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FOCUS4 was Britain's molecularly stratified platform in bowel cancer: after four months of chemotherapy, patients were sorted by their tumour's mutations and offered a matching maintenance drug or a break. Its two clear results were that a WEE1 inhibitor slowed cancers with both RAS and TP53 mutations, and that maintenance capecitabine delays progression but does not extend life.
FOCUS4 ran from 2014 to 2020 from the MRC Clinical Trials Unit at UCL, led by Tim Maughan, Matthew Seymour, Richard Adams and Richard Kaplan, with laboratory stratification at Leeds and Cardiff. Patients with metastatic colorectal cancer whose disease was stable or responding after 16 weeks of first-line chemotherapy had their tumour tested for BRAF, PIK3CA, RAS and TP53 and mismatch repair status, then entered the matching randomised comparison during a planned treatment break: FOCUS4-D for BRAF, PIK3CA and RAS wild-type tumours (the pan-HER inhibitor AZD8931 against placebo), FOCUS4-C for tumours with both RAS and TP53 mutations (the WEE1 inhibitor adavosertib against active monitoring), FOCUS4-B for PIK3CA-mutant tumours, and FOCUS4-N, open to any biomarker group, comparing maintenance capecitabine with active monitoring. The multi-arm multi-stage design allowed arms to stop early for lack of activity or add new drugs.
FOCUS4-D closed for futility in 2018 with no benefit from AZD8931. FOCUS4-C, published in the Journal of Clinical Oncology in 2021, found that adavosertib improved progression-free survival against active monitoring in RAS and TP53 co-mutated cancers (hazard ratio 0.35), the first clinical signal for WEE1 inhibition selected by this pair of mutations, with a non-significant trend to longer overall survival. FOCUS4-N, also in the Journal of Clinical Oncology in 2021, showed maintenance capecitabine improved progression-free survival (hazard ratio 0.40) but not overall survival, supporting treatment breaks as a reasonable choice. The platform closed in 2020 as the COVID-19 pandemic and the withdrawal of several planned drugs made further arms impractical; the full programme was published as a monograph in 2022 alongside a candid account of the lessons of running a stratified platform for a decade.
What FOCUS4 changed is British colorectal practice on maintenance therapy and the design of later UK platforms: it proved that a national trials unit could stratify by biomarker within the NHS, and it showed the cost of relying on industry to supply drugs to an academic platform when candidate agents are withdrawn. The adavosertib signal has not yet been taken into a confirmatory trial.
Numbers are from the trial as recorded here; see the source links in the table below. This is orientation, not medical advice: ask your team how closely the trial population matches you.
Numbers not yet public.
SourceOne trial page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
One trial page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
One trial page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
Shares Tim Maughan, MRC Clinical Trials Unit at UCL, Oxford Cancer (Oxford University Hospitals and University of Oxford), Colorectal cancer.
Shares Tim Maughan, Oxford Cancer (Oxford University Hospitals and University of Oxford), Capecitabine, Colorectal cancer.
Shares Interim analysis, readout and data cut-off, Seamless, adaptive and Bayesian trial designs, Master protocol (platform, basket and umbrella trials), Trial design, endpoints and cost.
Shares Master protocol (platform, basket and umbrella trials), Basket, umbrella, and platform trials, Trial design, endpoints and cost, Comprehensive genomic profiling.
Shares Seamless, adaptive and Bayesian trial designs, Master protocol (platform, basket and umbrella trials), Basket, umbrella, and platform trials, Cancer Research UK.
Shares Master protocol (platform, basket and umbrella trials), Basket, umbrella, and platform trials, Cancer Research UK, Comprehensive genomic profiling.
Shares Interim analysis, readout and data cut-off, MRC Clinical Trials Unit at UCL, Seamless, adaptive and Bayesian trial designs, Master protocol (platform, basket and umbrella trials).
Shares Interim analysis, readout and data cut-off, Seamless, adaptive and Bayesian trial designs, Master protocol (platform, basket and umbrella trials), Trial design, endpoints and cost.