Peripheral Blood Markers Identify Risk of Immune-Related Toxicity in Advanced Non-Small Cell Lung Cancer Treated with Immune-Checkpoint Inhibitors

Abstract

Background Immune‐checkpoint inhibitors (ICIs) are now standard of care for advanced non‐small cell lung cancer (NSCLC). Unfortunately, many patients experience immune‐related adverse events (irAEs), which are usually mild and reversible, but they require timely management and may be life threatening. No predictive markers of irAEs are available. Materials and Methods The neutrophil‐to‐lymphocyte ratio (NLR) and platelet‐to‐lymphocyte ratio (PLR) were evaluated in patients with NSCLC consecutively treated with ICIs. Prespecified cutoff values of NLR and PLR were used and related to outcome and onset of irAEs. A control group of patients with advanced NSCLC not receiving ICIs was included. Results The study included 184 patients: 26 (14.1%) received pembrolizumab upfront, and 142 (77%) received ICIs (pembrolizumab, nivolumab or atezolizumab) after one or more lines of chemotherapy. The median number of ICIs cycles was six (range, 1–61). The median progression‐free survival and overall survival were 4.8 (95% CI, 3.4–6.3) and 20.6 (95% CI, 14.7–26.5) months, respectively. Sixty patients (32.6%) developed irAEs, mainly grade 1–2 (65.0%), causing ICI interruption in 46 cases (25.0%). Low NLR and low PLR at baseline were significantly associated with the development of irAEs (odds ratio [OR], 2.2; p = .018 and OR, 2.8; p = .003, respectively). Multivariate analyses confirmed PLR as independent predictive marker of irAEs (OR, 2.3; p = .020). Conclusion NLR and PLR may predict the appearance of irAEs in non‐oncogene‐addicted aNSCLC, although this conclusion warrants prospective validation. Implications for Practice This study was designed to investigate the role of blood biomarkers in predicting the occurrence of immune‐related adverse events (irAEs) in patients with advanced non‐small cell lung cancer receiving immunotherapy. The results of the study suggest a potential predictive role of neutrophil‐to‐lymphocyte ratio and platelet‐to‐lymphocyte ratio as markers for irAE development in this category of patients. These data provide rationale for an easy and feasible application to be validated in clinical practice.

Association Between Immune-related Adverse Events and Clinical Outcome Following Nivolumab Treatment in Patients With Metastatic Renal Cell Carcinoma

“…They also reported that the occurrence of any irAE was associated with a baseline NLR <3.0 and a baseline PLR <180 by univariate analyses. Multivariate modeling confirmed a baseline PLR <180 as the only independent predictive factor (19). These findings agree with the findings of the present study.…”

“…Regarding the incidence of irAEs, a baseline PLR <156 was identified with multivariate logistic regression analysis as a significant risk factor (p=0.006). Pavan et al observed that a baseline PLR <180 was significantly associated with occurrence of any irAEs among non-small lung cancer patients (19). They also reported that the occurrence of any irAE was associated with a baseline NLR <3.0 and a baseline PLR <180 by univariate analyses.…”

Pretreatment Blood Parameters Predict Efficacy from Immunotherapy Agents in Early Phase Clinical Trials

“…Furthermore, circulating biomarkers can be also applied for predicting toxicity in patients treated with ICIs [51, 52]. For instance, low baseline levels of NRL and PLR have been found associated with a higher risk for developing immune‐related adverse events from anti–PD‐1/PD‐L1 immunotherapy in NSCLC [53].…”

Autoimmune complications of immunotherapy: pathophysiology and management

“…None of these biomarkers has been incorporated into clinical practice, but they may provide insight into irAE pathogenesis. For example, the association of neutrophil markers (CD177),35 neutrophil growth factors (G-CSF, GM-CSF),34 a high neutrophil:lymophocyte ratio,31 and high IL-6 and IL-17 levels3233 with high grade irAEs, particularly colitis, suggests there is an important role for Th17 adaptive immune responses and innate immunity, at least in ICI associated colitis. The association of B cell changes30 and baseline autoantibodies with irAE3637 suggests that humoral immunity may also play a role in some organ specific irAEs.…”