Dynamics of Serum Tumor Markers Can Serve as a Prognostic Biomarker for Chinese Advanced Non-small Cell Lung Cancer Patients Treated With Immune Checkpoint Inhibitors

Background: Serum tumor markers carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), cytokeratin 19 fragment (CYFRA21-1) and squamous-cell carcinoma-related antigen (SCC-Ag) are routinely used for monitoring the response to chemotherapy or targeted therapy in advanced-stage non-small cell lung cancer (NSCLC), however their role in immunotherapy remains unclear. The aim of this study was to investigate whether dynamics of these serum markers were associated with the efficacy and prognosis of Chinese late-stage NSCLC patients treated with programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors. Methods: We initiated a longitudinal prospective study on advanced NSCLC patients treated with PD-1/PD-L1 inhibitors in Chinese PLA general hospital (Beijing, China). Blood samples of baseline and after 6 weeks' treatment were collected. CT scan were used by all patients to evaluate treatment efficacy according to RECIST 1.1. Serum tumor markers levels were measured with an electrochemical luminescence for SCC-Ag and with a chemiluminescent microparticle immunoassay for serum CEA, CA125, and CYFRA21-1. At least 20% decreases of the biomarkers from baseline were considered as meaningful improvements after 6 weeks of treatment with immune checkpoint inhibitors (ICIs). Optimization-based method was used to balance baseline covariates between different groups. Associations between serum tumor biomarker improvements and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were analyzed. Results: A total of 308 Chinese patients with advanced NSCLC were enrolled in the study. After balancing baseline covariates, patients with meaningful improvements in <2 out of 4 biomarkers (CEA, CA125, CYFRA21-1, and SCC-Ag) was ended up with lower ORR (0.08 vs. 0.35, p < 0.001), shorten PFS (median: 5.4 vs. 12.5 months, p < 0.001), and OS (median: 11.7 vs. 25.6 months, p < 0.001) in the total population. Subgroup analysis of patients with adenocarcinoma revealed that patients with meaningful improvements in <2 out of 4 biomarkers had significant lower ORR (0.06 vs. 0.36, p < 0.001), shorten PFS (median: 4.1 vs. 11.9 months, p < 0.001), and OS (median: 11.9 vs. 24.2 months, p < 0.001). So as in patients with squamous cell carcinoma, meaningful improvements in at least 2 out of 4 biomarkers were linked to better ORR (0.42 vs. 0.08, p = 0.014), longer PFS (median: 13.1 vs. 5.6 months, p = 0.001), and OS (median: 25.6 vs. 10.9 months, p = 0.06). Conclusions: The dynamic change of CEA, CA125, CYFRA21-1, and SCC-Ag from baseline have prognostic value for late-stage NSCLC patients treated with PD-1/PD-L1 inhibitors. Decrease of associated biomarkers serum levels were associated with favorable clinical outcomes.