Cis-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature

Abstract

Samuel J Klempner,1,2 Pareen Mehta,3 Alexa B Schrock,4 Siraj M Ali,4 Sai-Hong Ignatius Ou5 1The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 3Department of Radiology, The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 4Clinical Development, Foundation Medicine, Inc., Cambridge, MA, USA; 5Department of Medicine-Hematology/Oncology, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA, USA Abstract: Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is a universal event and limits clinical efficacy. The third-generation EGFR inhibitor osimertinib is active in EGFR-mutant/T790M positive non-small-cell lung cancer. Mechanisms of acquired resistance are emerging, and here we describe a cis-oriented solvent-front EGFR G796S mutation as the resistance mechanism observed in a progression biopsy and circulating tumor DNA (ctDNA) from a patient with initial response followed by progression on osimertinib. This is one of the earliest reports of a sole solvent-front tertiary EGFR mutation as a resistance mechanism to osimertinib. Our case suggests a monoclonal resistance mechanism. We review the importance of the solvent-front residues across TKIs and describe known osimertinib resistance mechanisms. We observe that nearly all clinical osimertinib-resistant tertiary EGFR mutations are oriented in cis with EGFR T790M. This case highlights the importance of mutations affecting EGFR kinase domains and supports the feasibility of broad panel ctDNA assays for detection of novel acquired resistance and tumor heterogeneity in routine clinical care. Keywords: EGFR G796, lung cancer, ctDNA, resistance, osimertinib, T790M

Keywords

• EGFR G796
• lung cancer
• ctDNA
• resistance
• osimertinib
• T790M