Osimertinib, as a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), targeting EGFR exon 19 deletions, L858R, and T790M, has shown robust clinical efficacy and promising survival advantages in a subset of non-small cell lung cancer (NSCLC) patients. However, osimertinib-treated patients ultimately develop secondary resistance. Besides EGFR C797S mutation and EGFR amplification, a rare EGFR mutation, L718V, has been reported to confer osimertinib resistance in the literature, which is developed in about 8.0% of osimertinib-resistant NSCLC patients. Although the National Comprehensive Cancer Network or Chinese Society of Clinical Oncology NSCLC guidelines recommend radiotherapy, anti-angiogenesis therapy, chemotherapy and or immunotherapy for the treatment of NSCLC patients who acquire resistance to osimertinib, the feasible treatment options for patients harboring EGFR L718V remain elusive. There is an unmet need to develop effective strategies to treat EGFR L718X-positive NSCLC patients. Herein, we report that a lung adenocarcinoma patient with acquired EGFR L718V mutation-mediated resistance towards osimertinib derived durable response to the second-generation EGFR-TKI afatinib with a progression-free survival of 18 months and counting. Our work provides clinical evidence to administer afatinib in metastatic NSCLC patients who develop EGFR L718V at progression to osimertinib and paves the way for its potential clinical utilization.