# FOCUS4

Source: https://onco.cc/trials/focus4/  
OnCo record `focus4` (Trial). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Trial
- Status: completed
- Last checked: 2026-09-17
- Also known as: FOCUS4 trial; FOCUS4-N; FOCUS4-C; FOCUS4-D; MRC FOCUS4
- Registry id: ISRCTN90061546
- Phase: platform
- Setting: Metastatic colorectal cancer stable or responding after 16 weeks of first-line chemotherapy: tumours stratified by biomarker into parallel randomised maintenance comparisons against active monitoring or placebo
- Sponsor: MRC Clinical Trials Unit at UCL, funded by the Medical Research Council, the NIHR Efficacy and Mechanism Evaluation programme and Cancer Research UK
- Result: FOCUS4-C: adavosertib improved progression-free survival in RAS and TP53 co-mutated tumours (hazard ratio 0.35). FOCUS4-N: maintenance capecitabine improved progression-free survival (hazard ratio 0.40) without an overall survival gain. FOCUS4-D: no benefit from AZD8931.
- Outcomes: Progression-free survival, FOCUS4-C (RAS and TP53 mutant): Adavosertib vs Active monitoring, HR 0.35; Progression-free survival, FOCUS4-N: Maintenance capecitabine vs Active monitoring, HR 0.4

## Sources

- ISRCTN90061546: FOCUS4 registry entry: https://www.isrctn.com/ISRCTN90061546
- Seligmann et al., Journal of Clinical Oncology 2021: inhibition of WEE1 is effective in TP53- and RAS-mutant metastatic colorectal cancer (FOCUS4-C): https://doi.org/10.1200/JCO.21.01435
- Adams et al., Journal of Clinical Oncology 2021: capecitabine versus active monitoring in stable or responding metastatic colorectal cancer after 16 weeks of first-line therapy (FOCUS4-N): https://doi.org/10.1200/JCO.21.01436
- Molecular selection of therapy in metastatic colorectal cancer: the FOCUS4 molecularly stratified RCT, Efficacy and Mechanism Evaluation 2022: https://doi.org/10.3310/HTNB6908
- Experiences of running a stratified medicine adaptive platform trial: challenges and lessons learned from 10 years of the FOCUS4 trial, Clinical Trials 2022: https://doi.org/10.1177/17407745211069879

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/)
- drugs: [Adavosertib](https://onco.cc/drugs/adavosertib/), [Capecitabine](https://onco.cc/drugs/capecitabine/)
- institutions: [Cancer Research UK](https://onco.cc/institutions/cruk/), [University College London Hospitals / UCL Cancer Institute](https://onco.cc/institutions/uclh/)
- terms: [Basket, umbrella, and platform trials](https://onco.cc/terms/basket-umbrella-platform/), [Interim analysis, readout and data cut-off](https://onco.cc/terms/interim-analysis/), [Master protocol (platform, basket and umbrella trials)](https://onco.cc/terms/master-protocol/), [Seamless, adaptive and Bayesian trial designs](https://onco.cc/terms/seamless-adaptive/)
- bottlenecks: [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/)

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