• Peter Ballard, James W T Yates, Zhenfan Yang, Dong-Wan Kim, James Chih-Hsin Yang, Mireille Cantarini, Kathryn Pickup, Angela Jordan, Mike Hickey, Matthew Grist, Matthew Box, Peter Johnström, Katarina Varnäs, Jonas Malmquist, Kenneth S Thress, Pasi A Jänne, and Darren Cross.
• iMED Oncology, AstraZeneca, Macclesfield, United Kingdom. Darren.Cross@astrazeneca.com pbdmpk@gmail.com.
• Clin Cancer Res. 2016 Oct 15; 22 (20): 5130-5140.

PurposeApproximately 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 DesignWe 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).ResultsOsimertinib 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.ConclusionsOsimertinib 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.©2016 American Association for Cancer Research.

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