Dynamics of Serum Tumor Markers Predict Benefit from Immune Checkpoint Inhibitors in Chinese Patients with Advanced Non-Small Cell Lung Cancer

Abstract

Background and Purpose: 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 could predict prognosis of patients with late-stage NSCLC treated by 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 by 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 immune checkpoint inhibitors (ICIs) treatment. 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 patients with advanced NSCLC were enrolled in the study. After balancing the baseline covariates between different groups, patients with meaningful improvements in less than 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 (ADC) revealed that patients with meaningful improvements in less than 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 (SCC), 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 could predict efficacy of PD-1/PD-L1 inhibitors in late-stage NSCLC patients. Decrease of associated biomarkers serum levels were associated with favorable clinical outcomes.

Funding: This work was supported by People's Liberation Army General Hospital Medical Big Data R&D Projects (No: 2017MBD-013) and People's Liberation Army General Hospital Support
Fund Project (No: 2017FC-CXYY-3007).

Declaration of Interest: The authors declared that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical Approval: The study protocol was approved by the Ethics Committee of Chinese PLA General Hospital. The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines defined by the International Conference on
Harmonization. Written informed consent was collected from all patients before enrollment.

Keywords: Non-small cell lung cancer, serum tumor markers, Chinese patients, immune checkpoint inhibitors, efficacy