WCCS 2016

Developments in checkpoint immunotherapy

Dr James Larkin - The Royal Marsden NHS Foundation Trust, London, UK

I think at this conference there’s quite a lot of interesting new data but most of it is being presented in poster form, so at the basic science type of level and also in terms of clinical things. I think at this meeting there isn’t really that much new data that we are going to see that’s impacting on clinical practice. A lot of the discussion at this meeting will be about what we’ve seen pretty recently three months ago at ASCO in Chicago and, to some extent, how what we’ve seen in the last few years is going to impact the future. There are quite a few studies that we are looking forward to the results of which we’re going to get in the next year or two. That’s really how I would see this meeting.

Some of the big questions at the moment in treating melanoma, first of all there’s a big question about adjuvant treatment. There have now been a couple of adjuvant studies that have pretty much recruited in the last year or two of checkpoint inhibitors, in other words immunotherapy. We won’t have the results of those for a little while but there’s been quite a lot of interest in that. The same is true that the targeted adjuvant therapy studies basically recruited a little while ago now and it might be in the next year or two that we get some results so that will definitely be interesting.

I think in advanced disease, stage IV disease, there’s probably two or three big questions. One is the question of in BRAF mutant melanoma, should you start with BRAF targeted therapy or should you start with immunotherapy, in other words what’s the best sequence? Again, we don’t really have any trials that have reported that are helping us with that but there’s at least a couple of trials that are going on to address those kinds of questions.

One of the other really big questions in advanced disease at the moment with checkpoint inhibitors, immune checkpoint inhibitors, is should you go with a single agent, so something like nivolumab or pembrolizumab, or should you go with the combination of nivolumab and ipilimumab? All of those options are approved and really the big question is that we know that the combination immunotherapy has got more side effects. Certainly both options, in other words nivolumab or pembrolizumab alone or combination immunotherapy are better than ipi alone, but which patients should you be treating with each of those treatment options? We still really don’t have any good answers to that so that’s a hot topic still in the field.

What are your thoughts on public awareness of melanoma?

I think there is a lot of public awareness of melanoma. We all know that melanoma is increasing very quickly in pretty much most western countries. I think most people know also, certainly in my experience of treating patients at the Marsden, that sun exposure or sunburn is a risk factor for melanoma but translating that knowledge into action is a separate thing. In Australia there was a very successful public health campaign in the ‘80s and ‘90s, slip slap slop, which meant that sunburn, particularly amongst children, really went down. Actually the incidence of melanoma in Australia I think is now going down. Just anecdotally if you go on your summer holidays in Europe, to the Mediterranean or in the UK where we have a few days of hot weather, I still see people doing what I wouldn’t regard as particularly safe behaviour in the sun, you know with young children. I think that we know the message, everyone knows the message about avoiding sunburn but I’m not certain it’s clearly being translated into action on a day to day basis at least in Europe. I think there’s still more to do in terms of trying to address that.

Are there any recent results that are influencing clinical application?

In terms of the sorts of trial results that we’re waiting for in the near future, at least in advanced melanoma, the overall survival data from the CheckMate 067 study is the thing that we are most eagerly anticipating. This was a study with three different arms. Ipilimumab alone. ipi, nivolumab alone, or the combination of the two drugs together. What we know so far is that both the experimental arms, in other words nivolumab alone and the combination, were better than ipi in terms of progression free survival and in terms of response rate. But the trial isn’t mature for overall survival and we would anticipate having some overall survival data from that trial, certainly in the next twelve months or so or possibly slightly sooner.

That’s quite a big question because these are all approved treatment options but the combination of the two drugs together has a lot more side effects.  One question is actually do you need the two drugs together given the side effect profile or might there be certain patients, for example, and maybe this could be based on PD-L1 expression who you can reasonably treat with just say nivolumab, or pembrolizumab for that matter, because they are going to get significant efficacy. Then maybe think about using the combination treatment in tumours where there isn’t high PD-L1 expression. For me that’s one of the eagerly awaited results. Another result that’s pretty eagerly awaited actually is from the adjuvant trial of ipilimumab at 10mg/kg, so the higher dose, that’s the EORTC study. We already know that there’s a disease free survival advantage from that study which has lead to approval in the US, but a big question for everybody again is what about the overall survival data from that study as well.  I’d probably flag those two studies as being studies that everyone in the field is looking forward to seeing mature survival data which I hope we will get in the next six to twelve months.