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.

Recent evidence suggested that cancer patient-derived explant mouse models can maintain certain pathological and molecular features of the original diseases/patients, which offers potential opportunities for testing “personalized medicine” preclinically. We have established over 20 HCC explant models by directly implanting fresh tumor tissues derived from HCC patients into immunodeficient mice. To assess whether these HCC models would represent HCC clinical characteristics and individual patient diversity, we have compared the molecular profiles of these xenografts with their corresponding patient tissues (F0). This included gene copy variation by aCGH, mRNA expression by Affymetrix and gene mutations as well as protein expressions by immunohistochemistry. In addition, we also assessed the stability of the molecular profiles of various models by comparing different passages (F1-F10). Analysis of the data revealed that the xenograft tumors maintain fundamental genotypic features of the original patients, which recapitulate the genetic diversity of the HCC. The assessment on the stability of molecular profiles of individual model based on Pearson correlation coefficient (r) of aCGH data from different passages (F1-F10) suggests that those HCC models are very stable across passages (r > 0.8). In addition, no dramatic changes of the known molecular and histological features were observed throughout serial passages. AFP mRNA expressions of various models by Affymetrix are very different and mirror patient clinical data very well. Amplification of myc and cycline D1 and deletion of DLC1 and FHIT were detected in different individual models, as well as in corresponding patient HCC tissues, and those aberrations are consistent throughout the passages within various individual model. Furthermore, passages of the tumors in successive cohorts of mice did not change their sensitivity to sorafenib. In summary, we have developed preclinical HCC patient-derived explant models that can be used to further understand the disease and develop mechanism-based anti-cancer drugs for treatment of HCC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2412. doi:10.1158/1538-7445.AM2011-2412

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 >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 >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.