Kenneth S Thress1, Vivien Jacobs2, Helen K Angell3, James Chih-Hsin Yang4, Lecia V Sequist5, Fiona Blackhall6, Wu-Chou Su7, Martin Schuler8, Jürgen Wolf9, Kathryn A Gold10, Mireille Cantarini11, J Carl Barrett1, Pasi A Jänne12. 1. IMED Oncology Translational Sciences, AstraZeneca, Gatehouse Park, Waltham, MA. 2. IMED Oncology Translational Sciences, AstraZeneca, Alderley Park, Macclesfield, United Kingdom. 3. IMED Oncology Translational Sciences, AstraZeneca, Cambridge, United Kingdom. 4. Department of Oncology, National Taiwan University Hospital, Taipei, Republic of China. 5. Department of Hematology, Massachusetts General Hospital, Boston, Massachusetts; Department of Oncology, Massachusetts General Hospital, Boston, Massachusetts. 6. Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester, United Kingdom; Department of Medical Oncology, The Christie National Health Service Foundation Trust, Manchester, United Kingdom. 7. National Cheng Kung University Hospital, Tainan, Republic of China. 8. Clinic for Internal Medicine (Tumor Research), West German Cancer Center, University Duisburg-Essen and German Cancer Consortium, Partner Site University Hospital Essen, Essen, Germany. 9. Clinic for Internal Medicine, Uniklinik Köln, Köln, Germany. 10. Thoracic Center, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 11. AstraZeneca, Alderley Park, Macclesfield, United Kingdom. 12. Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts. Electronic address: Pasi_Janne@dfci.harvard.edu.
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.
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.
Authors: Kari J Kurppa; Yao Liu; Ciric To; Tinghu Zhang; Mengyang Fan; Amir Vajdi; Erik H Knelson; Yingtian Xie; Klothilda Lim; Paloma Cejas; Andrew Portell; Patrick H Lizotte; Scott B Ficarro; Shuai Li; Ting Chen; Heidi M Haikala; Haiyun Wang; Magda Bahcall; Yang Gao; Sophia Shalhout; Steffen Boettcher; Bo Hee Shin; Tran Thai; Margaret K Wilkens; Michelle L Tillgren; Mierzhati Mushajiang; Man Xu; Jihyun Choi; Arrien A Bertram; Benjamin L Ebert; Rameen Beroukhim; Pratiti Bandopadhayay; Mark M Awad; Prafulla C Gokhale; Paul T Kirschmeier; Jarrod A Marto; Fernando D Camargo; Rizwan Haq; Cloud P Paweletz; Kwok-Kin Wong; David A Barbie; Henry W Long; Nathanael S Gray; Pasi A Jänne Journal: Cancer Cell Date: 2020-01-13 Impact factor: 31.743
Authors: Benjamin C Creelan; Tammie C Yeh; Sang-We Kim; Naoyuki Nogami; Dong-Wan Kim; Laura Q M Chow; Shintaro Kanda; Rosemary Taylor; Weifeng Tang; Mei Tang; Helen K Angell; Martine P Roudier; Marcelo Marotti; Don L Gibbons Journal: Br J Cancer Date: 2020-10-05 Impact factor: 7.640