We report a case with a novel ALK-R3HDM1 and EML4-ALK dual fusion that might be a delicate mechanism for the acquired resistance of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI). A patient with EGFR L858R lung adenocarcinoma developed disease progression after 72.7 months of gefitinib therapy; rebiopsy was done, and next-generation sequencing showed the disappearance of the previous EGFR mutations. In addition, two new ALK fusions emerged, indicating that the emergence of dual ALK rearrangement may be the underlying mechanism of gefitinib resistance. The patient exhibits an excellent response to second-line alectinib treatment with a significant clinical benefit and a high quality of life. Finally, we summarized previous studies in which ALK fusion is a required resistance mechanism to EGFR-TKI.