Association between pretreatment neutrophil‐to‐lymphocyte ratio and immune‐related adverse events due to immune checkpoint inhibitors in patients with non‐small cell lung cancer

Fujimoto, Airi; Toyokawa, Gouji; Koutake, Yoshimichi; Kimura, Shigeru; Kawamata, Yosei; Fukuishi, Kazuhisa; Yamazaki, Koji; Takeo, Sadanori

doi:10.1111/1759-7714.14063

Cited by 26 publications

(28 citation statements)

References 34 publications

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“…Lastly, a recent retrospective analysis of 115 patients with NSCLC treated with PD-(L)1 inhibitors showed that a low pretreatment NLR may predict for the occurrence of immune-related adverse events (irAEs); whether dNLR changes may further correlated with the risk of irAE develop needs to be assessed in future studies. 25 There are an increasing number of continuous biomarkers associated with ICI efficacy, including PD-L1 expression, infiltrating immune cells, and TMB. [26][27][28] Likewise, dNLR appears to behave in a continuous fashion, both in terms of therapeutic outcomes to ICI, and also with the tumor immunophenotype.…”

Section: Discussionmentioning

confidence: 99%

Low peripheral blood derived neutrophil-to-lymphocyte ratio (dNLR) is associated with increased tumor T-cell infiltration and favorable outcomes to first-line pembrolizumab in non-small cell lung cancer

Alessi

Ricciuti

Alden

et al. 2021

J Immunother Cancer

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BackgroundAn elevated peripheral blood derived neutrophil-to-lymphocyte ratio (dNLR) is a negative prognostic marker for patients with non-small cell lung cancer (NSCLC) receiving chemotherapy and immune checkpoint inhibitors. Whether dNLR is also associated with clinical outcomes to first-line pembrolizumab among patients with NSCLC and a programmed cell death ligand 1 (PD-L1) Tumor Proportion Score (TPS) of ≥50% is uncertain. How dNLR relates to the tumor immune microenvironment is also unclear.MethodsIn two participating academic centers, we retrospectively analyzed the dNLR (defined as the absolute neutrophil count/white cell count – absolute neutrophil count) prior to initiation of first-line pembrolizumab in patients with metastatic NSCLC and a PD-L1 TPS ≥50% and lacking genomic alterations in EGFR and ALK. An unbiased recursive partitioning algorithm was used to investigate an optimal dNLR cut-off with respect to objective response rate (ORR). Multiplexed immunofluorescence for CD8+, FOXP3+, PD-1+, and PD-L1 was performed on a separate cohort of NSCLCs to determine the immunophenotype associated with dNLR.ResultsA total of 221 patients treated with first-line pembrolizumab were included in this study. The optimal dNLR cut-off to differentiate treatment responders from non-responders was 2.6. Compared with patients with a dNLR ≥2.6 (n=97), patients with dNLR <2.6 (n=124) had a significantly higher ORR (52.4% vs 24.7%, p<0.001), a significantly longer median progression-free survival (mPFS 10.4 vs 3.4 months, HR 0.48, 95% CI 0.35 to 0.66, p<0.001), and a significantly longer median overall survival (mOS 36.6 vs 9.8 months, HR 0.34, 95% CI 0.23 to 0.49, p<0.001). After adjusting for age, sex, tobacco use, performance status, histology, serum albumin level, oncogenic driver status, and PD-L1 distribution (50%–89% vs ≥90%), a dNLR <2.6 was confirmed to be an independent predictor of longer mPFS (HR 0.47, 95% CI 0.33 to 0.67, p<0.001) and mOS (HR 0.32, 95% CI 0.21 to 0.49, p<0.001). Among advanced NSCLC samples with a PD-L1 TPS of ≥50%, those with a dNLR <2.6 had significantly higher numbers of tumor-associated CD8+, FOXP3+, PD-1 +immune cells, and PD-1 +CD8+T cells than those with a dNLR ≥2.6.ConclusionsAmong patients with NSCLC and a PD-L1 TPS ≥50%, a low dNLR has a distinct immune tumor microenvironment and more favorable outcomes to first-line pembrolizumab.

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Section: Discussionmentioning

confidence: 99%

Low peripheral blood derived neutrophil-to-lymphocyte ratio (dNLR) is associated with increased tumor T-cell infiltration and favorable outcomes to first-line pembrolizumab in non-small cell lung cancer

Alessi

Ricciuti

Alden

et al. 2021

J Immunother Cancer

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“…Common hematological indicators, such as inflammatory factors, tumor markers and cell free DNA (cfDNA) have gradually been shown to play important roles in the microenvironment of NSCLC. There is considerable evidence regarding neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic markers in NSCLC patients treated with immunotherapy (11)(12)(13) and targeted therapy (14,15). However, few studies have explored the significance of these indicators in the alectinib treatment of ALK-positive NSCLC (16).…”

Section: What Is the Implication And What Should Change Now?mentioning

confidence: 99%

Efficacy and safety of alectinib in ALK-positive non-small cell lung cancer and blood markers for prognosis and efficacy: a retrospective cohort study

