Abstract 2337: Efficacy of the RAF/PI3Kα/anti-EGFR triple combination LGX818 + BYL719 + cetuximab in BRAFV600E colorectal tumor models.
Authors: Caponigro Giordano , Cao Z A. , Zhang Xiaobin , Wang Hui Q. , Fritsch Christine M. , Stuart Darrin D. 
Published: August 2014

Abstract
Selective RAF inhibitors have a significant role in the treatment of patients with metastatic melanoma whose tumors express BRAFV600E with the majority of patients experiencing significant tumor regression. However in patients with colorectal cancer (CRC) whose tumors express BRAFV600E, response-rates appear to be much lower, with only a few patients reported to experience a partial tumor response to vemurafenib (Kopetz et al., 2010) or the combination of dabrafenib plus trametinib (Corcoran et al., 2012).
LGX818 is a highly potent RAF inhibitor with selective anti-proliferative activity in cells expressing BRAFV600E. A distinguishing feature of LGX818 is its very long dissociation half-life from BRAFV600E which leads to strong and sustained target inhibition even following drug wash-out. In addition, LGX818 has a very wide therapeutic index, with tumor regression observed at doses as low as 3 mg/kg bid and excellent tolerability up to 300 mg/kg bid in melanoma xenograft models. In the CRC cell line Colo205 (BRAFV600E), LGX818 inhibits proliferation with an EC50 = 0.005 μM and in vivo leads to significant tumor regression at doses as low as 20 mg/kg. However, other BRAFV600E CRC cell lines do not appear to be as sensitive (EC50 = 0.018 to &gt;2.7 μM) and this intrinsic resistance translates in vivo in xenograft models generated from these cell lines.
Based on clinical and preclinical data, it is clear that combination strategies will be required if RAF inhibitors are going to play a significant role in the treatment of CRC. Recent publications have implicated feedback-mediated activation of EGFR in BRAFV600E CRC cells treated with RAF and MEK inhibitors and this led us to test combinations of LGX818 with anti-EGFR therapies such as cetuximab and erlotinib. In vitro and in vivo studies indicated that the combination of LGX818 with cetuximab or erlotinib can be highly synergistic, leading to enhanced cell killing. In vivo the combination of LGX818 + cetuximab led to complete inhibition of tumor growth at doses where no single-agent activity was observed. Since PIK3CA mutations often co-occur with BRAFV600E in CRC tumors, we also tested the alpha-selective PI3K inhibitor BYL719 in combination with LGX818 and cetuximab as a triple combination. In vitro, this triple combination produced synergistic anti-proliferative effects and in vivo resulted in tumor regression.
These preclinical data led to the initiation of an ongoing Phase I/II trial to evaluate the triple combination of LGX818, cetuximab and BYL719 in BRAFV600E CRC. Based on the preclinical results described above it is anticipated that the combination of a RAF inhibitor with anti-EGFR therapy and a PI3K inhibitor will have superior efficacy to single-agent RAF inhibitor in BRAFV600E CRC.
Citation Format: Giordano Caponigro, Z A. Cao, Xiaobin Zhang, Hui Q. Wang, Christine M. Fritsch, Darrin D. Stuart. Efficacy of the RAF/PI3Kα/anti-EGFR triple combination LGX818 + BYL719 + cetuximab in BRAFV600E colorectal tumor models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2337. doi:10.1158/1538-7445.AM2013-2337