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New Treatments for Melanoma: a Guide for Patients
Dr Pippa Corrie, Consultant Medical Oncologist,
Cambridge University Hospitals NHS Foundation Trust
Introduction
Melanoma is a relatively rare type of cancer but its incidence is increasing faster than
for any other cancer. The highest rise is in young women under the age of 30. Most
people will be cured by surgery, but in some patients melanoma recurs.
Melanoma spreads in three ways:

Locally, around the site where the surgery was performed;

Via the lymphatic system to lymph nodes (known as locoregional spread);

Via the bloodstream, reaching places in the body such as the liver, lungs, bones
or brain (these are called distant metastases or secondaries).
Once melanoma has spread to distant sites, it is rarely curable. However outcomes
are improving. Specialist teams aim to offer patients the best available treatments to
improve the quality and length of their lives.
New treatments have to be tested rigorously for safety and efficacy, by means of
clinical trials. Since 2011 two new drug treatments have become available for
metastatic melanoma patients after clinical trials showed they can extend life. These
new treatments are called:

Ipilimumab (manufactured by Bristol-Myers Squibb; also known as Yervoy);

Vemurafenib (manufactured by Roche; also known as Zelboraf).
Ipilimumab
This drug works by removing the brake on the immune system.
In 2010 the New England Journal of Medicine published the first report of beneficial
effects of ipilimumab in a randomised clinical trial. In this trial, ipilimumab was
compared with a control vaccine, gp100, in groups of patients with metastatic
melanoma who had received at least one previous drug treatment.
The graph above shows there was an improvement in patient life expectancy
(overall survival) amongst those who received ipilimumab compared with those
given the gp100 vaccine only. The lives of a higher proportion of patients were
prolonged.
A second study looked at the effect of combining ipilimumab with a standard
melanoma chemotherapy drug, dacarbazine (DTIC), compared with a group
receiving dacarbazine alone. Patients in this trial had not previously received any
treatment for metastatic melanoma.
This graph shows that, as in previously treated patients, ipilimumab treatment was
associated with a small but significant improvement in patient survival after 1, 2 and
3 years compared with dacarbazine alone.
In comparison with conventional chemotherapy, ipilimumab has some very
different and potentially serious side effects. Most of these are generated by the
immune response being stimulated against normal body tissues. Patients may
experience skin rash, colitis causing diarrhoea, hormonal problems and liver
damage. Some of the effects may themselves be life-threatening, but they can be
treated effectively if identified quickly. It is vital that patients being treated with
ipilimumab keep in close contact with their specialist team and inform them if
problems arise so that the right treatment can be given promptly.
Ipilimumab was licensed in the USA in March 2011 and in Europe in August 2011. It
has been available via Regional Cancer Drug Funds in England since licensing and
will become routinely available in England and Wales following the decision by the
National Institute for Health and Clinical Excellence (NICE) in December 2012 to
recommend it. Ipilimumab is at present not readily available in Scotland or Northern
Ireland.
As we have seen, ipilimumab has the potential to prolong the life of some melanoma
patients. But there are a number of issues:

In a situation where there have been no good treatments for metastatic
melanoma, the announcement of this ‘major milestone’ means that patients’
expectations are understandably very high.

Most patients, however, do not stand to benefit from this drug (as can be seen by
the previous graph showing that the minority of treated patients are alive one
year or more later).

Amongst those who do benefit, the advantage may be in terms of a significant
number of extra years' life extension. Since there is currently no way of knowing
who will benefit until a couple of years after treatment, the drug should be made
available to all patients where feasible.

Some people – but not many – may show a delayed response to ipilimumab
several months after completing treatment.

It is very expensive. The actual cost of the drug is around £75,000 for a full
course of four treatments. As a condition of NICE approval, the NHS cost price
has been significantly reduced.

The side effects of ipilimumab mean that patients need to be reasonably well at
the time of embarking on the treatment.

The mechanism of action of the drug means that it often takes months to gain the
full benefit from Ipilimumab; so patients with rapidly-growing melanoma
metastases are less likely to benefit.
Like most new drugs, ipilimumab is undergoing further development. The
following aspects, in particular, are being investigated:

How to predict who is likely to respond and who is not.

What is the right dose? For example, some trials have used a 3mg per kg of
body weight, while others have tested 10mg. We do not yet know whether the
dose makes a difference to patient outcomes.

Can patients be successfully re-challenged with repeat treatment some time in
the future?

What is its role as an ‘adjuvant’ therapy, given to patients who have had surgery
for melanoma but who are at high risk of recurrence of their disease?

