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.

Keywords: bacterial infections; cell death receptor; immune-check point blockade; inflammatory markers; procalcitonin; prognostic factors of response; programmed cell death ligand-1; real-world salvage therapy.

Figure 1

Overall survival (OS) of patients with metastatic non-small cell lung cancer (mNSCLC) subjected to nivolumab (solid line) or atezolizumab treatment (dashed line). No statistical differences in survival were correlated with the treatment (nivolumab vs. atezolizumab, p:0.378). Nivolumab subgroup median OS: 19 ± 0.8 months, mean OS: 27.9 ± 3.9 months, versus Atezolizumab subgroup median OS: 12.5 ± 2.1 months, mean OS: 12.1 ± 1.6 months.

Figure 2

Overall survival (OS) considering inflammation status markers in metastatic non-small cell lung cancer (mNSCLC) patients. (A–C) In our series, we found a significant cut-off of the baseline expression of CRP, ESR and PCT that was strongly correlated to a worse outcome in terms of OS; (A) Specifically, patients with a CRP ≤16 showed a median OS of 19.3 ± 0.6 months, mean: 30.5 ± 4.7 months, versus a median OS of 9.7 ± 1.4 months, mean: 15.9 ± 27 months in patients with a CRP >16, with a p-value of 0.033; (B) Patients with ESR ≤40 showed a median OS of 19.8 ± 1.5 months, mean: 36.5 ± 5.4 months, versus a median OS of 9.8 ± 1.9 months, mean: 17.7 ± 3.5 months in patients with an ESR >40, with a p-value of 0.01; (C) Finally, patients with a PCT ≤0.1 showed a median OS of 19.6 ± 0.4 months, mean: 31.0 ± 4.3 months, versus a median OS of 7.3 ± 0.6 months, mean: 10.1 ± 1.4 months, in patients with a PCT >0.10, with a p-value of 0.002. (D) OS in tree subgroups of patients: Subgroup A (Baseline ESR values ≤40 mm/h and baseline PCT values ≤0.10 mg/L, were detected in 37/95 patients) showed a median OS not reached, mean 40 ± 5.9 months; Subgroup B (baseline ESR values >40 mm/h or baseline PCT values >0.10 mg/L were detected in 43/95 patients) showed a mean OS of 15.5 ± 5.5 months, mean: 20.1 ± 4.0 months; Sugbroup C (baseline ESR values >40 mm/h and baseline PCT values >0.10 mg/L were detected in 15/95 patients) showed a median OS of 5.5 ± 1.6 months, mean OS: 8.3 ± 1.7 months.