Lung cancer is one of four cancers of substantial unmet need that we have identified as priorities for Cancer Research UK. Patient outcomes for lung cancer are typically poor, and progress has been slow compared to other cancer types. We are now working to close this gap, investing in new infrastructure and some of our most ambitious research programmes to date.
A new strategy for lung cancer research
Much of this can be attributed to the fact that two-thirds of people present with locally advanced or metastatic disease — the cancer is already incurable before it is diagnosed. But our knowledge of lung cancer biology and our understanding of the drivers of the disease have also lagged behind other tumour types.Lung cancer is the second most common cancer in the UK, with 40,000 patients receiving a diagnosis each year. Yet for all the advances in our understanding of cancer biology and all our innovations in cancer therapy, survival rates remain stubbornly low. While overall cancer survival rate has doubled to 1 in 2 since the 1970s, for lung cancer the statistics have barely shifted, remaining below 1 in 10.
“Traditionally lung cancer just wasn’t in the public eye as a cancer that merits much research or funding,” says Charlie Swanton, Professor of Personalised Medicine at UCL and The Francis Crick Institute. “But in the past few years, we’ve finally been seeing some results. Alongside breast, it’s one of the two big cancers where we have seen a real impact with personalised medicine. Lung cancer is one of the first tumour types where it was proven that targeting a biomarker-positive population is very beneficial.”
The recent introduction of precision medicines targeting ALK and EGFR positive tumours in lung cancer might finally mean we will see a shift in progression-free survival. “We’re now routinely screening patients for these driver events,” Swanton explains. “At first diagnosis we’re getting an approximation of what’s happening in a tumour and what the line of treatment should be. It’s a really good start.”
Clearly we’ve got a long way to go in understanding why drug resistance occurs and how to mitigate and block it, and how to make progress in metastatic disease. But we’ve made some significant inroads.
Cancer Research UK is aiming to build on this new momentum in lung cancer research and work towards transforming the outlook for patients. In our research strategy we pledged to increase our support for research which will enable us to achieve this and we’re already making progress. We know that tackling a task of this scale is going to require investment and innovation — and we’re committed to building the long-term infrastructure that is required.
A Centre of Excellence for Lung Cancer
In 2014 we opened the Lung Cancer Centre of Excellence at the University of Manchester and UCL, the first of several Centres that we promised in our Research Strategy would be devoted to tackling cancers of unmet need. Led by Swanton at UCL and Professor Caroline Dive at the University of Manchester, the Centre of Excellence for Lung Cancer brings together institutes, centres and hospitals at leading locations for lung cancer research. “UCL and Manchester have really complementary expertise,” says Dive. “Collaborations need positive working relationships, and Charlie and I have worked well together within CRUK for a long time — I think it’s fair to say as the two site leaders that the working partnership at the centre is really dynamic.”
“Complementary expertise is key to the Centre model”, says Dive. “We’ve drawn up eight themes, with theme co-leads across the two sites. But we’re not just getting people to work with colleagues they already know from their own fields. What’s really pleasing with the Centre is the multidisciplinary nature of everything we’re doing. We’ve got basic science, translational and clinical research all linking, which has really helped us to all pull together.”
“Right now, for example, the UCL biomarker theme lead Tony Ng is driving forward a translational research programme around radiotherapy. There are a large team of co-investigators from both sites, including Manchester’s lung cancer radiotherapy expert Corinne Faivre-Finn. There has been very little translational research around radiotherapy to help personalise this type of treatment, so we’re addressing that unmet need — bringing our biomarker, imaging and radiotherapy experts together.”
“Meanwhile, Tim Illidge and Sergio Quezada are designing a really exciting programme within our immunology theme. They’ll be building on UCL’s expertise in the tumour microenvironment and apoptosis, and Manchester’s specialist niche of immunotherapy-radiotherapy combinations.”
Alongside immunology and radiotherapy research, the eight themes will cover basic science, small molecule drug discovery (drawing on the resource of Manchester’s Drug Discovery Unit), early detection and pre-invasive disease, tumour evolution and heterogeneity, biomarkers, and clinical trials.
