Results from the registration period

Details of the methods used for the registration period can be found in Chapter 2.

Activation and recruitment

FOCUS4 was approved by the UK National Ethics Committee Oxford – Panel C (reference 13/SC/0111) and by the relevant regulatory body, the Medicines and Healthcare products Regulatory Agency (MHRA) (CTA 20363/0400/001 and EudraCT 2012-005111-12), in May 2013. FOCUS4 opened to recruitment in January 2014, with two subtrials activated (FOCUS4-D and FOCUS4-N). Over the following 6 years, 103 UK sites were opened and subsequent substantial amendments approved the inclusion of two further subtrials (FOCUS4-B and FOCUS4-C). The trial centres, investigators and co-investigators are listed in Report Supplementary Material 2. Considerable challenges were encountered in engaging pharmaceutical companies to test therapies in the platform, with 20 drug combinations explored for inclusion. Of the five subtrials that had been planned to open at the design stage (FOCUS4-A, -B, -C, -D and -N), only four were activated (FOCUS4-B, -C, -D and -N) and only three reported results (FOCUS4-C, -D and -N), with FOCUS4-B stopping early on grounds of futility (see Figure 1).

Results from registration

Between January 2014 and October 2020, 1434 patients were registered from 88 UK hospitals, and 316 were randomised into a comparison subtrial (25%). A flow chart of patients during the registration period is presented according to the Consolidated Standards of Reporting Trials (CONSORT) criteria in Figure 2.

FIGURE 2 The CONSORT flow diagram of patients during registration period of FOCUS4. (Figure not reproduced here; see the original article.)

Biomarker analysis was undertaken on 1382 samples and the median time from registration to the availability of the biomarker results was 6 weeks [interquartile range (IQR) 4.3–8.3 weeks]. Molecular stratification was successful in 1291 out of 1382 (93%) samples received and was processed with mutations identified in the following genes: BRAF (10%), PIK3CA (14%), KRAS (53%), NRAS (6%), TP53 (69%), RAS + TP53 (32%), BRAF-PIK3CA-RAS wild type (26%) and deficient MMR (3%), as presented in Table 1.

Three molecularly targeted subtrials were activated:

• FOCUS4-D –
  • February 2014 to March 2016
  • evaluated ErbB kinase inhibitor sapitinib (AZD8931, AstraZeneca UK, Cambridge, UK) in the BRAF-PIK3CA-RAS wild-type subgroup.
• FOCUS4-B –
  • February 2016 to July 2018
  • evaluated aspirin in the PIK3CA-mutant subgroup.
• FOCUS4-C –
  • June 2017 to October 2020
  • evaluated adavosertib (AstraZeneca Ltd, Cambridge, UK) in the RAS + TP53 double-mutant subgroup.
• FOCUS4-A for the BRAF-mutant subgroup was not activated, despite a full protocol being prepared, because the data emerging from studies of the planned triplet combination (dabrafenib, panitumumab and trametinib) were determined not to warrant further investigation by the company involved.

In addition, FOCUS4-N was active throughout and evaluated capecitabine monotherapy compared with a treatment break.

Of the 1315 patients completing 16 weeks of first-line therapy, 908 (68%) had disease stabilisation or response and were potentially eligible for randomisation. Of these, 361 were randomly allocated to one of the comparison subtrials: FOCUS4-B (n = 6), FOCUS4-C (n = 69), FOCUS4-D (n = 32) and FOCUS4-N (n = 254).

The choice of first-line therapies used during the registration period is summarised in Table 2.

Treatment with EGFR-targeted monoclonal antibodies was administered according to NHS access or Cancer Drug Fund restrictions.

Details on biomarker prevalence and rates of disease progression during the registration period are presented in Table 3 (see also Table 1).

Failed endeavours

The continuous pursuit of new agents for testing in the FOCUS4 platform accounted for a lot of the investigator’s time. During the course of the trial, a total of 20 therapeutic interventions were explored and presented to the joint National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME)/Cancer Reserch UK funding subboard for peer-review approval, but only four culminated in an activated comparison (Table 4). Reasons for non-activation were predominantly failure of drugs at early clinical testing in this advanced metastatic disease setting; however, protocol development and contract negotiations had often progressed a long way and considerable resource had been used up for ultimately futile collaborations. Other endeavours failed bceause of strategic shifts

within companies, including the selling of assets suddenly and unexpectedly. Markers with incidence below 5% were also generally deemed too infrequent to pursue, although we have seen the very successful evaluation and licensing of immune checkpoint inhibitors in the MSI-high subgroup, which occurs in only 4% of metatastic CRCs.

Discussion and conclusions

Parts of this section have been reproduced with permission from Brown et al.20 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.

