Resolving Resistance to Osimertinib Therapy using Afatinib in a NSCLC Patient with an EGFR L718Q Mutation

Abstract Objectives Previous studies have demonstrated EGFR L718Q as one of the resistant mechanisms to osimertinib. In vitro studies showed that EGFR L858R/L718Q mutant cancer cells were sensitive to second-generation EGFR-TKI. However, whether second-generation EGFR-TKI could offer equal therapeutic benefits clinically has not yet been reported. Materials and methods We performed capture-based sequencing on longitudinal plasma samples and pleural effusion samples obtained at various treatment milestones from an advanced lung adenocarcinoma patient undergoing targeted therapy. Results The EGFR-mutant patient underwent disease progression after 14 months of osimertinib administration. Targeted NGS sequencing identified a newly emerged EGFR L718Q mutation with remaining EGFR L858R and loss of T790M. Partial response was achieved one month after commencement of afatinib treatment; however, the patient experienced disease progression four months later with the emergence of a KRAS G12A mutation. Conclusions To the best of our knowledge, this is the first clinical evidence of afatinib’s efficacy targeting concomitant EGFR L858R and L718Q mutations after osimertinib resistance. We also demonstrate that EGFR L718Q might be a potential resistance mechanism.