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. 2023 Oct;41(5):727-736.
doi: 10.1007/s10637-023-01388-x. Epub 2023 Aug 21.

Early on-treatment C-reactive protein and its kinetics predict survival and response in recurrent and/or metastatic head and neck cancer patients receiving first-line pembrolizumab

Affiliations

Early on-treatment C-reactive protein and its kinetics predict survival and response in recurrent and/or metastatic head and neck cancer patients receiving first-line pembrolizumab

Markus Haas et al. Invest New Drugs. 2023 Oct.

Abstract

Purpose: First-line immune checkpoint blockade has improved the prognosis of recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC), but response rates remain low. In this study, we aimed to investigate the prognostic value of CRP and its early kinetics to predict response and survival in R/M HNSCC.

Methods: A total of 87 patients who received first-line pembrolizumab for R/M HNSCC were analyzed. Three-fold cross-validation was used to estimate cut-off points of CRP at baseline and on-treatment (day 40 ± 10). Treatment response and survival were analyzed according to early CRP kinetics. The neutrophil-to-lymphocyte ratio (NLR) was used as a benchmark for the prognostic performance of CRP.

Results: On-treatment CRP below 2 mg/dl, 4x the upper limit of normal (ULN), was associated with increased overall survival (OS), while on-treatment CRP below 3 mg/dl (6x ULN) was correlated with a higher disease control rate (DCR) and increased progression-free survival (PFS). CRP flare-responders and CRP responders showed a higher DCR and longer PFS than CRP non-responders. An NLR above 6 was a negative prognosticator for progression. In multivariable analysis, on-treatment CRP prevailed as the only significant prognosticator for OS (HR: 4.97, CI95%: 2.18-11.32, p < 0.001) and PFS (HR: 2.07, CI95%: 1.07-3.99, p = 0.030).

Conclusion: On-treatment CRP was identified as a prognostic biomarker for objective response and survival in R/M HNSCC patients receiving first-line pembrolizumab and could be easily incorporated into clinical practice as a widely available and cost-effective biomarker.

Keywords: Biomarkers; C-Reactive protein; Head and Neck Neoplasms; Immunotherapy; Kinetics.

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Conflict of interest statement

Thorsten Fuereder received honoraria from MSD, Merck Darmstadt, Roche, BMS, Accord, Sanofi, Boehringer Ingelheim, Amgen, Pfizer and Takeda, and research grants from Merck and MSD. The other authors declare no conflict of interest related to the publication of this article.

Figures

Fig. 1
Fig. 1
bOR according to on-treatment CRP (a), on-treatment NLR (b) and CRP kinetics (c). The difference in disease control (SD, PR or CR) between groups was compared using the Chi-squared or Fisher exact test. Abbreviations: bOR, best overall response; CR, complete response; CRP, C-reactive protein; NLR, neutrophil-to-lymphocyte ratio; PD, progressive disease; PR, partial response; SD, stable disease
Fig. 2
Fig. 2
CRP and NLR levels according to bOR and time points. CRP (a, b) and NLR (e, f) levels are shown according to the bOR at baseline and on-treatment (day 40 ± 10). PD was compared to SD, PR and CR, respectively, employing Kruskal-Wallis testing and multiple comparison using Dunn’s correction. The cross-validated on-treatment cut-off points for progression (CRP: 3 mg/dl; NLR: 6) are shown as a dashed line on baseline and on-treatment graphs. Kinetics of baseline and on-treatment CRP (c, d) and NLR levels (g, h) split according to patients presenting with PD and disease control (CR, PR, SD) are shown as individual line plots. CRP and NLR level differences between the two time points were compared by the Wilcoxon test for paired samples. Abbreviations: bOR, best overall response; CR, complete response; CRP, C-reactive protein; NLR, neutrophil-to-lymphocyte ratio; PD, progressive disease; PR, partial response; SD, stable disease
Fig. 3
Fig. 3
Survival analysis. Kaplan-Meier plots with CI95% (dashed lines) for OS and PFS dichotomized by the cross-validated cut-off points for on-treatment CRP in mg/dl (a, d), CRP kinetics (b, e), on-treatment NLR (c, f) levels are shown. Log-rank testing was used for comparison of the survival curves. Abbreviations: CI95%, 95% confidence interval; CRP, C-reactive protein; cvAUROC, cross-validated area under the receiver operating curve; NLR, neutrophil-to-lymphocyte ratio; OS, overall survival; PFS, progression-free survival

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