Pursuing precision medicine in a flagship lung cancer trial

Modern medicine has always been about advancement. From the earliest herbal remedies to the complexities of brain surgery, the ways in which we’re treated have steadily evolved.

And now, medicine has become more personal.

For the past 5 years, we’ve funded one of the world’s largest precision medicine clinical trials, helmed by Professor Gary Middleton at the University of Birmingham. A £25 million collaboration with pharmaceutical companies and the NHS, the National Lung Matrix Trial has been exploring how patients with non small cell lung cancer respond to more tailored, targeted treatments.

And now, the results are in.

You can stand under my umbrella

Non small cell lung cancer (or NSCLC) is the most common form of lung cancer and makes up 80-85% of all lung cancer cases. It groups together multiple forms of cancer –including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma – because, generally speaking, they behave in a similar way, including how they respond to treatments.

But that doesn’t mean they’re identical.

NSCLC tumours are incredibly diverse when you zoom in and look at their DNA. This got the Birmingham team thinking: how do you find a way to test a treatment for a tumour that can be so different in different people?

The answer: an umbrella trial.

On the surface, it works like any other clinical trial – it involves a group of patients with the condition that take an experimental treatment. The difference in this umbrella trial was that there wasn’t just one treatment – there were 19 – and they were tailored to each person’s tumour. Patients were genetically screened to understand more about their tumour type, with this information used as a biomarker to match them to a targeted treatment.

“That really is what the trial is. It’s using the genotype to match patients to their targeted therapy,” says Middleton “It’s not just having one biomarker targeted by one drug – but multiple biomarkers with multiple drugs so that we can make it a much more effective and efficient screening strategy.”

It’s too simple

An umbrella trial isn’t really one single trial, it’s multiple trials running in parallel, with the different patients (or “cohorts”) monitored by the research team. Because of this, one of the key features of the trial was flexibility – being able to work with their pharmaceutical collaborators to add and retire drugs as and when required to ensure that the different cohorts were receiving the best possible treatment for their tumour.

The trial opened in 2015 and over 4 years, recruited over just under 5,500 patients. However, only 288 people went on to be treated on the trial, 14 of whom received more than one targeted treatment.

The key result was that when focusing on tumours with single driver mutations – one single mutation that drives them to grow rapidly and avoid being destroyed – they were able to provide effective treatment. However, that was far less common in patients whose tumours weren’t just down to a single mutation: the genomically complex cancers.

One of the dangers of lung cancer caused by exposure to tobacco smoke is that it results in these complex tumours, which means more mutations, more genetic alterations and more genetic instability. This results in tumours that are far more difficult to treat and changing over time, meaning that they could become resistant to drugs.

“What is very apparent is that this trial design can pick up very active drugs very quickly. If we’ve got a good drug and a good target, stratified medicine in lung cancer works well. But it does show the stark differences between the genomically simple tumours and the more complicated ones”

By understanding the drugs that have proved effective, researchers will be able to develop even better and more personalised treatments for these patients.

For those with more complex lung cancers, Middleton says that “there’s got to be a lot more work done at the basic discovery science level to understand the causes of genomic instability and how tumours continue to evolve so we can stop that process.”

And there were more lessons to learn when it came to the trial itself, which involved patients who had already completed standard anti-cancer therapy. Unfortunately, a significant number of patients who could have been suitable for treatment were unable to take part because, by the time they would have entered the trial, their lung cancer had progressed too far.

This highlights the importance of making trials faster and more efficient at matching people to targeted drugs, as well as the need to start these trials earlier in the cancer journey, before someone’s cancer becomes very advanced.

But simply recruiting patients early won’t be the solution. Professor Middleton and the team know that targeting tumours more complex tumours will involve more sophisticated screening that takes into account the specifics of a patient’s tumour genetics and a better understanding of personalised medicine.

“The models we test drugs on are too simplistic – they don’t represent the genomic complexity of the tumour, or the trajectory of how they rapidly evolve. We need models that take into account the complexity and trajectory of a human tumour to decide if a drug is going to work.”

Fitter, leaner, meaner

Although they acknowledge the limitations of the study, the Middleton and the team believe these results and the lessons learnt are paving the way forward to the next wave of personalised medicine trials. Currently, they are recruiting patients for further testing, with new personalised treatments being added to the trial.

“I think the one thing I want people to take away is that we can use the lessons learnt to redesign the next wave of stratified medicine studies – I want this to be seen as a landmark trial in precision medicine that opens the way to the next generation of precision medicine trials.”

Alex

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