C-Reactive Protein (CRP) Levels in Immune Checkpoint Inhibitor Response and Progression in Advanced Non-Small Cell Lung Cancer: A Bi-Center Study

Abstract

Background: Biomarkers for predicting response to immune checkpoint inhibitors (ICI) are scarce and often lack external validation. This study provides a comprehensive investigation of pretreatment C-reactive protein (CRP) levels as well as its longitudinal trajectories as a marker of treatment response and disease outcome in patients with advanced non-small cell lung cancer (NSCLC) undergoing immunotherapy with anti PD-1 or anti PD-L1 agents. Methods: We performed a retrospective bi-center study to assess the association between baseline CRP levels and anti PD-(L)1 treatment outcomes in the discovery cohort (n = 90), confirm these findings in an external validation cohort (n = 101) and explore the longitudinal evolution of CRP during anti PD-(L)1 treatment and the potential impact of dynamic CRP changes on treatment response and disease outcome in the discovery cohort. Joint models were implemented to evaluate the association of longitudinal CRP trajectories and progression risk. Primary treatment outcomes were progression-free survival (PFS) and overall survival (OS), while the objective response rate (ORR) was a secondary outcome, respectively. Results: In the discovery cohort, elevated pretreatment CRP levels emerged as independent predictors of worse PFS (HR per doubling of baseline CRP = 1.37, 95% CI: 1.16–1.63, p < 0.0001), worse OS (HR per doubling of baseline CRP = 1.42, 95% CI: 1.18–1.71, p < 0.0001) and a lower ORR ((odds ratio (OR) of ORR per doubling of baseline CRP = 0.68, 95% CI: 0.51–0.92, p = 0.013)). In the validation cohort, pretreatment CRP could be fully confirmed as a predictor of PFS and OS, but not ORR. Elevated trajectories of CRP during anti PD-(L)1 treatment (adjusted HR per 10 mg/L increase in CRP = 1.22, 95% CI: 1.15–1.30, p < 0.0001), as well as a faster increases of CRP over time (HR per 10 mg/L/month faster increase in CRP levels = 13.26, 95% CI: 1.14–154.54, p = 0.039) were strong predictors of an elevated progression risk, whereas an early decline of CRP was significantly associated with a reduction in PFS risk (HR = 0.91, 95% CI: 0.83–0.99, p = 0.036), respectively. Conclusion: These findings support the concept that CRP should be further explored by future prospective studies as a simple non-invasive biomarker for assessing treatment benefit during anti PD-(L)1 treatment in advanced NSCLC.

Clinically relevant prognostic and predictive markers for immune-checkpoint-inhibitor (ICI) therapy in non-small cell lung cancer (NSCLC)

“…We recently could show that a doubling of baseline CRP level was associated with a 1.4-fold higher relative risk of disease progression or death and that a 10 mg/mL/ month faster increase in CRP levels over time predicted for 13-fold higher risk of experiencing a PFS event. In addition, a decreasing CRP during the first 8 weeks after ICI initiation was strongly associated with favorable PFS experience (10% reduction in CRP predicted for a 0.9fold reduction in PFS) [118].…”

Canakinumab with and Without Pembrolizumab in Patients with Resectable Non-Small-Cell Lung Cancer: CANOPY-N Study Design

“…Canakinumab being used as a single agent in the CANTOS trial has led to a reduction in CRP from baseline [43]. Several studies reported improved survival in patients with advanced NSCLC treated with anti-PD-L1 inhibitors who experienced a reduction in CRP level [49].…”

“…Considering that a systemic and locoregional inflammatory response is induced in the host from the earliest stages of cancer development, assessing the potential of IL-1β blockade in the neoadjuvant setting when the tumor mass and locoregional lymph nodes are intact is a possibility [48]. In a recent, retrospective bi-center study to assess the association between baseline CRP levels and anti-PD-1/PD-L1 treatment in patients with advanced NSCLC (discovery cohort, n = 90; validation cohort, n = 101), pretreatment CRP level was confirmed to predict progressionfree survival and OS [49]. Results of a retrospective analysis of 87 patients with advanced NSCLC receiving anti-PD-1 treatment demonstrated a significant association of baseline CRP with OS after immunotherapy [50].…”

Serum Levels of Soluble Urokinase Plasminogen Activator Receptor Predict Tumor Response and Outcome to Immune Checkpoint Inhibitor Therapy

“…A high neutrophil/lymphocyte ratio (NLR) correlated with an impaired outcome in NSCLC treated with ICI ( 26 ). In addition, serum CRP levels, a routine marker of inflammation, have been suggested to reflect treatment benefit during anti PD-(L)1 treatment in advanced NSCLC ( 27 ).…”