Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity

Clin Cancer Res. 2016 Oct 15;22(20):5130-5140. doi: 10.1158/1078-0432.CCR-16-0399. Epub 2016 Jul 19.


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.

Publication types

  • Comparative Study

MeSH terms

  • Acrylamides / pharmacology
  • Afatinib
  • Aniline Compounds
  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Biological Transport / physiology
  • Blood-Brain Barrier / drug effects
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / prevention & control
  • Brain Neoplasms / secondary
  • Caco-2 Cells
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Disease Progression
  • Dogs
  • Drug Evaluation, Preclinical
  • Drug Resistance, Neoplasm
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • Female
  • Gefitinib
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Madin Darby Canine Kidney Cells
  • Male
  • Mice
  • Mice, SCID
  • Middle Aged
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / pharmacology
  • Quinazolines / pharmacology
  • Rats
  • Xenograft Model Antitumor Assays


  • Acrylamides
  • Aniline Compounds
  • Antineoplastic Agents
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Quinazolines
  • osimertinib
  • Afatinib
  • rociletinib
  • EGFR protein, human
  • ErbB Receptors
  • Gefitinib

Associated data