Distinctive Role of the Systemic Inflammatory Profile in Non-Small-Cell Lung Cancer Younger and Elderly Patients Treated with a PD-1 Immune Checkpoint Blockade: A Real-World Retrospective Multi-Institutional Analysis.

Valerio Nardone,Rocco Giannicola,Luciano Mutti,Rita Emilena Saladino,Pierosandro Tagliaferri,Caterina Romeo,Pierpaolo Correale,Daniele Caracciolo,Luigi Pirtoli,Maria Rosaria Rizzo,Diana Giannarelli,Pierfrancesco Tassone,Vito Barbieri,Alfonso Reginelli,Pierpaolo Pastina,Michele Caraglia,Giovanna Bianco,Antonia Consuelo Falzea,Irene Di Meo,Antonio Nesci,Amalia Luce,Salvatore Cappabianca,Antonio Giordano,D Azzarello

doi:10.3390/life11111235

Abstract

An immune checkpoint blockade with mAbs to PD-1 and PD-L1 is an expanding therapeutic option for mNSCLC patients. This treatment strategy is based on the use of mAbs able to restore the anti-tumor activity of intratumoral T cells inhibited by PD-1 binding to PD-L1/2 on tumor and inflammatory cells. It has been speculated that a chronic status of systemic inflammation as well as the immunosenescence physiologically occurring in elderly patients may affect the efficacy of the treatment and the occurrence of irAEs. We performed a multi-institutional retrospective study aimed at evaluating the effects of these mAbs (nivolumab or atezolizumab) in 117 mNSCLC patients younger (90 cases) and older (27 cases) than 75 years in correlation with multiple inflammatory parameters (NLR, CRP, ESR, LDH and PCT). No differences were observed when the cohorts were compared in terms of the frequency of PFS, OS, inflammatory markers and immune-related adverse events (irAEs). Similarly, the occurrence of irAEs was strictly correlated with a prolonged OS survival in both groups. On the contrary, a negative correlation between the high baseline levels of inflammatory markers and OS could be demonstrated in the younger cohort only. Overall, PD-1/PD-L1-blocking mAbs were equally effective in young and elderly mNSCLC patients; however, the detrimental influence of a systemic inflammation at the baseline was only observed in young patients, suggesting different aging-related inflammation immunoregulative effects.

Highlights

A peripheral immune checkpoint blockade (ICB) with mAbs to the programmed cell death receptor-1 (PD-1; nivolumab or pembrolizumab) and to its main ligand (PD-L1; atezolizumab, durvalumab or avelumab) alone or in combination with a number of different chemo-radiation strategies is an expanding therapeutic option for common malignancies including metastatic non-small-cell lung cancer, malignant melanomas, head and neck carcinomas and urothelial and kidney cancer [1,2]. These immune-based treatments may be very effective but they are associated with frequent immune-related adverse events and high costs [3,4,5,6,7]. The efficacy of these treatments in mNSCLC patients has been demonstrated in several randomized clinical trials, poor information is available for the population of patients older than 75 years who may have frequent comorbidities and a compromised T cell-mediated immune response due to the physiological immunosenescence process
Our retrospective analysis was performed on a cohort of 117 patients with mNSCLC who had been consecutively enrolled to receive a salvage therapy with nivolumab or atezolizumab between November 2015 and April 2020
Our retrospective multi-institutional analysis conducted in a real-world setting confirmed the efficacy and safety of the progressive disease (PD)-1-ICB treatment in patients older than 75 years with mNSCLC

Summary

Introduction

A peripheral immune checkpoint blockade (ICB) with mAbs to the programmed cell death receptor-1 (PD-1; nivolumab or pembrolizumab) and to its main ligand (PD-L1; atezolizumab, durvalumab or avelumab) alone or in combination with a number of different chemo-radiation strategies is an expanding therapeutic option for common malignancies including metastatic non-small-cell lung cancer (mNSCLC), malignant melanomas, head and neck carcinomas and urothelial and kidney cancer [1,2] These immune-based treatments may be very effective but they are associated with frequent immune-related adverse events (irAEs) and high costs [3,4,5,6,7]. The efficacy of these treatments in mNSCLC patients has been demonstrated in several randomized clinical trials, poor information is available for the population of patients older than 75 years who may have frequent comorbidities and a compromised T cell-mediated immune response due to the physiological immunosenescence process In this light, there is a large amount of evidence showing a physiologically-based immunological impairment progressively occurring along with aging. Several pathogens such as the respiratory syncytial virus, influenza and para-influential viruses or Sars-Cov-2 that generally present a milder infection course in younger individuals may become fatal in elderly patients [10,11,12]

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Conclusion