Evaluation of CRP (c-reactive protein) flare phenomena as an early predictor of response to the Atezolizumab + Bevacizumab therapy in renal cell carcinoma

Lead Investigator: Jörg Ellinger, University Hospital Bonn
Title of Proposal Research: Evaluation of CRP (c-reactive protein) flare phenomena as an early predictor of response to the Atezolizumab + Bevacizumab therapy in renal cell carcinoma
Vivli Data Request: 7164
Funding Source: None
Potential Conflicts of Interest: None

Summary of the Proposed Research:
First-line treatment of metastatic renal cell carcinoma (mRCC) has changed substantially in recent years due to the introduction of immune checkpoint inhibition. Immune checkpoint inhibitors work by blocking checkpoint proteins from binding with their partner proteins. This prevents the “off” signal from being sent, allowing the T cells to kill cancer cells. The combination of immune checkpoint inhibitors as well as a combination of tyrosine kinase inhibitors are nowadays standard therapies in mRCC. The success of immunotherapy is based on the induction of an anti-tumor immune response. C-reactive protein (CRP) is a substance produced by the liver in response to inflammation and is widely used as a surrogate biomarker for the assessment of systemic inflammation.

The occurrence and kinetics of systemic inflammatory response reflected by serum CRP has been implicated with treatment response in various cancer entities. Recently, Fukuda et al. described the CRP “flare-response” phenomenon defined by an early CRP increase after immunotherapy initiation with a subsequent drop below baseline. These early CRP changes appear to mirror the dynamic phase of systemic inflammation after inducing the desired antitumoral immune response on immunotherapy. We observed in a retrospective multi-center cohort with patients undergoing immunotherapy (nivolumab/ipilimumab or pembrolizumab/axitinib) as first line therapy for mRCC.

This research proposal is designed to study the relevance of the CRP flare-response phenomenon in patients treated with the combination therapy Bevacizumab/Atezolizumab versus sunitinib in the IMmotion 151 trial as predictor of patients’ outcome.

Statistical Analysis Plan:

The patients will be classified into three C-reactive protein (CRP) response groups (“CRP flare-responders”, “CRP responders”, “Non-CRP responders”), by the definition of Fukuda et al. The classification is based on serum CRP dynamics during the first three months of therapy initiation. To evaluate whether the predictive CRP flare-response occurs only with Atezolizumab + Bevacizumabtherapy and not with sunitinib monotherapy, we want to compare the clinical data from the IMmotion151 trial. For accurate prospective characterization and determination of the early CRP-kinetics subgroups, we need the baseline CRP value, and ideally all CRP values collected during the study visits within the first 3 months after treatment start. We therefore would like to assemble the CRP serum concentration and the differential blood parameters (leukocytes, lymphocytes, neutrophils), to evaluate prognostic values such as the neutrophil-to-lymphocyte ratio in response to Atezolizumab + Bevacizumabtherapy and sunitinib, at baseline (max. 28 days prior to therapy) and at all further study visits within the first three months after treatment initiation.

According to the earlier definition by Fukuda et al. we define the early CRP-kinetics subgroups as follows:
– “CRP flare-responders” are defined as an early increase in CRP levels to more than double from baseline within one month after therapy initiation, and a subsequent decrease below the baseline within three months.
– “CRP responders” show a decrease of serum CRP levels by ≥ 30% from baseline within three months without flare-response.
– “CRP non-responders” include all other patients without the above specified CRP changes.

The evaluation of the predictive value of the early CRP-kinetics will be carried out with the 452 patients assigned to the Bevazizumab/Atezulizumab versus 461 patients assigned to sunitinib treatment within the IMmotion151 trial. Patients with missing data will be excluded from the analysis.

Fisher’s exact, Mann–Whitney U, and Kruskal–Wallis tests will be applied to perform intergroup comparisons. The progression-free (PFS) and overall survival (OS), including 95% confidence intervals will be estimated with the Kaplan–Meier method and compared with log-rank tests. To compare CRP dynamics (CRP-flare responder, CRP responder vs. CRP non-responder), baseline patient (age, gender, ethnicity, Karnofsky Index) and tumor-related parameters (e.g., MSKCC risk group, histology, PD-L1 expression, previous nephrectomy) on OS and PFS, univariate and multiple Cox regressions will be conducted. Independent variables will only be included in the multiple regression if the respective effect is significant in the univariate analysis; Forward Wald selection will be applied. Statistical analyses will be performed with SPSS version 25 (IBM, Armonk, USA), R (Version x64 4.0.3) and GraphPad Prism 9 (GraphPad Software Inc, CA, USA). All statistical tests will be two-sided, and p-values < 0.05 will be considered significant.

Requested Studies:
A Phase III, Open-Label, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Bevacizumab Versus Sunitinib in Patients With Untreated Advanced Renal Cell Carcinoma
Sponsor: Roche
Study ID: NCT02420821
Sponsor ID: WO29637

Public Disclosures:

  1. Saal J, Bald T, Hölzel M, Ritter M, Brossart P, Ellinger J, Klümper N. In the phase 3 IMmotion151 trial of metastatic renal cell carcinoma the easy-to-implement modified Glasgow prognostic score predicts outcome more accurately than the IMDC score. Ann Oncol. 2022 Jun 15:S0923-7534(22)01730-6. doi: 10.1016/j.annonc.2022.06.003
  2. Saal, T. Bald, M. Eckstein, D.J. Ralser, M. Ritter, P. Brossart, V. Grünwald, M. Hölzel, J. Ellinger, N. Klümper. A0332 – On-treatment modified Glasgow prognostic score (mGPS) improves imaging-only prediction of response and outcomes in metastatic renal cell carcinoma, European Urology, Volume 83, Supplement 1, 2023, Page S483,ISSN 0302-2838. doi: 10.1016/S0302-2838(23)00381-0
  3. Saal, J., Bald, T., Eckstein, M., Ralser, D.J., Ritter, M., Brossart, P., Grünwald, V., Hölzel, M., Ellinger, J. and Klümper, N., 2023. Integrating On-Treatment Modified Glasgow Prognostic Score and Imaging to Predict Response and Outcomes in Metastatic Renal Cell Carcinoma. JAMA oncology. doi: 10.1001/jamaoncol.2023.1822
  4. Saal J, Bald T, Eckstein M, Ralser D, Ritter M, Brossart P, Grünwald V, Hölzel M, Ellinger J, Klümper N. (2023). In the phase 2/3 IMmotion150/151 study, the Modified Glasgow Prognostic Score (mGPS) improves the imaging-only prediction of treatment response in patients with metastatic renal cell carcinoma. North Rhine-Westphalian Society for Urology. Doi: 10.3205/23nrwgu20
  5. Saal J, Bald T, Hölzel M, Ritter M, Brossart P, Ellinger J, Klümper N. P229 Der modifizierte Glasgow Prognostic Score (mGPS) sagt das Überleben in Patienten mit metastasiertem Nierenzellkarzinom in der Phase III IMmotion151 Studie besser voraus als der IMDC score. Jahrestagung der Deutschen, Österreichischen und Schweizerischen Gesellschaften für Hämatologie und Medizinische Onkologie, 7.–10. Oktober 2022. Oncol Res Treat 27 September 2022; 45 (Suppl. 2): 5–346, Page 318. doi: 10.1159/000526456