45P Rare and non-canonical ALK fusion in advanced NSCLC: Heterogeneous clinical outcomes with ALK inhibitors

Background: ALK rearrangements define a clinically relevant subset of non-small cell lung cancer (NSCLC) sensitive to ALK tyrosine kinase inhibitors (TKIs).While EML4-ALK is the most frequent fusion, next-generation sequencing (NGS) has enabled the identification of rare ALK fusion partners, whose clinical behavior and outcomes with ALK-targeted therapies remain poorly characterized in routine clinical practice.Methods: From January 2021 to June 2025, a retrospective analysis was conducted on patients with ALK-rearranged NSCLC treated at ASST Papa Giovanni XXIII (Bergamo).ALK rearrangements were assessed by immunohistochemistry and fluorescence in situ hybridization in 2021-2022, and from 2023 onward by DNA-based NGS, allowing a more comprehensive molecular characterization.Results: Twenty-three ALK-positive cases were identified, 12 detected by NGS.Nine cases harbored canonical EML4-ALK fusions with different breakpoints, while three carried non-canonical ALK rearrangements (HIP1-ALK, NCOA1-ALK, CAPN13-ALK) associated with markedly heterogeneous clinical outcomes.A 22-year-old patient with HIP1-ALK and concomitant TP53 mutation experienced rapid disease progression, with limited benefit from sequential ALK TKIs (PFS 8 months with alectinib and 4 months with lorlatinib) and fatal outcome.The patient with CAPN13-ALK achieved a PFS of 15 months on ALK-targeted therapy before rapid clinical deterioration and death.In contrast, the patient harboring NCOA1-ALK is experiencing durable disease control with first-line alectinib since February 2023. Conclusions:In a real-world setting, NGS identifies a non-negligible proportion of rare and non-canonical ALK fusions associated with markedly heterogeneous clinical outcomes.These findings suggest that rare ALK rearrangements may represent biologically distinct entities with variable sensitivity to ALK TKIs and support comprehensive molecular profiling and cautious interpretation beyond the canonical EML4-ALK paradigm.