“It has been both demanding and exciting launching this new Centre, but the great thing is that we can use our grant to be really integrated, designing our infrastructure and our programmes to be a perfect fit and bringing in the specialists we need.
“It has barely been a year, and we’ve had to work hard building up those relationships and developing ambitious programmes for each of the themes,” says Dive. “But almost everything is in place now to show the centre is working really well together, joint grants are being submitted and the momentum is definitely there.”
Dive’s own flagship research programme is using circulating biomarkers as a research tool. “One of our most exciting breakthroughs so far is creating CDX — circulating tumour cell-derived explant — mouse models. We’ve developed 15 small cell lung cancer models so far, and those are currently being characterised.
“The real advantage of CDX is you can generate them at patient presentation, before the patient has any treatment, by enriching tumour cells from just 10ml of blood. And you can generate another CDX from the same patient after their disease has responded but then become resistant to treatment. So for the first time in small cell lung cancer you have an approach to study the biology of drug resistant progressive disease using a routine blood sample, when traditional biopsies are almost never available.”
The project has caused quite a stir in the lung cancer community, says Dive, who has been inundated with requests to present the work internationally. The team are now working with pharmaceutical companies to make their models available for pre-clinical testing of new small cell lung cancer (SCLC) therapies with some very promising early results. “We’re now bringing in the UCL expertise into this project, so that we can learn more about the importance of tumour heterogeneity and evolution in these CDX models.”
With late presentation a major part of the lung cancer problem, detecting and diagnosing lung cancer earlier is also a key aim of the Centre, and Dive’s hope is that the Centre will drive a national emphasis on lung cancer. “That’s easier said than done, of course, and our priority is to get our programmes up and running. But at the same time we’re trying to design those as springboards to reach out across the country. So we’re in discussion with Cambridge, for example, to bring their early diagnosis expertise to bear on the lung cancer problem.”
And there are already signs of international recognition for the Centre, which hosts its inaugural conference in December. “It is the best line-up of speakers I’ve seen in a long time in lung cancer,” says Dive. “I’m really excited about that. Charlie and I invited them, and they all said yes straight away, which is just phenomenal! That willingness of world leading lung cancer researchers to come to our Centre really shows that the Centre has been recognised internationally.”
“The advisory board is all in place, with an amazing international team of top experts. And Charlie and I were made Fellows of the Academy of Medical Sciences at the same time, which we think is a really nice boost for the Centre. The Centre is in business!”
TRACERx: Tracking cancer evolution through treatment
Also launched in 2014, TRACERx is an ambitious programme taking a longitudinal look at tumour heterogeneity and aiming to understand exactly how it responds to treatment. “For the first time at this scale we’re looking at how a disease presents and changes over time,” says Swanton. “We’re getting to grips with some of the most important questions. What is the relationship between tumour heterogeneity and disease stage and outcome? Can we define the origins of the lethal subclone in the tumour? How does the host immune system impact upon the evolution of subclones? We hope for the first time to understand how regions of the tumour are related, and to decipher how the metastatic subclone evolves from the primary disease and the impact of cytotoxic therapy upon resistant disease.”
At £14 million and involving nearly 850 patients, TRACERx is our largest investment in a lung cancer programme to date. In addition to producing an unprecedented depth of sequence data from each patient, from which to construct individual phylogenetic trees, the team will take the opportunity to collect circulating tumour cells, circulating free DNA and tumour infiltrating lymphocytes from participants. In this way, they will create a longitudinal biobank which will help answer the question of how accurately these biomarkers reflect the genomic landscape of the disease. And they will look for the influence of the host immune system on the genomic landscape, in case there are lessons for the development of immunotherapy. Having such in-depth data for so many patients provides the opportunity to understand how drug resistance occurs in real time, which in turn may serve as a model for how clinical trials of the future could be conducted.
“It has been a challenge to organise a study on this scale,” says Swanton. “But we’ve been very fortunate to have a fantastic team around us both at UCL and Manchester and more widely within the UK. There haven’t been many studies that span the full infrastructure of respiratory medicine like this, or which integrate such a diversity of laboratory disciplines. At times that has been challenging and stressful, but actually it has been very rewarding. This really is teamwork, and it’s only possible because of the enthusiasm and vision of the scientists, trialists and clinicians involved nationally.”
