More data on survival with new skin cancer drug

Monday September 30 2013

“A cure for skin cancer,” trumpets The Mail on Sunday’s front page, with the announcement of a “historic breakthrough as 'spectacular' drugs bring hope to thousands”.

The Mail’s story was prompted by results discussed at the European Cancer Congress. The news is based on a “pooling” of longer-term data from trials in which people with advanced melanoma (where the cancer has spread to other parts of the body) received the new drug ipilimumab.

Melanoma is the most serious type of skin cancer. The main treatment for early stage melanoma is surgery, but if it spreads to other parts of the body (becomes advanced) treating it is difficult, and treatments have tended to only slow the cancer’s growth rather than stop it.

However, recent trials have shown that ipilimumab increased the average life expectancy of people with the condition whose previous treatment had failed or stopped working. The drug has already been licensed in Europe and recommended by NICE for use in the NHS for this purpose.

The current study reported that half of patients treated with ipilimumab survived to 11.4 months, about one in five patients lived to three years, with most of these patients going on to live to 10 years. One expert speculated that adding ipilimumab to new drugs called anti-PD1/PDL1 monoclonal antibodies, might mean “metastatic melanoma could become a curable disease for perhaps more than 50% of patients over the coming five to 10 years”.

Survival rates for advanced melanoma are low, and few treatment options are available, so ipilimumab offers a welcome improvement. The effects of combining ipilimumab with other new drugs are currently unknown, and we need to await the results of the trials to know if the promising predictions are correct.

Where did the story come from?

The analysis was carried out by researchers from the University Hospital of Essen in Germany and other research centres in France and the US. The analysis itself had no funding.

The analysis was presented at the European Cancer Congress (ECC) 2013 in Amsterdam – an annual medical conference where both cancer specialists and patients discuss new findings in the field of cancer treatments. Information on the analysis is so far published only as a conference abstract, which means that only limited detail of the methods and findings were available. This also means it has not been through the full peer-review process needed for publication in a peer-reviewed journal.

The advent of ipilimumab has represented an important step forward in the treatment of advanced melanoma. It does offer a better outlook, particularly for the one in five people who live up to three years. However, there is still a way to go before melanoma can be regarded as “cured”, as the Mail suggested.

The Mail does include a balancing quote from Dr James Larkin, of the Royal Marsden Hospital in London, who is reported as saying that: “It’s difficult to know that we have actually ‘cured’ people, because we have to wait to see if they die from something else. But all this new [ipilimumab] data points to the fact that if you respond to the drug and are still alive three years after treatment, then it’s very likely that you are clinically cured.”

What kind of research was this?

This was a meta-analysis (pooling) of the results of studies assessing the effects of the drug ipilimumab in people with advanced melanoma. Ipilimumab has already been shown to increase the lifespan of people with the condition, but the researchers wanted to pool all the most recent information on survival to get an even better estimate of the effects of the drug.

Melanoma is the most serious form of skin cancer, which unless caught early can quickly spread to nearby lymph nodes and then to the rest of the body. “Advanced” melanoma means the cancer has spread to other parts of the body, or that it cannot be removed surgically. Survival rates in melanoma are low. More than 2,000 people die every year in the UK due to melanoma.

Ipilimumab is a relatively new type of drug called a “monoclonal antibody” – it is an antibody that recognises and attaches to a specific protein found on certain cells in the body. Ipilimumab recognises a protein called CTLA-4, which is found on the surface of one kind of immune system cell called T cells. This protein usually “dampens down” the activity of T cells, but ipilimumab stops it from doing this. This means that the T cells are more likely to attack and kill tumour cells.

Ipilimumab has been approved by the European drug regulator, the European Medicines Agency, for use in adults who have previously been treated for advanced melanoma but the treatment has not worked, or has stopped working.

The National Institute for Health and Care Excellence (NICE) has reached an agreement with the manufacturer that the drug can be provided to the NHS at a discounted rate. NICE recommends that ipilimumab is an option for treating advanced melanoma in people who have received prior therapy, as long as the manufacturer provides the drug at this discounted rate.

What did the research involve?

The researchers pooled data from 12 studies. This included two phase III trials, eight phase II trials, and two retrospective observational studies. They then analysed the pooled data in order to see how long the people treated with the drug survived.

