Plasma ctDNA RAS status selects patients for anti-EGFR treatment rechallenge in metastatic colorectal cancer: a meta-analysis.

Background: Recently one randomized trial and several phase II studies underscored that patients with metastatic colorectal cancer who progressed after an initial clinical benefit from anti-epidermal growth factor receptor (EGFR) treatment may further benefit from rechallenge with anti-EGFR therapy. Testing circulating tumor DNA (ctDNA) RAS status prior to anti-EGFR rechallenge seems a promising non-invasive method to predict and monitor response to anti-EGFR readministration.

Aim: To assess the capability of liquid biopsy ctDNA in exploring RAS status and in predicting outcome of metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibody rechallenge.

Materials and methods: Systematic review of literature and meta-analysis of the available evidence.

Results: Data from four studies involving 117 patients were available. All patients harbored RAS wild type tumors and derived benefit from first line anti-EGFR therapy. Of these, 65 underwent plasma ctDNA before anti-EGFR treatment rechallenge and were eligible for analyses: 35 patients had RAS wild type ctDNA, and 30 RAS mutated, indicating that 46% of patients underwent RAS status conversion after primary anti-EGFR therapy. Anti-EGFR rechallenge among patients with plasma ctDNA RAS wild type status was associated with a consistent benefit in progression free survival (hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.22-0.70; p = 0.001; I² = 0) and overall survival (HR 0.37, 95% CI 0.16-0.85; p = 0.02; I² = 74%) when compared to its use among patients with plasma ctDNA RAS mutation. Patients with plasma ctDNA RAS wild type profile also performed statistically better in term of disease control rate, risk for disease progression at 3 and 6 months, and risk for death at 6 and 12 months.

Conclusion: RAS status assessment continues to be useful in predicting benefit for anti-EGFR treatment.