We’ve had a complete revolution in melanoma treatment, more so than any other tumour group. When I started as a registrar in training melanoma was essentially untreatable; we had dacarbazine and other chemotherapy regimes which didn’t particularly improve survival, which had response rates of less than 10%, it was a very dire situation with median survival of between 6-12 months. Then over the last less than ten years, both in terms of emerging scientific principle but then in terms of actually licensed drugs, we now have a plethora of agents at our disposal.
In particular these group into two main different types, they are the BRAF directed therapies and then the immunotherapy agents. Melanoma has now become the test bed, really, or the poster child for this precision medicine and also in terms of immunotherapy.
About 40-50% of all patients have mutations in BRAF which is a very strong driver of outcomes for melanoma and also that is very easily targetable. When it’s targeted the patients respond almost invariably. So with combination BRAF directed therapy which includes both a BRAF inhibitor and a MEK inhibitor we get response rates of over 70% and very good PFS, progression free survival, of 10-12 months and this has been one of the revolutions. The other side of things in those patients who have no BRAF mutation or who have either progressed after BRAF directed therapy or where we feel that they have more indolent disease we would target with immunotherapy. This, as everyone has heard lately, is a real change in paradigm.
So our own CD8 cells, our lymphocytes, have an incredible precision and power to destroy cancer cells within the body and they obviously can be activated to attack all different organs. What’s more, assuming you can engender memory, so you get the right T-cells activated, they can keep on patrolling and keep the cancer at bay in perpetuity. This all happened in melanoma only in 2011 when we had the licensing of ipilimumab compared to vaccination with gp100. On the face of things it wasn’t a very dramatic response in terms of how many patients had actual shrinkage of the cancer and progression free survival but what really came out of that is there were about 20% of patients who had long-term survival, what we call the tail of the curve now. That has been shown to be ongoing up to ten years and beyond with big pooled analyses that were subsequently put together. So we know that some of these patients are actually being cured of the disease which is obviously a big change.
Then with newer agents like PD-1 inhibitors, and with combinations of PD-1 inhibitors and with ipilimumab, we’ve then shifted up responses but also in the absence of ipilimumab reduced toxicity substantially. So now we’ve got these two major different groups.
Another agent that has recently been licensed is T-VEC as well, which is talimogene laherparepvec. This is a HSV virus that has been engineered to only replicate within the cancer cells but it also secretes a protein called GM-CSF. So essentially this leads to destruction of the cells within injected tumours, so just to say this is an injected treatment, it then leads to actually immune education within the melanoma metastasis. These cells can then travel distantly and attack other metastases elsewhere. We see within the studies that we can get responses in non-injected lesions and very substantial and durable overall responses, despite not injecting all the lesions.
So we’ve actually just presented a poster from the T-VEC 325 study where this was more a biomarker study. So we took biopsies of lesions at baseline and then at week 6 after injecting the lesions, so these were non-injected lesions at week 6, to compare them to the lesions before injection at the beginning. Then we looked at the density of CD8 cells within that. So our hypothesis was really to see whether we’re seeing CD8, the T-lymphocytes, infiltrating the distant metastases and whether that was in any way corresponding with outcome.
The first thing we showed was that within the other uninjected lesions we got a significant increase in CD8 cells of about 2.41-fold in median terms and much higher in terms of the overall mean. This is the first demonstration of what we considered the likely mechanism of action of T-VEC of actually driving these CD8 cells into distant metastases. Now a lot of the concentration that we’re working on now is to try and understand which CD8 cells are in there, which ones indicate response and so forth. So there’s a lot of translational research that I think will give us a very strong clue as to how to use T-VEC but also how we can increase the efficacy by adding in drugs and how we combine those drugs.
To bring this back to the UK’s perspective in modern melanoma treatment, you’ve seen and told us about all of these changes. For patients in terms of the access and affordability of getting hold of these drugs and seeing these benefits in their own lives, do you have any thoughts and considerations in regards to that?
This is an evolving field and actually overall we can access most treatments within the NHS. So the immunotherapy, including ipilimumab and nivolumab, is funded in the UK. We do have more constraints in terms of when the drugs can be used in terms of sequencing and so on and treatment after progression or re-challenge, but generally speaking most of these drugs are readily available. We’re just moving into the adjuvant setting, so using more of these drugs after a surgical complete resection. So we’ve got the first of those drugs come through, the dabrafenib and trametinib, which is now licensed and funded in the UK. But both nivolumab and pembrolizumab will likely be going through this process over the next few months; nivolumab’s initial application for funding hasn’t been successful but this is still an ongoing discussion. So overall we’ve got these drugs and they are making a real change in terms of patients’ lives.
You mentioned the role of surgery there for adjuvant, neoadjuvant treatments, how essential does the role of surgery remain in treating melanoma in the UK?
At the moment we don’t want to detract because we don’t know yet, most of these studies are not looking at removing surgery from treatment. There’s quite a lot of interest in this congress around neoadjuvant treatment and that is evolving and potentially will in the future lead to a reduction in surgery. We do know from trials looking at the need for completion, a lymphadenectomy, that we can actually not go ahead and just do a sentinel node biopsy which is of prognostic purpose and which helps guide our subsequent therapy but isn’t really impacting on survival. But, as it stands, in terms of treatment of the primary this would go as per standard procedures.
I know this isn’t in regards to melanoma treatment in the UK but in your practice have you seen any changing understandings from the public in the UK regarding melanoma – awareness of causes of skin cancers, different types of skin cancers, different behaviours to prevent them? Has any of that come through on a population level?
There is an evolution in that regard but what I would say is that we don’t often talk about that because I see patients who have already metastasised and I don’t particularly want to go backwards to discuss what could have happened because we’re looking forward. I would say that there is an increased awareness but probably not high enough, there is still quite high sunbed usage for example in the city I work in, Liverpool. This is obviously something I would like to see reduced substantially.