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Clinical and Translational Oncology

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Open Access 11-09-2023 | Tyrosine Kinase Inhibitors | RESEARCH ARTICLE

Early kinetics of C-reactive protein as prognosticator for survival in a real-world cohort of patients with metastatic renal cell cancer under first-line therapy with immune checkpoint inhibitors

Authors: Vayda Schüttke, Cathrin Kusiek, Susanne Fuessel, Christian Thomas, Bjoern Thorben Buerk, Kati Erdmann

Published in: Clinical and Translational Oncology | Issue 5/2024

Abstract

Purpose

This study investigated the prognostic potential of baseline C-reactive protein (CRP) levels and early CRP kinetics in a real-world cohort of patients with metastatic renal cell carcinoma (mRCC) under first-line (1L) therapy with immune checkpoint inhibitors (CPI).

Methods/patients

Analyses were performed retrospectively in a cohort of 61 mRCC patients under CPI-based 1L therapy. Patients were stratified based on baseline CRP (< 10 vs ≥ 10 mg/l) and CRP change within the initial three months of CPI therapy (normal: baseline < 10 mg/l, normalized: baseline ≥ 10 mg/l and nadir < 10 mg/l, non-normalized: baseline and nadir ≥ 10 mg/l). Finally, the association of baseline CRP and CRP change with progression-free (PFS) and overall survival (OS) was evaluated.

Results

Baseline CRP was not significantly associated with both PFS (p = 0.666) and OS (p = 0.143). Following stratification according to early CRP kinetics, 23, 25 and 13 patients exhibited normal, normalized and non-normalized CRP levels, respectively. Patients with normal and normalized CRP had a markedly prolonged PFS (p = 0.091) and OS (p = 0.008) compared to patients with non-normalized CRP. Consequently, significantly better PFS (p = 0.031) and OS (p = 0.002) were observed for the combined normal-normalized group. In multivariate analysis including ECOG and IMDC risk, normalized CRP kinetics alone or in combination with the normal group was identified as significant independent risk factor for OS, whereas a statistical trend was observed for PFS.

Conclusions

The present study emphasizes the prognostic potential of early CRP kinetics in CPI-treated mRCC. As a standard laboratory parameter, CRP can be easily implemented into clinical routine to facilitate therapy monitoring.

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Bedke J, Albiges L, Capitanio U, Giles RH, Hora M, Lam TB, et al. Updated European Association of Urology guidelines on renal cell carcinoma: nivolumab plus cabozantinib joins immune checkpoint inhibition combination therapies for treatment-naïve metastatic clear-cell renal cell carcinoma. Eur Urol. 2021;79(3):339–42. https://doi.org/10.1016/j.eururo.2020.12.005.CrossRefPubMed

Xu W, Atkins MB, McDermott DF. Checkpoint inhibitor immunotherapy in kidney cancer. Nat Rev Urol. 2020;17(3):137–50. https://doi.org/10.1038/s41585-020-0282-3.CrossRefPubMed

Ljungberg B, Albiges L, Abu-Ghanem Y, Bedke J, Capitanio U, Dabestani S, et al. European Association of Urology guidelines on renal cell carcinoma: the 2022 update. Eur Urol. 2022;82(4):399–410. https://doi.org/10.1016/j.eururo.2022.03.006.CrossRefPubMed

Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168(4):707–23. https://doi.org/10.1016/j.cell.2017.01.017.CrossRefPubMedPubMedCentral

Krieger T, Pearson I, Bell J, Doherty J, Robbins P. Targeted literature review on use of tumor mutational burden status and programmed cell death ligand 1 expression to predict outcomes of checkpoint inhibitor treatment. Diagn Pathol. 2020;15(1):6. https://doi.org/10.1186/s13000-020-0927-9.CrossRefPubMedPubMedCentral

Labriola MK, Zhu J, Gupta RT, McCall S, Jackson J, Kong EF, et al. Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma. J Immunother Cancer. 2020;8(1):e000319. https://doi.org/10.1136/jitc-2019-000319.CrossRefPubMedPubMedCentral

Wood MA, Weeder BR, David JK, Nellore A, Thompson RF. Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival. Genome Med. 2020;12(1):33. https://doi.org/10.1186/s13073-020-00729-2.CrossRefPubMedPubMedCentral

Sacdalan DB, Lucero JA. The association between inflammation and immunosuppression: implications for ICI biomarker development. Onco Targets Ther. 2021;14:2053–64. https://doi.org/10.2147/ott.S278089.CrossRefPubMedPubMedCentral

Ravindranathan D, Master VA, Bilen MA. Inflammatory markers in cancer immunotherapy. Biology (Basel). 2021;10(4):325. https://doi.org/10.3390/biology10040325.CrossRefPubMed

10.

