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Ref Type Journal Article
PMID (27928026)
Authors Yang Z, Guo Q, Wang Y, Chen K, Zhang L, Cheng Z, Xu Y, Yin X, Bai Y, Rabbie S, Kim DW, Ahn MJ, Yang JC, Zhang X
Title AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases.
Journal Vol Issue Date Pages Journal Short Title
Science translational medicine 8 368 2016 Dec 07 368ra172 Sci Transl Med
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
AZD3759 AZD3759 0 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
AZD3759 AZD-3759|zorifertinib EGFR Inhibitor (Pan) 61 AZD3759 inhibits EGFR, potentially resulting in decreased growth of EGFR-expressing tumors and is also able to fully penetrate the blood-brain barrier (PMID: 27928026, PMID: 29430654).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References