The place of FOCUS4 in the evolution of trial methodology and delivery in the UK
FOCUS4 has successfully demonstrated that the development of Clinical Research Networks enables the delivery of these large-scale, complex trials. The development of the adaptive trial methodology and MAMS by the MRC CTU, which was first implemented at scale in prostate cancer, has now been successfully used in both FOCUS4 and the RECOVERY trial.28
FOCUS4 was the first platform to test at scale the additional complexity of molecular stratification, which was initially piloted in FOCUS3.123 This built on initial work in the earlier haematological studies in acute myeloid leukaemia, but bridged this into solid tumour oncology. The place for FOCUS4 in the evolution of trial methodology is demonstrated by the observation that it has been rapidly mimicked by a major pharmaceutical company (Roche MODUL trial) and is also being used in other solid tumour oncology studies in the UK and elsewhere.
Was FOCUS4 in fact initiated too early before the evidence was really present for stratification in CRC? Colleagues in the USA devised a similar study, but it was not funded by the NCI because the NCI considered that there were insufficient therapeutics ready for testing in such a study. Perhaps the NCI’s view is correct. However, the attempt to undertake this study has moved the field in solid tumour oncology to think more deeply about the utility of umbrella trials – of which this is a prime example – and of basket studies. On review, the evidence shows that basket studies – testing the same intervention across multiple indications – are easier to perform and have been generally more successful in identifying positive indications for novel therapies. The great advantage of basket studies is that the triallists are dealing with one intervention, one biomarker and one company. They are nearly always initiated and sponsored by the pharmaceutical company and, therefore, overcome the key difficulty of engaging different pharma to collaborate on a generic platform.
Did FOCUS4 fulfil its ambitions?
FOCUS4 almost fulfilled its original ambitions in that four subtrials were activated (i.e. B, C, D and N), although five subtrials had been planned (i.e. A, B, C, D and N); three subtrials reported results (C, D and N),27,88,111 with FOCUS4-B stopping early on grounds of futility.
However, it is also worth noting that the group attempted to open a total of 20 trials, but the others were not activated for multiple reasons (see Table 4). During the course of the trial, a total of 20 drugs or drug combinations were explored and presented to the joint NIHR EME/CRUK funding subboard for peer-review approval but only four culminated in an activated comparison. Reasons for non-activation were predominantly because of the failure of drugs at early clinical testing in this advanced metastatic disease setting. Other endeavours failed owing to strategic shifts within companies, including the selling of assets suddenly and unexpectedly.
Recruitment to the trial was not as fast as originally planned. The proposed acrual number was 2400, which is comparable in size to the predecessor COIN trial. There were several drivers of slower recruitment, notably the lack of ‘exciting’ comparisons to energise investigators and the challenge of the NHS England rules regarding the use of EGFR inhibitors in all wild-type patients. We were able to negotiate with the National Cancer Research Network that registrations, as well as randomisations, attracted activity-based funding. We managed to obtain high-quality follow-up for FOCUS4, but this was based on the CTU commiting to funding per-patient payments at risk pending subsequent commercial support.
In terms of methodology, the following key features of the FOCUS4 design, as discussed Chapter 2, Key principles of the FOCUS4 trial design, all proved to be robust in the application:
- using molecularly enriched cohorts to maximise the possibility of detecting promising new treatments
- using multistage statistical design for early detection of insufficient activity
- providing a trial opportunity for all patients regardless of biomarker status
- adapting biomarker structure to include new biomarkers and exclude current biomarkers, as guided by evolving research findings
- testing multiple treatments at the same time, each against its own control.
In addition, the use of PFS in the maintenance setting as the primary end point was shown to be an effective indicator of agents with activity, which may not have been revealed through a more conventional assessment of response in end-stage patients.
How could FOCUS4 have carried out better?
A key area of potential improvement is the understanding of the molecular stratification of CRC. Over this period, it has been shown that gene expression signatures (consensus molecular subtypes)124 are an important window of CRC that is not reflected directly from genetic testing. The funding of the MRC stratification in CRC (S:CORT) consortium30 was provided in 2015 and with time has enabled deeper understanding of the subtypes within CRC and how they may be targeted.83
Timely and reproducible delivery of the biomarker-testing panel, understanding the prognostic impact of biomarker selection and the need to accommodate biomarker-negative patients was critical to success. During FOCUS4, the simple mutation-based stratification process for many of the biomarkers that were tested in FOCUS4 has become part of standard care. In the future, despite the now more widespread routine availability of NGS-based tumour profiling, trial-based stratification testing will continue to need to provide transcriptomic and other more sophisticated analyses. It may be that the revolution in digital pathology and artificial intelligence will enable some biological stratification to be achieved directly from routine images, as shown recently with consensus molecular subgroup subtyping.23
Better preclinical testing of novel agent combinations may have improved the success of FOCUS4. As noted in Chapter 3, Failed endeavours, a key drain on investigator time was the continual pursuit of new agents for testing in the FOCUS4 platform. During the course of the trial, a total of 20 drug combinations were explored but only four culminated in an activated comparison. Reasons for non-activation were predominantly because of the failure of drugs at early clinical testing in this advanced metastatic disease setting, but often protocol development and contract negotiations had progressed a long way and considerable resource had been used up for ultimately futile collaborations.The disease positioning of genetically engineered mouse models has increased exponentially in the last few years and this provides a strong platform on which to test novel therapeutic concepts in defined biological settings more representative of human cancer. The CRUK-funded ACRCelerate programme,31 which focused on preclinical novel agent development, might have been beneficial if run in parallel with or before FOCUS4 because of its ability to provide greater depth of scientific rationale for the specific therpautics within the biomarker subsets.
