Robust predictive biomarkers are of great clinical interest to maintain the balance between potential side effects and therapeutic benefits while identifying patients who will benefit from an extension of currently approved therapy. As antitumour immune activation is a dynamic process, inflammatory on-treatment biomarkers have great potential to map the interplay between tumour and immune system and thus serve as predictive biomarkers.
A particularly interesting, highly predictive longitudinal kinetics of the acute-phase protein C-reactive protein (CRP) occurring early after immunotherapy initiation was first described for mRCC in early 2021.1 The group led by Fukuda et al. described the so-called CRP flare-response phenomenon, which is defined by an early CRP increase after the start of ICB treatment with a subsequent drop below the baseline level. Overall, patients in this study were divided into three CRP kinetics subgroups: An early doubling of CRP levels in the first month on ICB followed by a fall below baseline within 3 months (CRP flare-response), a fall of at least 30% below baseline without a previous 'flare' (CRP response), or those remaining as non-CRP responders. CRP response and especially CRP flare-response were associated with improved treatment response and overall survival compared to non-CRP response (Figure 1). Remarkably, this new concept allowed accurate prediction of treatment outcome in a small cohort of only N=42 patients with mRCC treated with anti-PD-1 monotherapy.
Figure 1: Model of early C‐reactive protein (CRP) kinetics with the CRP flare‐response phenomenon, CRP response and non‐CRP response on ICB up to 1st radiological staging. Adapted from Fukuda et al.,1 created with BioRender.com.
As ICB combination therapies are currently used for mRCC, we investigated the predictive value of early on-treatment CRP flare-response in a multicentre cohort of patients with mRCC receiving ICB+ICB or ICB+TKI (N=95) as approved first-line therapy.2 CRP responders and especially CRP flare-responders showed a significant risk reduction of ~70-80% for tumour progression with a significantly prolonged progression-free survival (PFS) compared to CRP non-responders. In both the ICB+ICB and ICB+TKI subgroups, early CRP kinetics remained significantly associated with improved PFS (Figure 2). In addition, CRP flare-response kinetics were associated with a long-term treatment response ≥ 12 months.
Figure 2: Association of CRP kinetics subgroups and progression-free (PFS) survival after treatment initiation for the subgroup of patients receiving either first line (A) ICB+ICB (N=59) or (b) ICB+TKI (N=36).
Since immunotherapy is also used in uro-oncology practice as standard of care (SOC) in first- or second-line and more recently as maintenance therapy for patients with mUC, we additionally investigated the predictive potential of these early CRP kinetics on the clinical course of patients with ICB-treated mUC. We were able to confirm the predictive value of early on-treatment CRP kinetics in our multi-centre, retrospective observational study, which included N=154 patients with mUC who received ICB in the first-line (N=33, cisplatin-unfit) or after platinum-containing chemotherapy (N=121).3 CRP (flare) response was associated with ICB response as well as prolonged PFS and overall survival compared with non-CRP response, while PD-L1 did not predict response or outcome in our cohort (Figure 3). In multivariable Cox regression analysis, CRP flare-responders showed a risk reduction of ~70% for tumour progression and death compared to non-CRP responders.
Figure 3: A) Distribution of best RECIST-based response across CRP kinetics groups (PR=partial remission, CR=complete remission, SD=stable disease, PD=progressive disease). Progression free survival (PFS; B) and overall survival (OS; C) after ICB initiation stratified according to CRP kinetics groups. Median PFS/OS per subgroup is indicated as dotted line.
Early on-treatment CRP kinetics could potentially have predictive potential in additional tumour entities. We therefore also investigated the predictive value of CRP flare kinetics for patients with ICB-treated non-small cell lung cancer (NSCLC), where immunotherapy is also used as SOC. We confirmed the predictive value of longitudinal CRP kinetics in a retrospective discovery (N=105) and prospective validation (N=108) cohort of patients with ICB-treated NSCLC.4 Thus, in this study, for the first time, the same characteristic longitudinal CRP flare kinetics already described for ICB-treated mRCC and mUC could also be observed for patients with NSCLC. In two independent cohorts with a total of N=213 patients with NSCLC, we were able to prove that CRP flare also predicts response to anti-PD-1 monotherapy in NSCLC. In the study protocol of our prospective NSCLC validation cohort, CRP levels were measured at baseline and at weeks 1, 2, 4, 6, and 10 after initiation of ICB, which allowed more detailed analysis of early CRP kinetics on ICB. Whereas the original definition of CRP kinetics allowed the identification of ICB responders or non-responders at the time of the first radiological assessment at 12 weeks, individual CRP dynamics suggest that more refined criteria may allow discrimination between responders and non-responders at an earlier time point. Of note, the predictive value of early CRP kinetics remained stable in both the overall cohort and the anti-PD-1 monotherapy subgroup when the definition was changed to an observation interval of 4 weeks. Because the majority of CRP (flare) responders were identified after 4 weeks of treatment, whereas routine staging is usually performed after 12 weeks, the assessment of CRP flare kinetics thus opens a large therapeutic window for early assessment of ICB response and the possibility of treatment adjustment.
Interestingly, early on-treatment CRP kinetics appears to be a biological phenomenon independent of tumour type. Due to its wide clinical availability, early CRP kinetics could become an easy to determine, cost-effective, and non-invasive on-treatment biomarker that can robustly predict immunotherapy response for patients with mRCC, mUC, or NSCLC.
Our data represent an important starting point for the investigation of further predictive on-treatment biomarker models based on longitudinal inflammatory markers, such as CRP, for immuno-oncology. In the future, this could lead to an improvement in therapy monitoring for (uro)oncological patients undergoing immunotherapy. Rapid identification of therapy success and failure could thus enable immediate therapy adjustment, on the one hand, to save therapy-mediated toxicity, and on the other hand to be able to administer more effective therapies at an early stage.
Written by: Niklas Klümper1,2 Markus Eckstein3
- Department of Urology and Pediatric Urology, University Medical Center Bonn (UKB), Bonn, Germany
- Institute of Experimental Oncology, University Medical Center Bonn (UKB), Bonn, Germany
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg(FAU), Erlangen, Germany
References:
- Fukuda S, Saito K, Yasuda Y, Kijima T, Yoshida S, Yokoyama M, et al. Impact of C-reactive protein flare-response on oncological outcomes in patients with metastatic renal cell carcinoma treated with nivolumab. J Immunother Cancer. 2021 Feb;9(2).
- Klümper N, Schmucker P, Hahn O, Höh B, Mattigk A, Banek S, et al. C-reactive protein flare-response predicts long-term efficacy to first-line anti-PD-1-based combination therapy in metastatic renal cell carcinoma. Clin Transl Immunology. 2021;10(12):e1358.
- Klümper N, Sikic D, Saal J, Büttner T, Goldschmidt F, Jarczyk J, et al. C-reactive protein flare predicts response to anti-PD-(L)1 immune checkpoint blockade in metastatic urothelial carcinoma. Eur J Cancer. 2022 Mar 30;167:13–22.
- Klümper N, Saal J, Berner F, Lichtensteiger C, Wyss N, Heine A, et al. C reactive protein flare predicts response to checkpoint inhibitor treatment in non-small cell lung cancer. J Immunother Cancer. 2022 Mar;10(3):e004024.
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