Sotorasib (KRAS G12C inhibitor) + panitumumab (EGFR mAb) links early ctDNA clearance to longer survival in chemorefractory mCRC

Sotorasib is an oral covalent KRAS G12C inhibitor, and panitumumab is an anti-EGFR monoclonal antibody; in the Phase 3 CodeBreaK 300 trial (NCT05198934) in chemorefractory KRAS G12C–mutant mCRC, this analysis tested whether early ctDNA “clearance” predicts response and prognosis. Among patients with baseline and Cycle 2 Day 1 ctDNA (n=142), ≥80% KRAS G12C VAF clearance occurred in 77.3% (960 mg; n=44) and 65.9% (240 mg; n=44) vs 15% with investigator’s choice trifluridine/tipiracil or regorafenib (n=40)—therapies that typically deliver very low ORR and short mPFS (~2 months) in this chemorefractory setting. In the 960 mg arm, patients achieving ≥80% clearance had ORR 35.3% (12/34) by VAF (and 32.3% by cTF) and substantially longer outcomes (mPFS 5.8 months vs 1.9 months without clearance; mOS not evaluable vs 4.9 months), while increasing the stringency beyond ≥80% did not add prognostic value.