title: Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: iMED Oncology, AstraZeneca, Macclesfield, United Kingdom. Darren.Cross@astrazeneca.com pbdmpk@gmail.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Ballard
authors.affiliation: iMED Oncology, AstraZeneca, Cambridge, United Kingdom.
authors.forename: James W T
authors.initials: JW
authors.lastname: Yates
authors.affiliation: Asia and Emerging Markets iMED, AstraZeneca, Shanghai, China.
authors.forename: Zhenfan
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.affiliation: National Taiwan University Hospital, Taipei City, Taiwan.
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
authors.affiliation: Global Medicines Development, AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Mireille
authors.initials: M
authors.lastname: Cantarini
authors.affiliation: iMED Oncology, AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Pickup
authors.affiliation: iMED Oncology, AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Angela
authors.initials: A
authors.lastname: Jordan
authors.affiliation: AstraZeneca, Cambridge, United Kingdom.
authors.forename: Mike
authors.initials: M
authors.lastname: Hickey
authors.affiliation: iMED Oncology, AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Grist
authors.affiliation: iMED Oncology, AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Box
authors.affiliation: AstraZeneca Translational Science Centre, Stockholm, Sweden. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Johnström
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Varnäs
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Malmquist
authors.affiliation: iMED Oncology, AstraZeneca, Gatehouse Park, Waltham, Massachusetts.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Thress
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: iMED Oncology, AstraZeneca, Cambridge, United Kingdom. Darren.Cross@astrazeneca.com pbdmpk@gmail.com.
authors.forename: Darren
authors.initials: D
authors.lastname: Cross
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D000077716:Afatinib; D000814:Aniline Compounds; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000517:prevention & control / Q000556:secondary; D018938:Caco-2 Cells; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
chemical_list: D000178:Acrylamides; D000077716:Afatinib; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077156:Gefitinib; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; C000596361:osimertinib; D007211:Indoles; C000589977:rociletinib; C512478:EGFR protein, human