Stratified medicine and the lung cancer ‘Matrix’ trial – part of a cancer care revolution

We’ve often talked about the promise of personalised therapy for cancer – the idea that the genetic makeup of an individual patient’s cancer will guide their treatment.

Over the past few years, this vision has become closer and closer to reality, and today we’re announcing another step in the right direction.

Genetic testing is already used to spot a handful of key DNA changes in certain types of cancer that point to whether a patient will – or in a number of cases won’t – benefit from a particular drug.

With the help of research, we are learning more and more about the genetic diversity that fuels different types of cancer and finding potential new ways to define and test tumours based on their genetic makeup.

The goal is to translate this research into more refined ways of offering treatments to the patients who may benefit. But the challenge has been developing targeted treatments that show a long term benefit for patients while accommodating the cost of widespread molecular testing in the NHS.

All in all, making genetic testing routine practice for doctors across the country, and offering patients equal access, remains a big challenge for the health service.

In 2010 we launched the first part of our Stratified Medicine Programme. Looking to establish a network for nationwide molecular testing that will be crucial for accommodating potential new targeted treatments in the future.

We’ve reached several milestones along the way, and today we’re proud to announce our plans for the latest stage – an ambitious nationwide clinical trial opening this summer to test a new round of potential targeted treatments for lung cancer.

What is stratified medicine?

Stratified medicine identifies key molecular changes common to different people’s cancers. Patients can then be grouped based on these shared genetic faults, allowing some people to receive a targeted treatment matched to their group

There are a handful of projects around the world looking to make this challenging goal a reality. Nearly four years ago we launched the first stage of our Stratified Medicine Programme, which began building important collaborations between patients, the research community, the NHS, the pharmaceutical and diagnostics industry, and Government.

The aim was to establish a network of labs and hospitals that in the future could enable treatment to be given to patients based on precision molecular testing. So it would become routine to use what we know about cancer genetics to offer the best treatment as quickly as possible.

We’ve taken some important steps forward in our goal to establish this network.

And you can read about how the first stage of the programme worked in previous blog posts.

The end of the beginning

Over the course of stage one, generous support from our Catalyst Club and contributions from AstraZeneca, Pfizer and the Government’s Technology Strategy Board fuelled collaboration across eight clinical hubs within our Experimental Cancer Medicine Centre (ECMC) network.

Woven into this network were three technology hubs, accepting patient samples from clinical hubs – performing a swathe of genetic tests along the way – before reporting the results back to the hospitals.

Over the course of the first stage we’ve processed:

• Over 40,000 gene tests
• With 10,754 consenting patients
• Over 9,000 samples were sent for testing
• From 26 feeder hospitals
• Via eight clinical hubs
• Across six tumour types
• All processed by three technology hubs

But most striking of all is that this has been achieved via a single national network.

The programme laid the foundations for a nationwide network of molecular testing, proving it’s possible to link up expertise across the country in a cost-effective and efficient way. But as a pilot study it wasn’t designed to trial new drugs or change the way patients were treated.

That’s where the next stage comes in.

Part two of our Stratified Medicine Programme – known as SMP2 – has the ambitious goal of advancing treatment for people with late stage non small cell lung cancer (NSCLC).

Financial support for the latest stage will come from Cancer Research UK and our renewed partnerships with the companies AstraZeneca and Pfizer.

And with the funding, technology and expertise in place, our unified network is primed to start linking up potential new treatments with lung cancer patients, who based on a molecular test, may benefit from them.

So how will it work?

Taking it to the next level

Our focus for SMP2 is the development of an ambitious clinical trial, called the National Lung Matrix Trial, which is part of the next generation of flexible clinical trials, testing multiple drugs in multiple groups of patients.

It’s important to stress that the trial is not yet recruiting patients. But once it opens in the summer it will be divided up into multiple arms, with each arm being linked to a potential new drug treatment.

Each treatment has been developed to target precise genetic faults, which we’ll be testing for using our specialised ‘next generation sequencing’ system developed specifically for the programme. And the libraries of new drugs will initially come courtesy of our partners AstraZeneca and Pfizer.

• Watch an animation of how the trial will work

The trial is being led by chief investigator Professor Gary Middleton in conjunction with the Early Drug Development Team at the Cancer Research UK Clinical Trials Unit (CRCTU) in Birmingham, but nationwide participation will be made possible by the ECMC network across the UK.

