Pre-treatment C-reactive protein level is a prognostic marker of patients treated with immune checkpoint inhibitors for renal cell carcinoma: a systematic review and meta-analysis

Introduction

Previous studies have demonstrated the superior efficacy of immune checkpoint inhibitors (ICIs) in treating advanced renal cell carcinoma (RCC) compared with molecular targeted therapies such as everolimus (1) and sunitinib (2). CheckMate 025 trial showed that nivolumab resulted in longer overall survival (OS) compared to everolimus in second- or third-line therapy for advanced clear cell RCC [hazard ratio (HR): 0.73, 98.5% confidence interval (CI): 0.57–0.93] (1). The Checkmate214 study included previously untreated patients with advanced RCC and demonstrated that combination therapy with nivolumab plus ipilimumab was superior to sunitinib in terms of OS (HR: 0.72, 95% CI: 0.62–0.85) and progression-free survival (PFS) (HR: 0.86, 95% CI: 0.73–1.01). Notably, the safety profiles in both studies also in favored ICI treatment (1,2).

It is also well recognized that ICIs result in more distinct treatment outcomes compared to molecular targeted therapies. While ICIs may provide high rates of complete response in some patients (e.g., 11% for nivolumab plus ipilimumab in CheckMate214) (2), the rate of progressive disease (PD) is reported to be 35% when using nivolumab monotherapy (CheckMate025) (1) and 25% with nivolumab plus ipilimumab (CheckMate214) (2). Therefore, it is clinically valuable to identify patients who are likely to respond well or poorly to ICI therapy.

Programmed death ligand 1 (PD-L1) expression is a widely studied but debated prognostic marker in RCC. Some studies link it to poor outcomes (3-5), while others suggested that high expression of PD-L1 may be more treatment-responsive (6). Denize et al. showed that tumor-cell PD-L1 positive tumors were associated with longer PFS and higher objective response rate (ORR) on nivolumab compared to everolimus (6). Yet, in CheckMate 025 or CheckMate 214, OS benefit of nivolumab or nivolumab plus ipilimumab was observed regardless of PD-L1 status (1,7). Overall, PD-L1 expression remains an unreliable predictor of ICI response in RCC patients.

Several other clinical parameters have also been proposed as predictors of therapeutic response to ICIs in RCC. These predictors include neutrophil-to-lymphocyte rate (8-10), platelet count (11), elevated lactate dehydrogenase (LDH) (12) and low albumin levels (13). Unsurprisingly, most of these factors are related to inflammation. Since C-reactive protein (CRP) is one of the most important markers reflecting systemic inflammatory response (14), we conducted a systematic review and meta-analysis to explore the clinical impact of CRP levels in patients with advanced RCC treated with ICIs. Notably, recent treatment strategy includes the combination therapy of ICI plus tyrosine kinase inhibitor (TKI) (15). We aimed to investigate the pure relationship between CRP level and ICI treatment response. Therefore, studies on ICI monotherapy or ICI plus ICI combination therapies are only included for evaluation in the present study. We present this article in accordance with the PRISMA reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-526/rc) (16).

Methods

The protocol has been registered in the International Prospective Register of Systematic Reviews database (PROSPERO: CRD42023430905).

Study selection and characteristics

A comprehensive literature search of electronic databases (PubMed, Web of Science, and Cochrane Library) was conducted on July 4^th 2024. An initial screening of titles and abstracts was performed to identify eligible studies relevant to the topic of this review. Two reviewers (Y.Y. and S.K.) carried out this process independently. The following string terms were used for initial screening: (((((metastatic renal cell carcinoma) OR (renal cell carcinoma)) OR (kidney cancer)) AND (((biomarker) OR (prognostic marker)) OR (haematological))) AND (((nivolumab) OR (ipilimumab)) OR (check point inhibitor))) AND (((survival) OR (recurrence)) OR (response)). In addition, all full-text articles were assessed and excluded with reasons when deemed inappropriate. Manual searches of reference lists of relevant articles were also performed to identify additional studies of interest. Disagreements were resolved through consensus with co-authors.

