Efficacy of dual KRAS(G12D)-EGFR blockade versus triple combinations in patient-derived models of KRAS(G12D)-mutant colorectal cancer.

KRASG12D is one of the most prevalent and treatment-refractory mutations in colorectal cancer (CRC). The emergence of selective KRASG12D inhibitors offers new therapeutic opportunities, yet preclinical evidence indicates that monotherapy efficacy is constrained by signaling feedback and pathway redundancy, emphasizing the need for rational combination strategies. We systematically evaluated the biochemical, biological, and therapeutic activity of single, dual, and triple regimens combining the KRASG12D inhibitor MRTX1133 with cetuximab (EGFR inhibitor), alpelisib (PI3Kα inhibitor), or trametinib (MEK inhibitor) in a panel of patient-derived tumoroids and xenografts (PDXs) from metastatic CRC. MRTX1133 displayed mutation-specific activity in KRASG12D-mutant tumoroids.

Dual blockade of KRASG12D and EGFR with MRTX1133 + cetuximab achieved near-complete inhibition of MAPK and PI3K-AKT signaling, with only marginal additional suppression upon addition of alpelisib or trametinib. In PDX models, triple combinations conferred no survival advantage over MRTX1133 + cetuximab. Likewise, dual therapy with trametinib + cetuximab was as effective as the triple regimen, suggesting functional redundancy between direct KRAS inhibition and downstream MEK blockade when EGFR is co-targeted. In non-KRASG12D-mutant models, MRTX1133 + cetuximab modestly reduced KRAS pathway activity and slightly delayed tumor growth, consistent with a potential 'leakage effect'.

Collectively, our results identify dual KRASG12D - EGFR inhibition as the regimen delivering maximal pathway suppression and therapeutic benefit in clinically relevant CRC models, with no clear advantage from more complex triple combinations. This work encourages prioritizing KRAS-EGFR co-targeting over multi-agent strategies that risk added toxicity, and provides a strong rationale for advancing KRASG12D inhibitors + cetuximab as a backbone targeted therapy in future clinical trials for KRASG12D-mutant CRC.