Nakayama T, Saito K, Kumagai J, Nakajima Y, Kijima T, Yoshida S, et al. Higher serum C-reactive protein level represents the immunosuppressive tumor microenvironment in patients with clear cell renal cell carcinoma. Clin Genitourin Cancer. 2018;16(6):e1151–8. https://doi.org/10.1016/j.clgc.2018.07.027.CrossRefPubMed

11.

Yano Y, Ohno T, Komura K, Fukuokaya W, Uchimoto T, Adachi T, et al. Serum C-reactive protein level predicts overall survival for clear cell and non-clear cell renal cell carcinoma treated with ipilimumab plus nivolumab. Cancers (Basel). 2022;14(22):5659. https://doi.org/10.3390/cancers14225659.CrossRefPubMed

12.

Ishihara H, Tachibana H, Takagi T, Kondo T, Fukuda H, Yoshida K, et al. Predictive impact of peripheral blood markers and c-reactive protein in nivolumab therapy for metastatic renal cell carcinoma. Target Oncol. 2019;14(4):453–63. https://doi.org/10.1007/s11523-019-00660-6.CrossRefPubMed

13.

Suzuki K, Terakawa T, Furukawa J, Harada K, Hinata N, Nakano Y, et al. C-reactive protein and the neutrophil-to-lymphocyte ratio are prognostic biomarkers in metastatic renal cell carcinoma patients treated with nivolumab. Int J Clin Oncol. 2020;25(1):135–44. https://doi.org/10.1007/s10147-019-01528-5.CrossRefPubMed

14.

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;9(2):e001564. https://doi.org/10.1136/jitc-2020-001564.CrossRefPubMedPubMedCentral

15.

Ishihara H, Takagi T, Kondo T, Fukuda H, Tachibana H, Yoshida K, et al. Predictive impact of an early change in serum C-reactive protein levels in nivolumab therapy for metastatic renal cell carcinoma. Urol Oncol. 2020;38(5):526–32. https://doi.org/10.1016/j.urolonc.2019.12.008.CrossRefPubMed

16.

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 Immunol. 2021;10(12):e1358. https://doi.org/10.1002/cti2.1358.CrossRef

17.

Tachibana H, Nemoto Y, Ishihara H, Fukuda H, Yoshida K, Iizuka J, et al. Predictive impact of early changes in serum c-reactive protein levels in nivolumab plus ipilimumab therapy for metastatic renal cell carcinoma. Clin Genitourin Cancer. 2022;20(1):e81–8. https://doi.org/10.1016/j.clgc.2021.10.005.CrossRefPubMed

18.

Tomita Y, Larkin J, Venugopal B, Haanen J, Kanayama H, Eto M, et al. Association of C-reactive protein with efficacy of avelumab plus axitinib in advanced renal cell carcinoma: long-term follow-up results from JAVELIN Renal 101. ESMO Open. 2022;7(5):100564. https://doi.org/10.1016/j.esmoop.2022.100564.CrossRefPubMedPubMedCentral

19.

Noguchi G, Nakaigawa N, Umemoto S, Kobayashi K, Shibata Y, Tsutsumi S, et al. C-reactive protein at 1 month after treatment of nivolumab as a predictive marker of efficacy in advanced renal cell carcinoma. Cancer Chemother Pharmacol. 2020;86(1):75–85. https://doi.org/10.1007/s00280-020-04088-y.CrossRefPubMed

20.

Kankkunen E, Penttilä P, Peltola K, Bono P. C-reactive protein and immune-related adverse events as prognostic biomarkers in immune checkpoint inhibitor treated metastatic renal cell carcinoma patients. Acta Oncol. 2022;61(10):1240–7. https://doi.org/10.1080/0284186x.2022.2104132.CrossRefPubMed

21.

