Immunotherapy drug combo could combat melanoma

Behind the Headlines

Monday June 1 2015

It can be difficult in getting antibodies to target cancerous cells

Immunotherapy could potentially treat a range of cancers

"New era in the war on cancer," is the somewhat over-hyped headline on the front of the Daily Mail. The new era refers to the use of immunotherapy – using drugs to coax the immune system into attacking cancerous cells while leaving healthy cells unharmed.

The results of a number of studies on immunotherapy have recently been presented at a conference in Chicago. The study we are looking at investigated the use of a combination of two immunotherapy drugs, ipilimumab and nivolumab, in treating advanced melanoma; the most serious type of skin cancer.

The trial involved 945 people with advanced melanoma who were given either of these drugs alone or in combination. Overall, people taking the combination lived longer without the disease progressing (average 11.5 months) compared with either drug alone (average 6.9 months with nivolumab and 2.9 months with ipilimumab). People whose tumour displayed the protein that nivolumab targets (PD-L1), did just as well with nivolumab alone as the combination.

The study is ongoing and it’s not yet known whether people taking the combination treatment live longer overall than those taking the individual drugs. Side effects such as severe diarrhoea were quite common, affecting more than half of the people taking the combination. Therefore it will also be important to compare people’s quality of life while taking the different drugs and combinations.

The results, while promising, are unfortunately not a cure, but may provide another option for people with this hard to treat cancer.


Survivor bias

Many of the news sources carry individual case studies and interviews of people who benefited from immunotherapy. While this is positive news for the people involved, media reports specifically about those with the best outcomes could be considered a form of survivor bias.


Put simply, survivor bias is failing to realise that the people who “survived” or benefited from an intervention may not be representative. The people who found benefit from treatment need to be considered in the context of the trial as a whole, where some people did not respond, and some experienced severe side effects.

Where did the story come from?

The study was carried out by researchers from The Royal Marsden Hospital, London, South West Wales Cancer Institute, Singleton Hospital, Swansea, and other European and international institutions. Funding was provided by Bristol-Myers Squibb, which manufactures the drugs being tested.

The study was published in the peer-reviewed New England Journal of Medicine on an open-access basis so it is free to read online or download as a PDF.

Some of the wide media coverage of this study, arguably moves into the realm of hype. Much of the reporting could give the impression that immunotherapy is a new discovery. In fact it was first used in the late 1980s, and has been used in the treatment of various conditions.

Several papers cover immune therapies more broadly, describing the results of several studies in different cancers. A lot of these results have been reported at the American Society of Clinical Oncology’s annual conference in Chicago and an overview of the results can be found here.

Overall, although this particular study of immune therapy for advanced melanoma gives promising results, it is not demonstrating a cure as some of the headlines suggested. 

Some sources do carry quotes from independent experts warning about unrealistic expectations about immunotherapy. Prof Karol Sikora, the dean of the University of Buckingham's medical school, is quoted by the BBC as saying: "You would think cancer was being cured tomorrow. It's not the case, we've got a lot to learn."


What kind of research was this?

This was a randomised controlled trial (RCT) investigating a drug combination to treat advanced melanoma, which has a notoriously poor outlook.

Over the past years there have been advances in the development of treatments for advanced melanoma, particularly drugs that work via the immune system (immunotherapies). The drugs used in this study are synthetic drugs based on antibodies that occur naturally in the body. They are designed to attach to specific proteins displayed on the surface of cancerous cells and so destroy them.

One antibody drug called ipilimumab is licensed for the treatment of melanoma too advanced for surgical removal, or that has spread to other parts of the body (metastatic). A newer antibody treatment, nivolumab, has also recently been approved for the treatment of advanced melanoma following studies demonstrating its effectiveness.

This RCT investigated whether the combination of ipilimumab and nivolumab worked better than either drug used alone.


What did the research involve?

The international study carried out in multiple research centres enrolled 945 adults with advanced melanoma which was unsuitable for surgical removal and/or had spread elsewhere in the body. They were randomised to one of three treatment groups:

  • ipilimumab alone
  • nivolumab alone
  • ipilimumab plus nivolumab in combination

All treatments were given directly by infusion into the bloodstream. The people having just one drug were also given an inactive infusion (placebo) to match the schedule of infusions they would have had if they were also taking the second drug. This was to make the study "double blind" meaning that neither patients nor assessors examining the outcomes knew which treatment the patients had been given.

The patients were assessed at 12 weeks, then every six weeks for 49 weeks, then every 12 weeks until their disease progressed or treatment stopped.

The main outcomes the researchers assessed were progression-free survival and overall survival. This study presents only the results for progression-free survival, which is the amount of time a person lives without having their disease getting worse (progressing) or dying.

At the time of this assessment the patients had been followed up for an average of one year. Follow-up for the outcome of overall survival is ongoing and so the trial remains blinded (patients and assessors still not knowing what treatment they had).

Analyses were by intention to treat, where participants were assessed according to their assigned groups regardless of whether they completed treatment.


What were the basic results?

