Modulation of Biomarker Expression by Osimertinib: Results of the Paired Tumor Biopsy Cohorts of the AURA Phase I Trial
Kenneth S Thress, Vivien Jacobs, Helen K Angell, James Chih-Hsin Yang, Lecia V Sequist, Fiona Blackhall, Wu-Chou Su, Martin Schuler, Jürgen Wolf, Kathryn A Gold, Mireille Cantarini, J Carl Barrett, Pasi A Jänne, Kenneth S Thress, Vivien Jacobs, Helen K Angell, James Chih-Hsin Yang, Lecia V Sequist, Fiona Blackhall, Wu-Chou Su, Martin Schuler, Jürgen Wolf, Kathryn A Gold, Mireille Cantarini, J Carl Barrett, Pasi A Jänne
Abstract
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.
Trial registration: ClinicalTrials.gov NCT01802632.
Keywords: Biomarker; EGFR; NSCLC; Osimertinib; T790M.
Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Source: PubMed