Monoclonal antibodies against epidermal growth factor receptor (EGFR) are approved for the treatment of metastatic RAS-like colorectal cancer (WT), but the emergence of resistance mutations restricts their efficacy. Previous studies demonstrated that mutant alleles of RAS, BRAF and EGFR, which appear in circulating tumor DNA (ctDNA) during blockade, decrease upon withdrawal of therapy. CHRONOS hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti-EGFR antibodies. This phase 2 clinical trial exploits blood identification of RAS/BRAF/EGFR mutation levels to tailor a chemotherapy-free anti-EGFR rechallenge with panitumumumab. In CHRONOS, patients with tissue WT RAS tumors after prior treatment with antiEGFR-based regimens underwent ctDNA-based interventional screening. The majority of patients (63%) with wild-type RAS/BRAF/EGFR achieved a partial response or stable disease of more than 4 months’ duration when re-treated with panitumumumab monotherapy.
