BACKGROUND: CNS metastases-including brain and leptomeningeal metastases-from 
epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer 
(NSCLC) are associated with poor prognosis. AZD3759 is a novel EGFR tyrosine 
kinase inhibitor with high capability to penetrate the blood-brain barrier. We 
aimed to assess the safety, tolerability, pharmacokinetics, and efficacy of 
AZD3759 in patients with EGFR-mutant NSCLC with brain and leptomeningeal 
metastases.
METHODS: This open-label, multicentre, phase 1 study was undertaken at 11 
centres and hospitals in Australia, South Korea, Taiwan, and the USA. Eligible 
patients included those with histologically confirmed, advanced-stage, 
EGFR-mutant NSCLC. The study was done in two parts, with dose-escalation and 
dose-expansion phases. In the dose-escalation phase, patients who had progressed 
after treatment with an EGFR tyrosine kinase inhibitor received AZD3759 at 50 
mg, 100 mg, 200 mg, 300 mg, or 500 mg twice a day. In the dose-expansion phase, 
AZD3759 at 200 mg or 300 mg twice a day was administered to patients with either 
brain or leptomeningeal metastases who had never received an EGFR tyrosine 
kinase inhibitor and patients with leptomeningeal metastases who had been 
pretreated with an EGFR tyrosine kinase inhibitor. The primary objective was 
safety and tolerability, with severity of adverse events assessed with the 
National Cancer Institute's Common Terminology Criteria for Adverse Events, 
version 4.03. This trial is registered with ClinicalTrials.gov, number 
NCT02228369.
FINDINGS: Between Nov 18, 2014, and Sept 7, 2016, 67 patients with NSCLC were 
enrolled into the study, 29 to the dose-escalation phase and 38 to the 
dose-expansion phase. At data cutoff (Dec 12, 2016), three (10%) patients in the 
dose-escalation phase and 20 (53%) in the dose-expansion phase were still 
receiving treatment. Dose-limiting toxic effects occurred in two (67%) of three 
patients who received 500 mg twice a day in the dose-escalation phase (grade 3 
acne [n=1] and intolerable grade 2 mucosal inflammation [n=1]); hence, doses of 
200 mg and 300 mg twice a day were selected for further assessment in the 
dose-expansion phase. Drug-related skin and gastrointestinal disorders of any 
grade occurred in 35 (92%) and 29 (76%) patients in the dose-expansion phase, 
respectively, and led to treatment discontinuation in one (4%) patient treated 
with 200 mg twice a day (grade 3 increase of alanine aminotransferase and 
aspartate aminotransferase) and two (13%) patients given 300 mg twice a day 
(grade 3 diarrhoea [n=1] and grade 3 skin rash [n=1]). Grade 3 skin and 
gastrointestinal disorders occurred in four (17%) and two (9%) patients, 
respectively, at a dose of 200 mg twice a day, and in six (40%) and four (27%) 
patients, respectively, at a dose of 300 mg twice a day. No grade 4 disorders 
arose. Other grade 3 disorders included hepatobiliary and renal disorders (three 
[13%] at 200 mg twice a day), asthenia (one [7%] at 300 mg twice a day), 
infections and infestations (one [7%] at 300 mg twice a day), and metabolism and 
nutrition disorders (one [4%] at 200 mg twice a day and one [7%] at 300 mg twice 
a day).
INTERPRETATION: AZD3759 at a dose of 200 mg twice daily showed a tolerable 
safety profile in patients with NSCLC and CNS metastases who had either never 
received a tyrosine kinase inhibitor or who had been pretreated with a tyrosine 
kinase inhibitor. The good penetration of the blood-brain barrier by AZD3759, 
and its promising clinical activity, support further assessment of this compound 
in studies.
FUNDING: AstraZeneca.