C reactive protein flare predicts response to checkpoint inhibitor treatment in non-small cell lung cancer

Abstract

Biomarkers for predicting response to anti-programmed death-1 (PD-1) immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) remain in demand. Since anti-tumor immune activation is a process, early dynamic changes of the acute-phase reactant C reactive protein (CRP) may serve as a predictive on-treatment biomarker. In a retrospective (N=105) and prospective (N=108) ICB-treated NSCLC cohort, early CRP kinetics were stratified after the start of immunotherapy until weeks 4, 6, and 12 as follows: an early doubling of baseline CRP followed by a drop below baseline (CRP flare-responder), a drop of at least 30% below baseline without prior flare (CRP responders), or those who remained as CRP non-responders. In our study, we observed characteristic longitudinal changes of serum CRP concentration after the initiation of ICB. In the prospective cohort, N=40 patients were defined as CRP non-responders, N=39 as CRP responders, and N=29 as CRP flare-responders with a median progression-free survival (PFS) of 2.4, 8.1, and 14.3 months, respectively, and overall survival (OS) of 6.6, 18.6, and 32.9 months (both log-rank p<0.001). Of note, CRP flare-responses, characterized by a sharp on-treatment CRP increase in the first weeks after therapy initiation, followed by a decrease of CRP serum level below baseline, predict ICB response as early as 4 weeks after therapy initiation. Of note, early CRP kinetics showed no predictive value for chemoimmunotherapy or when steroids were administered concurrently. On-treatment CRP kinetics had a predictive value for both major histological NSCLC subtypes, adenocarcinoma and squamous cell carcinoma. The results were verified in an independent retrospective cohort of 105 patients. In conclusion, CRP flare predicted anti-PD-1 monotherapy response and survival in two independent cohorts including a total of 213 patients with NSCLC, regardless of histology. Due to its wide clinical availability, early CRP kinetics could become an easily determined, cost-efficient, and non-invasive biomarker to predict response to checkpoint inhibitors in NSCLC within the first month.

Keywords: biomarkers, tumor; immunotherapy; lung neoplasms.

Figure 1

Distinct early on-treatment C reactive protein (CRP) kinetics correlates with progression-free survival (PFS) and overall survival (OS) in immune checkpoint blockade-treated patients with NSCLC. (A) The bar plot shows the frequency of patients categorized into three CRP kinetic subgroups in the immune monitoring of immune therapy NSCLC validation cohort. (B, C) Kaplan–Meier survival curves showing the PFS and OS after ICB initiation stratified according to CRP kinetics groups. Median PFS/OS is depicted as dotted lines. Distribution of response at first staging according to RECIST among the different CRP kinetics groups (D), as well as for patients with non-elevated or elevated CRP (E), lactate dehydrogenase (F), and neutrophil-to-lymphocyte ratio (G) at baseline. P values in (D–G) are calculated using the χ² test for the objective response rate (ORR). NLR, neutrophil-to-lymphocyte ratio; NSCLC, non-small cell lung cancer; PD, progressive disease; PR, partial remission; SD, stable disease.

Figure 2

Early on-treatment CRP kinetics predicts treatment response and outcome of anti-PD-1 monotherapy. Kaplan–Meier survival curves showing the progression-free survival (PFS) (A) and overall survival (OS) (B) after immune checkpoint blockade initiation stratified according to CRP kinetics groups for the anti-PD-1 monotherapy subgroup of the immune monitoring of immune therapy non-small cell lung cancer validation cohort. (C) Distribution of response at first staging according to RECIST among the different CRP kinetics groups. p value based on χ² test for ORR. CRP, C reactive protein; ORR, objective response rate; PD, progressive disease; PR, partial remission; SD, stable disease.

Figure 3

Longitudinal CRP changes from baseline after initiation of immunotherapy in the three early on-treatment CRP kinetics subgroups. (A) For CRP non-responders, (B) for CRP responders, and (C) for CRP flare-responders: median CRP change from baseline in per cent is shown in the left panel; the CRP changes of the individual patients are shown in the right panel. The dashed lines indicate the thresholds for CRP responder and CRP flare-responder subgroups. (D) Integration of median change in baseline CRP of the three CRP kinetics subgroups in the immune monitoring of immune therapy non-small cell lung cancer validation cohort and (E) conceptual representation of early on-treatment CRP kinetics. CRP, C reactive protein.

Figure 4

Refined early on-treatment CRP kinetics criteria lead to robust prediction of immunotherapy response in NSCLC as early as week 4. Application of early CRP kinetics definition until week 4 after immunotherapy start for all patients included in the immune monitoring of immune therapy NSCLC validation cohort (A, B) and the ICB monotherapy subgroup (D, E). Progression-free survival (PFS) after ICB initiation stratified according to CRP kinetics groups is depicted in A+D, overall survival (OS) in B+E. CRP kinetics stratification predicts response to ICB, but this does not reach statistical significance based on χ² test for ORR (C, F). P value based on χ² test for ORR. CRP, C reactive protein; ICB, immune checkpoint blockade; ORR, objective response rate; PD, progressive disease; PR, partial remission; SD, stable disease.