EADO Congress 2015

Anti-PD1 or tyrosine kinase inhibitors?

Dr Mark Middleton - University of Oxford, Oxford, UK

We are surrounded by experts talking about new therapies for melanoma; there’s the immune therapies which are extremely interesting but then also the targeted ones. First of all, how do you see this field of therapy at the moment and how do you know where to start with your patient with advanced melanoma?

It’s very exciting at the moment because we’ve got lots of options after years of having very, very few. The first place we start is we look for activating mutations in the tumour because they rule the targeted treatments in or out. If the targeted treatments aren’t going to work because there isn’t a BRAF mutation then it’s pretty straightforward, we go for the immune checkpoint inhibitors and the question there is which one, which order. At the moment, in the UK at least, that’s defined by funding as much as by the clinical trial results that are coming through. Where the BRAF mutation is present we have a more difficult decision because we’ve got two different classes of agent that work in two very different ways and present different challenges for the patient. With the BRAF and MEK inhibitors we’ve got a much higher chance of response but some concern that that response is not enduring and can only be achieved by staying on treatment long term; with checkpoint inhibitors the chances of response and benefit are probably a bit lower but that response seems to be more enduring and you may be able to stop treatment and still remain in response.

I think I’m getting the message that you start with the immune checkpoint inhibitors and then usually would then sequentially follow that, if necessary, with the targeted therapies.

Broadly there’s a preference for that, I think there are some exceptions. If people are quite unwell because of their melanoma then we would reach for the BRAF and MEK inhibitors first because when they work they work more often and they work more rapidly. So if people are unwell or in special circumstances, such as we see significant amounts of tumour in the brain, then we’d use the targeted agents first. Otherwise generally people are reaching for the checkpoint inhibitors.

Of course, 60% of patients are not responding to this array of miraculous new therapies. At the moment you have got a few options, one came out recently, T-VEC, tell me first of all about that.

Although we’re pretty happy with where things have been going in the last few years it’s clear we’re a long way from having all the answers for all our patients. So the questions really are how can we make best use of the existing drugs and how can we bring along new drugs, either alone or in combination with the existing approaches to make them better. T-VEC is a good example of that, it’s an oncolytic virus that we inject direct into tumours and we had some very promising early trial results which have led to its acceptance by the FDA earlier this month. What we have seen there, though, is that activity does appear to be limited to people with relatively low amounts of disease and who have not had prior treatment. So the obvious question is if we give that with a checkpoint inhibitor is the sum of the parts greater as a result? So those trials are ongoing, both with pembrolizumab and with ipilimumab.

And you would then perhaps consider using the T-VEC quite early in the disease, then, even before checkpoint inhibitors?

For some patients that may be the case but it’s highly likely that in the longer term its place is going to be alongside things like checkpoint inhibitors. Generally where we find effective treatments, unless side effects prevent us, we like to combine them because you tend to get synergistic interactions between different classes of agents.

But you have another trick up your sleeve involving activating T-cells, tell me about this new one.

One of the trials with which we’ve been involved in Oxford is with a class of drugs called Imtack [?] of which the lead compound is called IMCgp100. This targets T-cells to melanoma by targeting peptide fragments from a protein called gp100 that are found on the surface of melanoma cells and very few other cells. In the clinical trials that we reported at the American Association of Cancer Research earlier this year we’ve seen some promising early activity which is going to lead to a wider programme of trials, including in combination with checkpoint inhibitors.

How do you sum up this field for cancer doctors right now? A lot of promise but you’ve not got all of the answers yet, have you?

Sure. Lots and lots of promise, considerable uncertainty that goes with that. With all these new drugs floating around how we order them, which patients benefit from which drugs requires significant sorting out and that’s probably going to take years rather than months. And it also encourages us because we’ve got the key first examples of oncolytic viruses working against cancer, of checkpoint inhibition working against cancer, which means that we can dust off some of our knowledge from ten, twenty years ago and reapply it knowing what works. This will lead to significant other therapeutic advances which is only going to make it more complicated but very much in a good way.

Although you are throwing a shotgun approach, do you have any ways of individualising therapy, any biomarkers coming along?

There’s a lot of interest in that, both in terms of getting the treatments in the right order but also in terms of affordability. New drugs tend to be expensive and therefore one wants to target them at the right patients at the right time in their illness. So there’s a lot of interest in PD ligand-1 and whether that can be used to sort which patients get which drugs. It doesn’t appear to be a good biomarker for saying yes or no but it may emerge as a biomarker for saying some patients need only one drug whereas other patients need two or more. We obviously have the BRAF mutation and the NRAS mutation present in about 40% and 20% of melanomas respectively which do at least very effectively sort out who gets the targeted agents targeting BRAF and MEK but there’s still a lot more to be done.

So final words, bottom line for busy cancer doctors?

There’s lots going on, melanoma treatment is generally centralised in regional centres and that’s probably the right place because it’s so fast moving, but within a very short period of time we’re going to see these treatments everywhere so that patients can have them closer to home. So watch, learn and hopefully apply very, very soon.

And watch this space.

Absolutely.