Phase 1 BAY 3771249 KRAS G12D-selective inhibitor ± EGFR antibody cetuximab in mCRC

Bayer (with partner Kumquat Biosciences) is running an open-label Phase 1 master protocol testing BAY 3771249 (also referenced as KQB548), an oral small-molecule KRAS G12D-selective inhibitor, given alone or combined with cetuximab (an EGFR-directed monoclonal antibody marketed by Eli Lilly and by Merck KGaA/Darmstadt outside the US/Canada). This colorectal adenocarcinoma substudy uses multi-cohort dose escalation to define a safe and active dose/range (DLTs, safety, PK/PD), followed by expansion to estimate preliminary antitumor activity (e.g., ORR by RECIST v1.1) in advanced/metastatic KRAS G12D–mutant CRC. The scientific angle is translating the “KRAS + EGFR blockade” paradigm—validated clinically in KRAS G12C CRC—into the harder, higher-need KRAS G12D segment, which represents a meaningful minority of CRC (~10–15%). Today’s care for previously treated metastatic CRC is sequential systemic therapy (fluoropyrimidine/oxaliplatin/irinotecan-based regimens, VEGF-targeted therapy, and later-line agents like trifluridine/tipiracil or regorafenib; anti-EGFR antibodies are used only for RAS–wild-type disease), so this program targets a population that currently lacks an approved KRAS G12D-directed option.