Abstract B120: Preclinical assessment of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC.
Authors: Simmons Andrew D. , Haringsma Henry J. , Walter Annette O. , Tjin Tham Sjin Robert , Weaver Zoe , Allen Andrew , Harding Thomas C. 
Published: August 2014

Abstract
Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations initially respond well to first generation reversible EGFR tyrosine kinase inhibitors. However, clinical efficacy is limited by acquired resistance, attributable in 60% of cases to a secondary mutation of EGFR at T790M. In addition, patients also experience skin and GI toxicity due to wild type (WT) EGFR inhibition. CO-1686 is a novel, irreversible and orally delivered kinase inhibitor that specifically targets the most frequently observed front-line and acquired resistance mutant forms of EGFR, while exhibiting minimal activity towards WT EGFR. Selectivity of CO-1686 was demonstrated using two separate biochemical assays in which CO-1686 was at least 10-fold more selective for mutant EGFR as compared to the WT receptor. In human cancer cell lines, CO-1686 potently inhibited in vitro proliferation of cells expressing mutant EGFR, while minimally affecting proliferation of WT EGFR-dependent cells. To confirm this selectivity in vivo, CO-1686 was evaluated in WT (A431), front line (HCC827, transgenic), and second line (NCI-H1975, LUM1868, transgenic) xenograft models. CO-1686 dosed at 50 mg/kg BID exhibited a minimal reduction in tumor growth in the A431 xenograft model with no significant alterations in body weight and EGFR WT pathway signaling. Comparatively, both erlotinib (75 mg/kg QD) and afatinib (20 mg/kg QD) administration resulted in profound tumor regression, but with concurrent body weight loss and EGFR WT pathway inhibition. CO-1686, when dosed as a single agent at 50 mg/kg BID and/or 100 mg/kg QD, caused tumor regressions in the HCC827 (del19), NCI-H1975 (L858R/T790M), and patient-derived lung tumor xenograft model LUM1868 (L858R/T790M). The efficacy of CO-1686 was also examined in EGFR-L858R and EGFR-L858R-T790M genetically engineered mouse (GEM) models that develop lung adenocarcinoma upon human mutant EGFR transgene induction in the lung epithelium. In both models, CO-1686 administration (50 mg/kg BID) resulted in potent anti-tumor activity as measured by MRI and histological assessment. Following a 3-week dosing period, animals treated with CO-1686 demonstrated a complete regression of established lesions. Comparatively, in the EGFR-L858R-T790M GEM model, afatinib dosed at the maximum tolerated dose (20 mg/kg QD) resulted in limited efficacy. In summary, CO-1686 exhibits potent and significant anti-tumor activity as a single agent in xenograft models driven by the most frequently observed front-line and acquired resistance mutant forms of EGFR, while exhibiting minimal activity towards WT EGFR. These data suggest that CO-1686 may have utility in both front-line and acquired resistance EGFR-mutated NSCLC, and CO-1686 is currently being evaluated in a phase I/II clinical trial in previously treated mutant EGFR NSCLC patients (ClinicalTrials.gov identifier: NCT01526928).
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B120.
Citation Format: Andrew D. Simmons, Henry J. Haringsma, Annette O. Walter, Robert Tjin Tham Sjin, Zoe Weaver, Andrew Allen, Thomas C. Harding. Preclinical assessment of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B120.