Published: 06 June 2021
The NIHR research infrastructure, embedded in the NHS, has been supporting the delivery of novel, complex and innovative clinical trials for over a decade.
Trendsetting in complex trial delivery
Is it possible that the cancer precision medicine trials of the past decade have helped to pave the way for the UK’s successful COVID-19 research response?
First let’s rewind 20 years to the sequencing of the first genome, after which an explosion of scientific discoveries followed, leading to a rapid expansion of potential new cancer treatments. The cancer research community was quick to realise that a logical, systematic way to quickly and efficiently find out which drugs hit which tumours, and in which patients, was needed.
Consequently, molecular oncology (the investigation of the chemistry of cancer and tumors at the molecular scale), is now widely recognised as being critical to precision medicine (also referred to as stratified, personalised or targeted medicine). But conducting precision medicine research is challenging. Here’s why.
The molecular characteristics of a patient's cancer allows matching to a targeted agent based on the genomic aberrations found, and which are thought to drive the proliferation and survival of the cancer cells. Genome sequencing is used to identify these molecular biomarkers, organise patients into groups with similar disease characteristics, and predict which treatments those patients are most likely to respond to.
However, with such a targeted, molecular approach to treatment, there are often only a small number of patients with any given biomarker who are eligible to enter trials for these personalised treatments. Professor Gary Middleton is a Consultant Medical Oncologist and Chief Investigator of the National Lung Matrix Trial, based at the University of Birmingham. He explains why this presents difficulties when delivering precision medicine trials:
“In precision medicine, because the patient cohorts are often small, researchers may have to screen 100 patients to find just one or two with the biomarkers that match the targeted treatment being trialled. Then, even if patients have these biomarkers, they may not be eligible to join the trial due to other health conditions. Consequently, single biomarker/single drug trials take a lot of sequencing of patients to recruit a sufficient number of participants. It’s a lengthy process and frustrating for patients who often do not have the required genomic change fueling their cancer.
“In contrast, platform design trials or umbrella trials as they are also known, when run in a single disease, are able to overcome this issue.
“The National Lung Matrix Trial, which is intrinsically linked to Cancer Research UK’s Stratified Medicine Programme 2, is genetically screening up to 2,000 lung cancer patients per year for multiple different molecular abnormalities and then matching them to a number of different drugs selected based on the abnormality they have. The structure of the trial, where multiple arms and multiple drugs are tested concurrently, is a much more efficient way of working. Not only does it increase the chances of a patient being eligible to take part, and reduce the number of screening fails, it also means that we avoid the delays and cost implications of having to set up a new trial for each new drug candidate.”
The National Lung Matrix Trial, led from the UK, is the largest precision medicine trial in lung cancer in the world. It first opened to recruitment in 2015 and has since recruited over 380 non-small cell lung cancer patients across 19 arms of the study, and tested eight different treatments from different pharmaceutical partners, principally Astra Zeneca and Pfizer. Professor Middleton reflects on the clinical research landscape when the trial was first established:
“When the National Lung Matrix Trial was set up, about six years ago, the idea of having a really large precision platform study with lots of different molecular subtypes and genotype matching was fairly novel. The National Lung Matrix Trial and other platform trials from the same time, such as FOCUS4, were trendsetters in a way because the multi-arm, and in the latter multi-stage design, was considered a very new way of working back in 2014 and 2015.”
In fact, the UK’s history of delivering platform trials goes back even further. The STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial opened for recruitment in 2005 using an adaptive platform approach called a Multi Arm Multi Stage (MAMS) design. The trial is ongoing having now recruited over 11,500 participants and has already produced practice-changing results in the way we treat prostate cancer - dramatically improving life expectancy.
