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Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Outcomes with Nivolumab in Pretreated Non-Small Cell Lung Cancer (NSCLC): A Large Retrospective Multicenter Study

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Abstract

Introduction

Immune checkpoint inhibitors have provided substantial benefit in non-small cell lung cancer (NSCLC) with unprecedented results in terms of survival. However, the identification of reliable predictive biomarkers to these agents is lacking and multiple clinicopathological factors have been evaluated. The aim of this study was to analyze the potential role of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) levels in patients with pretreated NSCLC receiving nivolumab.

Methods

This was a retrospective multicenter study involving 14 Italian centers, evaluating the role of some laboratory results in patients with NSCLC treated with nivolumab in the second or later lines of therapy for at least four doses and with a disease re-staging.

Results

A total of 187 patients with available pretreatment laboratory results were included. NLR levels below 5 were associated with an improvement in terms of both progression-free survival (PFS) (p = 0.028) and overall survival (OS) (p = 0.001), but not in terms of overall response rate (ORR) or disease control rate (DCR). Moreover, PLR levels below 200 were associated with longer PFS (p = 0.0267) and OS (p = 0.05), as well as higher ORR (p = 0.04) and DCR (p = 0.001). In contrast, LDH levels above the upper normal limit (UNL) were not associated with significant impact on patient outcomes.

Conclusions

Patients with pretreated NSCLC and high pretreatment levels of NLR and PLR may experience inferior outcomes with nivolumab. Therefore, in this subgroup of patients with poor prognosis the use of alternative therapeutic strategies may be a valuable option, especially in programmed cell death ligand 1 (PD-L1)-negative patients and/or in the presence of other additional poor prognostic factors.

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Abbreviations

AJCC:

American Joint Committee on Cancer

CR:

Complete response

DCR:

Disease control rate

dNLR:

Derived neutrophil-to-lymphocyte ratio

ECOG:

Eastern Cooperative Oncology Group

HR:

Hazard ratio

IHC:

Immunohistochemistry

iSEND:

Immunotherapy, sex, ECOG PS, neutrophil-to-lymphocyte ratio, and delta NLR model

LDH:

Lactate dehydrogenase

NLR:

Neutrophil-to-lymphocyte ratio

NSCLC:

Non-small cell lung cancer

ORR:

Overall response rate

OS:

Overall survival

PD-1:

Programmed cell death 1

PD-L1:

Programmed cell death ligand 1

PD:

Progressive disease

PFS:

Progression-free survival

PLR:

Platelet-to-lymphocyte ratio

PR:

Partial response

PS:

Performance status

Pts:

Patients

SD:

Stable disease

TNM:

Tumor, node, metastasis

UNL:

Upper normal limit

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Acknowledgements

Funding

The authors received no financial support for the research, authorship, and/or publication of this article. The journal’s Rapid Service Fee was funded by the authors.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Authorship Contributions

Alessandro Russo, Marco Russano, Giuseppe Tonini, Daniele Santini, and Vincenzo Adamo contributed to the design of the study; Alessandro Russo, Marco Russano, Tindara Franchina, Maria R. Migliorino, Giuseppe Aprile, Giovanni Mansueto, Alfredo Berruti, Alfredo Falcone, Michele Aieta, Alain Gelibter, Sandro Barni, Michele Maio, Olga Martelli, Francesco Pantano, Daniela Iacono, Lorenzo Calvetti, Silvia Quadrini, Elisa Roca, Enrico Vasile, Marco Imperatori, Mario Occhipinti, Giulia Pasquini, Salvatore Intagliata, Giuseppina R. R. Ricciardi, Giuseppe Tonini, Daniele Santini, and Vincenzo Adamo contributed to the clinical management of patients and database, providing clinical, pathological and molecular data; Alessandro Russo, Marco Russano, Daniele Santini, Vincenzo Adamo performed data analysis and interpretation; Alessandro Russo, Marco Russano, Vincenzo Adamo, and Daniele Santini wrote the manuscript; all authors read and approved the final version of the manuscript.

Compliance with Ethics Guidelines

The trial protocol was previously approved by the Ethics Committee of the coordinating Center (Campus Bio-Medico University of Rome) on 2 March 2018 (approval n. 23/18 OSS ComEt CBM) and all the patients provided written informed consent before enrollment. The study was conducted in accordance with the Declaration of Helsinki.

Disclosures

All named authors (Alessandro Russo, Marco Russano, Tindara Franchina, Maria R Migliorino, Giuseppe Aprile, Giovanni Mansueto, Alfredo Berruti, Alfredo Falcone, Michele Aieta, Alain Gelibter, Antonio Russo, Sandro Barni, Michele Maio, Olga Martelli, Francesco Pantano, Daniela Iacono, Lorenzo Calvetti, Silvia Quadrini, Elisa Roca, Enrico Vasile, Marco Imperatori, Mario Occhipinti, Antonio Galvano, Fausto Petrelli, Luana Calabrò, Giulia Pasquini, Salvatore Intagliata, Giuseppina R.R. Ricciardi, Giuseppe Tonini, Daniele Santini, Vincenzo Adamo) have nothing to disclose.

Data Availability

The data that support the findings of this study are available from the corresponding author, Prof. Vincenzo Adamo, upon reasonable request.

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Correspondence to Vincenzo Adamo.

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Russo, A., Russano, M., Franchina, T. et al. Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Outcomes with Nivolumab in Pretreated Non-Small Cell Lung Cancer (NSCLC): A Large Retrospective Multicenter Study. Adv Ther 37, 1145–1155 (2020). https://doi.org/10.1007/s12325-020-01229-w

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