Now, we’ve been hearing a great deal, Professor Eggermont, at this meeting about therapies for melanoma, a lot about metastatic melanoma, but you’ve got a different setting here and a very important one, resectable melanoma. What have you been doing for it?

What we have been presenting here at ESMO is a more detailed analysis of the EORTC 18071 trial. This is the first randomised adjuvant trial with ipilimumab in stage 3 melanoma patients. Stage 3 melanoma patients are patients with regionally node positive situation. They go for surgery and after surgery, because they are at very high risk of relapse, of recurrent disease, they qualify for an indication of adjuvant therapy and the patients were randomised between receiving ipilimumab or placebo in a double blind randomised study design.

How many patients did you have?

951.

So this is a definitive study, then. What results did you get?

It’s a definitive study for the primary endpoint. The primary endpoint in this study is recurrence free or relapse free survival. What it shows is that ipilimumab at a dose of 10mg/kg given according to a schedule where you get induction therapy with four administrations over the first twelve weeks, so every three weeks one administration, and then three monthly for up to three years compared to placebo, that the result of the trial indicates first of all that the primary endpoint is met, it has a significant impact on relapse-free survival with a hazard ratio of 0.75 and a p-value associated with that of 0.0013, primary endpoint.

In months what difference does it make?

In months there are a number of ways of looking at the curve because we know that ipilimumab creates a tail on the curve in advanced melanoma so that the benefit of immunomodulatory agents like this emerges more at the right hand of the curve because there is a certain percentage of the patients who remain to be capable to keep the tumour under control…

So you get a plateau?

… is that we have done two types of analyses. First of all the hazard ratio indicates that there is an overall 25% relative risk reduction for relapse or death. In terms of months for the median relapse free survival it goes from 17 in placebo to 26 in the ipilimumab treatment arm but when you look at landmark points like what is the difference at two years and at three years, so the difference at three years is a 12% difference in relapse-free survival favouring, of course, the ipilimumab treatment.

What do you think could this imply for potential overall survival differences between the treated and the untreated group in resectable melanoma?

Since ipilimumab in more advanced patients, systemically disseminated demonstrable disease patients, has provided a survival benefit that, in terms of median terms, goes from six to ten months but in terms of long-term observations basically leads to a doubling of the percentages. So, if it’s 9% in the other treatment arms at 3 years it’s 18% or 20% at the ipilimumab advanced stage treatment scenario. So it’s not, therefore, unlikely that what we are seeing now in the impact on relapse free survival will translate also into an overall survival benefit, the magnitude of which we cannot really infer yet at this point. But the number of events for overall survival are at this particular point too low for a definitive report on it so all the patients are still followed for that secondary endpoint, overall survival.

What are the preliminary, then, clinical implications for doctors?

We all know that ipilimumab is not a simple drug to handle because it is associated with the induction of immune related adverse events. We know basically how to handle immune related adverse events which are dermatitis, rash, but on an immune basis; colitis – gastrointestinal problems but the colitis is the difficult one because you must intervene in patients who have the early signs of colitis with diarrhoea with corticosteroids intervention, stopping treatment, corticosteroids intervention to stop that, let’s say, immune reaction at the colon immediately. There is another side effect which is an auto-immune hepatitis but this is mostly just liver function determines this and not a very severe type of thing. We have endocrine related auto-immune events with ipilimumab which is hypophysitis, so it’s your pituitary gland, that’s very bothersome because you need really, with corticosteroids etc., complete hormonal replacement for that kind of an event which happens in about 4% of patients.

Provisionally, then, what’s your verdict?

What’s the verdict? Where are we in the balance of side effects and benefit? When you follow the algorithms to treat the side effects, we know that we can handle that very well but you need experience with the drug and you need very clear instruction of the patient that in case of certain symptoms he must consult his prescribing physician immediately and not go to a different physician who would not have the same interpretation of those symptoms. Secondly, because in the ipilimumab subgroup analysis we showed great likelihood that it’s actually effective across the board in all subgroups, also in the most advanced palpable nodal disease stage of melanoma patients for which we have basically nothing of any efficacy on the market, is that there is an indication for adjuvant ipilimumab but in secure hands, I would say.

I read your caution, that’s obviously well placed. Let me just ask you very, very briefly because there are some other treatments coming down the road like RAF inhibition, MEK inhibition, these potentially could also be contenders for use in the adjuvant setting. Do you think these and the combination of new wave of treatments could prove their worth in adjuvant treatment?

Yes, well a BRAF or a BRAF/MEK inhibitor combination would, of course, only work in BRAF mutated melanomas so that already cuts the target population in half or below in half. So that’s already an important observation because ipilimumab is across the board, it doesn’t matter whether you have a BRAF mutation yes or no. We will launch in early 2015 the anti-PD1 adjuvant trial so that will be another EORTC trial with pembrolizumab which is the approved anti-PD1, it was just approved in advanced melanoma. There will be a number of advantages to that particular approach because the side effect profile of anti-PD1 is much more favourable and the impact on tumours in advanced melanoma is much greater in terms of response rates while it still has great durability and responses. So we will just move on immediately to asking the next question in the adjuvant immune therapy field by doing it by launching that trial.

How would you sum up, then, the findings from the EORTC 18071 study and the knowledge that’s emerging in melanoma at the moment in the adjuvant setting?

Well you know that in the adjuvant setting definitive data takes many years to actually be created which means that at this particular point in time for the activity demonstrated with adjuvant ipilimumab. It is a target for serious consideration for approval under the conditions that I mentioned. It needs to be in expert hands to be successfully handled because adjuvant definitive data for BRAF/MEK inhibitors in the adjuvant setting for just that 40% of the patient population or for anti-PD1 in the total patient population, of course, will only come in in about five years from now or in four years from now. So we will see how the dynamic translation of what’s happening in advanced melanoma will eventually also translate and settle itself in the adjuvant setting.

Professor Eggermont, thank you very much.

You're welcome.