Swanton hopes that the TRACERx lung study might serve as a model for research across the spectrum of cancer types, and the lessons learned from assembling the multidisciplinary teams and complex infrastructure are already being put to good use. A renal study this year started recruiting towards its target of 300 patients, and an oesophageal study is in the planning stages, while an evolving European network is looking to address similar questions in breast cancer.
“The exciting thing once we start getting several of these studies online,” Swanton says, “is that we can start to look for the tumour evolution rule book, if there is such a thing. We know that tumour evolution is very constrained, but we don’t yet understand quite how constrained it is. TRACERx-like studies will shed light on that.”
Innovation in trials for the precision medicine age
Our drive towards improvements in lung cancer outcomes does not stop there. The £25 million Lung Matrix Trial — a collaboration with industry and healthcare partners — is testing an innovative adaptive trial design to get new treatments to people with lung cancer faster. “This is the largest ever personalised medicine study in cancer,” says Professor Gary Middleton, Consultant Oncologist and Professor of Clinical Oncology at the University of Birmingham.
Matrix, which began recruiting its first patients in the spring, is a multi-armed trial. So far Pfizer has contributed two agents and AstraZeneca has 12 drugs in the trial. Meanwhile, a panel of 28 biomarkers has been selected from The Cancer Genome Atlas against which to test the new drugs.
“This is a very flexible and nimble design,” says Middleton. “New biomarkers and drugs can be introduced quickly without the difficulty and expense of setting up a new trial each time. And the fact that we will be discontinuing arms of the trial as soon as it is clear that a particular drug and biomarker combination is not worth pursuing is itself important.”
In addition to testing the biomarkers and drugs themselves, the trial is testing the infrastructure that is required to make personalised medicine a reality.
“I think Matrix is going to show us where we should be in 10 years’ time in terms of personalised medicine in the clinic,” says Middleton. “We’re testing the whole pipeline — the feasibility of the methods for biopsy, sequencing and validation, and the turnaround times. Can we really use the biopsies we’re getting from patients? Is it feasible to use next generation sequencing to stratify patients? While Matrix is the testbed, we have to work out how to generalise what we’re doing to the rest of the NHS.”
Patients participating in the trial will be recruited from all 18 Experimental Cancer Medicine Centres (ECMCs) that Cancer Research UK funds in partnership with the devolved Departments of Health and NHS, and the study will make use of the SMP2 platform developed by our Stratified Medicine Programme.
“Setting up the partnerships has been a very exciting part of the project,” says Middleton. “This wouldn’t have been possible without CRUK bringing together academics, industry and healthcare infrastructure. And it wouldn’t be feasible without the SMP2 platform — you just wouldn’t be able to do these tests separately for 28 separate trials.”
“Brokering the deals with pharma and getting them to commit their agents has been fundamentally important. From a pharma point of view, you need to know that development is going to be done competently and safely. Knowing that the study has the backing of CRUK and the safe hands of the ECMC network gives them that confidence.”
“We’ve lagged behind in lung cancer personalised medicine in the UK,” Middleton concludes. “Now we can claim the biggest personalised medicine study. We’re back in the lead.”
Realising the future
Immunotherapy is a promising branch of today’s lung cancer research and it’s one of the areas that’s exciting Charlie Swanton. “I really think heterogeneity is an Achilles heel — it opens the door to immunotherapy. For example, we’ve seen in the literature the association between mutational load and outcome on checkpoint inhibitors, so this is an area that we’re pursuing in our projects. What we don’t know yet is whether heterogeneity is also associated with failure, but I expect that will start to emerge over the coming months.”
“But five years ago, if somebody had told me that we would be looking at cures in metastatic melanoma with immunotherapeutic agents, I would have said: you’re barking mad. That’s actually a reality now. And that makes you realise that in modern oncology anything is possible.”
This story was originally published in Pioneering Research: Cancer Research UK’s annual research publication for 2014/15. Find more at cruk.org/pioneeringresearch