In-Treatment Kinetics of Peripheral Blood Immune Markers in PD-L1 High Non-Small Cell Lung Cancer and Prognostic Relevance for Immunotherapy Outcomes

Background: A substantial proportion of patients with non-small cell lung cancer (NSCLC) derive limited clinical benefit from immunotherapy. Monitoring of peripheral blood immune markers (PBIMs) may emerge as a useful tool to predict treatment outcomes with immune checkpoint inhibitors (ICIs). Patients/Methods: We prospectively measured several PBIMs in a PD-L1 high (TPS ≥ 50%) NSCLC cohort of patients treated with first-line pembrolizumab monotherapy. Kinetics over the first year of treatment were assessed at baseline (T0) and at 21 days (T1), 3 months (T2), 6 months (T3) and at 1 year (T4) post-treatment initiation. Associations with clinical outcomes were explored after a 2-year follow-up period. Results: In total, 31 patients with PD-L1 high locally advanced or metastatic NSCLC were prospectively enrolled. Over the first year of treatment, levels of CRP, IL-17α, IL-6, and IL-8 were significantly decreased. Early kinetics analysis showed significant decrease in total leukocytes, neutrophils, CRP, and MIP-3α/CCL20, as well as significant transient elevation of ITAC/CXCL11, IL-1β, IL-7, and TNFα, during the first 3 months of treatment. Early percent changes (Δ% at T1 and at T2) of ‘low’ vs. ‘high’ pretreatment levels showed significant differences for LDH, ITAC/CXCL11, GM-CSF, MIP-1α/CCL3, IL-2, IL-4, IL-5, and sPD-L1. Longitudinal analysis, stratified per responders and for pre-progression fluctuations, did not reveal significant findings. Among markers with acceptable discriminative performance, higher baseline CRP, complement C4, and IL-6 levels were associated with poorer clinical outcomes. In multivariable analysis, only C4 retained independent prognostic significance; however, integration of these PBIMs into composite indices improved prognostic performance. Conclusions: In this prospective study, longitudinal monitoring of PBIMs provided descriptive insights into immune and inflammatory dynamics during pembrolizumab treatment; however, no significant associations were observed between in-treatment biomarker kinetics and clinical outcomes. In exploratory analyses, baseline CRP, complement C4, and IL-6 levels were associated with clinical outcomes, and their integration into composite indices improved prognostic performance. These findings suggest that specific baseline PBIMs may carry prognostic relevance, while the role of in-treatment monitoring remains to be further clarified in larger prospective studies.