Research ArticleCancer

AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases

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Science Translational Medicine  07 Dec 2016:
Vol. 8, Issue 368, pp. 368ra172
DOI: 10.1126/scitranslmed.aag0976

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Crossing the BBB to pursue tumors

Non–small-cell lung cancer remains difficult to treat despite recent advances in targeted therapy. One reason for this is metastasis to the central nervous system. Drugs that inhibit the epidermal growth factor receptor (EGFR), a common target in this cancer, do not effectively penetrate the blood-brain barrier, which means that metastatic tumors can grow unchecked once they spread to the brain or spinal cord. Yang et al. have now developed a drug that not only can inhibit EGFR as effectively as clinically approved therapeutics but also can cross the blood-brain barrier to target metastases. This drug shows promising effectiveness in multiple different mouse models, as well as signs of antitumor activity in human patients.


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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