NSCLC patients with EGFR mutations respond to EGFR-TKIs; however, the management of refractory tumors to EGFR-TKIs remains unclear. We demonstrated that repeated genetic testing might be useful for detecting resistance mechanisms as well as for decision-making in EGFR mutated NSCLC patients, following the emergence of resistance to the initial EGFR-TKIs. A 69-year-old man was diagnosed with lung adenocarcinoma with an EGFR exon 19 deletion. After tumor re-growth treated with erlotinib and chemotherapy, he was diagnosed with an SCLC transformation and administered chemotherapy to treat the SCLC. After the resistance of chemotherapy, the EGFR-T790M mutation by liquid biopsy was detected and treated him with osimertinib, which resulted in a clinical response.