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

Abstract

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.

FIG 1.

Flowchart of patients through the trial. CR, complete response; ITT, intention-to-treat; PPA, per-protocol analysis; PR, partial response; SD, stable disease.

FIG 2.

(A) PFS (primary analysis) in PPA population: Cox regression, adjusted for minimization factors—HR = 0.35 (95% CI, 0.18 to 0.68), P = .0022. Minimization factors: location of primary tumor (left, right, and rectum), baseline WHO performance status, baseline disease assessment, number of metastases, and first-line therapy (fluoropyrimidine, oxaliplatin or irinotecan, and monoclonal antibody). (B) OS (secondary analysis) in PPA population: Cox regression, adjusted for minimization factors—HR = 0.86 (95% CI, 0.39 to 1.86), P = .70. Minimization factors: location of primary tumor (left, right, and rectum), baseline WHO performance status, baseline disease assessment, number of metastases, and first-line therapy (fluoropyrimidine, oxaliplatin or irinotecan, and monoclonal antibody). AM, active monitoring; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PPA, per-protocol analysis.

FIG 3.

Subgroup analyses for PFS by intention to treat. CAPOX, capecitabine and oxaliplatin; FOLFIRI, fluorouracil, leucovorin, and irinotecan; FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin; PFS, progression-free survival; PTL, primary tumor location.

FIG 4.

Prognostic impact of biomarker subgroups on OS in previous FOCUS trial. HR, hazard ratio; MSI-H, microsatellite instability-high; OS, overall survival.

FIG 5.

Cumulative reported toxicity, within FOCUS4-C treatment groups and with initial AZD1775 doses separated: (A) active monitoring (n = 25), (B) AZD1775 250 mg (n = 23), and (C) AZD1775 300 mg (n = 21). G, grade; PPE, palmar plantar erythema.