Jiyun Lee1, Hong Sook Kim1,2, Boram Lee3,4, Hee Kyung Kim1, Jong-Mu Sun1, Jin Seok Ahn1, Myung-Ju Ahn1, Keunchil Park1, Se-Hoon Lee1,3. 1. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 2. Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea. 3. Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Korea. 4. Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea.
Abstract
BACKGROUND: EGFR tyrosine kinase inhibitors (TKIs) have shifted the treatment paradigm in advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, patients who are treated with TKIs inevitably develop acquired resistance by mechanisms that are not fully understood. The purpose of this study was to investigate the mechanism of acquired resistance after treatment with third-generation EGFR TKIs. METHODS: Advanced EGFR-mutant NSCLC patients treated with olmutinib or osimertinib who underwent a rebiopsy before treatment or after progression were analyzed retrospectively. Targeted sequencing was performed on 113 specimens (77 pretreatment and 36 posttreatment, including 15 paired samples) obtained via tissue biopsy. RESULTS: A total of 98 patients were included, 53 (54%) of whom were treated with osimertinib and 45 (46%) of whom were treated with olmutinib. Of the 36 patients with posttreatment biopsies, EGFR-dependent mechanisms, including C797S and L718Q mutations, were observed in 10 (28%) patients: 29% (5/17) in the osimertinib group and 26% (5/19) in the olmutinib group. EGFR-independent mechanisms were detected in 21 patients (21/36, 58%): 65% (11/17) in the osimertinib group and 53% (10/19) in the olmutinib group. The disappearance of EGFR T790M was detected in 14 patients (39%); of these patients, 59% (10/17) were treated with osimertinib and 21% (4/19) were treated with olmutinib. Patients who lost the T790M mutation were more inclined to show EGFR-independent pathways as a secondary resistance mechanism. CONCLUSION: Resistance acquired after third-generation EGFR TKIs is associated with diverse pathways; however, treatment with osimertinib is primarily associated with a loss of EGFR T790M and the subsequent emergence of EGFR-independent resistance mechanisms.
BACKGROUND: EGFR tyrosine kinase inhibitors (TKIs) have shifted the treatment paradigm in advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, patients who are treated with TKIs inevitably develop acquired resistance by mechanisms that are not fully understood. The purpose of this study was to investigate the mechanism of acquired resistance after treatment with third-generation EGFR TKIs. METHODS: Advanced EGFR-mutant NSCLC patients treated with olmutinib or osimertinib who underwent a rebiopsy before treatment or after progression were analyzed retrospectively. Targeted sequencing was performed on 113 specimens (77 pretreatment and 36 posttreatment, including 15 paired samples) obtained via tissue biopsy. RESULTS: A total of 98 patients were included, 53 (54%) of whom were treated with osimertinib and 45 (46%) of whom were treated with olmutinib. Of the 36 patients with posttreatment biopsies, EGFR-dependent mechanisms, including C797S and L718Q mutations, were observed in 10 (28%) patients: 29% (5/17) in the osimertinib group and 26% (5/19) in the olmutinib group. EGFR-independent mechanisms were detected in 21 patients (21/36, 58%): 65% (11/17) in the osimertinib group and 53% (10/19) in the olmutinib group. The disappearance of EGFR T790M was detected in 14 patients (39%); of these patients, 59% (10/17) were treated with osimertinib and 21% (4/19) were treated with olmutinib. Patients who lost the T790M mutation were more inclined to show EGFR-independent pathways as a secondary resistance mechanism. CONCLUSION: Resistance acquired after third-generation EGFR TKIs is associated with diverse pathways; however, treatment with osimertinib is primarily associated with a loss of EGFR T790M and the subsequent emergence of EGFR-independent resistance mechanisms.
Authors: Francesco Passiglia; Paolo Bironzo; Valentina Bertaglia; Angela Listì; Edoardo Garbo; Giorgio Vittorio Scagliotti Journal: Transl Lung Cancer Res Date: 2022-05
Authors: Tyler S Beyett; Ciric To; David E Heppner; Jaimin K Rana; Anna M Schmoker; Jaebong Jang; Dries J H De Clercq; Gabriel Gomez; David A Scott; Nathanael S Gray; Pasi A Jänne; Michael J Eck Journal: Nat Commun Date: 2022-05-09 Impact factor: 17.694