Epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer is a dynamic entity, with tumor progression and resistance to tyrosine kinase inhibitors (TKIs) stemming from the accumulation of mutations over time and across different disease sites, leading to temporal and spatial heterogeneity.1 Based on the presence of EGFR T790M and the allelic background of C797S-T790M, four subgroups of patients after three-generation EGFR-TKI resistance can be distinguished: EGFR T790M-C797S in cis subtype; EGFR T790M-C797S in trans subtype; EGFR T790M-C797S in trans and cis subtype; and wild-type EGFR codon T790M but carrying the C797S mutation, hereinafter referred to as C797S-only.2 While treatment modalities have emerged for the different mutant subtypes, a recent study has found that the prognosis for the EGFR T790M-C797S in trans and cis subtype and the C797S-only subtype remains poor.2 This may be due to dynamic changes in EGFR clones under therapeutic stress. Here, we report data for the evolution of the EGFR mutation in a patient with non-small cell lung cancer during disease progression under the pressure of EGFR-TKI therapy. In the patient's latest genetic test, we identified the coexistence of five different EGFR mutations, including EGFR L858R, EGFR T790M-C797S both in cis and in trans and EGFR L718Q. Then she was treated with a triplet therapy of EGFR-TKIs, and stabled for three months.