Preclinical comparison of the blood-brain barrier permeability of osimertinib with other EGFR TKIs

Nicola Colclough*, Kan Chen, Peter Johnstrom, Nicole Strittmatter, Yumei Yan, Gail L. Wrigley, Magnus Schou, Richard Goodwin, Katarina Varnas, Sally J. Adua, Minghui Zhao, Don X. Nguyen, Gareth Maglennon, Peter Barton, James Atkinson, Lin Zhang, Annika Janefeldt, Joanne Wilson, Aaron Smith, Akihiro TakanoRyosuke Arakawa, Mikhail Kondrashov, Jonas Malmquist, Evgeny Revunov, Ana Vazquez-Romero, Mohammad Mahdi Moein, Albert D. Windhorst, Natasha A. Karp, Raymond V. Finlay, Richard A. Ward, James W.T. Yates, Paul D. Smith, Lars Farde, Zack Cheng, Darren A.E. Cross

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Purpose: Osimertinib is a potent and selective EGFR tyrosine kinase inhibitor (EGFR-TKI) of both sensitizing and T790M resistance mutations. To treat metastatic brain disease, blood–brain barrier (BBB) permeability is considered desirable for increasing clinical efficacy. Experimental Design: We examined the level of brain penetration for 16 irreversible and reversible EGFR-TKIs using multiple in vitro and in vivo BBB preclinical models. Results: In vitro osimertinib was the weakest substrate for human BBB efflux transporters (efflux ratio 3.2). In vivo rat free brain to free plasma ratios (Kpuu) show osimertinib has the most BBB penetrance (0.21), compared with the other TKIs (Kpuu ≤ 0.12). PET imaging in Cynomolgus macaques demonstrated osimertinib was the only TKI among those tested to achieve significant brain penetrance (Cmax %ID 1.5, brain/blood

Kp 2.6). Desorption electrospray ionization mass spectroscopy images of brains from mouse PC9 macrometastases models showed osimertinib readily distributes across both healthy brain and tumor tissue. Comparison of osimertinib with the poorly BBB penetrant afatinib in a mouse PC9 model of subclinical brain metastases showed only osimertinib has a significant effect on rate of brain tumor growth. Conclusions: These preclinical studies indicate that osimertinib can achieve significant exposure in the brain compared with the other EGFR-TKIs tested and supports the ongoing clinical evaluation of osimertinib for the treatment of EGFR-mutant brain metastasis. This work also demonstrates the link between low in vitro transporter efflux ratios and increased brain penetrance in vivo supporting the use of in vitro transporter assays as an early screen in drug discovery.

Original languageEnglish
Pages (from-to)189-201
Number of pages13
JournalClinical Cancer Research
Issue number1
Publication statusPublished - 1 Jan 2021

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