Inhibition of WEE1 Is Effective in TP53- and RAS-Mutant Metastatic Colorectal Cancer: A Randomized Trial (FOCUS4-C)
Jenny F Seligmann1, David J Fisher2, Louise C Brown2
1Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom.
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.
Insights
Adavosertib improved progression-free survival in patients with RAS/TP53-mutant metastatic colorectal cancer (mCRC). This WEE1 kinase inhibitor shows potential as a well-tolerated therapy for this difficult-to-treat population.
Area of Science:
- Oncology
- Molecular Biology
- Clinical Trials
Background:
- Metastatic colorectal cancer (mCRC) with RAS mutations has poor outcomes and limited treatment options.
- WEE1 kinase is a target for cancer therapy, particularly in tumors with DNA replication stress.
- RAS and TP53 mutations are common in mCRC and may sensitize tumors to WEE1 inhibition.
Purpose of the Study:
- To evaluate the efficacy of adavosertib, a WEE1 kinase inhibitor, in patients with RAS/TP53-mutant mCRC.
- To test the hypothesis that DNA replication aberrations in mCRC with RAS and TP53 mutations sensitize tumors to WEE1 inhibition.
Main Methods:
- A Phase II randomized trial (FOCUS4-C) enrolled patients with newly diagnosed mCRC.
- Patients with both RAS and TP53 mutations, stable or responding after chemotherapy, were randomized to adavosertib or active monitoring.
- Progression-free survival (PFS) was the primary outcome, with secondary outcomes including overall survival (OS).
Main Results:
- Adavosertib significantly improved PFS compared to active monitoring (median 3.61 vs 1.87 months; HR=0.35; P=.0022).
- No significant improvement in OS was observed with adavosertib versus active monitoring (median 14.0 vs 12.8 months; HR=0.92).
- Adavosertib showed greater activity in left-sided tumors and was generally well-tolerated with manageable toxicities.
Conclusions:
- Adavosertib demonstrated improved PFS in patients with RAS/TP53-mutant mCRC, suggesting its potential as a targeted therapy.
- Adavosertib is a well-tolerated treatment option for this patient population with significant unmet need.
- Further investigation in larger trials is warranted for this sizable patient group.
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