Inclusion and exclusion criteria

We used the PECO (Population, Exposure, Comparator, Outcome) framework to formulate the clinical question. Eligible studies included those evaluating baseline high CRP levels (Exposure) in comparison to low CRP levels (Comparator) as indicators of treatment response or prognostic predictors (Outcome) in patients with RCC undergoing ICI-treatment (Population). The primary outcome was OS and the secondary outcome was PFS, cancer-specific survival (CSS), and ORR. References of the included manuscripts were also reviewed to identify additional relevant studies. Exclusion criteria included studies without the original data (reviews, letters, comments, books, description of trials, meeting abstracts), case reports, and articles published in languages other than English.

Data extraction

Two authors (Y.Y. and S.K.) independently extracted the data. Information on clinical parameters including age, clinical T stage (cT stage), and prognosis, was collected from the included studies. Data on outcomes such as OS, PFS, CSS, and ORR were also extracted. All discrepancies in data extraction were resolved through consensus with the co-authors. For studies that did not provide information on the percentage of patients with intermediate to high risk, these values were calculated using available data provided within the studies.

Risk-of-bias assessment

The quality of the included studies and risk of bias were evaluated using the ROBINS-I tool for non-randomized studies, as outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Tables S1,S2) (17,18). The ROBINS-I assessment for each study was conducted independently by two authors (A.M. and S.K.).

Statistical analyses

Meta-analysis

We conducted a formal meta-analysis of OS, PFS using the HRs with their 95% CIs, which were directly extracted from the selected articles directly to calculate pooled HRs. Statistical heterogeneity among studies was assessed using the Chi-squared test and I² statistic, with significance thresholds set at P<0.10 and I²<50%, respectively. We used a random-effects model since the included studies were all retrospective and potentially harbor heterogeneity. Publication bias was evaluated using Egger’s linear regression and funnel plot analysis. All statistical analyses were performed using R version 4.3.0 (R Foundation for Statistical Computing, Vienna, Austria) with the metafor package. Statistical significance was set at P<0.05.

Results

Study selection and characteristics

The search string is presented in Figure 1. The initial search identified a total of 817 articles (Figure 1). Two articles that were identified from the reference lists of the original search were added. After removal of the duplicates, 703 articles were identified for further processing. Subsequently, 549 articles were excluded after title and abstract assessment. Finally, 12 studies that reported the prognosis relevant to CRP (both baseline CRP and CRP kinetics) were included for qualitative and quantitative analyses after full-text reading. The general characteristics of the eligible studies are summarized in Table 1 (baseline CRP) and Table 2 (CRP kinetics). We identified 12 non-randomized controlled studies (NRCTs) relevant to baseline CRP levels and CRP kinetics (19-30). There were no randomized controlled trials (RCTs).

Figure 1 PRISMA flow-chart of the systematic review and meta-analysis.

Risk of bias assessment

Results for the risk of bias for each domain across the searched studies are shown in Table S2. The majority of the searched studies showed low or moderate overall risk of bias.

Meta-analysis

The prognostic value of baseline CRP (high vs. low)

OS in treatment with ICIs (nivolumab plus ipilimumab or nivolumab alone)

Five studies were included in the overall analysis. In the high CRP group, worse OS (HR: 3.97, 95% CI: 2.27–6.94) was observed (Figure 2A). There was very low heterogeneity (I²=25%, P=0.893) among the studies.

Figure 2 Forest plots showing the prognostic value of baseline CRP level. A comparison of high baseline CRP level and low baseline CRP level is performed for (A) overall survival in ICI-treated patients and (B) progression-free survival in nivolumab-treated patients. CI, confidence interval; CRP, C-reactive protein; HR, hazad ratio; ICI, immune checkpoint inhibitor.

