Mouse PDX Trial Suggests Synergy of concurrent Inhibition of RAF and EGFR in Colorectal Cancer with BRAF or KRAS mutations

Purpose: It is to evaluate the anti-tumor efficacy of cetuximab in combination with LSN3074753, an analogue of LY3009120 and pan-RAF inhibitor in 79 colorectal cancer (CRC) patient derived xenograft (PDX) models. Experimental Design: 79 well characterized CRC PDX models were employed to conduct a single mouse per treatment group (n=1) trial. Results: Consistent with clinical results, cetuximab was efficacious in wild type KRAS and BRAF PDX models, with an overall response rate (ORR) of 6.3% and disease control rate (DCR) of 20.3%. LSN3074753 was active in a small subset of PDX models that harbored KRAS or BRAF mutations. However, the combination treatment displayed the enhanced antitumor activity with DCR of 35.4%.  Statistical analysis revealed that BRAF and KRAS mutations were the best predictors of the combinatorial activity, and were significantly associated with synergistic effect with a p value of 0.01 compared with cetuximab alone. In 12 models with BRAF mutations, the combination therapy resulted in a DCR of 41.7%, whereas either monotherapy had a DCR of 8.3%. Among 44 KRAS mutation models, cetuximab or LSN3074753 monotherapy resulted in a DCR of 13.6% or 11.4%, respectively, and the combination therapy increased DCR to 34.1%. Molecular analysis suggests that EGFR activation is a potential feedback and resistant mechanism of pan-RAF inhibition. Conclusions: MAPK and EGFR pathway activations are two major molecular hallmarks of CRC. This mouse PDX trial recapitulated clinical results of cetuximab. Concurrent EGFR and RAF inhibition demonstrated synergistic anti-tumor activity for CRC PDX models with a KRAS or BRAF mutation.