Multi-institutional observational study evaluating the efficacy of anti-epidermal growth factor antibody re- challenge in RAS/BRAF wild-type metastatic colorectal cancer

Abstract Purpose: We aimed to investigate the incidence of circulating tumor DNA (ctDNA) RAS mutant (MT) before salvage-line treatment and explore the clinicopathological features and molecular biological factors associated with the efficacy of anti-epithelial growth factor receptor (EGFR) monoclonal antibody (mAb) re-challenge for tissue RAS/BRAF wild type (WT) metastatic colorectal cancer (mCRC). Methods: This multi-institutional retrospective observational study included 74 mCRC patients with tissue RAS/BRAF WT refractory to first-line chemotherapy containing anti-EGFR mAb, whose RAS status in ctDNA was assessed using the OncoBEAMTM RAS CRC Kit. We explored the clinicopathological features associated with RAS status in ctDNA and the factors related to the efficacy of re-challenge of anti-EGFR mAb in multivariate Cox proportional hazard regression. Results: The incidence of RAS MT in ctDNA was 40.5% (30/74), which was associated with primary tumor resection (P=0.016), liver metastasis (P<0.001), and high tumor marker levels (P<0.001). Among the 39 patients treated with anti-EGFR mAb re-challenge, those with ctDNA RAS WT showed significantly longer progression-free survival (PFS) than those with ctDNA RAS MT (median 4.1 vs. 2.7 months, hazard ratio [HR]=0.39, P=0.045). Similarly, patients who responded to first-line anti-EGFR mAb showed significantly longer PFS than those with stable disease. In multivariate analysis, response to first-line anti-EGFR mAb was significantly associated with longer PFS (HR=0.21, P=0.0026) and overall survival (HR=0.23, P=0.026). Conclusions: The incidence of ctDNA RAS MT mCRC was 40.5%, which was associated with liver metastases and high tumor volumes. Anti-EGFR mAb re-challenge may be effective for mCRC patients who responded to first-line chemotherapy containing anti-EGFR mAb. No patients with RAS MT in ctDNA responded to Anti-EGFR mAb re-challenge.