Abstract 122: Preclinical update on targeting KRAS wild-type colorectal cancer with an EGFR-targeted monoclonal tri-body mixture, MM-151 (2017)

Abstract Within KRAS wild-type colorectal cancer (KRAS-wt CRC), standard of care treatment includes EGFR-directed monoclonal antibodies (mAb) in combination with an irinotecan-based chemotherapy regimen. While such combinations have clinically established synergy, the underlying mechanisms of synergy remain elusive, and resistance invariably develops against either the EGFR-targeted therapy or irinotecan, leaving patients with limited treatment options. MM-151 consists of three anti-EGFR IgG1 mAbs that bind simultaneously to non-overlapping epitopes on the EGFR extracellular domain (ECD). Preclinical and clinical studies have demonstrated that oligoclonal targeting of EGFR with MM-151 results in blockade of the EGFR pathway via potent inhibition of ligand-driven signal amplification and receptor downregulation. Critically, these activities are uniquely maintained in the presence of high-affinity EGFR ligands as well as mutations in the ECD of EGFR, both of which drive resistance to cetuximab and panitumumab. Here, we tested the preclinical hypothesis that comprehensive inhibition of the EGFR pathway by MM-151 leads to enhanced antitumor activity when combined with chemotherapy in models of KRAS-wt CRC. In vitro studies to investigate the activity of MM-151 in combination with SN-38, the active metabolite of irinotecan, showed that MM-151 potentiates SN-38-induced cell death in KRAS-wt CRC models. Treatment with MM-151 potently suppresses EGFR pathway activation caused by SN-38, and the combination enhances stress and pro-apoptotic signaling, leading to increased apoptosis. Notably, these synergistic activities are maintained in the presence of two key mechanisms of resistance to cetuximab: high-affinity ligands and EGFR ECD mutations. Dose scheduling studies demonstrated that sustained treatment with MM-151 following transient SN-38 exposure - a hallmark of small molecule therapy - partially overcomes the sub-optimal activity of chemotherapy alone. Finally, data from in vivo xenograft and PDX studies strongly supports the addition of MM-151 to irinotecan-based chemotherapy regimens for KRAS-wt CRC. In summary, we present data supporting the hypothesis that comprehensive antagonism of the EGFR pathway via oligoclonal targeting of EGFR with MM-151 leads to antitumor activity when combined with chemotherapy in preclinical KRAS-wt CRC models. The ability of MM-151 and SN-38 to overcome both de novo and acquired mechanisms of resistance within CRC models supports further clinical evaluation of this combination in metastatic CRC patients. Citation Format: Shawn P. Carey, Hongfang Wang, Erika Handly, Brittany Ahlstedt, Daniel Gaddy, Jeffrey D. Kearns, Greg Finn, Birgit Schoeberl, Rachel Nering. Preclinical update on targeting KRAS wild-type colorectal cancer with an EGFR-targeted monoclonal tri-body mixture, MM-151 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 122. doi:10.1158/1538-7445.AM2017-122