Activity and safety of AZD3759 in EGFR-mutant non-small-cell lung cancer with CNS metastases (BLOOM): a phase 1, open-label, dose-escalation and dose-expansion study
Journal
The Lancet Respiratory Medicine
Journal Volume
5
Journal Issue
11
Pages
891-902
Date Issued
2017
Author(s)
Ahn M.-J
Kim D.-W
Cho B.C
Kim S.-W
Lee J.S
Ahn J.-S
Kim T.M
Kim H.R
John T
Kao S
Goldman J.W
Su W.-C
Natale R
Rabbie S
Harrop B
Overend P
Yang Z
Abstract
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. ? 2017 Elsevier Ltd
SDGs
Other Subjects
alanine aminotransferase; aspartate aminotransferase; azd 3759; bilirubin; creatinine; epidermal growth factor receptor kinase inhibitor; unclassified drug; antineoplastic agent; AZD3759; EGFR protein, human; epidermal growth factor receptor; piperazine derivative; quinazoline derivative; acne; adult; advanced cancer; aged; alanine aminotransferase blood level; Article; aspartate aminotransferase blood level; asthenia; Australia; bilirubin blood level; brain metastasis; cancer growth; controlled study; creatinine blood level; decreased appetite; diarrhea; disease association; disease severity; drug blood level; drug cerebrospinal fluid level; drug dose escalation; drug safety; drug tolerability; dry skin; eczema; female; folliculitis; furunculosis; human; infection; infestation; inflammation; leptomeningeal metastasis; major clinical study; male; meningeal metastasis; metabolic disorder; mouth inflammation; multicenter study; nail disease; non small cell lung cancer; nutritional disorder; open study; paronychia; phase 1 clinical trial; priority journal; pruritus; rash; side effect; South Korea; stomatitis; Taiwan; United States; vomiting; xerosis; central nervous system tumor; clinical trial; dose response; drug effect; genetics; lung tumor; meningioma; middle aged; mutation; non small cell lung cancer; pathology; secondary; treatment outcome; very elderly; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Australia; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Meningeal Neoplasms; Middle Aged; Mutation; Piperazines; Quinazolines; Receptor, Epidermal Growth Factor; Republic of Korea; Taiwan; Treatment Outcome; United States
Publisher
Lancet Publishing Group
Type
journal article