Del Giudice M, Gangestad SW. Rethinking IL-6 and CRP: why they are more than inflammatory biomarkers, and why it matters. Brain Behav Immun. 2018;70:61–75. https://doi.org/10.1016/j.bbi.2018.02.013.CrossRefPubMed

22.

Jabs WJ, Busse M, Krüger S, Jocham D, Steinhoff J, Doehn C. Expression of C-reactive protein by renal cell carcinomas and unaffected surrounding renal tissue. Kidney Int. 2005;68(5):2103–10. https://doi.org/10.1111/j.1523-1755.2005.00666.x.CrossRefPubMed

23.

Alberti L, Thomachot MC, Bachelot T, Menetrier-Caux C, Puisieux I, Blay JY. IL-6 as an intracrine growth factor for renal carcinoma cell lines. Int J Cancer. 2004;111(5):653–61. https://doi.org/10.1002/ijc.20287.CrossRefPubMed

24.

Koo AS, Armstrong C, Bochner B, Shimabukuro T, Tso CL, deKernion JB, et al. Interleukin-6 and renal cell cancer: production, regulation, and growth effects. Cancer Immunol Immunother. 1992;35(2):97–105. https://doi.org/10.1007/bf01741856.CrossRefPubMed

25.

Miki S, Iwano M, Miki Y, Yamamoto M, Tang B, Yokokawa K, et al. Interleukin-6 (IL-6) functions as an in vitro autocrine growth factor in renal cell carcinomas. FEBS Lett. 1989;250(2):607–10. https://doi.org/10.1016/0014-5793(89)80805-1.CrossRefPubMed

26.

Sang YB, Yang H, Lee WS, Lee SJ, Kim SG, Cheon J, et al. High serum levels of IL-6 predict poor responses in patients treated with pembrolizumab plus axitinib for advanced renal cell carcinoma. Cancers (Basel). 2022;14(23):5985. https://doi.org/10.3390/cancers14235985.CrossRefPubMed

27.

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;167:13–22. https://doi.org/10.1016/j.ejca.2022.02.022.CrossRefPubMed

28.

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;10(3):e004024. https://doi.org/10.1136/jitc-2021-004024.CrossRefPubMedPubMedCentral

29.

Saal J, Bald T, Eckstein M, Ritter M, Brossart P, Ellinger J, et al. Early C-reactive protein kinetics predicts immunotherapy response in non-small cell lung cancer in the phase III OAK trial. JNCI Cancer Spectr. 2023;7(2):pkad027. https://doi.org/10.1093/jncics/pkad027.CrossRefPubMedPubMedCentral

30.

Tomisaki I, Harada M, Tokutsu K, Minato A, Nagata Y, Kimuro R, et al. Impact of C-reactive protein flare response in patients with advanced urothelial carcinoma who received pembrolizumab. In Vivo. 2021;35(6):3563–8. https://doi.org/10.21873/invivo.12659.CrossRefPubMedPubMedCentral

31.

Santoni M, Massari F, Myint ZW, Iacovelli R, Pichler M, Basso U, et al. Global real-world outcomes of patients receiving immuno-oncology combinations for advanced renal cell carcinoma: the ARON-1 study. Target Oncol. 2023. https://doi.org/10.1007/s11523-023-00978-2.CrossRefPubMed

Title: Early kinetics of C-reactive protein as prognosticator for survival in a real-world cohort of patients with metastatic renal cell cancer under first-line therapy with immune checkpoint inhibitors
Authors: Vayda Schüttke
Cathrin Kusiek
Susanne Fuessel
Christian Thomas
Bjoern Thorben Buerk
Kati Erdmann
Publication date: 11-09-2023
Publisher: Springer International Publishing
Keywords: Tyrosine Kinase Inhibitors
Tyrosine Kinase Inhibitors
Kidney Cancer
Kidney Cancer
Kidney Cancer
Checkpoint Inhibitors
Published in: Clinical and Translational Oncology / Issue 5/2024
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI: https://doi.org/10.1007/s12094-023-03317-z

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Purpose

Methods/patients

Results

Conclusions

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