The 12 studies included 1,861 people. Most of these people had received a previous treatment (68%, 1,257 people), while about a third had not received any treatment before (32%, 604 people). Ipilimumab is only currently licensed in Europe for people who have had previous treatment for their melanoma.

About half of the people (52%) were given ipilimumab at its approved dose (3mg/kg of bodyweight), 38% of people had a higher dose that had been investigated in some trials (10mg/kg of bodyweight), while the dose in the remaining 10% of people was not reported. The drug was given every three weeks for four doses. In most studies “eligible participants” (eligibility was not defined) could have ongoing “maintenance” treatment, or received another treatment with ipilimumab if needed.

The researchers say that they also looked at survival with other treatments using data from phase II and III studies.

They also say that they looked at data from an additional 2,985 patients from an “expanded access programme”. This means that they were not part of the clinical trials, usually because they would not have met the inclusion criteria for taking part, but they had been treated with ipilimumab outside of these trials, and there was available data on their outcomes.

This included people whose cancer had spread to their brain, those whose cancer did not start in the skin, and those whose cancer was not affecting them as severely.

What were the basic results?

The analysis of the 1,861 patients treated with ipilimumab showed that half of the patients lived longer than 11.4 months – the median. Not all patients were followed up for the same period, and only 254 patients had been followed for three years or more.

Overall, 22% of the patients treated with ipilimumab survived for three years. Among patients who had not had any previous treatment before ipilimumab, 26% survived for three years. Among patients who had received previous treatment before ipilimumab, 20% survived for three years.

Among the 1,861 patients the proportion of patients dying was reported to begin to level off around year three, and stay at this level throughout year 10. At seven years, 17% of patients were alive, and no deaths were reported after this point. The longest survival documented so far was just under a decade (9.9 years).

This pattern of survival was reported to be the case regardless of how many treatments the patients received, dose of ipilimumab used, or whether ipilimumab continued to be used as a maintenance treatment after the initial four doses.

The observed survival with ipilimumab in phase II or phase III trials was reported to appear to be better than what would be expected based on the predicted survival of the patients, taking into account key factors that usually predict their survival.

In the larger analysis of the 4,846 patients, including those who were in the expanded access programme, the median survival was 9.5 months. The levelling off in survival beginning around year three was also seen in this larger group, with 21% of patients surviving to three years.

How did the researchers interpret the results?

The researchers stated that their analysis looked at survival in the largest number of patients with advanced melanoma treated with ipilimumab to date. They say that it showed a “plateau” in survival at around three years that extends through at least 10 years. They suggest that these long-term survival figures “should be considered as a benchmark for future melanoma therapies”.


The current analysis provides pooled, longer-term data to what is already known about survival in people taking ipilimumab for advanced melanoma. It suggests that half of the patients treated with ipilimumab for advanced melanoma live for 11 months or longer. It also suggests that about a fifth of those treated live for three years, and that after this survival rates appear to stay at this level to about 10 years.

Survival rates with melanoma are low, so drugs that improve this are important advances. Previous research had shown that ipilimumab increased average (median) overall survival to about 10 months, compared to six months with an alternative treatment called gp100. This was the basis for the drug being approved for use by European drug regulators. NICE also recommended - after negotiating a discounted price with the manufacturer – that the drug be used by the NHS for people with advanced melanoma who have already had at least one other treatment.

When considering these reults it’s worth bearing in mind:

  • The drug is relatively new, so only a relatively small number of people in these trials have been followed up for three years or longer (254 people). People who participated in the studies of this drug are likely to continue to be followed up over time to obtain more data on long-term survival.
  • The analysis pooled patients with different characteristics, treated with different doses of the drug, and for different periods. The overall patterns of survival seemed similar across these groups, but this will need to be confirmed once enough people are treated with the drug to be able to get reliable estimates for each of these groups separately. One of the study authors importantly notes, “as this was not a randomised comparison, one cannot draw direct conclusions on differences between the doses or the populations”.
  • The current analysis has also only been reported as a conference abstract. This means not a lot of detail is available about the methods or results. Also, it won’t have undergone the peer review that is part of being published in most medical journals.

However, overall, these results suggest that ipilumumab does improve survival for people with advanced melanoma, for whom the outlook is usually quite poor.

Analysis by Bazian
Edited by NHS Choices