Adaptive trials not only provide significant advantages in the evaluation of multiple novel therapies in a disease setting, but also provide major challenges in their design, funding and delivery. FOCUS4 was jointly funded by the MRC/NIHR EME programme and Cancer Research UK (CRUK), with a combined budget (£3.6M) that was large in 2012 but small compared with current major molecularly stratified platform studies. Joint funding added a delay to trial initiation and review of amendments (performed via a sub-board representing both funders). For these trials to fulfil their aim of flexibility and nimbleness, it is important to learn and implement the lessons of undertaking complex trials in the era of the pandemic, particularly in terms of protocol and amendment approval, as recently espoused in the UK.21

The key features of the FOCUS4 design have all proved to be robust in the application. The use of PFS in the maintenance setting as the primary end point has been 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. This is of particular relevance for trials in the maintenance therapy setting. It was not possible to progress a therapy as planned through to evaluate whether or not the activity was specific to the molecular subgroup initially identified. Nor did it prove possible to move from Phase II to Phase III testing. These limitations were due to timing and funding availability rather than design failure.

The setting of the interval after 16 weeks of induction chemotherapy for patients with metastatic disease is a novel one. The registration of olapraib (Lynparza, Astrazeneca) in this setting of olaparib in platinum-sensitive ovarian cancer has made this a more recognisable route to registration. It builds on a pattern of practice of allowing patients a complete break from therapy following several months of induction chemotherapy, which is evidence based. Although this method is not unique to the UK, it is perhaps more widely utilised in the UK than in many other countries. This may change as a result of the COVID-19 pandemic, as patients now choose to spend more time away from hospitals and many have preferred a move to remote monitoring.

Adding the complexity of molecular stratification to allocate patients into the optimal biomarker-defined subgroup adds an extra layer of challenges, including the developmental status of the biomarker, the predictive power of the biomarker and selectivity for the therapy being evaluated (which is usually underdeveloped for any novel agent). Timely and reproducible delivery of the biomarker-testing panel, understanding the prognostic impact of the biomarker selection and the need to accommodate biomarker-negative patients remains critical to success. During FOCUS4, the simple mutation-based stratification process for many of the biomarkers that we tested 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.22

Rates of allocation into biomarker-selected groups are often very low in precision medicine studies, as exemplified by the Lung-Matrix Trial23 and the Lung-Map Trial.24 In the largest study of this kind, National Cancer Institute (NCI)-Match,25 5954 patients were enrolled with refractory malignancies, of whom 17.8% were assigned to a targeted therapy. Among these, 848 patients with CRC were registered, 13.7% of whom were assigned and 10% enrolled into a specific therapy trial.26 In FOCUS4, rather than assigning patients in non-randomised cohorts to therapies with hypothesised efficacy, 361 out of 1434 (25%) registered patients were randomised into a specified subtrial, and 107 (7.5%) of the registered patients were randomised into molecularly stratified subtrials. This attrition related to three main factors: (1) inadequacy of sample submission or analysis (10%), (2) death or progressive disease during induction therapy (27%) or (3) lack of availability of a suitable molecular subtrial or lack of patient consent when the patient was eligible for randomisation (60% of those potentially eligible). However, as shown in the evaluation of adavosertib in FOCUS4-C,27 randomisation against a control arm was critical to demonstrating efficacy, which would probably have been overlooked in a non-randomised design.

It is notable from the RECOVERY trial28 that negative results are more likely but are just as important as positive results in tackling diseases of high unmet clinical need. To date, the RECOVERY trial28 has identified four positive results [dexamethasone, tocilizumab, baricitinib (Olumiant^®, Eli Lilly and Company, Indianapolis, IND, USA) and the combination of Casirivimab and imdevimab (Ronapreve, Roche, Basel, Switzerland)] and seven negative results since its set-up in March 2020. NCI-Match has 39 cohorts: 12 have published final results to date,29 of which six have shown positive results. In FOCUS4, two positive results (capecitabine and adavosertib) were reported, one clear negative result and one feasibility failure.

Although non-commercial organisations may be best placed to set up and run such studies enabling collaboration with different pharmaceutical companies for different agents, engagement with the pharmaceutical and biotechnology industries is critical to success. A large amount of investigator time was spent negotiating with companies to test their agents in the platform, but only 4 out of 20 drug combinations explored came to fruition. To obtain approval from companies to include their agents, a very robust approach to the development of preclinical data packages to support the selection of particular drug/biomarker combinations is essential. This requires a well-funded, preclinical testing collaboration, ideally with disease subtype-specific models using genetically engineered mouse models, patient-derived xenograft and patient-derived organoids linked to detailed disease stratification information. From this basis, strong applications can be made to pharma to include agents in such precision medicine studies with a higher likelihood of success than was observed in FOCUS4. Only in the last 2 years has this been available through separate funding streams (the MRC stratified medicine consortium S:CORT30 and the ACRCelerate collaboration31 jointly funded by CRUK, the Italian Association for Cancer Research and the Spanish Association Against Cancer) and the fruit of this is yet to be seen to feed into an updated precision medicine study in CRC.

The enterprise of precision medicine adaptive platform trials is a massive exercise in team science. It is a tribute to the large body of investigators, research nurses and data managers at sites, laboratory scientists and trial unit staff, with the support from the institutions, funders and pharmaceutical companies, and, central to all of this, our patients, who have enabled us to complete this FOCUS4 trial.