# Inhibition of WEE1 Is Effective in TP53 - and RAS -Mutant Metastatic Colorectal Cancer: A Randomized Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring

Source: https://onco.cc/key-papers/paper-seligmann-j-clin-oncol/  
OnCo record `paper-seligmann-j-clin-oncol` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Paper cited by one trial page, indexed on Europe PMC as PubMed record 34538072 and published in Journal of Clinical Oncology; the citing page links this DOI, which is how the record was matched.

## Summary

Purpose: Outcomes in RAS -mutant metastatic colorectal cancer (mCRC) remain poor and patients have limited therapeutic options. Adavosertib is the first small-molecule inhibitor of WEE1 kinase. We hypothesized that aberrations in DNA replication seen in mCRC with both RAS and TP53 mutations would sensitize tumors to WEE1 inhibition.

Methods: Patients with newly diagnosed mCRC were registered into FOCUS4 and tested for TP53 and RAS mutations. Those with both mutations who were stable or responding after 16 weeks of chemotherapy were randomly assigned 2:1 between adavosertib and active monitoring (AM). Adavosertib (250 mg or 300 mg) was taken orally once on days 1-5 and days 8-12 of a 3-week cycle. The primary outcome was progression-free survival (PFS), with a target hazard ratio (HR) of 0.5 and 80% power with a one-sided 0.025 significance level.

Results: FOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) were RAS/TP53 -mutant. Sixty-nine patients were randomly assigned from 25 UK hospitals (adavosertib = 44; AM = 25). Adavosertib was associated with a PFS improvement over AM (median 3.61 v 1.87 months; HR = 0.35; 95% CI, 0.18 to 0.68; P =.0022). Overall survival (OS) was not improved with adavosertib versus AM (median 14.0 v 12.8 months; HR = 0.92; 95% CI, 0.44 to 1.94; P =.93). In prespecified subgroup analysis, adavosertib activity was greater in left-sided tumors (HR = 0.24; 95% CI, 0.11 to 0.51), versus right-sided (HR = 1.02; 95% CI, 0.41 to 2.56; interaction P =.043). Adavosertib was well-tolerated; grade 3 toxicities were diarrhea (9%), nausea (5%), and neutropenia (7%).

Conclusion: In this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for RAS/TP53 -mutant mCRC. Further testing is required in this sizable population of unmet need.

Indexed on Europe PMC as PubMed record 34538072 (DOI 10.1200/jco.21.01435). Matched by DOI alone: one trial page cites this DOI among its external links (the pages are listed under Related), and this page was written so that the citation resolves inside OnCo. No figure has been checked by an editor.

## Fields

- Kind: Key paper
- Last checked: 2026-09-22
- Tags: europepmc-ingest
- Journal: Journal of Clinical Oncology
- Year: 2021
- DOI: 10.1200/jco.21.01435
- Authors: Seligmann JF, Fisher DJ, Brown LC, et al.
- What it means: 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.
- Caveats: Matched to the citing OnCo records by DOI alone; the summary reproduces the Europe PMC abstract and no figure has been verified against the full paper.

## Sources

- J Clin Oncol 2021: https://doi.org/10.1200/jco.21.01435
- PubMed: https://pubmed.ncbi.nlm.nih.gov/34538072/
- Europe PMC: https://europepmc.org/article/MED/34538072

## Connected records

- trials: [FOCUS4](https://onco.cc/trials/focus4/)
- journals: [Journal of Clinical Oncology](https://onco.cc/journals/jco/)

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