EADO Congress 2015
New challenges in drug combination and strategies
Dr Paul Lorigan - The Christie NHS Foundation Trust, Manchester, UK
Resistance to melanoma treatment is a crucial issue because patients inevitably get resistance. When the treatment stops working you then maybe use another drug. What is your interest in resistance and why are you talking about it right here at the melanoma meeting in Marseilles?
As you rightly say, resistance to targeted therapy for many, if not the majority of, patients is inevitable and there’s a lot of effort going into understanding the mechanisms of resistance and, with that, hopefully to design treatments for patients who become resistant or to try and prevent them becoming resistant. But the particular area that I’m interested in, and others are as well, is that there are group of patients who will become resistant to treatment, who progress on treatment after a period of time of a benefit, and then they will have a second line therapy, usually with immunotherapy, and they may get a benefit from that, then they progress on immunotherapy. And there are a number of case reports and observations that if you re-treat that group of patients with targeted therapy, the drugs that they’ve become resistant to, actually a significant proportion of them get a benefit from that.
Now what might be happening, then, at the molecular level to explain that?
That’s the critically important question. Our basic understanding, based on the hypothesis is that tumours accrue mutations and this is how they become resistant. But in fact what we are understanding much more is that there is a phenotypic diversity, in other words that the tumour, once it has become resistant, once the driver to select out that resistance is removed, then the tumour cells may change and that they may then become more sensitive to that tumour again. It’s not necessarily based on some molecular change but probably more fine control in terms of epigenetic phenomena.
In the world of practical medicine, then, how should the clinician be using this?
The answer to that is we don’t really know. It has huge implications for us because if suddenly we’re saying that we’re going to be re-treating all of those patients who previously benefitted and then had a period of time off treatment, that has implications for patients. That’s great for patients if we’ve got another treatment that might help them; it has implications for clinicians and it has implications for payers. But what we really need to know is to understand this scheduling. So the EORTC has proposed a trial looking at starting with treatment A, moving on to treatment B when patients progress on treatment A, and then re-treating with treatment A when patients have a second progression on treatment B. We would do ABA or BAB and clearly link into that a lot of translational research to try and understand the underlying mechanisms of the resistance.
You were mentioning particularly targeted therapies, so targeting RAF, MEK, this sort of target, does this apply to those specifically?
Certainly it does apply to targeted therapies. We know far less about mechanisms of resistance, if that’s the correct term, to immunotherapy and we certainly know far less again about re-treatments. We’ve got some data from the initial studies with ipilimumab, the anti-CTLA-4 antibody,that patients who benefit and then progress, if you re-treat them at a later stage a proportion of those will benefit. But in terms of the newer, the anti-PD1 antibodies or the combinations we’ve got little or no data. So that’s an unanswered question.
So what’s the take-home message for doctors on this question of resistance and re-treatment?
We’re redefining what we mean by resistance. The fact that when a tumour becomes resistant doesn’t mean that it will never again respond to that treatment but we need more information, better understanding and that usually comes from a clinical trial and that’s what we’re designing through the EORTC.
