What is advanced melanoma and who does it affect?
Advanced melanoma affects around 2,000 people per year in the UK. Advanced melanoma describes a melanoma that has spread from its site of origin to other areas of the body.
Why have malignant melanoma incidence rates in the UK increased over the last three decades?
The main risk factor we know about is sunburn. Over the last thirty years or so, there has been an increase in the incidence of sunburn while people are on holiday, for example, and it’s the episodes of severe sunburn that we think is a risk factor for the development of melanoma.
How are patients with advanced melanoma currently treated and why is there a need for new treatments for advanced melanoma?
Currently, melanoma that has spread is treated with drug therapy, which can be divided into two main groups: B-Raf inhibitors and immunotherapy agents.
B-Raf inhibitors target a particular abnormality inside the cell arising from mutations in the BRAF gene, which are found in about forty percent of melanomas.
B-Raf inhibitors often work very quickly to control melanoma but the problem is that melanomas usually become resistant to these drugs after about six months. Therefore, while the development of these drugs has been a big breakthrough, resistance poses a problem.
The main immunotherapy agent we are now using to treat advanced melanoma is ipilimumab (IPI). This drug can stimulate the immune system to attack melanomas. If it’s successful in doing that, melanomas can sometimes be controlled for years and maybe even cured altogether.
However, the problem is that this drug is only effective in about fifteen or twenty percent of people. So, if it works, it can work very well, but most people don’t benefit from treatment.
What hurdles need to be overcome when designing a treatment for advanced melanoma?
That’s quite a complicated question actually. I suppose the ideal treatment would work for all patients, require only a brief treatment course and have long lasting effects.
For example, ipilimumab is currently given as four intravenous infusions and then the treatment is finished. The patient basically has three months of treatment and then if it works, they don’t need to have any treatment ever again.
On the other hand, B-Raf inhibitors are taken in the form of tablets every day for as long as they are effective. This means the patient is inconvenienced by side effects and frequent visits to hospital, for example, and these issues need to be taken into consideration in the design of new treatments.
Please can you outline the recent data announced for a novel investigational therapy for malignant melanoma?
Currently, there is a lot of excitement about the trials of anti-PD-1 drugs. These drugs work in a similar way to IPI but the early data in nonrandomized trials is suggesting that anti-PD-1 drugs could benefit more than fifteen to twenty percent of patients, with up to thirty to forty percent maybe benefitting.
At the moment, we are conducting randomized trials to compare these drugs with benchmark products, so that we can investigate this more thoroughly as these early results do need to be interpreted with a degree of caution.
Another benefit of anti-PD- 1 therapy seems to be that people are getting durable control of melanoma – there appears to be a definite amount of patients in whom the melanoma is controlled over a year, which is obviously good news.
The main drugs in this area are nivolumab, made by Bristol-Myers Squibb and MK3475, made by Merck.
How promising does immunotherapy look as a treatment for advanced melanoma?
I personally think it is very promising indeed. We’ve been trying to develop drugs that can stimulate the immune system to recognize and attack melanoma for a long time and now we have drugs that show promise in achieving that, without causing negative side effects.
A lot of the older immunotherapy treatments that have been used for decades can have quite significant side effects and only benefit a small number of people, as is the case with high dose interleukin-2, for example. Now, we’ve got drugs that don’t have major side effects and actually seem to be helping more patients. I think the future does look very promising.
What do you think the future holds for advanced melanoma treatments?
In the future, we will be using more immunotherapy. We will be exploring whether immunotherapy and other treatments used earlier on in disease course before melanoma has spread, can reduce the risk of spread.
For example, clinical trials of breast or bowel cancer performed over the last ten or twenty years have shown that administering drug therapy after surgery significantly reduces the risk of relapse or future spread of the cancer. At the moment, we’re beginning to explore this possibility in clinical trials of melanoma.
Where can readers find more information?
I normally refer people to the Macmillan website. There are also some very good patient information websites such as the Melanoma International Foundation, which is a good website for patients in the US.
About Dr. James Larkin
Dr James Larkin is a Consultant Medical Oncologist specialising in the treatment of patients with cancer of the kidney and cancers of the skin, including melanoma.
Dr Larkin took a first in Natural Sciences from Cambridge University and undertook clinical training at Oxford University, qualifying in 1996. He underwent general medical training in London and in 2001 won a Medical Research Council Fellowship for a Clinician, carrying out laboratory research at The Institute of Cancer Research (ICR) which led to the award of a PhD.
He completed specialist training at The Royal Marsden and was appointed a Consultant in 2008. His research interests include the individualisation of patient treatment in renal cancer and melanoma, and the combination of novel targeted therapies to treat these diseases.
He is UK Chief Investigator for a number of clinical trials in melanoma and kidney cancer and has been awarded research grants from bodies including Cancer Research UK, Wellcome Trust and the European Framework Programme 7. He is a member of the NCRI Melanoma Clinical Studies Group and Chair of both the the NCRI Renal Cancer Clinical Studies Group and The Royal Marsden / ICR Committee for Clinical Research.
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