We also conducted a sub-analysis depending on types of treatment (nivolumab plus ipilimumab or nivolumab alone). There were 2 studies evaluating baseline CRP in patients treated with nivolumab plus ipilimumab. Higher baseline CRP levels were associated with worse OS (HR: 3.34, 95% CI: 1.63–6.85) (Figure 2A). The heterogeneity was low in this analysis (I²=25%, P=0.293).

There were 3 studies analyzing the data on patients treated with nivolumab monotherapy. Patients with higher baseline CRP levels had worse OS (HR: 5.67, 95% CI: 2.12–15.12) (Figure 2A). There was moderate heterogeneity among the studies (I²=43%, P=0.173).

PFS in treatment with nivolumab alone

There were 3 studies for this sub-analysis. Worse PFS was observed in the group with higher baseline CRP level (HR: 1.62 (95% CI: 1.01–2.61) (Figure 2B). There was very low heterogeneity among the studies (I²=0%, P=0.893).

Impact of CRP kinetics (flare responder vs. responder vs. normal) on PFS

There were 2 studies evaluating the association between CRP kinetics and PFS. With regards to PFS, the “CRP-flare responder” group showed better PFS (HR: 0.34 (95% CI: 0.06–1.88) but the difference did not meet statistical significance (Figure 3A). Heterogeneity was moderate in this analysis (I²=68%, P=0.078) (Figure 3A). The “CRP responder” group also showed a statistical difference regarding PFS (HR: 0.67 (95% CI: 0.32–1.37) (Figure 3B). There was moderate heterogeneity in this analysis (I²=32%, P=0.227).

Figure 3 Forest plots showing the progression-free survival of (A) CRP-flare responder and (B) CRP-responder. CRP flare-responder, CRP elevation of at least double the baseline during the first month after ICI-initiation followed by a decrease below the baseline within 2 months; CRP responder, decrease in CRP levels of at least 30% from baseline within 3 months. CI, confidence interval; CRP, C-reactive protein; HR, hazad ratio.

Discussion

The mechanism of ICI-treatment is promoting T-cell mediated immune responses against cancer cells. Therefore, inflammation-related biomarkers and immune-related adverse events may provide insights into treatment efficacy. Inflammation promotes cancer progression by enabling immune evasion and modulating tumor microenvironment through mechanisms such as direct effect on cancer cells, cytokine network activation, and epithelial-to-mesenchymal transition, and metastasis facilitation (31,32). Tumor-driven inflammation may promote interleukin-6 levels, leading to elevated CRP production (33). Thus, CRP may serve as a surrogate marker of tumor aggressiveness. A meta-analysis assessing the prognostic value of CRP demonstrated that elevated CRP levels were associated with worse OS (HR: 1.51, 95% CI: 1.09–1.93), CSS (HR: 3.91, 95% CI: 2.18–5.64), advanced stage (risk ratio (RR): 2.90, 95% CI: 2.52–3.32), and higher tumor grade (RR: 4.31, 95% CI: 3.35–5.56) (34). However, that meta-analysis was conducted prior to the ICI era, warranting an updated review. We therefore performed a systematic review and meta-analysis to investigate the prognostic value of CRP in patients with advanced RCC treated with ICIs.

Our review included three studies on patients treated with nivolumab monotherapy and two studies on combination therapy with ipilimumab and nivolumab. One key finding was the prognostic significance of pretreatment CRP levels. Low pretreatment CRP levels were significantly associated with improved OS in both treatment groups (ipilimumab + nivolumab: HR 3.34 (95% CI: 1.63–6.85), nivolumab alone: 5.67 (95% CI: 2.12–15.12). Ishihara et al. also highlighted other inflammatory markers with prognostic relevance, including neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio, and platelet-to-lymphocyte ratio, alongside pretreatment CRP (19). Suzuki et al. also reported the prognostic value of NLR (21). Additional predictors of OS include prior nephrectomy (21) and histological type of tumor (24).

