targeted therapy. As I said, we cannot really directly compare these trials but in the daily basis we need to decide which patient needs to receive immunotherapy first line or targeted therapy first line and this needs to be discussed with the patient.

Another aspect that I found interesting is that in the previous reports we always saw that the combination of immunotherapy is more toxic which was confirmed in the IMMUNED study. But, again, these patients that received the combination immunotherapy didn’t seem to have the duration of their quality of life in this report that we saw now and was published in The New England. So all these aspects need to be discussed with the patient. The longer time that we have without further therapies the higher number of patients alive at five years without further therapies and the toxicity associated with these therapies, this needs to be all put into context when we discuss with the patients when they start therapy in this setting.

Finally, I would like just to mention another trial in the metastatic setting that is the update that was done in the ABC trial that was presented by Georgina Long. This trial studied a combination of immunotherapy, ipilimumab plus nivolumab, versus nivolumab, the randomised part of the trial in patients that have asymptomatic brain metastases. So this is a particular population of patients and what we see in this update is that again the combination immunotherapy seems to do better than the monotherapy. The rate of intracranial complete responses is actually very high in the combination arm. What is also interesting to see is that for patients that received previous therapies, namely BRAF MEK inhibitor therapies the combination immunotherapy and the PD-1 monotherapy, the patients that received these therapies after being treated with BRAF MEK have low response rates. So it looks like if we are going to give these therapies we should give them first line in this collective of patients. They do significantly worse when given afterwards and when given to patients that have leptomeningeal or symptomatic diseases. There were no further safety issues, that was something that some colleagues had at the beginning with the combination immunotherapy in patients with brain metastases but it doesn’t seem to be like this. Also an aspect that is in every trial that we see and in every report is that PD-L1 doesn’t seem to play a role in terms of biomarker in this setting, also for patients with brain metastases.

So questions to take home based on what was presented here. One, obviously need to see and need to mention that we are going apart from one biomarker that we can use in all patients that we probably are going into the combination biomarker perspective so we probably need to use more than one. What we saw more promising was the combination of TMB and interferon gamma signature. Obviously we need to consider whether, based on the data that was presented here, we really need to treat the patients for as long as we are treating them now. We saw both in the IMMUNED trial and in the neoadjuvant setting that with shorter therapy durations we probably achieve very good responses. Also the question of the dosing – do we really need to use a higher dose or can we use reduced doses? A little bit similar to the results that were published from the CheckMate-511 where we used a reduced dose of ipilimumab and although the follow-up is shorter we don’t see a difference in terms of outcomes but a better safety profile.

Then another question that we need to address – is it better to do this therapy in the neoadjuvant setting to educate the immune system with immunotherapy or is it better to use it in the adjuvant setting. This obviously needs to be addressed in further trials. It looks like in the settings that we were analysing and the data that we saw that the combination immunotherapy performs better than the monotherapy so one needs to actually discuss if all the patients need combination immunotherapy or if we still should treat patients with monotherapy, PD-1 based monotherapy. Then, again, with all these results and all these very good outcomes that we have with these therapies should we move further into earlier stages of the disease? In stage 2 patients that have melanoma in stage 2 we really should move into this setting and which patients should we treat in this setting based on the results that we have now? So this is already being addressed in some trials but is the question which patients do we really need to treat and if we can select them somehow based on the results that we have already in the other settings.