Elsevier

Lung Cancer

Volume 145, July 2020, Pages 18-26
Lung Cancer

Serum markers associated with treatment response and survival in non-small cell lung cancer patients treated with anti-PD-1 therapy

https://doi.org/10.1016/j.lungcan.2020.04.034Get rights and content

Highlights

  • dNLR is a novel serum inflammatory marker.

  • dNLR is calculated from white blood cell concentration and neutrophil count.

  • dNLR was associated with treatment response in NSCLC treated with anti-PD-1 drugs.

  • dNLR was an independent prognostic factor in NSCLC treated with anti-PD-1 drugs.

  • dNLR might be the most important factor for the efficacy of anti-PD-1 therapy.

Abstract

Background

Several serum markers have been associated with treatment response and clinical outcome in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors.

Materials and methods

We performed univariate and multivariate analyses on 226 patients with advanced or recurrent NSCLC treated with anti-programmed cell death-1 (PD-1) therapy. The cut-off values for body mass index (BMI), albumin (Alb), and serum inflammatory markers were determined by receiver operating characteristic curve analyses. Tumor response was assessed by computed tomography according to the Response Evaluation Criteria in Solid Tumors, version 1.1.

Results

BMI ≥ 19.1 kg/m2 and derived neutrophil-lymphocyte ratio (dNLR) < 2.79 were independent predictors of overall response, and Alb ≥ 3.5 g/dL and dNLR < 2.79 were independent predictors of disease control. Analyses of survival revealed that Alb < 3.5 g/dL, dNLR ≥ 2.79, lymphocyte-monocyte ratio < 2.12, and red blood cell distribution width ≥ 15.9 % were independent predictors of both progression-free and overall survival. Moreover, these markers tended to have a strong impact on survival, especially among patients with programmed cell death-ligand 1 tumor proportion score ≥ 50 %.

Conclusions

dNLR might be the most important factor for predicting the efficacy in NSCLC patients treated with anti-PD-1 therapy.

Introduction

Immune checkpoint inhibitors, such as nivolumab, pembrolizumab, atezolizumab, and durvalumab, have been approved by the US Food and Drug Administration for use in non-small cell lung cancer (NSCLC). The identification of reliable biomarkers for cancer immunotherapy other than programmed cell death-ligand 1 (PD-L1) expression in tumor tissues is considered very important. Multiple reports have suggested several potential predictive markers for immune checkpoint inhibitors in NSCLC, including tumor mutation burden (TMB) in tumor tissue, TMB in blood, interferon-γ, and blood-based immune biomarkers, such as plasma PD-L1, neutrophil-lymphocyte ratio (NLR) and C-reactive protein (CRP) [[1], [2], [3], [4], [5], [6], [7]]. Among these candidates, serum inflammatory markers are easy to evaluate because they are measurable from peripheral laboratory variables obtained in routine clinical settings. Various studies have shown associations between serum inflammatory markers and treatment responses in NSCLC patients treated with immune checkpoint inhibitors [4,[8], [9], [10], [11], [12]]. However, many serum inflammatory markers show associations with treatment response and survival in NSCLC patients treated with anti-programmed cell death-1 (PD-1) therapy, and the precise serum inflammatory marker with the most significant effect on treatment response and survival is unknown.

Eastern Cooperative Oncology Group (ECOG) performance status (PS) is a simple tool to indicate the general condition of patients. The safety and efficacy of anti-PD-1 therapy in patients with poor PS have not been established. Kanai et al. reported that patients with poor PS or central nervous system metastasis discontinued treatment because of severe exacerbation or manifestation [13]. Many patients with poor PS may experience cachexia with disease progression, leading to loss of weight and skeletal muscle [14]. Therefore, lower body mass index (BMI), which is also easily calculated using weight and height, or patients’ nutritional status might be associated with treatment response and survival in patients with NSCLC treated with anti-PD-1 therapy.

In this study, we evaluated the influence of clinical factors including BMI and albumin (Alb) and serum inflammatory markers such as NLR, derived NLR (dNLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio (PLR), red blood cell distribution width (RDW), serum CRP, and serum lactate dehydrogenase (LDH) on treatment response and survival in NSCLC patients treated with anti-PD-1 therapy nivolumab or pembrolizumab.

Section snippets

Patients and samples

We retrospectively identified and enrolled 226 patients with advanced or recurrent NSCLC who were treated with anti-PD-1 therapy (nivolumab or pembrolizumab) between January 2016 and August 2018 at Kyushu University Hospital and National Hospital Organization Kyushu Cancer Center. The patients received nivolumab intravenously at a dose of 3 mg/kg every 2 weeks or pembrolizumab intravenously at a fixed dose of 200 mg every 3 weeks. Patients’ clinicopathological features, including age at the

Patient characteristics

The clinical characteristics of the 226 patients with NSCLC included in this study are listed in Table 1. Driver oncogene mutation (EGFR or ALK) status data were available for 197 patients (87.2 %), and PD-L1 tumor expression data were available for 146 patients (64.6 %). The median values of BMI, Alb, and serum inflammatory markers NLR, dNLR, LMR, PLR, RDW, serum CRP, and serum LDH were 21.7 kg/m2 (range: 13.9–36.2), 3.5 g/dL (range: 1.1–4.7), 3.90 (range: 0.97–54.04), 2.28 (range:

Discussion

While several markers were independent predictors of overall response or disease control, dNLR < 2.79 was an independent predictor of both overall response and disease control. In the analyses of survival excluding PD-L1 tumor expression status, Alb < 3.5 g/dL, dNLR ≥ 2.79, LMR < 2.12, and RDW ≥ 15.9 % were independent predictors of both PFS and OS, while dNLR ≥ 2.79, LMR < 2.12, RDW ≥ 15.9 %, CRP ≥ 9.72 mg/dL, and LDH ≥ 350 U/L were independent predictors of PFS or OS in the analyses of

Funding statement

This work was not supported by any funding sources.

CRediT authorship contribution statement

Kazuki Takada: Conceptualization, Data curation, Formal analysis, Investigation, Writing - original draft. Shinkichi Takamori: Data curation. Yasuto Yoneshima: Data curation, Writing - review & editing. Kentaro Tanaka: Data curation, Writing - review & editing. Isamu Okamoto: Supervision, Writing - review & editing. Mototsugu Shimokawa: Formal analysis, Investigation, Methodology. Taro Oba: Data curation. Atsushi Osoegawa: Data curation. Tetsuzo Tagawa: Supervision, Writing - review & editing.

Declaration of Competing Interest

The authors have declared no conflicts of interest.

Acknowledgments

We thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

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