Written by Prof Tim Maughan, Principal Investigator of the FOCUS4 project
This weekend (Saturday 18th September 2021) a key outcome from the FOCUS4 trial was presented at oral session in the European Society of Medical Oncology (ESMO) annual meeting. In parallel two papers have been published in the Journal of Clinical Oncology. So what is FOCUS4 and why has it been considered a flagship precision medicine cancer trial?
FOCUS4 opened back in 2014, following approval of funding from both EME/ NIHR and Cancer Research UK. It is a randomised trial investigating treatments for metastatic colorectal cancer using a complex adaptive methodology which is known as Multi-Arm, Multi-Stage (MAMS) design. Such trials, also called umbrella or platform trials, allow for multiple treatments to be tested simultaneously against the standard of care (the control). However, FOCUS4 has the added complexity of stratified medicine, which requires that all eligible patients undergo genome sequencing to identify genetic biomarkers relating to their cancer. Patients are then matched to the trial arm/treatment to which they are most likely to respond.
This new way of working emerged following a rapid increase in the number of new cancer treatments being developed by life science companies which needed a systematic approach to quickly understand which treatments worked against which cancers. The adaptive, multi-arm, multi-stage (MAMS) approach provided a more efficient way of working compared to traditional back-to-back randomised clinical trials which only test one treatment at a time. Not only does it avoid the delays and costs of setting up a new trial for each new drug candidate, it also makes the screening process more efficient. Patients are screened for a match to all the drugs being trialled and have a higher probability of being able to join the trial and access a treatment suited to their molecular phenotype. But more importantly - and this is where the adaptive bit comes in - new arms can be added to the trial platform as new drugs become available. Equally, where drugs are showing no benefit, that arm of the trial can be closed and further participants can be switched to a different treatment.
The FOCUS4 trial design was considered groundbreaking when it opened in 2014 as it was one of the first large-scale, molecularly stratified, MAMS cancer trials in the UK. It successfully enrolled 1,434 patients from 88 hospitals. Patients with newly diagnosed metastatic CRC were eligible for registration, and this led to their molecular studies being done on their tumour sample at the two FOCUS4 trial laboratories in Leeds and Cardiff. Prior to this the FOCUS3 study, opening in February 2010, established the feasibility of this approach, recruiting 240 patients at 24 centres, showing how valuable it is to have two trial labs collaborating for reciprocal quality assurance and to provide resilience in case any problems arise at one centre or the other.
At the end of an induction period of 4 months chemotherapy, patients with stable or responding disease were eligible for randomization into the subtrial that was relevant for their molecular phenotype or into the non-stratified trial FOCUS4-N. In all trials the primary end-point was Progression free survival from randomisation and the active arms were compared with either placebo or active monitoring (AM).
So what has FOCUS4 shown?
The FOCUS4-C trial was published in JCO on 18th of September 2021 with further announcements about its findings in the press. The study shows that the wee1 inhibitor adavosertib (astrazeneca) improves progression free survival in a novel subgroup of colorectal cancer, carrying mutations of both TP53 and RAS, who comprise about one third of all colorectal cancer patients.
Comparing 44 patients who took adavosertib with 25 patients who did not, we found that the drug delayed tumour growth by about two months on average and had relatively few side effects. The drug had more effect in the 31 patients with left-sided/rectal tumours, the drug increased overall survival – that is, patients lived longer. These are early results and a larger trial is needed to establish whether the drug improves survival for these patients compared to standard treatment. Adavosertib kills cancer cells by inhibiting WEE1, a protein that helps to regulate the process of cell division in the tumour by ensuring that any DNA damage is repaired before cells cross the G2?M checkpoint and commence cell division. We hypothesised that tumours with the mutations RAS and TP53 would be particularly sensitive to this form of attack, as the G1/S checkpoint is compromised through the TP53 mutation and the RAS mutation drives replication stress.
