Serum CYFRA 21-1 as a Prognostic Marker in Non-Small-Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors

<b>Background:</b> A prognostic marker in patients with non-small-cell lung cancer (NSCLC) treated with anti-PD-1/PD-L1 antibodies must be established. This study explored serum cytokeratin fraction 21-1 (CYFRA 21-1), which represents a squamous cell histology, as a prognostic factor in anti-PD-1/PD-L1 antibody treatment, stratifying by histology and treatment regimen. <b>Methods:</b> This study retrospectively evaluated patients with advanced NSCLC without driver mutations receiving anti-PD-1/PD-L1 antibodies between November 2015 and March 2023. Cutoff values for CYFRA 21-1 and carcinoembryonic antigen (CEA) were 3.5 and 5.0 ng/mL, respectively. The Kaplan-Meier method and a log-rank test were conducted. The Cox proportional hazards model was utilized for univariate and multivariate analyses. <b>Results:</b> This study included 258 patients. The squamous NSCLC group demonstrated a shorter overall survival (OS) than the non-squamous NSCLC group (median, 17.8 vs. 23.7 months, <i>p</i> = 0.141). Patients with high serum CYFRA 21-1 and CEA levels exhibited a significantly shorter OS than those with normal levels (median, 11.7 vs. 32.7 months, <i>p</i> < 0.005; 15.8 vs. 29.7 months, <i>p</i> < 0.005). The multivariate analysis identified a performance status (PS) of ≥2, a PD-L1 expression of ≥50%, and a serum CYFRA 21-1 of >3.5 ng/mL as independent prognostic factors. Patients with high serum CYFRA 21-1 levels exhibited a significantly shorter OS even focusing on non-squamous NSCLC, anti-PD-1/PD-L1 antibody and chemotherapy combination therapy, or anti-CTLA-4 antibody combination therapy. <b>Conclusion:</b> Serum CYFRA 21-1 is a poor prognostic marker for patients with NSCLC receiving anti-PD-1/PD-L1 antibody treatment even when stratifying by histology or treatment regimen.