Objectives: There is some controversy surrounding theBRAFV600E mutation in patients with lung adenocarcinomas. Although the BRAFV600E mutation is sensitive to BRAF inhibitors, the efficiency of these inhibitors on patients harboring an EGFRL858R/del19/EGFRT790M/BRAFV600E pattern remains unknown. Materials and methods: Here, we presented the case of a patient with initial response followed by progression on osimertinib. Resistance mutations (EGFRT790M, EGFRC797S, BRAFV600E, MET amp and HER2 amp) were assessed in the tissue or plasma DNA using NGS and digital droplet PCR at progression and during osimertinib treatment. Results: Resistance to osimertinib coincided with the emergence of an additional tumor cell subpopulation carrying the knownBRAFV600E resistance mutation. The patient exhibited two tumor subclones (EGFRdel19/T790M and BRAFV600E) that displayed distinct responses to successive tyrosine kinase inhibitors. Conclusion: We report the first successful example of using sequential treatment with dabrafetinib/trametinib and osimertinib. Our finding provided that unique tumor biopsies deliver incomplete genetic information, and highlighted the complementary role of circulating tumor DNA to tissue biopsies and CT-scans to efficiently monitor response to osimertinib.