Superior clinical outcomes in patients with non-small cell lung cancer harboring multiple ALK fusions treated with tyrosine kinase inhibitors

Background: Patients with non-small cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) fusions may benefit from ALK-tyrosine kinase inhibitors (ALK-TKIs). However, few studies have analyzed the clinical outcome in patients harboring multiple ALK fusions, including double or triple ALK fusions. Here, our study aimed to analyze the impact of harboring multiple ALK fusions on the efficacy of receiving ALK-TKIs in NSCLC patients.Methods: A total of 125 patients with ALK-rearranged NSCLC detected by targeted capture DNA-based next-generation sequencing (NGS) at West China Hospital were enrolled. The literature on patients harboring multiple ALK fusions was systematically reviewed. The clinical response to ALK-TKIs was evaluated according to ALKfusion patterns in 62 patients: 56 from our center and 6 from the literature. Results: Among the 125 patients, a single canonical echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion was detected in 65.6% (82/125), a single non-EML4-ALK fusion was detected in 13.6% (17/125), and multiple ALK fusions were detected in 20.8% (26/125). Among the 62 patients with ALK fusion treated with ALK-TKIs, the median progression-free survival (PFS) was significantly longer in patients with multiple ALK fusions than in those with a single ALK fusion (26.9 vs. 11.2 months, P=0.009), irrespective of brain metastasis, type of TKI drug, and treatment lines. The multiple ALK fusion group also tended to have a longer overall survival (OS) (P=0.26). Multivariate Cox regression analysis revealed that harboring multiple ALK fusions had the potential to be an independent predictor of better PFS for ALK- positive NSCLC [hazard ratio (HR) =0.490; 95% confidence interval (CI), 0.229-1.049].Conclusions: Harboring multiple ALK fusions could serve as an independent predictive marker of better clinical outcome for patients with NSCLC and ALK rearrangement who have received ALK-TKIs treatment.