Inflammatory Markers and Procalcitonin Predict the Outcome of Metastatic Non-Small-Cell-Lung-Cancer Patients Receiving PD-1/PD-L1 Immune-Checkpoint Blockade

Abstract

Peripheral-immune-checkpoint blockade (P-ICB) with mAbs to PD-1 (nivolumab and pembrolizumab) or PD-L1 (atezolizumab, durvalumab, avelumab) alone or combination with chemotherapy represents a novel active treatment for mNSCLC patients. However, this therapy can be associated to immune-related adverse events (irAEs) and high cost. Therefore, finding reliable biomarkers of response and irAEs is strongly encouraged to accurately select patients who may potentially benefit from the immuno-oncological treatment. This is a retrospective multi-institutional analysis performed on ninety-five mNSCLC patients who received real-world salvage therapy with nivolumab or atezolizumab between December 2015 and April 2020. The outcome of these patients in term of PFS and OS was evaluated in comparison with different serum levels of C-reactive protein (CRP), Erythrocyte Sedimention Rate (ESR) and Procalcitonin (PCT) by performing Kaplan–Meier and Log-rank test and multivariate analysis. We found that high baseline levels of CRP, ESR, and PCT were strongly predictive of poor outcome (P <0.05) with the worse prognosis detected in those patients with a baseline levels of both ESR and PCT over the pre-established cut off (median OS recorded in patients with no marker over the cut off vs. those with just one marker over the cut off vs. those with both markers over the cut off: 40 ± 59 vs. 15.5 ± 5.5 vs. 5.5 ± 1.6 months, respectively; P <0.0001). Our results suggest the predictive value of systemic inflammation and suggest a potential role of PCT in predicting a poor outcome in mNSCLC receiving PD-1/PD-L1 blocking mAbs. This finding also suggests a potential role of subclinical bacterial infections in defining the response to PD-1/PD-L1 blocking mAbs that deserves further and more specific investigations.

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

“…The correlation between the rise in the neutrophil counts and the poor outcomes could also be related to a rise in procalcitonin due to a bacterial influence or to other causes, as previously reported by our group [41].…”

“…In elderly patients, a coexisting chronic inflammation in mNSCLC patients may still affect the immune balance between the immune system and cancer growth, affecting the anti-tumor activity of T cells and promoting the mechanisms of cancer-immune escape [39][40][41][42][43]. This hypothesis was supported by the rise in the neutrophil counts occurring upon ICB administration, predicting a worse prognosis in the older cohort of patients but not in the younger one where there was only a trend towards a significance.…”

PD-1/PD-L1 immune-checkpoint blockade induces immune effector cell modulation in metastatic non-small cell lung cancer patients: A single-cell flow cytometry approach

“…This study is part of a retrospective real-world evidence (RWE) multi-institutional study including a total of 119 pretreated mNSCLC patients who had received therapy with nivolumab or atezolizumab, according to the standard international guidelines at the Medical Oncology Unit of The Hospital of Reggio Calabria (OM-RC) and at the Radiotherapy Unit of the University Hospital of Siena (RT-SI), Italy, between September 2015 and April 2020 ( 16 ). The current study was focused on 28 of the abovementioned patients who consented to get their blood drawn and anonymously stored for scientific purposes.…”

“…We previously showed that the frequency of mild irAEs and autoantibody [AAb; mainly represented by the extractable nuclear antigen (ENA) antibodies, antinuclear antibodies (ANAs), anti-smooth cell antibodies (ASMAs), and c/pantineutrophil cytoplasmic antibodies (ANCAs)] increase predict positive outcome in patients with metastatic NSCLC (mNSCLC) and metastatic colorectal cancer receiving immunecheckpoint blockade and chemo-immunotherapy, respectively (9,(12)(13)(14). We subsequently, demonstrated that high baseline levels of inflammatory markers (15) and procalcitonin (16) are correlated to a very poor outcome in NSCLC patients on nivolumab or atezolizumab. In the same group of patients, we identified specific class I/II human leucocyte antigen (HLA) alleles involved in CTL-mediated immune reaction and inflammatory response that were statistically predictive of good response to the treatment (17) or predictive of autoimmune pneumonitis (18).…”

The Molecular Role of IL-35 in Non-Small Cell Lung Cancer

“…Pre-treatment high inflammatory state and high levels of IL-6, and IL-8 cytokines are poor prognostic indicators of PD-1 inhibitor therapy, and high levels of IFN-g are markers of good ICI treatment effect and prognosis (121). Additionally, high baseline levels of C-reactive protein, erythrocyte sedimentation rate, and procalcitonin during ICI treatment of NSCLC indicate poor prognosis (124). A series of adverse events, including CIP, can occur with ICI treatment.…”