At follow-up of around one year, 16% of the ipilimumab-only group were still receiving treatment, 37% of the nivolumab-only group, and 30% of the combination group. The main reasons for stopping treatment were disease progression in the two single drug groups, and side effects in the combination group.

Average (median) progression-free survival was significantly longer for people taking both ipilimumab and nivolumab than those taking either drug alone:

  • ipilimumab and nivolumab: 11.5 months
  • ipilimumab alone: 2.9 months
  • nivolumab alone: 6.9 months

Participants had 58% reduced risk of death or disease progression during follow up with the combination compared with ipilimumab alone (hazard ratio (HR) 0.42, 99.5% confidence interval (CI) 0.31 to 0.57) and 26% reduced risk with the combination compared with nivolumab alone (HR 0.74, 95% CI, 0.60 to 0.92). People taking nivolumab alone also had 43% reduced risk of death or disease progression during follow up compared with people taking ipilimumab alone (HR 0.57, 99.5% CI 0.43 to 0.76).

The nivolumab antibody targets a particular protein called PD-1. The presence of a related protein which binds to PD1 called PD-L1 has been reported to predict how well people respond to drugs that target PD1. In this study, people whose tumours displayed the PD-L1 protein showed equally good progression-free survival with nivolumab alone or the drug combination (both average 14 months) compared with 3.9 months for ipilimumab alone. For people whose tumours didn’t express PD-L1, progression-free survival was best with the combination (11.2 months) and they didn’t get as much benefit from nivolumab alone (5.3 months) or ipilimumab alone (2.8 months).

Overall, 19% of the ipilimumab group showed a response to their treatment, 44% of the nivolumab group, and 58% of the combination group.

Severe side effects were seen in 55% of those taking the combination, 27% of the ipilimumab group and 16% of the nivolumab group. The most common of these side effects were diarrhoea and bowel inflammation.


How did the researchers interpret the results?

The researchers conclude: "Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1–negative tumours, the combination was more effective than either agent alone."



This randomised controlled trial examined the effects of different immune treatments for advanced melanoma.

It demonstrated that overall, people taking the combination of two antibody treatments – ipilimumab and nivolumab – lived longer without disease progression or dying compared with either drug alone. People whose tumours expressed the protein that nivolumab targets, did just as well with nivolumab alone as the combination. Even for people whose tumours didn’t show this protein, they still did better with the combination than ipilimumab alone.

Ipilimumab is currently a licensed immune treatment for advanced melanoma. Nivolumab has recently been recommended for approval for the treatment of advanced melanoma by the European Medicines Agency, which regulates medicines in the European Union. It is not yet available as a treatment though, as it still needs to be granted the final marketing authorisation for this use by the European Commission.

The trial has several strengths, including its relatively large sample size, blinding of participants and assessors to treatment allocation (which should reduce bias), and that the nivolumab was compared with the currently licensed antibody treatment ipilimumab.

Overall the results are promising, but headlines stating immune "milestones", "breakthroughs" or even cures for terminal cancer should be viewed cautiously. Though many of these headlines do cover other studies investigating immune treatments for cancer, this study does not demonstrate that this drug combination cures advanced melanoma. So far it has only been shown to prolong the period before the disease progressed. Also, not all people responded to the drug combination. The study is ongoing and it has yet to be seen whether the drug combination, or nivolumab alone, can increase how long people live overall.

Side effects of the drugs were also a considerable problem. After one year, only a relatively small proportion of people in all treatment groups were still taking the drugs. In the combination group people had often stopped taking the drugs because of side effects. It will be important to compare people’s quality of life while taking these different drugs and their combination.

Another factor that has been overlooked in some sections of the media is cost. Both ipilimumab and nivolumab are expensive, with a typical course of combined treatment estimated to cost more than $200,000 (around £131,000 at today’s exchange rates).

When considering new treatments, the effect gained from a particular treatment needs to be balanced against its cost and compared with existing treatments.  

The further study results on overall survival and quality of life will need to be considered alongside cost if and when the National Institute for Health and Care Excellence (NICE) assess whether to recommend nivolumab or the combination as a cost-effective treatment option for the treatment of advanced melanoma. 

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

Analysis by Bazian

Edited by NHS Choices

Links to the headlines

New era in the war on cancer: Revolutionary treatment that will save thousands hailed as 'biggest breakthrough since chemotherapy. Daily Mail, June 1 2015

Cancer drug combination 'shrinks 60% of melanomas'. BBC News, June 1 2015

Doctors hail 'spectacular' cancer treatment breakthrough. ITV News, June 1 2015

Immunotherapy: 'Major milestone' as drugs stimulate body to fight off deadly cancers. The Independent, May 31 2015

Immunotherapy: the big new hope for cancer treatment. The Guardian, June 1 2015

'Cure for terminal cancer' found in game-changing drugs. The Daily Telegraph, June 1 2015

Welcome to the ‘new era’ of cancer treatment. Metro, June 1 2015

Links to the science

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. The New England Journal of Medicine. Published online May 31 2015

Further reading

American Society of Clinical Oncology. New Immunotherapies for Multiple Hard-to-Treat Cancers (Press Release). May 29 2015


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