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Predictive Impact of Early Changes in Serum C-reactive Protein Levels in Nivolumab plus Ipilimumab Therapy for Metastatic Renal Cell Carcinoma - Beyond the Abstract

Nivolumab plus ipilimumab (NIVO-IPI) is one of the treatment standards for previously untreated clear cell renal cell carcinoma (RCC). Furthermore, the 20% progressive disease (PD) criterion as the best objective response was reportedly higher in the NIVO-IPI clinical trial than that in the other immune checkpoint inhibitor (ICI) combined regimens.1-4 There is an urgent need for predictive biomarkers for clinical outcomes and early detection of PD in NIVO-IPI therapy.


Serum C-reactive protein (CRP) is a biomarker for inflammatory reactions, whose level is reportedly associated with prognosis for patients with metastatic RCC (mRCC) during treatment, including surgery, cytokine therapy, and molecular targeted therapy.5-9 In the era of ICI therapy for mRCC, evidence regarding the predictive value of CRP for survival is lacking. In this multi-institutional retrospective study, we evaluated the predictive value of the change in serum CRP levels during the early period of NIVO-IPI therapy in the clinical outcome of patients with previously untreated mRCC.

The results showed that the change in serum CRP level within the first 3 months of NIVO-IPI therapy was significantly associated with progression-free survival (PFS) for previously untreated patients with mRCC. Compared to the non-normalized CRP group, the normal CRP (2.7 vs. 28.1, P=0.0002) and normalized CRP (2.7 vs. 11.0, P=0.0094) groups showed significantly high PFS, and the objective response rate was high in the normal CRP (57.1% vs. 18.7%, P=0.015) and normalized CRP (81.8 vs. 18.7%, P=0.0008) groups. Multivariate analyses showed that CRP normalization may be an independent favorable factor for PFS.

Serum CRP is easy to monitor and assess in clinical practice. Therefore, it is expected to be a useful predictor for the oncological outcomes of mRCC. To the best of our knowledge, this is the first report to demonstrate that an early change in CRP was associated with PFS and objective response rate in NIVO-IPI therapy. Our data suggest that despite a high initial CRP in patients, prolonged PFS could be achieved if CRP levels were normalized and tumor response was obtained during NIVO-IPI therapy. The patients with normalized CRP could have survival benefits similar to patients with normal CRP. Furthermore, patients with non-normalized CRP had poor survival. Detecting PD in the early phase of NIVO-IPI therapy and quickly changing to subsequent therapy is essential in clinical practice. This study demonstrated that CRP change during NIVO-IPI therapy was related to PFS and was helpful in predicting the therapeutic effect. This result will help physicians to detect patients who show low efficacy with NIVO-IPI and decide on a subsequent therapy for mRCC.

Written by: Hidekazu Tachibana,1 Yuki Nemoto,2 Hiroki Ishihara,1 Hironori Fukuda,3 Kazuhiko Yoshida,3 Junpei Iizuka,3 Yasunobu Hashimoto,2 Tsunenori Kondo,1 Kazunari Tanabe,3 Toshio Takagi3

  1. Department of Urology, Tokyo Women’s Medical University Medical Center East, Tokyo, Japan
  2. Department of Urology, Saiseikai Kawaguchi Hospital, Saitama, Japan
  3. Department of Urology, Tokyo Women's Medical University, Japan

References:
  1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 2018; 378: 1277-90.
  2. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2021; 384: 829-41.
  3. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019; 380: 1103-15.
  4. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019; 380: 1116-27.
  5. Takagi T, Fukuda H, Kondo T, et al. Prognostic Markers for Refined Stratification of IMDC Intermediate-Risk Metastatic Clear Cell Renal Cell Carcinoma Treated with First-Line Tyrosine Kinase Inhibitor Therapy. Target Oncol 2019; 14: 179-86.
  6. Bhindi B, Abel EJ, Albiges L, et al. Systematic Review of the Role of Cytoreductive Nephrectomy in the Targeted Therapy Era and Beyond: An Individualized Approach to Metastatic Renal Cell Carcinoma. Eur Urol 2019; 75: 111-28.
  7. Casamassima A, Picciariello M, Quaranta M, et al. C-reactive protein: a biomarker of survival in patients with metastatic renal cell carcinoma treated with subcutaneous interleukin-2 based immunotherapy. J Urol 2005; 173: 52-5.
  8. Miyake H, Miyazaki A, Imai S, Harada K, Fujisawa M. Early Tumor Shrinkage Under Treatment with First-line Tyrosine Kinase Inhibitors as a Predictor of Overall Survival in Patients with Metastatic Renal Cell Carcinoma: a Retrospective Multi-Institutional Study in Japan. Target Oncol 2016; 11: 175-82.
  9. Saito K, Kihara K. C-reactive protein as a biomarker for urological cancers. Nat Rev Urol 2011; 8: 659-66.

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