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, [11 C]osimertinib showed markedly greater exposure in the cynomolgus monkey brain than [11 C]rociletinib and [ 11 C]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.
Background-Atherosclerotic plaque rupture is usually a consequence of inflammatory cell activity within the plaque.Current imaging techniques provide anatomic data but no indication of plaque inflammation. The current "gold standard" imaging technique for atherosclerosis is x-ray contrast angiography, which provides high-resolution definition of the site and severity of luminal stenoses, but no information about plaque inflammation.There is a need to quantify plaque inflammation to predict the risk of plaque rupture and to monitor the effects of atheroma-modifying therapies. This is important because recent experimental and clinical studies strongly suggest that hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) promote plaque stability by decreasing plaque macrophage content and activity without substantially reducing plaque size and therefore angiographic appearance. 4 [ 18 F]-fluorodeoxyglucose ( 18 FDG) is a glucose analogue that is taken up by cells in proportion to their metabolic activity. 5 We tested the hypothesis that plaque inflammation could be visualized and quantified non-invasively using 18 FDG-PET in patients with symptomatic carotid artery disease. Methods Patient RecruitmentWe recruited 8 patients who had experienced a recent carotidterritory transient ischemic attack and had an internal carotid artery stenosis of at least 70%. Patients were excluded if they had either carotid artery occlusion or diabetes. The study protocol was approved by the local ethics committee and the UK Administration of Radioactive Substances Advisory Committee. All patients gave written informed consent. PET ProtocolPET was carried out using a GE Advance PET scanner (GE Medical Systems). We administered 370 MBq 18 FDG intravenously over 60 seconds. PET images (as 4ϫ5 minute frames) were acquired in 3D mode, at 190 (Ϯ6) minutes after 18 FDG administration. This timepoint was chosen after preliminary dynamic studies indicated that late imaging provided optimal contrast between the 18 FDG concentration in plaque and the main background region, namely blood.A stiff cervical collar was worn to minimize patient movement. PET images were reconstructed using the 3D reprojection algorithm, 6 with corrections applied for attenuation, dead time, scatter, and random coincidences. Rigid body co-registration with CT was performed, using a combination of fiducial markers and internal anatomical landmarks (spinal cord and muscles of the jaw and neck). This resulted in co-registration typically to within 1 mm in each dimension around the stenosis. To estimate plaque 18 FDG concentration, three-dimensional volumes of interest (VOI) were drawn CT ProtocolUsing a GE Hispeed Advantage CT scanner (GE Medical Systems), helical contrast CT angiograms were acquired from skull base to 3 cm below the level of the carotid bifurcation. Plaque HistologyAfter imaging, carotid endarterectomy samples from all 8 patients imaged were fixed and stained with hematoxylin and eosin. Immunohistochemistry was performed using anti-macr...
Preclinical data highlight AZD1390 as a potentially powerful new therapy to enhance brain tumor patient responses to radiotherapy.
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