Serum Metabolite Biomarkers Predictive of Response to PD-1 Blockade Therapy in Non-Small Cell Lung Cancer.

Xiaoqun Nie,Yaxian Yao,Zhiwei Chen,Huangqi Duan,Chen Yang,Yingying Chen,Shun Lu,Lixia Liu,Ying Wang,Yi Yang,Liliang Xia,Fang Gao

doi:10.3389/fmolb.2021.678753

Abstract

Background: Despite remarkable success of immunotherapies with checkpoint blockade antibodies targeting programmed cell death protein 1 (PD-1), the majority of patients with non-small-cell lung cancer (NSCLC) have yet to receive durable benefits. We used the metabolomic profiling of early on-treatment serum to explore predictors of clinical outcomes of anti-PD-1 treatment in patients with advanced NSCLC. Methods: We recruited 74 Chinese patients who had stage IIIB/IV NSCLC-proven tumor progression and were treated with PD-1 inhibitor. The study was comprised of a discovery cohort of patients treated with nivolumab and two validation cohorts of patients receiving tislelizumab or nivolumab. Serum samples were collected 2–3 weeks after the first infusion of PD-1 inhibitor. Metabolomic profiling of serum was performed using ultrahigh performance lipid chromatograph-mass spectrometry. The serum metabolite biomarkers were identified using an integral workflow of nontargeted metabolomic data analysis. Results: A serum metabolite panel consisting of hypoxanthine and histidine was identified and validated as a predictor of response to PD-1 blockade treatment in patients with advanced NSCLC. High levels of both hypoxanthine and histidine in early on-treatment serum were associated with improved progression-free survival [hazard ratio (HR) = 0.078, 95% confidence interval (CI), 0.027–0.221, p < 0.001] and overall survival (HR = 0.124, 95% CI, 0.039–0.397, p < 0.001) in the discovery cohort. The serum metabolite panel showed a high sensitivity and specificity in distinguishing responders and non-responders in the validation cohorts 1 and 2, with an area under the receiver-operating characteristic curve of 0.933 and 1.000, respectively. High levels of serum hypoxanthine and histidine were correlated with improved progression-free survival in the validation cohort 1 (HR = 0.137, 95% CI, 0.040–0.467, p = 0.001) and in the validation cohort 2 (HR = 0.084, 95% CI, 0.009–0.762, p = 0.028). Conclusion: Our results revealed that hypoxanthine and histidine in early on-treatment serum are predictive biomarkers of response to PD-1 blockade therapy in patients with advanced NSCLC. The serum biomarker panel would enable early identification of NSCLC patients who may benefit from PD-1 blockade therapy.

Highlights

Non-small cell lung cancer (NSCLC) is the leading cause of cancerrelated mortality worldwide and generally has a poor prognosis (Bray et al, 2018)
High levels of both hypoxanthine and histidine in early on-treatment serum were associated with improved progression-free survival [hazard ratio (HR) 0.078, 95% confidence interval (CI), 0.027–0.221, p < 0.001] and overall survival (HR 0.124, 95% CI, 0.039–0.397, p < 0.001) in the discovery cohort
High levels of serum hypoxanthine and histidine were correlated with improved progression-free survival in the validation cohort 1 (HR 0.137, 95% CI, 0.040–0.467, p 0.001) and in the validation cohort 2 (HR 0.084, 95% CI, 0.009–0.762, p 0.028)

Summary

Introduction

Non-small cell lung cancer (NSCLC) is the leading cause of cancerrelated mortality worldwide and generally has a poor prognosis (Bray et al, 2018). An anti-PD-1 antibody tislelizumab has been approved in China for treatment of NSCLC and other cancers (Liu and Wu, 2020). These PD-1/PD-L1 inhibitors block the binding of PD-1 to its PD-L1 ligand and restore the capacity of cytotoxic T cells to recognize and kill cancer cells. Given the distinct response patterns, combined with potentially severe toxicity and high costs, there is an urgent need to identify biomarkers that can predict which patients are likely to benefit from PD-1/PD-L1 blockade therapies. Despite remarkable success of immunotherapies with checkpoint blockade antibodies targeting programmed cell death protein 1 (PD-1), the majority of patients with non-small-cell lung cancer (NSCLC) have yet to receive durable benefits. We used the metabolomic profiling of early on-treatment serum to explore predictors of clinical outcomes of anti-PD-1 treatment in patients with advanced NSCLC

Methods

Results

Conclusion