Epidermal growth factor receptor (EGFR) inhibitors have been used
clinically in the treatment of non-small-cell lung cancer (NSCLC)
patients harboring sensitizing (or activating) mutations for a
number of years. Despite encouraging clinical efficacy with these
agents, in many patients resistance develops leading to disease
progression. In most cases, this resistance is in the form of the
T**0M mutation. In addition, EGFR wild type receptor inhibition
inherent with these agents can lead to dose limiting toxicities of
rash and diarrhea. We describe herein the evolution of an early,
mutant selective lead to the clinical candidate AZD***1, an
irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T**0M
resistance mutations with selectivity over the wild type form of
the receptor. Following observations of significant tumor
inhibition in preclinical models, the clinical candidate was
administered clinically to patients with T**0M positive EGFR-TKI
resistant NSCLC and early efficacy has been observed, accompanied
by an encouraging safety profile.
