Despite better understanding, glioblastoma – an aggressive form of brain cancer – patients have been left in limbo, with few new treatment options in recent decades. But a pioneering new clinical trial – 5G – is set to offer more options to UK patients and kick-start progress.
Brain tumours are devastating. As well as affecting a person’s ability to walk or move, or communicate, they can take away what makes people who they are – their self-identity.
And despite incredible progress in understanding the biology of cancers that affect the brain and central nervous system, advances in the way people are treated have been much slower – particularly when it comes to drug therapies.
This stands in stark contrast to other cancer types. For example, between 2000 and 2023, the US FDA approved 26 new breast cancer treatments. For glioblastoma, just two new drugs – temozolomide and bevacizumab – have been licensed over the same period.
That might soon be set to change. A groundbreaking new Cancer Research UK-funded trial is jump-starting UK brain tumour drug discovery, by rapidly identifying promising drug candidates for further research.
Overcoming nihilism
Underpinning the historic slow progress, argues Richard Mair, a consultant neurosurgeon at Addenbrookes Hospital in Cambridge who heads up a research group at the Cancer Research UK Cambridge Institute, is a series of overlapping ‘nihilisms’.
“Initially, there was surgical nihilism, where neurosurgeons didn’t feel it was worth doing proper operations,” he says. “That’s largely finished, but not completely. And certainly, when I was training 10, 15 years ago, that was still commonplace.”
This has been accompanied by what Mair calls ‘therapeutic nihilism’, an attitude among some researchers that developing drugs for brain tumours is just too difficult. “People have thought, ‘we can’t get the drugs into the brain, they don’t cross the blood-brain barrier’,” he says.
Then, Mair says, there’s ‘pharmaceutical’ nihilism – the reluctance of drug manufacturers to trial existing drugs for brain cancer patients, on the grounds that they’re exceptionally fragile.
“Of course, brain tumour patients are very, very delicate – if you have a bleed from the tumour, or swelling, all of that can cause incredibly serious problems for the patient –more so than for other tumour types,” says Mair. “And if they get lots of complications, that can cause problems with taking the drug forward commercially. So again, these are things that have been historically used to exclude brain cancer patients from trials.
Beyond this, another challenge is that – compared to other cancer types, brain tumours are relatively rare.
“So then there’s financial nihilism, the idea that there aren’t enough patients with brain cancer to make a business model to get a drug to market,” he says.
And then there’s the challenge of recruiting enough people to the trial. In a larger field like breast cancer, for example, carrying out a large-scale, 1,000-person trial can take months or years, meaning even if it’s negative, researchers can quickly explore the next promising idea.
But with brain cancers like glioblastoma, which affects around 3,200 people a year in the UK, a 600-patient trial may take half a decade from start to finish, with setbacks from negative trials lowering appetite to press on.
It’s a risk-benefit balance that puts off many pharmaceutical companies.
Challenging biology
But ‘de-risking’ drug development first means overcoming some even more fundamental challenges – namely the incredible complexity of the brain, and of tumours that grow within it.
Unlike other cancers, where researchers can often pinpoint a single faulty gene or pathway to target, glioblastoma involves a tangled mix of genetic, molecular, and environmental changes. Scientists now understand a great deal about this biology, but turning that knowledge into effective treatments has proved far harder.
One major obstacle has been the lack of good lab models that truly reflect how brain tumours behave in patients. For years, the animal models used in research didn’t mimic the biology of human tumours very well, so results often didn’t translate into the clinic. New and more realistic models have started to appear, but there are still far fewer of them than for cancers like breast or lung, where researchers can test and cross-check potential drugs much more easily.
Another issue is how drugs are tested for safety before reaching patients. Most toxicology studies are done in animals with an intact blood–brain barrier – the natural defence that prevents many substances from entering the brain. Because of this, many promising drugs are dismissed as unable to reach brain tumours. But in patients with brain tumours, the barrier is often damaged, meaning more drugs may be able to get through than once thought. In fact, growing evidence from people with cancer that has spread to the brain shows that a range of treatments, from standard chemotherapy to targeted therapies and antibody-based drugs, can work effectively there.
Yet people with primary brain tumours are still routinely excluded from early clinical trials that test new drugs for the first time in humans. This cautious approach has meant lost opportunities to discover which experimental treatments might actually help them.
In the rare cases where such patients have taken part, some have had surprisingly long-lasting responses. Allowing more of them to join these trials could not only open up new treatment options but also give researchers the chance to learn directly from their experiences – turning each patient’s journey into a source of insight for future therapies.
Turnaround times
Several years ago, at Addenbrookes Hospital in Cambridge, Richard Mair had been trying to answer a very different question: how best to deploy new technologies like next-generation sequencing to understand a cancer’s molecular make-up, and so improve how patients with brain cancer are managed.
