Evaluating for Correlations between Specific Metabolites in Patients Receiving First-Line or Second-Line Immunotherapy for Metastatic or Recurrent NSCLC: An Exploratory Study Based on Two Cohorts

Abstract

Immune checkpoint inhibitors (ICI) have displayed impressive clinical efficacy in the context of non-small cell lung cancer (NSCLC). However, most patients do not achieve long-term survival. Minimally invasive collected samples are attracting significant interest as new fields of biomarker study, and metabolomics is one of these growing fields. We concentrated on the augmented value of the metabolomic profile in differentiating long-term survival from short-term survival in patients with NSCLC subjected to ICIs. We prospectively recruited 97 patients with stage IV NSCLC who were treated with anti-PD-1 inhibitor, including patients treated with monoimmunotherapy as second-line treatment (Cohort 1), and patients treated with combination immunotherapy as first-line treatment (Cohort 2). Each cohort was divided into long-term and short-term survival groups. All blood samples were collected before beginning immunotherapy. Serum metabolomic profiling was performed by UHPLC-Q-TOF MS analysis. Pareto-scaled principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis were performed. In Cohort 1, the mPFS and mOS of long-survival patients are 27.05 and NR months, respectively, and those of short-survival patients are 2.79 and 10.59 months. In Cohort 2, the mPFS and mOS of long-survival patients are 27.35 and NR months, respectively, and those of short-survival patients are 3.77 and 12.17 months. A total of 41 unique metabolites in Cohort 1 and 47 in Cohort 2 were screened. In Cohorts 1 and 2, there are 6 differential metabolites each that are significantly associated with both progression-free survival and overall survival. The AUC values for all groups ranged from 0.73 to 0.95. In cohort 1, the top 3 enriched KEGG pathways, as determined through significant different metabolic pathway analysis, were primary bile acid biosynthesis, African trypanosomiasis, and choline metabolism in cancer. In Cohort 2, the top 3 enriched KEGG pathways were the citrate cycle (TCA cycle), PPAR signaling pathway, and primary bile acid biosynthesis. The primary bile acid synthesis pathway had significant differences in the long-term and short-term survival groups in both Cohorts 1 and 2. Our study suggests that peripheral blood metabolomic analysis is critical for identifying metabolic biomarkers and pathways responsible for the patients with NSCLC treated with ICIs.