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
Abstract
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 passive permeability (29.5x10-6 cm/sec) and is not a substrate of the efflux transporters Pgp or BCRP at the BBB. In vivo, AZD3759 reached distribution equilibrium in rats, mice and monkey (Kpuu,brain and Kpuu,CSF > 0.5), suggesting BBB penetration. In the BM model, AZD3759 induced profound tumor regression and significantly improved animal survival. A correlation between free brain exposure and pEGFR modulation was also detected in tumor tissues on AZD3759 treatment. To date, 4 patients with measurable BM have been enrolled into 50mg bid and 100mg bid cohorts (3 patients and 1 patient, respectively). In the 2 evaluable patients with BM, one unconfirmed PR and one SD in the brain have been observed. Ctrough CSF concentrations of these patients were 7.7 and 6nM, respectively, close to the pEGFR IC50 of AZD3759. No DLTs were reported to date and two cases of grade I skin rash were observed. Conclusions: Preclinical and initial clinical evidence indicate that AZD3759 is an EGFR TKI with BBB penetration with potential to treat EGFRm+ NSCLC patients with BM. Updated clinical data will be shared at the meeting. Clinical trial information: NCT02228369.
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Newer-generation EGFR TKIs, including osimertinib and AZD3759, have been reported to show activity against leptomeningeal disease.
“More recently, newer-generation EGFR TKIs have been reported to show activity against leptomeningeal disease (e.g., osimertinib 122 and the CNS-penetrant EGFR TKI AZD3759).73”
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“NSCLC (BLOOM; NCT02228369), AZD3759 was well tolerated and was associated with intracranial tumor shrinkage (42).”
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BackgroundInfluential
- Authors
- Kim, D.-W., Yang, J. C.-H., Chen, K., Cheng, Z., Yin, L., Martin, P. D., Yang, Z., Jiang, H., & Ahn, M.-J.
- Affiliations
- Seoul National University Hospital (KR)
- National Taiwan University (TW)
- Innovation Center China, Innovative Medicines and Early Development, AstraZeneca, Shanghai, China
- Innovation Center China, Innovative Medicines & Early Development, AstraZeneca, Shanghai, China
- Innovation Center China, Innovative Medicines & Early Development, Shanghai, China
- AstraZeneca, Alderley Park, Macclesfield, United Kingdom
- AstraZeneca China, Shanghai, China
- Samsung Medical Center (KR)
- Venue
- Journal of Clinical Oncology
- Published
- 2015-05-20
- Volume
- 33
- Issue
- 15_suppl
- Pages
- 8016-8016
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2614546142
- Cited by
- 33
- References
- 0
- Citations by year
- 2024: 1 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 8 · 2016: 12 · 2015: 2
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Brain Metastases and Treatment
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- EGFR tyrosine kinase inhibitors, blood-brain barrier penetration, non-small cell lung cancer, brain metastases, EGFR mutation, P-glycoprotein, ABCG2, efflux pumps, CNS penetration, brain tumor models, cerebrospinal fluid concentration, drug safety and tolerability
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