“We reasoned that there would be two ways this could help: to improve diagnosis, and to help predict optimum treatment.”
The problem was, at the time, programmes aiming to answer this were taking around nine months to return results to clinicians, “by which point, it was too late for many of the patients,” recalls Mair.
To try to speed things up, with funding from the Minderoo Foundation, in 2021 Mair set up the Precision Brain Tumour Programme.
Building on existing sample processing infrastructure, Mair’s team established close links with the hospital’s genomic laboratory hub, allowing them to carry out tumour analyses within 20 days. This meant they could start to understand how these technologies could help.
After sequencing more than 300 patients’ tumours it turned out that this didn’t seem to dramatically change the diagnosis for most patients, but it did seem to suggest some tumours had weaknesses that might be exploited.
“But to answer that question, we hit another issue,” says Mair. By now, the Precision Brain Tumour Programme had enabled Mair to establish a UK-wide group of clinicians who’d become comfortable looking at genetic data on their patients and discussing its implications. “And it became very clear was that there wasn’t a good way of referring our patients into clinical trials,” he says.
But that began to change when Mair was introduced to The ICR’s Juanita Lopez – an expert in clinical trial design – by a mutual acquaintance, and the pair began discussing how to kick-start progress.
Getting going against glioblastoma
“I rang Juanita, and it turned out she was interested in seeing whether it was possible to trial existing targeted medicines in patients with known biomarkers in real time. And that’s what drew us together,” Mair recalls. “She was very interested in targeting drugs, and I had a way of getting those targets in a clinically actionable time. It’s a great synergistic: me with my molecular hat, her with her clinical trials hat.”
With their complementary skillsets and “shared language” of understanding the patients and the biological challenges, Mair and Lopez were clear on the challenge they needed to solve.
Ultimately, this led them to bid, successfully, for £3m funding from Minderoo and Cancer Research UK, enabling the pair to launch, in October 2024, a first-of-its-kind platform trial for UK patients with glioblastoma: the next-Generation aGile Genomically Guided Glioma platform trial, or ‘5G’ for short.
“It’s a precision adaptive platform trial,” says Mair. “We’re using specific drug/biomarker pairings for each arm. And this is something that hasn’t been done traditionally in brain cancer. Instead, we’ve tended to give precision drugs to everyone on the trial and hope that the stats would mean we’d see something.”
“It’s ‘adaptive’ because if we see signal early on, we can adjust the subsequent enrolment to recruit patients more likely to benefit, to make sure we get a positive or negative signal that’s appropriate,” he says.
What’s particularly promising, he says, are three unique innovations baked into the trial design. The first is that it allows for iteration. So, if, for example, patients on a given arm, who have both mutation A and B, never respond, but patients with A, but without B, do another cohort can be set up, specifying A minus B.
The second allows the trial much greater flexibility with drug combinations. For example, if patients who don’t respond all have an additional mutation for which drugs are available, the trial allows for the creation of ‘sub-protocols’ to allow those patients to receive that drug under trial conditions.
The third adaptation allows 5G to start giving promising drugs to patients right after their initial surgery and radiotherapy – rather than waiting for people to relapse. In theory, at this point their tumours will be less advanced, and so less able to develop resistance.
Since launching, 5G has launched several different sub-trials, or ‘arms’, testing different combinations of therapies in people whose tumours contain different mutations. One, for example, is testing a combination of two drugs that have recently shown promise in ovarian cancer: avutometinib and dafectinib.
Perhaps the most notable feature of the 5G trial is that, rather than being ‘first-in-human’, it’s ‘first-in-brain’ – these are existing therapies that have already been proven broadly safe, and to hit their targets in other cancer types.
“It’s been busy since we launched the trial,” says Mair. “We’ve got three more arms in set-up phase, and our regular weekly meetings for brain tumour clinicians around the UK are really well attended, and we can discuss which patients might be suitable for 5G.
“I think that ultimately what we want is for every patient, irrespective of whether they have an operation in Scotland, in the Southwest or in London, to be offered the suitable clinical trial for them – and eventually, a suitable treatment that we’ve hopefully shown works.”
The first tranche of preliminary results are expected soon, says Mair. “The unfortunate thing with brain cancer is, you know pretty quickly whether your drug’s going to work.”
A new hope
Ultimately, Mair says, this is all about hope – something that’s in short supply among people with brain tumours.
“There’s a lot of charlatans and snake oil salesmen out there,” he says. “And we need to remove these vulnerable patients from their clutches and give them a viable alternative that doesn’t cost their life savings. They deserve a better chance of finding an alternative to standard of care, which we know will ultimately fail them.”
“One of the things the late Tessa Jowell said is that we need to enable and empower patients to make decisions on their care. And that’s a real key driving force for what we’re trying to do.”