Acquired EGFR L718V Mutation as the Mechanism for Osimertinib Resistance in a T790M-Negative Non-Small-Cell Lung Cancer Patient.

BACKGROUND: The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib has demonstrated significant clinical benefit in EGFR T790M-mutated non-small-cell lung cancer (NSCLC) patients, with extensive research focusing on the mechanisms of acquired resistance. However, there are limited studies on second-line treatment options for EGFR T790M-negative patients and their clinical outcomes.
OBJECTIVE: We aimed to provide better understanding of the resistance mechanisms to osimertinib treatment as well as the therapeutic options for T790M-negative NSCLC patients. PATIENTS AND METHODS: In this case study, a patient was admitted and diagnosed with stage IV lung adenocarcinoma. Tissue specimen and blood samples collected from baseline and during the course of treatment were subjected to genomic profiling of 416 cancer-related genes using hybridization capture-based targeted next-generation sequencing.
RESULTS: Following progression on initial chemoradiotherapy, the patient received EGFR TKI treatment with icotinib upon the confirmation of carrying an EGFR L858R mutation. However, the patient was negative for the EGFR T790M mutation when he became resistant to icotinib. The patient received subsequent osimertinib treatment and achieved a progression-free survival (PFS) of 10.4 months. Upon disease progression, an acquired L718V mutation within the EGFR kinase domain was found, which may interfere with the binding of osimertinib to the kinase domain and confer resistance regardless of T790M status.
CONCLUSIONS: This is the first clinical evidence of EGFR L718V giving rise to osimertinib resistance in a T790M-negative context, which provides valuable information for the discovery of resistance mechanisms to osimertinib and guidance for personalized NSCLC treatment in such patients.