Sotorasib (KRAS G12C inhibitor) + panitumumab (EGFR mAb) + FOLFIRI drives 56.5% ORR in pretreated KRAS G12C mCRC

Sotorasib is an oral covalent KRAS G12C inhibitor and panitumumab is an EGFR-targeting monoclonal antibody; here they were combined with irinotecan/leucovorin/5-FU (FOLFIRI) in the CodeBreaK 101 Phase 1b subprotocol H dose-exploration/expansion study (NCT04185883) in previously treated KRAS G12C-mutated metastatic colorectal cancer (n=46; median 2 prior lines, spanning 2L to ≥4L). At the RP2D of sotorasib 960 mg QD + panitumumab 6 mg/kg Q2W + standard FOLFIRI Q2W, confirmed ORR was 56.5% (95% CI 41.1–71.1), median PFS was 8.3 months (95% CI 7.0–11.0), and median OS was 17.9 months (95% CI 13.0–23.3). That is numerically above the now FDA-approved sotorasib + panitumumab doublet in previously treated KRAS G12C mCRC, which produced an ORR of 26.4% and median PFS of 5.6 months in CodeBreaK 300. Grade ≥3 TRAEs occurred in 50%; common toxicities included acneiform dermatitis (65.2%), dry skin (60.9%), and neutropenia/neutrophil-count decrease (56.5%), with no dose-limiting toxicities at the starting dose level.