Collaboration with pharmaceutical companies could have been more efficient from the onset of the FOCUS4 trials. How this can be accomplished is one of the ongoing challenges in academic-led clinical trials. High-level engagment with companies with a broad portfolio of agents is one potential approach that is more likely to be successful, as in the National Lung Matrix trial,23 which was mediated through high-level and effective support from the funder CRUK. Major governmental involvement through the NCI in the USA is also a very powerful mechansim, as shown in the IMPACT study. In the DISCOVERY trial, a committee at the Department of Health and Social Care level was also able to enable access to medicines within the context of a pandemic in a much more effective way that a research group can. A further reason for the failed endeavours to engage company support was the change in strategies within the collaborating pharmaceutical companies, including the sudden and unexpected selling of assets. One strategy, which is more within the grasp of academic triallists, is to have the strongest preclinical rationale for the specific intervention in the proposed subset. Obtaining that data set is challenging and requires timely funding of both stratification efforts and preclinical platforms to bring together data to make the case more strongly to pharma.
The alternatives to using a platform design of this umbrella style are to undertake individual molecularly stratified trials that each have their own design, entry criteria and setting. This is frequently undertaken and benefits from flexibilty – fitting the design to the specific intervention – but suffers from requiring every trial to be set up individually and a plethora of biomarker labs using differing techniques. Basket studies are very efficient when testing one intervention across a number of differing cohorts. These are very widely used by pharmaceutical companies looking to establish clinical efficacy of their drug/combination in whichever patient cohort may be sensitive. We did not pursue this because our focus was on CRC patients and we wanted to investigate treatments of potential benefit for our patient group.
Perhaps a better way ahead is for an academic funder to support a biomarker/diagnostic platform, complementary to what is available in the routine health-care setting. To this would be linked a number of discrete trials, all using the shared biomarker infrastructure, but allowing the flexibility and simplicity of individual interventions. This would leverage the benefits of national genomic diagnostics, but would enable the use of more advanced or emerging diagnostic methods, such as transcriptomic-, proteomic- or digital pathology-based allocation, supported by the biomarker research-funded infrastructure.
Summary of clinical findings from FOCUS4
In addition to the aforementioned trial methodology findings, the clinical findings from FOCUS4 are summarised below.
Data from FOCUS4-C showed that this subtrial met its primary end point; patients with RAS/TP53-mutant metastatic CRC had PFS advantage with the Wee1 inhibitor adavosertib compared with active monitoring following induction chemotherapy. This activity was clearly limited to the two-thirds of patients with primary tumours arising in the left colon and rectum (left PTL). Assessment of longer-term outcomes also showed an OS benefit with adavosertib compared with active monitoring in RAS/TP53-mutant patients with left PTL. These results are particularly encouraging because RAS/TP53-mutant metastatic CRC patients are a poor prognostic population who have limited treatment options and warrant further testing, which is now in discussion. Adavosertib was well tolerated and patients found it preferable to conventional chemotherapy.
Data from FOCUS4-D showed that the pan-HER inhibitor AZD8931 does not improve outcome in all wild-type CRC, as it failed to pass the first stage of assessment within the MAMS trial design, that is the predefined critical HR of 1.0 at stage 1 (lack of sufficient activity) was not reached.
FOCUS4-N was the non-stratified arm of FOCUS4 and shows the importance of including at least one non-stratified component within trials of this type. This trial built on previous UK trials exploring treatment holidays and confirmed that capecitabine is as effective as a maintenance therapy and probably as effective as capecitabine plus bevacizumab, the current international standard in this setting. Capecitabine alone, however, is much more cost-effective and also completely avoids the need for intravenous administration. However, none of these conventional agents improve OS (as we showed in the IPD meta-analysis117) so there is a balance to be struck for individual patient management about use of maintenance therapy. In future studies, capecitabine monotherapy would be a suitable control for testing of novel maintenance therapies.