Jiang¹,

Shi²,

Liu³

et al. 2022

Transl Lung Cancer Res

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Background: Alectinib is a second generation of ALK-tyrosine kinase inhibitors (ALK-TKIs), which has attracted much attention in the treatment of ALK-positive non-small cell lung cancer (NSCLC). At present, there are few reports on the efficacy and safety of alectinib in Chinese population. Moreover, biomarkers reflecting prognosis and efficacy are exceedingly needed. This study assessed the efficacy of alectinib in patients with ALK-positive NSCLC and analyzed the prognostic factors. Methods: Patients with ALK-positive NSCLC who were confirmed by histopathology or cytology at the Affiliated Cancer Hospital of Nanjing Medical University between October 2018 and October 2021 were enrolled. All patients were treated with alectinib. The clinical characteristics and circulating tumor biomarkers before and after treatment were collected. Kaplan-Meier test was used to calculate the progression-free survival (PFS). Univariate and multivariate Cox regression analyses were used to explore the influencing factors on PFS. Incidence of adverse events was observed. Results: Twenty patients progressed after first-line treatment (n=59) with alectinib, and 21 patients progressed following second-line treatment (n=36) with alectinib. The median PFS of first-line treatment patients was not achieved, and the median PFS of patients undergoing second-line treatment was 15.0 months ^ ORCID:

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“…A low NLR re ects a low peripheral neutrophil count and high lymphocyte count, indicating maintenance of the immune system. We have previously reported that a low pretreatment NLR may be a predictive factor for the occurrence of irAEs with ICI monotherapy [4]. Despite the effect of cytotoxic chemotherapy on neutrophil and lymphocyte counts, this study showed that a low pretreatment NLR is a useful predictive factor for irAE development in ICI plus platinum agent therapy, similar to ICI monotherapy.…”

Section: Discussionmentioning

confidence: 52%

“…Furthermore, large case series studies of NSCLC and other tumors have shown that irAE development is associated with improved survival outcomes [3]. Therefore, numerous previous studies on risk factors for the development of irAEs have been conducted, and several risk factors were reported, such as a low neutrophil-to-lymphocyte ratio (NLR), high body mass index (BMI), high serum albumin (ALB) level, and low Eastern Cooperative Oncology Group (ECOG) performance status (PS) [4][5][6][7][8].…”

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confidence: 99%

Risk factors indicating immune-related adverse events with combination chemotherapy with immune checkpoint inhibitors and platinum agents in patients with non-small cell lung cancer: A multicenter retrospective study

Fujimoto

Kotake

Hisamatsu

et al. 2022

Preprint

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Purpose Immune checkpoint inhibitors (ICI) ushered in a new era for the treatment of non-small cell lung cancer (NSCLC). However, they carry the risk of immune-related adverse events (irAEs). Recently, various studies have been conducted on the predictive factors for irAEs, but there are no reports focusing only on ICI plus platinum agents. The present study aimed to identify the risk factors for irAEs due to ICI combined with platinum-based chemotherapy in NSCLC patients, focusing only on the period of combined use. Methods This retrospective study included 315 NSCLC patients who started ICI combined with platinum-based chemotherapy treatment at 14 hospitals between December 2018 and March 2021. A logistic regression analysis was used to explore the predictive factors. Results A multivariate analysis revealed that squamous cell carcinoma (P = 0.021; odds ratio [OR]: 2.30; 95% confidence interval [Cl]: 1.14–4.65), anti-programmed death 1 antibody (anti-PD-1) plus anti-cytotoxic T-lymphocyte antigen-4 antibody (anti-CTLA-4) regimens (P < 0.01; OR: 22.10; 95% Cl: 5.60–87.20), and neutrophil-to-lymphocyte rate (NLR) < 3 (P < 0.01; OR: 2.91; 95% Cl: 1.35–6.27) were independent predictive factors for irAEs occurrence. Conclusion Squamous cell carcinoma, anti-PD-1 plus anti-CTLA-4 regimens, and NLR < 3 may be predictive factors for the occurrence of irAEs in patients with NSCLC due to ICI combined with platinum-based chemotherapy. By focusing on the potential risk of irAEs in patients with these factors, irAEs can be appropriately managed from an early stage.

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Association between pretreatment neutrophil‐to‐lymphocyte ratio and immune‐related adverse events due to immune checkpoint inhibitors in patients with non‐small cell lung cancer

Cited by 26 publications

References 34 publications

Low peripheral blood derived neutrophil-to-lymphocyte ratio (dNLR) is associated with increased tumor T-cell infiltration and favorable outcomes to first-line pembrolizumab in non-small cell lung cancer

Low peripheral blood derived neutrophil-to-lymphocyte ratio (dNLR) is associated with increased tumor T-cell infiltration and favorable outcomes to first-line pembrolizumab in non-small cell lung cancer

Efficacy and safety of alectinib in ALK-positive non-small cell lung cancer and blood markers for prognosis and efficacy: a retrospective cohort study

Risk factors indicating immune-related adverse events with combination chemotherapy with immune checkpoint inhibitors and platinum agents in patients with non-small cell lung cancer: A multicenter retrospective study

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