Adaptability is another key advantage of the approach taken in these trials. The trial adapts as the science evolves and existing arms can be stopped or new arms can be added. Crucially, The National Lung Matrix Trial design allows the data to be analysed throughout the trial, rather than at its conclusion. Professor Gary Middleton describes why this approach is better than a traditional trial design:
“One of the main benefits of platform trials is the Bayesian statistics that we use. This approach allows us to generate and analyse data as the trial runs. So, from five or six patients we are able to predict whether the drug we are testing is likely to be beneficial. This is called the ‘predictive probability of success’ and is a measure of the likelihood of achieving a go decision for later testing if we were to fully accrue based on the current data. It also means that if a drug looks like it has no benefit, we are able to stop that arm of the trial early and reassign those patients to an alternative treatment, rather than continuing on with ineffective therapies. This is very important in small cohorts where the time to fully accrue can be significant. This is great for researchers as we need to know what doesn’t work just as much as we need to know what does work. It’s also really valuable for patients as they can transfer to a different arm of the trial and a treatment which may be more beneficial for them.”
Unique clinical research environment
The success of trials like the National Lung Matrix Trial is partly due to the UK’s unique clinical research environment.
First and foremost, we have the NHS, a national healthcare system, free at the point of care, and free from commercial influences. But equally important is the fact that the UK’s collaborative research culture is second to none. This is well exemplified in cancer where long-standing relationships have existed between the NHS, the NIHR and Cancer Research UK: spanning decades.
Add to this the UK’s world-leading cancer clinical expertise and you have a combination which provides a solid foundation for collaborative delivery of complex clinical trials - the value of which was never more evident than in the UK’s rapid research response to COVID-19. Professor Gary Middleton echoes this sentiment:
“Our trial infrastructure in the UK is very good. We have the NHS which is quite different to most healthcare systems around the world. Embedded within the NHS, we’ve got the NIHR’s research infrastructure and an excellent network of oncologists and doctors who work collaboratively - especially in the lung network this works really well. So I think for a country of its size, the UK really does punch above its weight in terms of delivering complex trials.
“The excellent cancer research conducted in the UK for the past couple of decades has shown that precision medicine and umbrella or platform trials are an excellent method of conducting large scale clinical research quickly and efficiently. We have used the lessons learnt in this field to rapidly launch research into potential COVID-19 treatments.”
Lessons from molecular oncology
This was certainly the case in trials like RECOVERY, PRINCIPLE and REMAP-CAP. However, Professor Middleton warns that as we look to expand the platform approach into other disease areas, there are important lessons to be learned:
“It is important to consider whether a complex trial design is the best approach, especially in life limiting diseases. The drugs trialed within the Lung Matrix Trial are offered as a last line treatment, which means the participants have already tried standard therapies and are therefore usually in the later stages of their disease. We have seen that such precision medicine trials work well for early-phase discovery, but we have found that it is not always suitable for last line treatment as we must consider the impact of the trial on patients when they have already had a lot of therapy.
“This is also an important factor in how we engage companies to test their drug candidates within our platform trials. If a company thinks there is a good chance of a treatment working, they will want to see it being trialed as a second, or even first line treatment and many targeted therapies are given after surgery to prevent the disease returning. Therefore we must accept the learnings that come out of the Lung Matrix trial, particularly the significant number of patients that do not enter such trials because of becoming too poorly during the course of their treatment journey to be well enough to participate.
“Whereas the emergency situation necessitated by the COVID-19 pandemic meant that it was all hands on deck to find effective treatments for the novel coronavirus. Going forward the most successful platform trials will need to align with the line of sight of the pharmaceutical industry. Bearing this in mind, along with the collaborative mindset fostered in the UK by the NIHR, NHS and Cancer Research UK, the knowledge we have gained so far stands us in good stead for the future of complex trial delivery.”
- Nature Journal Publication: The National Lung Matrix Trial of personalized therapy in lung cancer (15 July 2020)
- The Lung Matrix Trial website
- Visit our web page describing how the NIHR supports the delivery of complex and innovative trials.
- Case study: The FOCUS4 Trial - foundations for fighting COVID-19
- Case study: STAMPEDE - a turning point in trial design
- Case study: The UK's flagship COVID-19 treatment trial - the RECOVERY trial
- Case study: REMAP-CAP tests treatments for COVID-19
- Case study: Testing treatments for COVID-19 at home - the PRINCIPLE trial