Fluctuation of Acquired Resistance Mutations and Re-Challenge with EGFR TKI in Metastatic NSCLC: A Case Report

Osimertinib has become the preferred first-line therapy for epidermal growth factor receptor (EGFR) mutation-positive metastatic non-small cell lung cancer (NSCLC) in recent years. Originally, it was approved for second-line treatment after epidermal growth factor receptor EGFR tyrosine kinase inhibitors (TKIs) of the first and second generations had failed and EGFR T790M had emerged as a mode of resistance. Osimertinib itself provokes a wide array of on- and off-target molecular alterations that can limit therapeutic success. Liquid biopsy ctDNA (circulating tumor DNA) analysis by hybrid capture (HC) next-generation sequencing (NGS) can help to identify alterations in a minimally invasive way and allows for the detection of common as well as rare resistance alterations. We describe a young female patient who was initially diagnosed with metastatic EGFR L858R-positive NSCLC. She received EGFR TKI therapy at different timepoints during the course of the disease and developed sequential EGFR resistance alterations (EGFR T790M and C797S). In the course of her disease, resistance alteration became undetectable, and the tumor was successfully rechallenged with the original first-generation EGFR TKI as well as osimertinib and altogether showed prolonged response despite a prognostically negative TP53 alteration. To date, the patient has been alive for more than seven years, though initially diagnosed with a heavy metastatic burden.