EADO Congress 2015

Management of acute metastatic melanoma

Dr Paul Lorigan - The Christie NHS Foundation Trust, Manchester, UK

In an ideal world you get melanoma early, you treat it, you may have patients who do eventually have metastatic disease But I know you’re particularly interested in the very ill patient. What do you mean by that – a very ill patient with melanoma?

I absolutely agree that in general we’re moving towards more intensive follow-up of patients who are at high risk of developing metastatic disease, if they do develop metastatic disease to pick that up early and so be able to offer them better treatments, more lines of treatment. But it’s not at all unusual for us to see a patient who perhaps had a melanoma diagnosed 10-15 years ago, maybe even a misdiagnosis. So a classical example would be a patient admitted to a local hospital with perhaps confusion, weight loss and found on a scan to have metastatic disease, perhaps brain metastases and in their past history we find that they’ve had a pigmented lesion removed ten years ago, it might have been a melanoma, it might not. How do you manage that patient? They are very ill, what will you do for them?

That’s the world of real, practical medicine and quite a crisis too. So what is your approach?

It is recognising that it is a difficult clinical problem. But going forward the first thing is that we need to establish a histological diagnosis; we need to know that this is melanoma and not another cancer because it would be treated very differently. But also it’s critically important to access tumour for molecular testing because we know that if the patient has a targetable mutation, this BRAF mutation, then we can salvage patients who are very unwell, who have active brain metastases, who have poor performance status. So it’s critically important to get a biopsy done as quickly as possible and to get that tissue to the laboratory. Actually that is usually the rate limiting step, it’s not the time to do the molecular test, that can be done in a day or two usually, but it’s actually getting the biopsy done, making sure it doesn’t sit on a desk somewhere but it goes straight to the laboratory. Then we can make a decision based on that.

So some patients have got actionable mutations, others haven’t. So what approach do you take for all of your patients?

For the patients who have actionable mutations their outcome is going to be better, there’s no doubt about that. For the patients who don’t have actionable mutations, in other words you don’t have a targeted therapy, then you are going to try and improve their general health, get them a bit fitter for treatment. So that would be controlling any symptoms, controlling any metabolic problems, hypercalcaemia etc., if they have brain metastases controlling the oedema related to those. But that group of patients have a much poorer prognosis.

And they can, however, take some of the immunotherapy drugs presumably?

That is an unanswered question actually and I’m looking forward to the debate here about that because we know that immunotherapy works relatively quickly for some patients and we know that it has little in the way of toxicity. But the question is whether there is a benefit for that group of patients who are very unwell and I think that’s an unanswered question.

Can you run me through the molecular targets that you have found are actionable and that doctors could practically think about targeting and treating right from the get-go?

The main targetable mutation is BRAF, an oncogenic mutation, it’s mutated in about 50% of melanoma patients. Higher likelihood if you’re younger, lower likelihood if you’re older. In that group of patients they will benefit from targeted therapy ideally with combination BRAF MEK inhibitor; in the UK we’re limited at present to single agent BRAF inhibitor. Trials have shown this: you can pull those patients back from the brink, you can pull them back from being bed-bound and very ill and control their symptoms, control the disease and improve their quality of life for quite a significant period of time. If they don't have a BRAF mutation then their treatment options are fewer. There’s a lot of discussion about radiotherapy for patients with brain metastases; there are well derived scores to try and predict who will or won’t benefit from that. The question about immunotherapy, as I said, is an unanswered question.

And other actionable mutations are not in the mix yet?

Not really, no. The other mutation that we’re looking at is for rare subgroups of melanoma: acral melanomas, mucosal melanomas are c-kit mutations but we do not have a drug that’s licensed for c-kit mutated melanoma at present. We do have clinical trials.

So what’s the bottom line, then, for doctors who might be faced with a very ill patient with metastatic melanoma?

For that group of patients over and above just improving, controlling symptoms and improving quality of life for a short period of time, the critical question at present, and this may change, but the critical question is do they have a BRAF mutation? So that needs to be the major focus initially. Getting a biopsy or tracking down a previous biopsy and dedicating time to getting that to the lab and getting an answer back because that’s the one single thing that will make the biggest difference for that patient.