AZD3759, an EGFR inhibitor with blood brain barrier (BBB) penetration for the treatment of non-small cell lung cancer (NSCLC) with brain metastasis (BM): Preclinical evidence and clinical cases.

8016 Background: Increasing numbers of EGFRm+ NSCLC patients with BM have been reported, while effective treatment is lacking due to limited BBB penetration of currently available EGFR TKIs. Here we report preliminary data on AZD3759, an EGFR TKI with BBB penetration, for the treatment of BM. Methods: Preclinically, AZD3759 was assessed in both in vitro and in vivo assays, including MDCKII/Pgp and BCRP assays and CNS penetration in rats, mice and monkeys. PC-9 cells (Exon19Del) were transfected with luciferase and implanted through intra-carotid artery injection to establish a BM model in mice. Tumor growth was monitored weekly by a Xenogen Imaging System and the animal survival time was recorded. Blood and brain tissues were collected for pharmacokinetics, histopathology and pEGFR expression analyses. An ongoing, open label, dose escalation phase I study (NCT02228369; sponsor AstraZeneca) is investigating safety and tolerability of AZD3759 in patients with EGFRm+ advanced NSCLC. Results: AZD3759 has high...