Association of early on-treatment cytokine dynamics following induction chemo-immunotherapy with progression-free survival in squamous non–small cell lung cancer.

Abstract

e20560 Background: Despite advances in immunotherapy-based combinations for advanced non–small cell lung cancer (NSCLC), biomarkers that reflect early on-treatment immune and angiogenic dynamics remain limited. LUNG-IST-127 is an investigator-initiated trial evaluating induction chemo-immunotherapy followed by maintenance pembrolizumab plus cabozantinib, a multitargeted tyrosine kinase inhibitor. We conducted an exploratory correlative analysis to assess whether longitudinal plasma cytokine changes are associated with progression-free survival (PFS). Methods: Peripheral blood samples were collected longitudinally from patients enrolled on LUNG-IST-127 at baseline, post-induction, and during maintenance therapy. Plasma cytokines were quantified using CodePlex Innate bulk cytokine profiling. Associations between cytokine dynamics (baseline, post-induction, and early change) and PFS were assessed using Spearman correlation. Analyses were exploratory and hypothesis-generating. Cytokine concentrations were log10-transformed. Within-patient changes from baseline to post-induction were calculated and assessed using Spearman rank correlations with progression-free survival (PFS). Exploratory comparisons used nonparametric methods, and p-values were nominal and hypothesis-generating due to the pilot sample size. Results: Seven patients with available cytokine data and PFS outcomes were included; six had paired baseline and post-induction samples. Baseline cytokine levels alone were not strongly associated with PFS. In contrast, early on-treatment cytokine changes demonstrated notable associations with clinical outcome. An increase in IL-10 from baseline to post-induction was strongly associated with longer PFS (p = 0.015), while an increase in VEGF over the same interval was associated with shorter PFS (p = 0.021). Higher post-induction VEGF levels were also inversely associated with PFS (p = 0.021). Maintenance-phase longitudinal analysis was underpowered, with only three patients contributing ≥2 maintenance samples. Conclusions: In this exploratory correlative analysis of LUNG-IST-127, early cytokine dynamics following induction chemo-immunotherapy were more informative than baseline measurements. Increases in IL-10 were associated with prolonged PFS, while increases in VEGF identified patients with poorer outcomes. These findings suggest that early angiogenic and immunoregulatory shifts may stratify patients by risk and raise the hypothesis that VEGF-high tumors following induction may represent a biologically relevant subgroup for intensified anti-angiogenic strategies during maintenance. Ongoing accrual and longitudinal sampling will be critical to validate these observations. Clinical trial information: NCT05613413 .