Tyrosine kinase inhibitor (TKI) has greatly improved the survival of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-TKI sensitive mutations. However, TKI resistance constantly occur, although multiple lines of different generations of TKIs are adopted during the progression. For example, in the case when T790M, which is the most common resistance mechanism of first generation TKIs, occurs, alteration to osimertinib (the third generation TKI) could always be effective. Unfortunately, some cases gradually become resistant even to osimertinib leaving limited therapy choice for clinical practitioners. Few cases have been reported in the situation after EGFR tertiary mutations occurred, such as C797S, G724S, etc. Herein, we report the first clinical evidence that sequential therapy with erlotinib, osimertinib, afatinib plus endostar, brigatinib plus cetuximab, almonertinib, almonertinib plus afatinib achieved long-term control in a NSCLC patient demonstrating EGFR 19Del/T790M/G724S/ cis-C797S evolution in response to TKI treatment. EGFR targeted therapy introduced successful management for more than 36 months until now. ctDNA NGS was performed at the time of important clinical event. The EGFR 19Del was discovered in October 2017, and erlotinib was administered for 10 months with PR in the beginning. Then T790M was detected and osimertinib was used for 9 months with SD condition. Subsequently, EGFR G724S was identified in ctDNA with the remaining 19Del and loss of T790M. Afatinib plus endostar was administered and PR was achieved after 1.5 months. PD occurred 6 months later with the emergence of EGFR cis-C797S. Then brigatinib plus cetuximab was chosen and lasted for 4 months with the best response of SD. And then EGFR 19Del and T790M were still detected with loss of G724S and C797S. Almonertinib, another third-generation TKI, was administered for 3 months with SD condition. Finally, 19Del/T790M/G724S/cis-C797S recurred, and whole dose of almonertinib plus afatinib was prescribed until now with a PR at 2 months until now. The side effect was acceptable during the whole period of therapies. Plasma ctDNA NGS provided information of EGFR mutation evolution and inform appropriate therapy regimen during the progression.