Lead author Dr Jenny Seligmann, of the University of Leeds, said:
These results show promising signs that adavosertib may be effective in delaying re-growth of bowel cancer in some patients and is well tolerated. The findings are particularly encouraging as the subset of patients involved represent a third of all bowel cancer patients and, while other patients have treatments developed specifically for their tumour types, this group currently has very limited treatment options.
Co-author Professor Louise Brown (MRC Clinical Trials Unit at UCL), leader of the FOCUS4 trial, said:
Our UK-wide trial is the first in the world to investigate potential treatments for bowel cancer by stratifying patient groups according to the chemical make-up of their tumours. This allowed us to test a number of new approaches at the same time. The results for the adavosertib arm of the trial are potentially important and represent a glimmer of hope for patients in this group.
Side effects of the drug included fatigue, diarrhoea, neutropenia (involving low levels of white blood cells called neutrophils), and nausea, but none of these occurred in more than 11% of patients.
A second new study from a separate arm of the FOCUS4 trial, also published in the Journal of Clinical Oncology in September 2021, looked at outcomes among patients who had a complete break from treatment following chemotherapy, comparing them to outcomes among those who continued chemotherapy using a simpler tablet called capecitabine. We found that, among those who had a complete break, the cancer started to grow somewhat sooner than in those on continued maintenance therapy, but that maintenance therapy did not lead to an increase in how long people lived. This builds on a series of trials of intermittent chemotherapy led by the UK group. In 2001 the results from CR06B first showed that a break from therapy was safe, enhance quality of life without detriment to overall survival. The COIN trial in the arm A v arm C comparison confirmed a similar effect in patients with oxaliplatin based chemotherapy though failed to confirm non-inferiority of intermittent therapy. FOCUS4-N has shown that the oral chemotherapy tablet capecitabine extends progression free survival but has no impact on overall survival. These three trials from the UK provide a strong rationale showing a break in chemotherapy does not lead to a detriment in overall survival, which was further demonstrated from an international Individual patient meta-analysis we published earlier this year.
Lead author Professor Richard Adams, of Cardiff University said;
The findings will help to inform discussions between patients and clinicians about treatment options at the end of 4 months of therapy, whether to stay on oral chemotherapy long-term of have a complete break in treatment, giving patients better control of their cancer management.
The first molecular cohort to report from FOCUS4 showed comprehensive negative results, and we were able to close it after only 32 patients had been accrued to FOCUS4-D - one arm of the FOCUS4 trial. That was published back in 2017 and you'll see in many platform designs that a number of negative results come out. That's important because we're showing that things don't work as well as the things that do work.
FOCUS4 has now closed to recruitment in October 2020, after conducting three molecularly targeted sub-trials and one non-molecularly stratified trial in six years, and has generated some interesting results. When we embarked on FOCUS4 we knew it would be a challenge, and we have learnt a huge amount along the way. It’s really important now that we share this learning and continue to improve the way we do clinical trials in the future.
The whole research ecosystem of the UK presents an unparalleled opportunity for complex and innovative trials. We have the NHS as a single health care provider, the NIHR Clinical Research Network as a coordinated research delivery organisation, collaborative laboratory scientists delivering the sequencing, the collective work of the funders, forward-thinking regulators, and the National Cancer Research Institute. All this facilitates a really collaborative clinical research culture within the UK where organisations don’t have to compete with each other for patients, for example.
Links to previous FOCUS 4 publications & website
- Evaluating Many Treatments and Biomarkers in Oncology: A New Design, Journal of Clinical Oncology, 2013
- FOCUS4-C: results from a randomised trial of AZD1775 in TP53+RAS mutant CRC, Journal of Clinical Oncology 2021
- FOCUS4-N: results from a randomised trial of capecitabien versus active monitoring in CRC. Journal of Clinical Oncology 2021
- Editorial JCO
- FOCUS4-D: Results from a randomised, placebo controlled trial of AZD8931
- Focus 4 website