FOCUS4: Molecular selection of therapy in colorectal cancer
Research type
Research Study
Full title
FOCUS4 – Molecular selection of therapy in colorectal cancer: a molecularly stratified randomised controlled trials programme
IRAS ID
119459
Contact name
Timothy S Maughan
Contact email
Sponsor organisation
University College London
Eudract number
2012-005111-12
ISRCTN Number
n/a
Clinicaltrials.gov Identifier
n/a
Research summary
Summary of Results
FOCUS4 opened to recruitment in January 2014, following approval of funding from both Efficacy and Mechanism Evaluation/National Institute for Health Research (NIHR) and Cancer Research UK. It was a randomised trial investigating treatments for metastatic colorectal cancer (CRC) using a complex adaptive methodology 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 (i.e., the control). However, FOCUS4 had 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 that needed a systematic approach to quickly understand which treatments worked against which cancers. The adaptive MAMS approach provided a more efficient way of working compared to traditional back-to-back randomised clinical trials, which only test 1 treatment at a time. Not only does this approach 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. More importantly however - 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 ground breaking 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 2 FOCUS4 trial laboratories in Leeds and Cardiff. Prior to this, the FOCUS3 study, which opened in February 2010, established the feasibility of this approach, recruiting 240 patients at 24 centres, showing how valuable it is to have 2 trial laboratories collaborating for reciprocal quality assurance and to provide resilience in case any problems arise at 1 centre or the other.At the end of an induction period of 4 months chemotherapy, patients with stable or responding disease were eligible for randomisation into the subtrial that was relevant for their molecular phenotype or into the non-stratified trial FOCUS4-N. The primary end-point in all subtrials was progression free survival (PFS) from randomisation and the active arms were compared with either placebo or active monitoring.
So what has FOCUS4 shown?
Results from the FOCUS4-C trial were published in the Journal of Clinical Oncology in September 2021 and showed that the wee1 inhibitor adavosertib (AstraZeneca) improves PFS in a novel subgroup of CRC, carrying mutations of both TP53 and RAS, who comprise about one third of all CRC patients. Comparing 44 patients who took adavosertib with 25 patients who did not, we found that the drug delayed tumour growth by about 2 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 (i.e., 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 G2M 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 d rives replication stress.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.
FOCUS4-N
The FOCUS4-N trial was also published in the Journal of Clinical Oncology in September 2021, and 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 a trial called CR06B first showed that a break from therapy was safe and enhanced quality of life without detriment to overall survival. The later COIN trial confirmed a similar effect in patients with oxaliplatin based chemotherapy, though it failed to confirm non-inferiority of intermittent therapy. FOCUS4-N has shown that the oral chemotherapy tablet capecitabine extends PFS but has no impact on overall survival. These 3 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.FOCUS4-D
FOCUS4-D was the first molecular cohort to report from FOCUS4 and showed comprehensive negative results, and we were able to close it after only 32 patients had been recruited. The results were published in 2018 and you'll see in many platform designs that a number of negative results come out. It is important to report the things that do not work as well as the things that do work.
FOCUS4 has now closed to recruitment and follow-up in October 2020, after conducting 3 molecularly targeted subtrials and 1 non-molecularly stratified trial in 6 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 is 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 National Health Service 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 do not have to compete with each other for patients, for example.REC name
South Central - Oxford C Research Ethics Committee
REC reference
13/SC/0111
Date of REC Opinion
10 May 2013
REC opinion
Further Information Favourable Opinion