Monday June 3 2013
Melanomas can be caused by over-exposure to sunlight
“A cocktail of drugs can reduce advanced skin cancer tumours by more than 80 per cent,” reports the Mail Online.
The news is based on a small early stage trial of a combination of two drugs, nivolumab and ipilimumab, in people with advanced melanoma (an often fatal form of skin cancer). Both of these ‘monoclonal antibody’ drugs work by encouraging the immune system to attack cancerous cells.
Nivolumab and ipilimumab work in slightly different ways, so the researchers hoped that combining the two would lead to a more effective treatment.
The study found that just over half (535) of the people treated with the highest dose of the drugs (and who had acceptable side effects) showed a measurable response to the drugs. All of these people showed at least an 80% reduction in the size of their tumour.
Advanced melanoma is difficult to treat so the results are encouraging. Unfortunately shrinkage of the tumours does not necessarily mean that the cancer has been cured. Longer-term studies are needed to assess what effect the combination has on life expectancy and overall survival.
The results of the current trial mean it is likely that this will be tested in further trials.
Read more about clinical trials into melanoma in the UK, many of which are recruiting participants.
Where did the story come from?
The study was carried out by researchers from the Memorial Sloan-Kettering Cancer Center and other research centres in the US, as well as researchers from Bristol-Myers Squibb and Dako North America. It was funded by Bristol-Myers Squibb and Ono Pharmaceutical, the manufacturers of the drugs being tested. The study was published in the peer-reviewed New England Journal of Medicine.
A conflict of interest, made clear in the research paper, is that many of the researchers are employees or hold stock in the pharmaceutical company that makes both drugs (Bristol-Myers Squibb).
The Mail Online’s report of the study was of a good quality.
What kind of research was this?
This was a paper reporting an ongoing phase I trial of a new combination of drugs in people with advanced melanoma. The drugs used were nivolumab and ipilimumab: both are antibodies that block different proteins which normally help the cancer to evade the immune system.
Ipilimumab has already been granted a license in the UK for use in adults with advanced melanoma who have been previously treated, but whose treatment has not worked or has stopped working. The National Institute for Health and Care Excellence (NICE) has more information on the use of ipilimumab in the NHS.
Nivolumab is a newer drug, has not yet been granted a license for use in the UK, and is currently only available for people who are taking part in clinical trials.
Ipilimumab alone has previously been shown to improve survival in people with advanced melanoma. Different types of cancer, including melanoma, have also been shown to respond to treatment with nivolumab alone. This study wanted to test what happened if both drugs were used together.
A phase I study is the first stage of testing a new drug or combination of drugs in a small number of people to see if their disease shows a response and what the side effects are. If the results are favourable, the drugs would go on to phase II testing of dosing and safety issues in more people and then finally phase III trials to compare it to other accepted treatments.
What did the research involve?
The researchers recruited 86 adults with advanced melanoma skin cancer that had spread to the lymph nodes or spread further in the body (stage III or IV), which could be measured and could not be surgically removed.
To be eligible, people had to be relatively well, with no symptoms or symptoms that only restricted strenuous activity, and have a life expectancy of at least four months.
People who had been treated with these types of drugs before, whose cancer had spread to their nervous system and had not been treated, or who had autoimmune disease, HIV, or hepatitis B or C were excluded.
The researchers were testing two different approaches:
- a concurrent regimen: giving nivolumab and ipilimumab together every three weeks for a total of four doses, followed by nivolumab alone every three weeks for a total of four doses, and then both nivolumab and ipilimumab together every 12 weeks for up to eight doses
- a sequenced regimen: giving nivolumab every two weeks for up to 48 doses in people who had already had at least three doses of ipilimumab. People who had complete response to ipilimumab, or progression of their cancer with evidence of clinical deterioration, or a history of serious adverse effects with ipilimumab were excluded
The two drugs were injected into a vein, and the researchers tested increasing doses of the drugs in successive groups of patients. The participants had their responses monitored using a modified version of standard World Health Organization criteria. These criteria rate response to treatment as complete or partial. Complete response means disappearance of all measurable tumours for at least four weeks, partial response was a reduction by in the size of the measurable tumours by 50% for at least four weeks and no new lesions.
Participants were followed for up to 2.5 years after the start of their treatment. If they initially had a complete response, a partial response, or stable disease for at least 24 weeks but then progressed, they could have the treatment they originally received, again.
What were the basic results?
The researchers treated 53 people with the drugs at the same time, and 33 with the drugs in sequence.
Overall, 40% of people treated concurrently showed an objective response – responded to the treatment – (either complete or partial). Most people who responded had a partial response (16 people), with a few having a complete response (5 people). Of these people, 31% showed a reduction in tumour size of at least 80%. Among the 17 people who received the highest dose of the concurrent regimen that had an acceptable level of side effects, just over half (nine people, 53%) showed an objective response (three complete and six partial). These people all showed a reduction in tumour size of at least 80%.
Almost all participants given the drugs at the same time (93%) had some side effects, mainly rash (55%), itchy skin (47%), fatigue (38%), and diarrhoea (34%). Just over half (53%) had more serious side effects (called grade 3 and 4 events), and in 21% these events meant the dose had to be adjusted.
Fewer people receiving the drugs in sequence showed an objective response (20%), with 73% having side effects, and 18% having the more serious grade 3 or 4 side effects.
With both treatment methods, the side effects were manageable and could be reversed with appropriate treatment. There were no treatment-related deaths.
How did the researchers interpret the results?
The researchers concluded that nivolumab and ipilimumab given together had a “manageable safety profile” and gave rapid responses which appeared to be larger than that previously seen with either of the drugs alone.
This phase I study has suggested that combining two drugs – nivolumab and ipilimumab – can produce a response in people with advanced melanoma with an acceptable safety profile. This type of study is a first step in human studies of new drugs or combinations of drugs.
The authors themselves note that some caution is required due to the small size of the study and the potential for the participants not to be representative of the wider patient population. The results in this study mean the researchers are likely to carry out larger studies comparing this combination of drugs against the combined drugs alone and possibly against other treatments.
The National Institute for Health and Care Excellence (NICE) has recommended ipilimumab given alone as an option for treating advanced melanoma (that has spread (metastatic) or cannot be surgically removed) in people who have received previous treatment.
Nivolumab is a new drug which has not yet gone through the procedure to be granted a license for general use in Europe. Given the generally positive results of this study, it is likely the manufacturer will seek a licence at some point in the future. This usually requires the results of phase III trials to be available.
If this does happen, it is likely that NICE will review the evidence on the drug either alone or in combination with ipilimumab to make a decision on whether it should be made available on the NHS for people with advanced melanoma.
Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter.