Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity
Published version of a preprint
Abstract
Purpose: Approximately one-third of patients with non–small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions. Experimental Design: We performed preclinical assessments of brain penetration and activity of osimertinib (AZD9291), an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M resistance mutations, and other EGFR-TKIs in various animal models of EGFR-mutant NSCLC brain metastases. We also present case reports of previously treated patients with EGFRm-advanced NSCLC and brain metastases who received osimertinib in the phase I/II AURA study (NCT01802632). Results: Osimertinib demonstrated greater penetration of the mouse blood–brain barrier than gefitinib, rociletinib (CO-1686), or afatinib, and at clinically relevant doses induced sustained tumor regression in an EGFRm PC9 mouse brain metastases model; rociletinib did not achieve tumor regression. Under positron emission tomography micro-dosing conditions, [11C]osimertinib showed markedly greater exposure in the cynomolgus monkey brain than [11C]rociletinib and [11C]gefitinib. Early clinical evidence of osimertinib activity in previously treated patients with EGFRm-advanced NSCLC and brain metastases is also reported. Conclusions: Osimertinib may represent a clinically significant treatment option for patients with EGFRm NSCLC and brain metastases. Further investigation of osimertinib in this patient population is ongoing. Clin Cancer Res; 22(20); 5130–40. ©2016 AACR.
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Osimertinib is able to effectively penetrate the blood-brain barrier, providing a good therapeutic effect on BMS in advanced NSCLC, and significantly extending progression-free survival in cases of central nervous system metastases.
“In addition, multiple studies have demonstrated that osimertinib is able to effectively penetrate the blood-brain barrier,134,135 providing a good therapeutic effect on BMS in advanced NSCLC, and significantly extending progression-free survival in cases of central nervous system (CNS) metastases.136,137”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [134]
Osimertinib is an oral irreversible EGFR-TKI selective for EGFR and T790M resistance mutations with CNS activity.
“Osimertinib is an oral, irreversible EGFR-TKI that is selective for both EGFR and T790M resistance mutations with activity in the central nervous system (CNS).19–21”
From Osimertinib or Platinum–Pemetrexed in <i>EGFR</i> T790M–Positive Lung Cancer (2017) · cites this paper as [20]
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- Authors
- Ballard, P., Yates, J. W. T., Yang, Z., Kim, D.-W., Yang, J. C.-H., Cantarini, M., Pickup, K., Jordan, A., Hickey, M., Grist, M., Box, M., Johnström, P., Varnäs, K., Malmquist, J., Thress, K. S., Jänne, P. A., & Cross, D.
- Affiliations
- AstraZeneca (United Kingdom) (GB)
- 3Asia and Emerging Markets iMED, AstraZeneca, Shanghai, China.
- Seoul National University Hospital (KR)
- National Taiwan University Hospital (TW)
- Karolinska Institutet (SE)
- AstraZeneca (United States) (US)
- 11Dana-Farber Cancer Institute, Boston, Massachusetts.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2016-10-13
- Volume
- 22
- Issue
- 20
- Pages
- 5130-5140
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2494292000
- Cited by
- 718
- References
- 43
- Citations by year
- 2026: 34 · 2025: 61 · 2024: 64 · 2023: 62 · 2022: 77 · 2021: 91 · 2020: 72 · 2019: 89 · 2018: 93 · 2017: 66 · 2016: 8 · 2015: 1
- FWCI
- 76.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- AstraZeneca
- Karolinska Institutet
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Brain Metastases and Treatment
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- osimertinib, EGFR-mutant non-small cell lung cancer, brain metastases, EGFR tyrosine kinase inhibitors, blood-brain barrier penetration, brain penetration, gefitinib, rociletinib, afatinib, T790M mutation
- MeSH terms
- Gefitinib, Afatinib, Acrylamides, Aniline Compounds, Animals, Antineoplastic Agents, Biological Transport, Blood-Brain Barrier, Brain Neoplasms, Carcinoma, Non-Small-Cell Lung, Dogs, Drug Evaluation, Preclinical, Female, Humans, Indoles, Lung Neoplasms, Male, Middle Aged, Piperazines, Pyrimidines, Quinazolines, Mice, SCID, Disease Progression, Caco-2 Cells, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Rats, Madin Darby Canine Kidney Cells, ErbB Receptors
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