Abstract LB-004: Mouse PDX Trial Suggests Combination Efficacy of Raf and EGFR Inhibition in Colorectal Cancer with BRaf or KRas mutation
Authors: Yao Yung-mae M. , Donoho Gregory P. , Iversen Philip W. , Webster Yue Wang , Yue Yong Gang , Henry James R. , Plowman Gregory D. , Peng Sheng-Bin 
Published: August 2015

Abstract
MAPK activation through KRas, NRas or BRaf mutation occurs in approximately 70% of colorectal cancer patients. Due to their epithelial origin, colorectal tumors generally have high levels of EGFR expression and activation. EGFR therapies such as cetuximab are effective for treatment of a subset of colorectal cancer, particularly patients with wild type (WT) KRas. EGFR signaling is also recently identified as a key resistance mechanism in BRaf mutant colorectal cancer to BRaf inhibitors. In this study, we have genetically characterized 78 patient-derived xenograft (PDX) models of colorectal tumors, and conducted an “n = 1” (single mouse per treatment group) trial in these PDX models with cetuximab, LSN3074753, a pan-Raf and Raf dimer inhibitor, and their combination in collaboration with Oncotest GmbH and Champions Oncology. Among these 78 PDX models, 42 (53.8%) have a KRas mutation, 12 (15.4%) have BRaf V600E or an atypical BRaf mutation, and 26 (33.3%) are WT KRas and BRaf. Consistent with clinical results, cetuximab is primarily active in WT KRas and BRaf PDX models, with disease control rate (DCR) of 53.8% (14/26) in this subgroup. These results suggest that the mouse n = 1 PDX trial paradigm could reliably predict clinical results. For pan-Raf and Raf dimer inhibitor LSN3074753, it is active in a subset of PDX models, particularly those with BRaf or KRas mutation(s), with DCR of 21.2% among models with a KRas or BRaf mutation. Importantly, a synergistic effect is observed when cetuximab and LSN3074753 are combined for treatment of these 78 PDX models. The overall DCR in the combination arm is 50% (39/78), while cetuximab or LSN3074753 alone has an overall DCR of 24 or 18%, respectively. Further statistical analyses reveal that BRaf mutations including V600E or other atypical mutations (G469E, G76E, G596V, G203V, etc) are the best predictor of combination synergy, and are significantly associated with synergistic effect with a p value of 0.004. In models with BRaf mutations, the combination arm has a DCR of 50% (6/12), whereas cetuximab or LSN3074753 alone has a DCR of 8.3 or 17%, respectively. BRaf or KRas mutations are also
significantly associated with combination synergy with p value of 0.01. Among 42 KRas mutation models, LSN3074753 or cetuximab alone has a DCR of 21.4 or 16.7%, and the combination arm has a DCR of 43%. Overall, these results indicate that combination of EGFR and Raf inhibition by cetuximab and a pan-Raf inhibitor has the potential for treatment of colorectal cancer patients with BRaf or KRas mutation.
Citation Format: Yung-mae M. Yao, Gregory P. Donoho, Philip W. Iversen, Yue Wang Webster, Yong Gang Yue, James R. Henry, Gregory D. Plowman, Sheng-Bin Peng. Mouse PDX Trial Suggests Combination Efficacy of Raf and EGFR Inhibition in Colorectal Cancer with BRaf or KRas mutation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-004. doi:10.1158/1538-7445.AM2015-LB-004