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Epidermal growth factor receptor ( EGFR ) gene mutations play an important role in the treatment management of non-small cell lung cancer (NSCLC) patients. After a first- or second-generation EGFR tyrosine kinase inhibitor (TKI) therapy, the most common resistance mechanism involves the selection of a resistant clone carrying the exon 20 p.T790M point mutation. However, also for these patients, treated with a third-generation TKI (osimertinib) several mechanisms of acquired resistance are described. Here we report the case of a 68-year-old man with an EGFR exon 19 deletion treated with gefitinib in first line and osimertinib in second line besides on the presence of a p.T790M mutation, who developed an uncommon EGFR exon 20 p.L792Q point mutation at the progression to osimertinib, with the concomitant modification of the original sensitizing EGFR exon 19 deletion and the loss of p.T790M mutation., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2018.09.13). The series “Targeted Therapy and Non-Small Cell Lung Cancer: A New Era?” was commissioned by the editorial office without any funding or sponsorship. UM served as the unpaid Guest Editor of the series. The authors have no other conflicts of interest to declare., (2019 Translational Cancer Research. All rights reserved.)