EADO Congress 2015

Long response and long responders in melanoma immunology

Prof Georgina Long - University of Sydney, Sydney, Australia

You describe yourself as a melanoma-ologist, what do you mean by that?

I treat melanoma; I only, exclusively, treat melanoma at this point and have a very busy clinical practice and translational research interest. So we’re a rare breed but we exist and increasingly we’re finding specialists in medical oncology narrowing down to one or two cancers, so mine is melanoma. I’m a melanoma-ologist meaning I will treat patients, I’m a medical oncologist, I will treat patients with drugs that look interesting in pre-clinical, under clinical trials or have activity in melanoma. I don’t distinguish between targeted immunotherapy, I’m just in it for the patient and trying to find drugs to prolong survival and prevent melanoma.

You’ve got a bit of a crisis at the moment because too many of your patients are living, aren’t they?

Yes, and I wouldn’t use the word too many. It’s fantastic, but we do. Survivorship is a real issue and our clinics are full and we’re now thinking about how to handle that.

All the promise of immunotherapy and the targeted therapies and combinations I know you’ve been looking at, how do you distinguish which patients are the ones who really will get those long-term survivals that are raising all of the eyebrows at the moment?

That is the million dollar question; it’s the Holy Grail for both targeted therapies and immunotherapies. We have some indicators with immunotherapies that expression of PD-L1 may predict for response but it’s not a very good predictor at all. The bottom line is it’s the clinical things we see in the clinic that drive our understanding, or we can actually suspect patients might progress more quickly than others if they’ve got a high LDH, high burden of disease, low performance status, all the classic things we’ve been using for decades. They’re there, they’re still there, they still tell us a lot about whether patients are going to respond or not or for how long they’ll respond. What we’re missing in the puzzle is biomarkers, things we can look at in the melanoma tissue, things we can look at in the blood that will tell us before we start treatment who will respond and who will not. We don’t have that.

What have you found so far and what are you using when you choose between either an anti-CTLA-4, an anti-PD1, immunotherapy or go on to the targeted therapies, combinations? How do you choose?

First of all I am a triallist and I put patients on clinical trials, that’s my number one. Although we have this great promise and these wonderful results and we’ve extended survival from 6-9 months to way over two years, it’s not good enough until everybody responds and everybody survives. So number one, I put patients on clinical trials and will continue to do so. However, if a patient is not trial eligible how do I choose between the treatments? It’s again driven by those clinical things I just mentioned. Unfortunately we don’t have a test that we can do on the tissue and say, ‘You are going to definitely respond and respond for a long time,’ we don’t know. So I use the clinical things, we also need to know whether they have a BRAF mutation or not. We know that anti-PD1 first line is better than ipilimumab first line so if they don’t have a BRAF mutation we’ll select an anti-PD1 drug, but we’ve got the combinations coming up soon of ipilimumab and anti-PD1 together which will then be another decision tree in our daily clinical practice. But ultimately what I’m interested in and what our laboratory is interested in is trying to determine whether there are any predictors of those who respond and why do people become resistant to treatment? Why do their tumours grow on treatment at times? So that’s what we’re doing. We don’t have the answer yet but we are biopsying patients. It’s very important that patients contribute to that to understand that.

But busy oncologists do have patients coming in the door very frequently. What do you counsel doctors to be doing about these patients? The sort of decision hierarchy that you would yourself go through?

I individualise it for each patient; I take into account their BRAF mutation status, their symptoms, their comorbidities, their performance status, how far away they live from an infusional centre. But I do recommend that patients with melanoma are seen at a big melanoma centre. I am very much into that because not 100% of patients respond and they don’t respond for ever and then you’re left going, ‘OK, they’re resistant now, what do I do? Now let’s get in the troops, now let’s send to a specialist centre.’ Often you may not have done the best thing by the patient if you haven’t taken them to a multidisciplinary team meeting, discussed their case, discussed their LDH, as I mentioned baseline LDH, discussed their performance status, find out what their BRAF mutation status, what their NRAS mutation status is and design the right treatment for them. But having said all that, I think that’s an important point, patients should be seen at big melanoma centres. Having said all that, what I tend to do is if they’re BRAF mutant and they’re very well and have time I would prefer to try immunotherapy first. This is again without data, we have no head-to-head data of targeted therapy versus immunotherapy, none whatsoever. Both fields have developed in isolation and we’re now just starting trials bringing them together. But that’s what I do, I tend to try for an immunotherapy first because they do take a little longer to work and if you’re in that 40% with anti-PD1 that really respond well it tends to be for a long, long time and it’s a very well tolerated drug, excellent quality of life and toxicities are very well tolerated and managed very easily. If not, if a patient has very rapidly progressive disease and they have a BRAF mutation I might go for the BRAF and MEK inhibitor in combination, always thinking about, especially if they have a high LDH we know that they tend to not do very well on any drug, I try to normalise their LDH, bring the tumour under control and then consider a switch to immunotherapy, trying to get that longevity because I’ve brought the tumour under control. But again we have no trial data which is why I prefer to put them on a trial that’s exploring all these questions I just mentioned.

And there are some very exciting trials around. So for the time being, how would you sum up in a few words what the take home message is for doctors?

Exciting times for patients with melanoma, lots of treatment options for doctors, complex area, patients should be discussed in a multidisciplinary team. Try for a clinical trial if they can and if not take into account the patient’s clinical things we’ve been using for decades as to select the therapy that that patient needs. If you can get immunotherapy into them early go with an immunotherapy because that requires a little time to see if they’re responding and sometimes patients don’t have the time.