Long term benefits of immunotherapy emerging for some patients, though key questions remain

A number of cancer clinical trials involving immunotherapy treatments appear to be showing promise, according to new research. 

Results of various trials have been presented at the annual American Association for Cancer Research (AACR) conference in Washington, D.C.

The findings follow initial excitement around the drugs in recent years, and make early estimates of the possible long term benefits for some patients. 

But questions still remain over which patients should receive the treatments, how extensive side effects are, and how to address where immunotherapy hasn’t been successful.

“Using the body’s own immune system we’re now able to find and kill cancer cells that for years have evaded us,” said Professor Tim Elliott, director of the Southampton Centre for Cancer Immunology and funded by Cancer Research UK. 

“Clinical trial results are showing that immunotherapy can lead to long term survival with around 1 in 5 patients living cancer-free, well beyond the historical rate seen for conventional treatments.”

The first success story for immunotherapy came in advanced melanoma patients treated with the drug ipilimumab (Yervoy). And further promising results followed for another drug called nivolumab (Opdivo).

The drugs, called checkpoint inhibitors, have been described as releasing the ‘brakes’ on immune cells so that they can target cancer cells more effectively. 

“The approval of checkpoint inhibitors like ipilimumab and nivolumab has transformed the treatment of advanced melanoma in the past few years, with about 30–40% of patients having remarkable and durable responses,” said Dr James Larkin, a consultant medical oncologist at The Royal Marsden in London, whose team presented new promising findings at the conference.  

There are now around 900 clinical trials that are testing different combinations of these drugs, including Larkin’s.

Results from the large, phase III trial of 945 patients showed that combining nivolumab and ipilimumab in advanced melanoma patients improved survival beyond what was seen for each drug alone.

64% of patients were still alive 2 years after starting treatment, compared to 59% and 45% for each drug alone respectively. 

Find out more: What are ‘checkpoint’ immunotherapy drugs?

In those whose tumours did respond to the drugs, people treated with both drugs saw the longest response. Elliott said that follow up of these patients over the next 5-10 years would be important to see how long these effects might last.

Professor Edd James, a cancer immunology expert at the University of Southampton, added that, because the treatments are associated with increased adverse side effects, though most were successfully managed they would require careful consideration for use in patients.

Follow-up of a small, early-phase trial of advanced non-small cell lung cancer (NSCLC) patients offered some idea of the potential long-term benefits of immunotherapy for those patients whose tumours responded. 

Around 16% were still alive 5 years after starting treatment with nivolumab, compared to 5% as would be expected of the US patient group. The trial involved 129 patients for whom all other treatments had failed. 

While survival was higher than expected, the researchers said they were unable to make predications based on these results for which advanced lung cancer patients would be most likely to benefit from immunotherapy. 

This is an ongoing challenge with immunotherapy trials, and many have a low response rate in patients. To try to tackle this, an early stage (phase 1b) trial treating patients with advanced melanoma has included the common cold virus with ipilimumab treatment. 

The small study of 22 patients found that half responded to the combination treatment. Previous work has shown that the two treatments by themselves produce a response rate of around a quarter or less. 

Importantly, these responses were seen in patients that previously hadn’t responded to a checkpoint drug.

While the research is at an early stage, it demonstrates the potential of using such a combination, said James. “The idea is that infecting the cancer with the virus boosts the immune response which is induced following immunotherapy,” he added.

Another combination against melanoma is also showing promise. A small, early phase trial of 60 patients looked at adding indoximod, a drug that normally keeps the immune system from responding inappropriately, to pembrolizumab (Keytruda), another checkpoint inhibitor. 

Just over half of patients (52%) responded to the combination, compared to 33% for pembrolizumab alone based on data from a previous trial. 

The study’s authors pointed out that the comparison to older trial results limits the conclusions that can be drawn. A larger clinical trial to compare the two treatment approaches directly is needed to confirm the results.

This was also the limitation of a phase I study in 112 so-called ‘triple-negative’ breast cancer patients who were treated with atezolizumab (Tecentriq), another checkpoint drug.

“Triple-negative breast cancer is an aggressive subtype of breast cancer often affecting younger women and, unfortunately, the current treatment options for metastatic disease remain limited, said Professor Peter Schmid, from the Cancer Research UK-funded Barts Cancer Institute in London, who led the study.

The results report that only 11 if the patients responded to the treatment. However all of these patients were alive after 2 years, compared to 1 in 10 of those patients who didn’t respond.

The effects of successful immunotherapy treatments seem to be longer-lasting than conventional therapies thanks to the immune system’s potential to ‘remember’ what the cancer cells look like, which protects against relapse, said Elliott. “For the first time, difficult to treat cancers such as lung cancer are responding to immunotherapy.” 

But he cautioned that more investigation is needed to work out why some patients respond while others don’t. 

“We need to devise variations of immunotherapy that are more specifically tailored to each individual diagnosis, and to find out how we can minimise side effects of these treatments in some people,” said Elliott. “Understanding all of this will help match the right immunotherapy to the right person at the right time.”

Results for one small study looking to do just this for neuroblastoma, a cancer that develops from nerve cells, were described as “exciting”. Researchers looked at genetic differences of patients’ immune cells and found that 49 patients with a certain genetic ‘fingerprint’ had better survival following immunotherapy treatment than 125 patients with a different ‘fingerprint’. 

“This is a small study and so the results are preliminary,” said James. “However, the discovery is exciting as it may allow identification of patients who would best benefit from immunotherapy.”

Elliott agreed: “This could help direct future therapies: activating these cells specifically, in patients who have them, while focusing attention on different treatments for patients who do not.”