Dual EGFR/HER2 Blockade Combined With Irinotecan for the Treatment of HER2-Positive Metastatic Colorectal Cancer

In colorectal cancer (CRC), HER2 has emerged as a significant therapeutic target, with clinical studies demonstrating promising yet transient responses to HER2-targeted therapies in HER2-positive (overexpressed/amplified) advanced cases, highlighting the need for improved strategies. Mechanistically, in the 65-75% of CRCs exhibiting EGFR overexpression, HER2 promotes heterodimerization with EGFR, impairing internalization of HER2-targeted ADCs and reducing drug uptake. Preclinical evidence suggests EGFR monoclonal antibodies (cetuximab/panitumumab) may overcome this limitation by inducing EGFR internalization and enhancing HER2-targeted drug efficacy. However, HER2-positive advanced CRC lacks validated predictive biomarkers and thorough translational research. Our study will clinically evaluate trastuzumab plus cetuximab and irinotecan in this population, while performing longitudinal biomarker analyses of paired blood and tumor samples to identify response predictors, elucidate resistance mechanisms, and optimize this promising therapeutic approach.