Phase 2 trastuzumab rezetecan (SHR-A1811) HER2-directed topoisomerase I inhibitor ADC in 1L mCRC

HORIZON-CRC221 is a global, multicenter, randomized, dose-optimization Phase 2 study testing two dose levels of trastuzumab rezetecan (SHR-A1811)—a HER2-targeted monoclonal antibody–drug conjugate delivering a topoisomerase I inhibitor payload—in combination with mFOLFOX6 chemotherapy (dose level -1) plus bevacizumab (anti-VEGF antibody). The primary purpose is to characterize safety and identify a recommended Phase 3 dose in a Western-focused first-line setting for unresectable/metastatic colorectal cancer with HER2 expression (including IHC 2+ equivocal or 3+ using gastric cancer scoring criteria). The sponsor is Jiangsu Hengrui Medicine, positioning this as an early global move to bring a China-generated HER2-ADC signal into broader regulatory pathways. Clinically, it aims to “front-load” HER2-directed ADC benefit before resistance to oxaliplatin/fluoropyrimidine backbones develops. Today’s first-line care for most unresectable/metastatic colorectal cancer remains doublet chemotherapy (FOLFOX/CAPOX or FOLFIRI) with bevacizumab (or anti-EGFR therapy for selected RAS/RAF–wild-type left-sided tumors), with HER2-targeted regimens typically used later-line rather than up front.