Herein, we firstly report that coexistence of a novel histone methyltransferase (SETD2)-ALK, EML4-ALK double-fusion is sensitive to alectinib as first-line therapy, and response to immunotherapy combined with chemotherapy after resistant. The patient responded to alectinib as a first-line therapy and achieved progression-free survival (PFS) for 26 months...this is the first report of an advanced and metastatic lung adenocarcinoma patient harbored EML4-ALK and SETD2-ALK double-fusion variation and successively response to alectinib...