Non-small-cell lung cancer patients with activating mutations in epidermal 
growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitor (TKI) 
treatment. Nevertheless, patients often develop central nervous system (CNS) 
metastases during treatment, even when their extracranial tumors are still under 
control. In the absence of effective options, much higher doses of EGFR TKIs 
have been attempted clinically, with the goal of achieving high enough drug 
concentrations within the CNS. Although limited tumor responses have been 
observed with this approach, the toxicities outside the CNS have been too high 
to tolerate. We report the discovery and early clinical development of AZD3759, 
a selective EGFR inhibitor that can fully penetrate the blood-brain barrier 
(BBB), with equal free concentrations in the blood, cerebrospinal fluid, and 
brain tissue. Treatment with AZD3759 causes tumor regression in subcutaneous 
xenograft, leptomeningeal metastasis (LM), and brain metastasis (BM) lung cancer 
models and prevents the development of BM in nude mice. An early clinical study 
in patients with BM and LM treated with AZD3759 confirms its BBB-penetrant 
properties and antitumor activities. Our data demonstrate the potential of 
AZD3759 for the treatment of BM and LM and support its further clinical 
evaluation in larger trials.