title: AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases.
abstract: 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.
authors.affiliation: Asia Innovative Medicines, AstraZeneca, Shanghai 201203, China.
authors.forename: Zhenfan
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Asia Innovative Medicines, AstraZeneca, Shanghai 201203, China.
authors.forename: Qiuli
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Asia Innovative Medicines, AstraZeneca, Shanghai 201203, China.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Asia Innovative Medicines, AstraZeneca, Shanghai 201203, China.
authors.forename: Kan
authors.initials: K
authors.lastname: Chen
authors.affiliation: Asia Innovative Medicines, AstraZeneca, Shanghai 201203, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Asia Innovative Medicines, AstraZeneca, Shanghai 201203, China.
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Asia Innovative Medicines, AstraZeneca, Shanghai 201203, China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Asia Innovative Medicines, AstraZeneca, Shanghai 201203, China.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Yin
authors.affiliation: Asia Innovative Medicines, AstraZeneca, Shanghai 201203, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Early Clinical Development, AstraZeneca, Cambridge, Hertz SG8 6EE, U.K.
authors.forename: Sarit
authors.initials: S
authors.lastname: Rabbie
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, South Korea.
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Irwon-ro, Gangnam-gu, Seoul 135-710, South Korea.
authors.forename: Myung-Ju
authors.initials: MJ
authors.lastname: Ahn
authors.affiliation: Department of Oncology, National Taiwan University Hospital and National Taiwan University Cancer Center, 7, Chung-Shan South Road, Taipei 10002, Taiwan, ROC.
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
authors.affiliation: Asia Innovative Medicines, AstraZeneca, Shanghai 201203, China. xiaolin.zhang@astrazeneca.com.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use*; D013116:Spinal Cord / Q000473:pathology
chemical_list: C000604577:AZD3759; D000970:Antineoplastic Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors