Somatic copy number alterations profiling in non-small cell lung cancer and their correlation with clinical efficacy in first-line treatment

Background: Immune checkpoint inhibitors (ICI) are the current standard-of-care first-line treatment for advanced non-small cell lung cancer (NSCLC) without actionable genomic alterations. Yet some patients do not achieve clinical benefit, underscoring the need for predictive biomarkers. High burden of somatic copy number alterations (SCNAs), including chromosomal arm- and whole-chromosome-level changes, has been linked to reduced benefit from ICI. However, its predictive value in chemotherapy or combination regimens remains largely unexplored. Here, we evaluated SCNA burden across multiple first-line treatment strategies in a cohort of patients with NSCLC. Methods: We assembled a cohort of 258 patients with NSCLC treated with first-line ICI (n=86), chemotherapy (ChT; n=107), or a combination of both (ICI+ChT; n=65). Tumor DNA was analyzed using shallow whole-genome sequencing (sWGS). SCNA burden was quantified as the fraction of the genome altered at the chromosomal arm and whole-chromosome level (FGA ^a+c ). We performed Kaplan-Meier and Cox regression analyses to assess its value across treatment groups. Additionally, we examined associations between recurrent SCNAs, clinical efficacy, and tumor microenvironment (TME) features using data from The Cancer Genome Atlas (TCGA). Results: High SCNA burden (FGA ^a+c > 4.25) was significantly associated with diminished progression-free survival (PFS) in patients treated with ICI (p-val=0.0097). In contrast, FGA ^a+c did not associate with PFS following ChT (p-val=0.9566) or ICI+ChT (p-val=0.6472). Specific SCNAs in chromosome 9p were independently associated with reduced ICI benefit (p-val=0.0469), even after adjusting for FGA ^a+c (p-val=0.0229). This SCNA was negatively associated with immune infiltration in the TME and was linked to differences in the immune cell type composition. Conclusions: Our findings suggest that FGA ^a+c may help identify patients with differential benefit from ICI monotherapy in NSCLC, without evidence of a prognostic role in other treatment modalities. These findings warrant prospective studies to validate its clinical utility in guiding treatment selection.