Modulation of Biomarker Expression by Osimertinib: Results of the Paired Tumor Biopsy Cohorts of the AURA Phase I Trial

Introduction: Osimertinib is an oral, potent, irreversible EGFR tyrosine kinase inhibitor (TKI) selective for EGFR TKI and T790M resistance mutations. To enhance understanding of osimertinib's mechanism of action, we aimed to evaluate the modulation of key molecular biomarkers after osimertinib treatment in paired clinical samples from the phase I AURA trial. Methods: Paired tumor biopsy samples were collected before the study and after 15 plus or minus 7 days of osimertinib treatment (80 or 160 mg daily). Clinical efficacy outcomes were assessed according to whether viable paired biopsy samples could be collected; safety was also assessed. Immunohistochemical analyses assessed key pathway and tumor/immune-relevant markers (phospho-EGFR, phospho-S6, phospho-AKT, programmed death ligand 1, and CD8), with samples scored by image analysis or a pathologist blinded to treatment allocation. Results: Predose tumor biopsy samples were collected from 61 patients with EGFR T790M tumors; 29 patients had no viable postdose biopsy sample because of tumor regression or insufficient tumor sample. Evaluable predose and postdose tumor biopsy samples were collected from 24 patients. Objective response rate (ORR) and median progression-free survival (mPFS) were improved in patients from whom a postdose biopsy sample could not be collected (ORR 62% and mPFS 9.7 months [p = 0.027]) compared with those from whom paired samples were collected (ORR 29% and mPFS 6.6 months). Osimertinib modulated key EGFR signaling pathways and led to increased immune cell infiltration. Conclusions: Collection of paired biopsy samples was challenging because of rapid tumor regression after osimertinib treatment, highlighting the difficulties of performing on-study biopsies in patients treated with highly active drugs. (C) 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved

Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer

Purpose The AURA study (ClinicalTrials.gov identifier: NCT01802632) included two cohorts of treatment-naive patients to examine clinical activity and safety of osimertinib (an epidermal growth factor receptor [EGFR] -tyrosine kinase inhibitor selective for EGFR-tyrosine kinase inhibitor sensitizing [EGFRm] and EGFRT790M resistance mutations) as first-line treatment of EGFR-mutated advanced non-small-cell lung cancer (NSCLC). Patients and Methods Sixty treatment-naive patients with locally advanced or metastatic EGFRm NSCLC received osimertinib 80 or 160 mg once daily (30 patients per cohort). End points included investigator-assessed objective response rate (ORR), progression-free survival (PFS), and safety evaluation. Plasma samples were collected at or after patients experienced disease progression, as defined by Response Evaluation Criteria in Solid Tumors (RECIST), to investigate osimertinib resistance mechanisms. Results At data cutoff (November 1, 2016), median follow-up was 19.1 months. Overall ORR was 67% (95% CI, 47% to 83%) in the 80-mg group, 87% (95% CI, 69% to 96%) in the 160-mg group, and 77% (95% CI, 64% to 87%) across doses. Median PFS time was 22.1 months (95% CI, 13.7 to 30.2 months) in the 80-mg group, 19.3 months (95% CI, 13.7 to 26.0 months) in the 160-mg group, and 20.5 months (95% CI, 15.0 to 26.1 months) across doses. Of 38 patients with postprogression plasma samples, 50% had no detectable circulating tumor DNA. Nine of 19 patients had putative resistance mechanisms, including amplification of MET (n = 1); amplification of EGFR and KRAS (n = 1); MEK1, KRAS, or PIK3CA mutation (n = 1 each); EGFR C797S mutation (n = 2); JAK2 mutation (n = 1); and HER2 exon 20 insertion (n = 1). Acquired EGFRT790M was not detected. Conclusion Osimertinib demonstrated a robust ORR and prolonged PFS in treatment-naive patients with EGFRm advanced NSCLC. There was no evidence of acquired EGFRT790M mutation in postprogression plasma samples. (C) 2017 by American Society of Clinical Oncology

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, [C-11] osimertinib showed markedly greater exposure in the cynomolgus monkey brain than [C-11] rociletinib and [C-11] 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. (C) 2016 AACR.

Soil analysis in discussions of agricultural feasibility for ancient civilizations: A critical review and reanalysis of the data and debate from Chaco Canyon, New Mexico

<div><p>Questions about how archaeological populations obtained basic food supplies are often difficult to answer. The application of specialist techniques from non-archaeological fields typically expands our knowledge base, but can be detrimental to cultural interpretations if employed incorrectly, resulting in problematic datasets and erroneous conclusions not easily caught by the recipient archaeological community. One area where this problem has failed to find resolution is Chaco Canyon, New Mexico, the center of one of the New World’s most vibrant ancient civilizations. Discussions of agricultural feasibility and its impact on local population levels at Chaco Canyon have been heavily influenced by studies of soil salinity. A number of researchers have argued that salinized soils severely limited local agricultural production, instead suggesting food was imported from distant sources, specifically the Chuska Mountains. A careful reassessment of existing salinity data as measured by electrical conductivity reveals critical errors in data conversion and presentation that have misrepresented the character of the area’s soil and its potential impact on crops. We combine all available electrical conductivity data, including our own, and apply multiple established conversion methods in order to estimate soil salinity values and evaluate their relationship to agricultural productivity potential. Our results show that Chacoan soils display the same salinity ranges and spatial variability as soils in other documented, productive fields in semi-arid areas. Additionally, the proposed large-scale importation of food from the Chuska Mountains region has serious social implications that have not been thoroughly explored. We consider these factors and conclude that the high cost and extreme inflexibility of such a system, in combination with material evidence for local agriculture within Chaco Canyon, make this scenario highly unlikely. Both the soil salinity and archaeological data suggest that there is no justification for precluding the practice of local agriculture within Chaco Canyon.</p></div

Estimated time and labor efforts for Chaco residents to transport maize to the canyon based on varying population sizes, carrying capacities, and travel times.

<p>Round trip lengths are based on a distance of 85 km between Chaco Canyon and the Chuska Mountains. Six-day trips were suggested by Benson [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0198290#pone.0198290.ref033" target="_blank">33</a>] based on traveling 26.67 km/day, while 9.5 and 27 days—assuming a speed of 18 km/day and 6.34 km/day respectively—were derived from travel times determined by Malville [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0198290#pone.0198290.ref137" target="_blank">137</a>] and reported by Windes and McKenna ([<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0198290#pone.0198290.ref142" target="_blank">142</a>] p136). Drennan [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0198290#pone.0198290.ref132" target="_blank">132</a>] used loads of 20 and 50 kilograms in his studies of long distance transport, both of which are paired with Benson’s assertion that the trip could be made in six days. The second two weight estimates derive from Malville [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0198290#pone.0198290.ref131" target="_blank">131</a>], as reported in Windes and McKenna ([<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0198290#pone.0198290.ref142" target="_blank">142</a>] p136) and are directly linked to the trip lengths determined in the first column. Number of trips and travel days are rounded based on the completion of an entire trip.</p

General location of Chaco Canyon Cultural Historical Park in relation to the Chuska Mountains.

<p>Four Corners is in upper left corner of figure at intersection of black state lines. Only selected major drainages contributing to or near Chaco Wash are represented. Black triangles are the three closest pedons to Chaco Canyon that have been sampled by the USDA.</p