The design allows multiple drugs, in early stages of development, to be tested in a single trial. Small groups of 15-20 patients will be placed onto an arm of the trial based on genetic matchmaking between their lung tumour and the targeted treatments. They will then receive the genetically matched drug and researchers will monitor their response.

If a treatment shows promise – defined by improvements in survival, tumour shrinkage or an alleviation of symptoms – then there’s the potential for that arm to break off from the main trial and grow into a larger independent trial with more patients who share that genetic profile.

Expanding these patient groups will depend on the number of people available for larger trials who match that particular profile as well as the stage of development the corresponding drug has reached.

If the treatment doesn’t provide any benefit for that group of patients, the arm can be reassessed and removed from trial.

As arms are lost or grow, new arms can be added to test more new drugs as they become available – demonstrating the flexibility of this new age of clinical trial design.

So what’s different?

The breadth of genetic faults we’ll be testing for – combined with the potential number of drugs in the trial – make the setup of SMP2 particularly exciting.

Genetic tests are commonly used to pinpoint the single spelling mistakes – known as point mutations – present in a cancer cell’s genetic code that produce faulty proteins and drive uncontrolled cell growth. But there are also situations where excessive cell growth is caused by genetic errors that produce key growth proteins in vast excess, amplifying the signals these molecules give out.

And further genetic mistakes can result in chunks of genetic material being stuck together, producing a hybrid protein that operates outside normal cellular controls.

In terms of lung cancer there are many genetic faults linked to the disease that fall into these diverse categories. The panel of molecular tests we’ve assembled for SMP2 span each of these categories and include faults in 28 different genes, 18 of which will link directly to treatment arms on the trial.

Once the trial opens this summer, patients will initially have access to six new drugs – provided by our pharmaceutical partners – with the potential to increase this over the course of the trial as new drugs become available.

Why lung cancer?

Lung cancer is a devastating disease and the UK’s biggest cancer killer.

It accounts for more than one in five cancer deaths and is the second most common cancer in men and women in the UK.

We want to change these odds for people with lung cancer.

Progress has been made over the last four decades as lung cancer cases in men have dropped by 50 per cent. But the number of women being diagnosed with the disease has increased by 75 per cent in the same period.

This largely mirrors changes in smoking patterns from several decades ago, but clearly more needs to be done to diagnose and treat the disease earlier.

We also need to change the perception of a disease that nobody deserves to die from.

Greater awareness of the early signs and symptoms and more research will all make a difference. And SMP2 has the potential to take our understanding of lung cancer to a new level, but it’s just part of our wider commitment to beat lung cancer sooner.

Our pioneering TRACERx project is another great example of how our scientists are advancing research into lung cancer. It has the ambitious goal of charting the evolutionary journey of the disease, looking to pinpoint the precise twists and turns that could offer unique opportunities for new treatments in the future.

Focussing on the future

The approach that SMP2 is taking is not limited to tackling lung cancer. And the trial itself is part of the next generation of clinical trials that are pushing the boundaries of flexibility and grouping of patients.

The specialised panel of genetic changes we’ll be testing for are also linked to other cancers. We’ve written before about how the way we define cancer could be changing as lines are drawn between tumours in different parts of the body based on shared genetic faults. And the results of the Matrix trial could point to other cases where patients may benefit from these potential treatments.

Of huge importance is the impact SMP2 could have in becoming a rich source of data for further research to improve our understanding of the molecular landscape of lung cancer. In the case of patients who don’t respond to these treatments, this information will be vital in answering why.

Linking up genetic tests and targeted treatments across the NHS remains a challenge, and there will be many more challenges in assessing whether these potential new treatments show benefit for lung cancer patients. But the Matrix trial and SMP2 are another great example of how we’re facing up to these challenges.

By focussing on the future we can ensure that our unified research and healthcare community is best placed to try and bring the latest treatments to cancer patients quicker than ever before.

We believe that this pioneering venture can reinforce the growing need for more nationwide lung cancer trials that are already emerging for other types of cancer – translating the reams of genetic data painstakingly processed by researchers into more personalised treatments for patients. And, ultimately, we hope this will mean boosting survival and saving more lives.

Nick

Image credits: Pill image and Genetic code image from Flickr