The wide implementation of next generation sequencing (NGS) technology has led to the identification of a greater number of uncommon partners of anaplastic lymphoma kinase (ALK) fusion. The clinical significance of the intergenic-ALK fusion was deemed limited due to the ambiguous functional partner. Herein, we reported a case of lung adenocarcinoma harboring a novel intergenic (between REG3A and CTNNA2-AS1)-ALK fusion which is sensitive to alectinib.Hematoxylin-eosin staining (HE), immunohistochemistry (IHC), and DNA-based next-generation sequencing (NGS) based on a 168-gene panel were performed on the biopsy sample.A 50-year-old Chinese male patient diagnosed with stage IVA adenocarcinoma of the upper lobe of the right lung. A novel ALK fusion, resulting from the intergenic region between REG3A and CTNNA2-AS1 fusing with intron 19 of ALK, was unveiled by NGS analysis. Furthermore, positive expression of ALK was confirmed through IHC analysis. The patient was administered alectinib at a dose of 600 mg twice daily as first-line therapy, and partial response was assessed. To date, the progression-free survival (PFS) has exceeded 14 months without any observed serious toxicities.To the best of our knowledge, this represents the inaugural report of a patient harboring a novel intergenic-ALK fusion with a breakpoint situated between REG3A and CTNNA2-AS1, who exhibited favorable response to alectinib. This case warrants further investigation and offers valuable insights into the response of this novel intergenic-ALK fusion to alectinib.Copyright © 2023. Published by Elsevier B.V.