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

Abstract

Outcomes in <i>RAS</i>-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 <i>RAS</i> and <i>TP53</i> mutations would sensitize tumors to WEE1 inhibition. Patients with newly diagnosed mCRC were registered into FOCUS4 and tested for <i>TP53</i> and <i>RAS</i> 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. FOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) were <i>RAS/TP53</i>-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 <i>v</i> 1.87 months; HR = 0.35; 95% CI, 0.18 to 0.68; <i>P</i> = .0022). Overall survival (OS) was not improved with adavosertib versus AM (median 14.0 <i>v</i> 12.8 months; HR = 0.92; 95% CI, 0.44 to 1.94; <i>P</i> = .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 <i>P</i> = .043). Adavosertib was well-tolerated; grade 3 toxicities were diarrhea (9%), nausea (5%), and neutropenia (7%). In this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for <i>RAS/TP53</i>-mutant mCRC. Further testing is required in this sizable population of unmet need.