Preclinical Comparison of Osimertinib with Other EGFR TKIs in EGFR Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity
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. (c)2016 AACR.
Clinical Cancer Research