In recent years, CRP kinetics have emerged as a potential predictor of ICI response. Fukuda et al. categorized patients into three groups based on CRP kinetics during the first 3 months of treatment (26). They found that a temporary CRP spike followed by decline was associated with favorable outcomes (26). However, this categorization included both normal and high pretreatment CRP levels within the “flare-responder” and “responder” groups. To address this, Barth et al. modified the classification into 4 groups; “All-normal CRP” as having CRP levels consistently below the upper limit of normal CRP level, “CRP flare-responder” as having CRP elevation of at least double the baseline during the first month after ICI-initiation followed by a decrease below the baseline within 2 months, “CRP responder” as having a decrease in CRP levels of at least 30% from baseline within 3 months, and “CRP non-responder” as having all other CRP kinetics (30). Although Barth’s study used a pan-cancer cohort, a subgroup analysis in RCC patients did not demonstrate significant differences in PFS or OS. Similarly, our meta-analysis did not find a statistically significant association between CRP kinetics and prognosis. However, this conclusion is limited by the small number of included studies (only two), one of which had a high risk of bias. Therefore, the predictive value of CRP kinetics for ICI response in RCC remains inconclusive.

In the past decade, 3 RCTs have been conducted to show the impact of combination therapy with ICI plus TKI as first-line therapy against metastatic RCC (35-37). The KEYNOTE-426 showed a superior OS in patients treated by pembrolizumab plus axitinib to sunitinib monotherapy (35,36). In the PD-L1 positive patients, a significantly longer PFS was observed in the avelumab plus axitinib combination therapy when compared to sunitinib monotherapy in the JAVELIN Renal 101 trial (37). And the third RCT showed superior OS, PFS, and ORR for nivolumab plus cabozantinib therapy when compared to sunitinib monotherapy (38). A recent meta-analysis included these 3 RCTs and showed that ICI-TKI combination therapy was significantly associated with better OS when compared with sunitinib monotherapy in metastatic RCC patients ≥65 years old (38). A recent real-world data from the ARON-1 study included an analysis comparing the outcome of OS and PFS in ICI plus ICI combination therapy versus ICI plus TKI combination therapy in intermediate-risk metastatic RCC patients (15). They revealed better OS for ICI plus TKI combination therapy than for ICI plus ICI combination therapy (55.7 and 40.2 months, respectively, P=0.047) (15). PFS was also better for ICI plus TKI combination therapy than for ICI plus ICI combination therapy (30.7 and 13.2 months, respectively, P<0.001) in intermediate-risk metastatic RCC patients (15). Reflecting this background, biomarkers including CRP levels may be recommended for investigation to see association with treatment response in patients treated with ICI plus TKI combination therapy.

There are some limitations regarding this study. Due to the relatively low incidence of advanced RCC cases treated with ICIs compared to resectable tumors, most available studies had small sample sizes, introducing a risk of bias. This scarcity of data prompted our meta-analysis. Nevertheless, aggregating small studies introduces potential bias in pooled estimates and heterogeneity. Another limitation involves the treatment type. Recent trials have reported favorable outcomes using ICI and TKI combinations (39,40). Our meta-analysis focused solely on ICI monotherapy or dual-ICI therapy to isolate the relationship between CRP and ICI efficacy. The different cutoff levels of baseline CRP and different distribution of IMDC (International Metastatic RCC Database Consortium) risks may influence the heterogeneity among studies. Lastly, our analysis of CRP kinetics was limited and biased due to the inclusion of only two studies—one relying on univariate analysis. More robust and comprehensive studies are required to clarify the clinical utility of CRP kinetics as a biomarker for ICI response in RCC.

Conclusions

We conducted a systematic review and meta-analysis to evaluate the prognostic value of CRP in patients with RCC receiving ICIs. The key finding of the present study is that a high pretreatment CRP level is a significant prognostic factor associated with worse OS and PFS. In contrast, the prognostic value of CRP kinetics in ICI-treated RCC remains unclear. The current evidence is insufficient, and larger-scale studies are warranted to further evaluate the prognostic implications of CRP kinetics in patients treated with ICI therapy.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-526/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-526/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-526/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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