By serial genetic tests of circulating tumor DNA (ctDNA) from peripheral blood and sediment cell genomic DNA (PE-sDNA) from pleural effusion, a novel chronological combination treatment of icotinib, osimertinib, and crizotinib was adopted for the present genetic mutations, including <i>EGFR</i> exon 19 deletion, <i>EGFR</i> p.T790M, and <i>MET</i> amplification. The gene discussed is EGFR; the disease is Pleural effusion.