Introduction: Non-small cell lung cancer (NSCLC) patients with activating EGFR mutations initially respond well to the EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. However, clinical efficacy is limited by the development of resistance. The most common mechanism of resistance is a second site mutation within exon 20 of EGFR (T790M), observed in ∼50% of cases. CO-1686 is an irreversible kinase inhibitor that targets the mutant forms of EGFR by inhibiting the common activating mutations (L858R, delE746-A750) and the gatekeeper mutation (T790M) but not the wild-type receptor. Therefore, CO-1686 has the potential to effectively treat first- and second-line NSCLC patients with EGFR mutations without causing the dose limiting toxicities associated with approved EGFR kinase inhibitors or those in clinical development. Experimental procedures: Using structure-based drug design, CO-1686, a covalent, irreversible small molecule, which selectively inhibits mutant EGFR, was identified. CO-1686 potency was assessed against four common EGFR mutations (L858R, delE746-A750, L858R/T790M and delE746-A750/T790M) using in vitro biochemical and cell-based assays. Antitumor activity of CO-1686 as a single agent was assessed in NSCLC xenograft models harboring EGFR mutations: H1975 (L858R/T790M) and HCC827 (delE746-A750). Pharmacodynamic studies were performed to evaluate effects on cell survival and EGFR signaling. Results: In vitro and in vivo pharmacology studies focused on evaluating CO-1686 potency in four EGFR mutations common in NSCLC patients: L858R, delE746-A750, L858R/T790M and delE746-A750/T790M. CO-1686 was shown to be active against all four EGFR mutants. Effects of CO-1686 on cell proliferation and EGFR signaling were evaluated in HCC827 cells (delE746-A750) and its erlotinib-resistant clone, HCC827-EPR harboring the second site mutation T790M (delE746-A750/T790M). CO-1686 inhibited cell proliferation in both cell lines equally (GI50 values of 12 nM in the parental line and 19 nM in the T790M-positive clone). In mouse xenograft studies, oral dosing of CO-1686 in H1975 double mutant (L858R/T790M) and in HCC827 single mutant (delE746-A750) models caused tumor shrinkage as a single agent in a dose-dependent manner. Different dosing schedules were explored. Conclusions: Our results establish CO-1686 as a potent, mutant-selective EGFR inhibitor with excellent in vivo activity in mice bearing tumors with activating EGFR mutations as well as the resistance mutation T790M. These data suggest that treatment with CO-1686 as a single agent can overcome T790M-mediated drug resistance in NSCLC. Initially, clinical development will focus on NSCLC patients with mutant EGFR.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1791. doi:1538-7445.AM2012-1791