Results: In vitro and in vivo pharmacology studies were conducted to evaluate 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. In mouse
xenograft studies, oral dosing of CO-1686 in double mutant (L858R/T790M) and in 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 may overcome T790M-mediated drug resistance in NSCLC.
Initially, clinical development will focus on NSCLC patients with mutant EGFR.
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