As reported in the Journal of Clinical Oncology by Seligmann et al, the phase II FOCUS4-C trial has shown activity of the WEE1 kinase inhibitor adavosertib in patients with TP53- and RAS-mutant metastatic colorectal cancer with disease control after first-line chemotherapy.

As state by the investigators, “Outcomes in RAS-mutant metastatic colorectal cancer 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 metastatic colorectal cancer with both RAS and TP53 mutations would sensitize tumors to WEE1 inhibition.”

Study Details

In the open-label multicenter trial, which enrolled newly diagnosed patients with both mutations  between April 2017 and March 2020, 69 patients (intention-to-treat [ITT] population) who had stable disease or achieved response after 16 weeks of chemotherapy were randomly assigned 2:1 to receive oral adavosertib at 250 mg (first 21 patients) or 300 mg once daily on days 1 to 5 and 8 to 12 of 3-week cycles (n = 44) or active monitoring (n = 25).

The primary outcome measure was progression-free survival in the per-protocol population, consisting of 40 patients in the adavosertib group vs 24 in the active monitoring group. Analyses were adjusted for location of primary tumor, World Health Organization performance status, baseline disease assessment, number of metastases, and first-line therapy.

Progression-Free Survival

In the primary analysis in the per-protocol population, median progression-free survival was 3.61 months in the adavosertib group vs 1.87 months in the active monitoring group (adjusted hazard ratio [HR] = 0.35, 95% confidence interval [CI] = 0.18–0.68, P = .0022). In the ITT population, the adjusted hazard ratio was 0.40 (95% CI = 0.21–0.75, P = .0051). Disease control rates were 47% vs 28%. In the ITT population, median overall survival was 14.0 vs 12.8 months (adjusted HR = 0.92, 95% CI = 0.44–1.94, P =.93).

In a prespecified subgroup analysis, a progression-free survival benefit was observed in patients treated with adavosertib with left-sided primary tumors (median = 3.61 vs 1.87 months, HR = 0.24, 95% CI = 0.11–0.51) but not in those with right-sided tumors (median = 1.87 vs 1.91 months, HR = 1.02, 95% CI = 0.41–2.56; P = .043 for interaction). In an unplanned subgroup analysis, an overall survival benefit was observed for left-sided tumors (median = 14.1 vs 11.3 months, HR = 0.37, 95% CI = 0.15–0.87) but not in right-sided tumors (median = 6.5 vs 15.5 months, HR = 6.5, 95% CI = 0.72–6.43; P = .0032 for interaction).

Adverse Events

The most common adverse events of any grade in the adavosertib group included fatigue (75% vs 56% in active monitoring group), nausea (68% vs 32%), diarrhea (61% vs 28%), and vomiting (41% vs 4%). Grade ≥ 3 adverse events observed in the adavosertib group and not in the active monitoring group included fatigue in 11% of patients, diarrhea in 9%, nausea in 5%, and vomiting in 2%; grade ≥ 3 neutropenia occurred in 7% of patients in the adavosertib group. Grade 3 diarrhea occurred more frequently at the 300 mg vs 250 mg dose (14% vs 4%), with the toxicity profile otherwise being similar for the two doses.

The investigators concluded, “In this phase II randomized trial, adavosertib improved progression-free survival compared with active monitoring and demonstrates potential as a well-tolerated therapy for RAS/TP53-mutant metastatic colorectal cancer. Further testing is required in this sizable population of unmet need.”

Timothy S. Maughan, MD, of the MRC Oxford Institute for Radiation Oncology, University of Oxford, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by the MRC/NIHR Efficacy and Mechanism Evaluation program, Cancer Research UK, and AstraZeneca Ltd. For full disclosures of the study authors, visit ascopubs.org.