Leadership of complex studies
The experience from FOCUS4 has shown that leadership of these complex studies is challenging, with strong input required from a well-funded CTU. In addition, multiple skill sets are essential to the successful leadership of such trials, including expert contribution from the clinical, pathology, biomarker, trial delivery, governance and statistical analysis aspects.
Furthermore, a strong TMG is critical to success. The FOCUS4 TMG met monthly over the decade of activity for 1 hour by teleconference, with detailed minutes and review of action points at the start of each meeting; this was an effective mechanism. Face-to-face meetings were interspersed especially to discuss broader trial design or novel interventions. Feedback from FOCUS4 stakeholders showed that, with respect to leadership, the role of the chief investigator was paramount and more critical to trial success that that of the co-ordinating investigator in a standard trial.
Funder perspectives
FOCUS4 was jointly funded, with an equal split in costs between the MRC–NIHR-funded EME programme and CRUK. Extensive work was required by the research team, the NIHR evaluation, trials and studies co-ordinating centre EME team and the CRUK team to carefully divide and calculate costs in accordance with the different NIHR and CRUK funding rules. Although this resulted in agreement of costs between the funders, it was clearly a complex and time-consuming process. Learning from this project helped to develop the simpler and more streamlined approaches for future use.
Patient and public involvement perspectives
Throughout FOCUS4, there was a strong patient voice on the TMG, provided by Malcolm and Janet Pope, to whom we are deeply indebted. This was supported by strong patient and public involvement representation on the Trial Steering Committee. These studies are strongly attractive to patients who appreciate the efforts to tailor treatments to their own tumour characteristic. In contrast to the triallists perspective, patients with a particular diagnosis – in this case CRC – value the umbrella trial methodology because there is one study for the whole group of patients with the same disease, and each may find their particular space under that umbrella. This can lead to a sense of collaboration, partnership and collegiality: ‘this is our study and we all have our place within it’. By contrast, biomarker-selective studies can appear exclusive: you get in only if you have the ‘right’ tumour. In a fruitful collaboration with Joshua Hordern (Faculty of Theology and Religion, University of Oxford, UK), we explored the moral aspects of the promissory nature of precision medicine and the danger of hype, wherein targeted or personalised therapies can appear to be of much greater worth than appears to be the case.125 Furthermore, we explored the superiority that this inflated value may imply for the selected group and what effects that might have on the other people who end up in ‘the molecularly unstratified group’.126 We made an application to the Wellcome Trust (London, UK) for a multidisciplinary analysis of this area, which unfortunately was not supported. This interest in the well-being of patients extended to a concern for those staff running studies, which revealed an interesting mixture of excitement, sense of privilege and unending stress for the personnel working in the trials unit on major platform studies of this nature.121
The COVID-19 pandemic
FOCUS4 came to an end as the COVID-19 pandemic developed. Thankfully, for this study, sufficient patients had already participated in the study and we had accrued sufficient data to be able to present interim findings to the IDMC. The interim analyses for both FOCUS4-C and FOCUS4-N were so resoundingly positive that the IDMC were very ready to advise that we could close recruitment, follow-up the remaining patients for a few more months and then report. We are hugely grateful to the unseen work of both our IDMC and our Trial Steering Committee members in their oversight of the study and enabling us to draw it to its conclusion. We recognise that, as a result, the FOCUS4 studies under-accrued compared with the original statistical estimates. Despite this, FOCUS4-C, FOCUS4-D and FOCUS4-N all have reported clear outcomes.
Beyond the COVID-19 pandemic, our oversight committees consisted of highly experienced oncologists, statisticians and patient representatives. The members provided constant support and guidance at some particularly difficult times during the study. In particular, the chairpersons navigated the issues with clear and prompt recommendations despite the relative newness of this approach to trial design. We thank them.
Conclusions
FOCUS4 was an experiment at multiple levels. It was an experiment in clinical trial design that largely succeeded; certainly, the key points from the methodology paper were largely shown to be feasible and correct. Each individual subtrial was a defined experiment, two of which were successful in terms of reaching their primary end point; another was shown not to be feasible and one was negative. Sixteen others were developed but failed to be implemented for various reasons.
The prior knowledge that is required before setting out on such an enterprise needs to include in-depth understanding of the therapeutic vulnerabilities of different subgroups of the disease in question. That, in turn, requires detailed multi-omic stratification of the disease linked to clinical outcome to define those subgroups with different biology and preclinical evidence of efficacy of the selected therapeutic class or agent.
Such studies are a manifestation of team science: the clinicians, biomarker scientists, pathologists, statisticians and clinical trial team at the CTU; the research delivery personnel in the network and in multiple hospitals; the patients and their carers; the physicians and nurses who enrol, care for and monitor those patients; and the various companies who collaborate through provision of their novel agents. Without this whole team working together, the enterprise cannot hope to accomplish its goals.