Abstract: Precision therapy for non-small cell lung cancer (NSCLC) relies on accurate molecular subtyping. Driven by advances in genetic testing technologies and in-depth research on tumor-associated signaling pathways, an increasing number of genes and loci relevant to NSCLC treatment have been identified. Herein, we report a male NSCLC patient initially diagnosed at the age of 46 years. Next-generation sequencing (NGS) revealed two rare concurrent mutations: anaplastic lymphoma kinase (ALK) rearrangement combined with SMARCA4 deletion. The patient has been followed up for more than seven years since first presenting to our hospital in 2018. During 7 years of targeted therapy, the pathological subtype of the tumor transformed from adenocarcinoma to adenosquamous carcinoma. EML4-ALK fusion was detected on the initial genetic assay, and a de novo SMARCA4 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 4) mutation emerged 6 years later. These findings suggest that under long-term targeted treatment pressure, tumors may acquire immune evasion and undergo histological transformation via epigenetically regulated gene deletion.