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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The term "disease" conjures a plethora of graphic imagery for many, and the use of drugs to combat symptoms and treat underlying pathology is at the core of modern medicine. However, the effects of the various gastrointestinal diseases, infections, co-morbidities and the impact of gastrointestinal surgery on the pharmacokinetic and pharmacodynamic behaviour of drugs have been largely overlooked. The better elucidation of disease pathology and the role of underlying cellular and molecular mechanisms have increased our knowledge as far as diagnoses and prognoses are concerned. In addition, the recent advances in our understanding of the intestinal microbiome have linked the composition and function of gut microbiota to disease predisposition and development. This knowledge, however, applies less so in the context of drug absorption and distribution for orally administered dosage forms. Here, we revisit and re-evaluate the influence of a portfolio of gastrointestinal diseases and surgical effects on the functionality of the gastrointestinal tract, their implications for drug delivery and attempt to uncover significant links for clinical practice.

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