Background: The resistance mechanisms to osimertinib encompass on-target molecular alterations, such as the well-known epidermal growth factor receptor (EGFR) C797S resistance mutation, and off-target molecular alterations, such as the high-frequency MET amplification, but there's no further clear-cut therapeutic option to date for these individuals yet. Here we reported a lung adenocarcinoma (LUAD) patient who progressed on osimertinib benefited from multiline combination target-therapy and obtained a long-term progression-free survival (PFS).Case Description: A 70-year-old Chinese woman without a smoking history presented with stage IV advanced LUAD harboring EGFR 19del and then developed EGFR T790M mutation after 6-month treatment of gefitinib [a first-generation EGFR tyrosine kinase inhibitor (TKI)]. Osimertinib (a third-generation EGFR TKI) was immediately initiated, and the PFS was 11 months. After disease progression, next-generation sequencing (NGS) identified MET amplification, in addition to EGFR 19del. Combination therapy of osimertinib and cabozantinib (a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2)/capmatinib (a MET inhibitor) was administrated to the patient and the best overall response (OR) was stable disease (SD) with the PFS of 10 months. NGS detected the emergence of novel mutations EGFR S784Y and EGFR L799Q, together with EGFR C797S and all in cis with EGFR T790M, and retention of EGFR 19 del. The patient received pemetrexed (a chemotherapy drug) and bevacizumab (a VEGFR inhibitor) and achieved a partial response (PR). After 6 months of PFS, combination therapy of brigatinib (an inhibitor of ALK and EGFR) and cetuximab (an EGFR inhibitor) was initiated and the patient achieved a long-term PFS of 18 months and SD. Her overall survival (OS) was 51 months.Conclusions: This case highlights the importance of NGS on repeated biopsy which could offer better treatment options.