Abstract LB-217: Antitumor activities of AZD3759, a novel EGFR inhibitor with excellent penetration across central nervous system (CNS), in preclinical animal models
Authors: Yang Zhenfan , Guo Qiuli , Wang Yingchun , Zhang Lin , Chen Kan , Cheng Ziqiang , Yin Xiaolu , Zhang Xiaolin 
Published: July 2016

Abstract
Background: NSCLC with central nervous system (CNS) metastases become an increasing unmet medical need due to lack of effective treatment. AZD3759 was the first EGFR inhibitor primarily designed to effectively across CNS to treat these diseases. AZD3759 is currently being developed in a Phase I/II study in patients with brain metastasis (BM) and leptomenigeal metastasis (LM). Here we reported the evaluation of anti-tumor activities of AZD3759 in a variety of animal models, which potentially help clinical study design. Materials and Methods: Four types of animal models, including subcutaneous (SC), brain metastasis (BM), leptomeningeal metastasis (LM), and BM prevention models, were established. AZD3759 was administered to the animals at different doses according study design. Erlotinib was used as a control. Tumor growth was monitored by measuring tumor size (SC) or luciferin signals using Xenogen imaging system. Animal survival was also recorded. Blood, brain and cerebral spinal fluid (CSF) were collected to measure drug concentrations and assess histological changes as well as modulations of biomarkers. Results: In SC models, AZD3759 demonstrated comparable efficacy with erlotinib (15mg/kg, clinical relevant dose) at the dose of 3.75mg/kg qd. With increased doses, more profound tumor regression was observed in AZD3759 treated animals. In BM model, luciferin signals in the brain kept increasing in erlotinib treated animals with 90% of animals died during 60 day study period. In contrast, AZD3759 induced significant tumor regression in the brain and 90% of animals were still alive by the end of study without obvious body weight loss. In LM model, tumor progressed more aggressively than BM, with 80% of animals died within 30 days in erlotinib group, while AZD3759 induced significant tumor regression in the brain and spinal cord, with 90% of animals survived longer than 30 days. In BM prevention model, erlotinib failed to prevent BM development in &gt;80% of animals, while no tumor formation was observed in AZD3759 treated animals by histological assessment. AZD3759 achieved free brain and CSF concentrations continuously covering pEGFR IC50 for &gt;7hr by a single dosing, with significant modulations of pEGFR, pERK and pAKT signals in tumor tissue/CSF tumor cells at the parallel timepoints with PK measurement. Conclusion: AZD3759 is a promising agent with potent anti-tumor activities and excellent CNS penetration for the treatment of NSCLC with CNS metastases.
Citation Format: Zhenfan Yang, Qiuli Guo, Yingchun Wang, Lin Zhang, Kan Chen, Ziqiang Cheng, Xiaolu Yin, Xiaolin Zhang. Antitumor activities of AZD3759, a novel EGFR inhibitor with excellent penetration across central nervous system (CNS), in preclinical animal models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-217.