Its use in combination with other drugs, such as vemurafenib; this is being tested
in ongoing clinical trials.
Vemurafenib
The second new drug, vemurafenib (also known as Zelboraf or PLX4032), acts by
blocking the action of a particular gene called BRAF, which is known to be abnormal
in around 50% of all melanoma cells. This treatment only has a chance of working in
patients whose tumours contain the BRAF V600 mutation.
In the international phase III BRIM3 study, a comparison was made between two
randomised groups, together numbering 675 patients. One group was given
vemurafenib, the other group received the standard chemotherapy, dacarbazine.
As can be seen from the graph above, 84% of the patients in this trial randomised to
receive vemurafenib were alive 6 months after starting treatment, compared with
64% of those treated with dacarbazine. Longer follow-up of patients in this study has
confirmed that those receiving vemurafenib had at least 4 months’ life extension
compared with patients in the dacarbazine arm. This is likely to be a conservative
estimate, however, because many patients who were allocated dacarbazine went on
to receive vemurafenib afterwards and this, too, will have had a positive impact on
their life expectancy.
Although vemurafenib is not a curative treatment, the graph above shows that
virtually all patients had significant shrinkage of their cancer. Experience has shown
that tumours start to shrink within 2-4 weeks following the introduction of
vemurafenib, and this is frequently associated with a significant improvement in
quality of life and a reduction in cancer-related symptoms. Thus patients starting
vemurafenib can expect to benefit from it at least in the short term, which is an
indication that the drug is truly targeting the process in the melanoma cells driving
cancer growth.
Like all cancer treatments, vemurafenib can cause a number of side effects. However
the pattern of side effects is different to conventional chemotherapy and immunotherapy. The drug can affect normal skin in a variety of ways. First, people can
become very sensitive so sunlight (photosensitivity) and be at risk of burning even in
small amounts of UK sunshine. Patients are advised to wear a hat and apply high
factor sunblock to exposed skin when going outside. Vemurafenib can cause a rash,
which may be mild or more severe. Finally, a variety of skin nodules can occur.
These may vary from tiny papules to larger nodules called keratoacanthoma. These
may represent the early stages of squamous cell carcinomas of the skin. Because
these are visible, they can usually be identified and treated by freezing or removing
if necessary.
Vemurafenib can also cause aches and pains in joints and muscles, as well as general
tiredness.
Most of these side effects will resolve by stopping treatment. By adjusting the
number of tablets to take, most patients can find a dose that suits them and keeps the
cancer at bay.
Its important for patients taking vemurafenib to keep in touch with their specialist
team, especially in the first few weeks of treatment, in order to make sure any side
effects are dealt with straight away.
The progress of licensing vemurafenib has been similar to that of ipilimumab: the
drug was licensed in the USA in August 2011 and in Europe since March 2012. It
was made available via Regional Cancer Drug Funds in England and will become
routinely available in England and Wales following the decision by the National
Institute for Health and Clinical Excellence (NICE) in December 2012 to approve it.
Currently vemurafenib is not readily available in Scotland or Northern Ireland.
The pros and cons of vemurafenib can be summarised as:

It only works in patients whose tumour contains the BRAF mutation.

Patients respond rapidly, generally within weeks; the vast majority of patients
respond in the short term.

However most patients relapse at some point.

It is expensive, although a condition of NICE approval was a significant
reduction in cost to the NHS; competitor treatments targeting the BRAF pathway
are on their way.
Management of Advanced Melanoma Patients
As we have seen, vemurafenib is only effective where a tumour contains the BRAF
mutation. It is therefore essential to identify the BRAF mutation status of tumours.
There is a clear advantage in testing early for this, especially because any tissue from
a tumour removed previously is acceptable, while testing is currently free in the UK
and the test is quick and reliable; and there is no evidence that the status of the
mutation changes over time.
All melanoma specialist teams in the UK have the ability to arrange for BRAF
genotyping for patients with advanced melanoma. Patients who have had surgery
for melanoma but are considered to be at a high risk of melanoma may also have
their tumour tissue sent for testing, since BRAF-targeted drugs will be being tested
in trials as adjuvant therapy to try to reduce the risk of the melanoma coming back.
For patients with advanced disease, if the BRAF mutation is identified in the sample
tested standard practice is for vemurafenib or similar BRAF-targeted drugs to be
offered as an initial treatment.
Ipilimumab may be used in patients irrespective of their BRAF status. Currently the
licensing of ipilimumab in Europe requires that it can only be offered to patients
who have previously received another anticancer drug.
Where there is no BRAF mutation (also known as BRAF wild type), the first-line
treatment may be cytotoxic chemotherapy such as dacarbazine. Patients may be
offered a clinical trial of new treatments, since the benefits of dacarbazine are
limited. Again, ipilimumab is offered as a second-line treatment.
Future Melanoma Treatments
As a consequence of our better understanding of the processes driving melanoma
growth, other new treatments are rapidly becoming available. We are learning that
genetic mutations other than BRAF drive the cancer process in certain groups of
tumours and testing is being introduced for these new mutations.
New drugs targeting BRAF, other key new gene pathways and the immune system
are all being developed. These state-of-the-art treatments are first being tested in
clinical trials to assess safety as well as efficacy. Melanoma patients will be offered
entry into clinical trials wherever possible, as a method of enabling rapid access to
these new drugs. The advantages of entering a trial include the best possible chance
of an improved outcome, even closer monitoring compared with standard
healthcare, and the opportunity to contribute to the improvement of outcomes for
others in the future.
If you (or someone you know) would like to be considered for a clinical trial, or you
are unsure about whether to take part in a study that has been offered, you should
feel free to discuss the options with your specialist. Some key weblinks to assist you
are provided below.
To find melanoma trials that are recruiting:
http://www.cancerresearchuk.org/cancer-help/trials/searchresults/?AdvancedSearchFormType=clinical_trials_adv_search_form&cancertype=157%2318
8%23Melanoma%20skin%20cancer&stillrecruiting=Open
Taking part in a clinical trial:
http://www.macmillan.org.uk/Cancerinformation/Cancertreatment/Clinicaltrials/Takingpart
.aspx
Summary
Melanoma treatment is a rapidly changing field. Ipilimumab and vemurafenib are
the first of a series of new treatments entering the clinic for melanoma patients,
offering real benefits compared with the situation a few years ago.