The NIVOREN–GETUG AFU 36 study evaluated the safety and activity of nivolumab in an unselected population. This study included an integrated translational research program investigating tissue and circulating biomarkers. We reported in European Urology the final safety and efficacy results, together with all ancillary analyses.3
We included 720 patients who had more adverse baseline characteristics than in the pivotal trial of nivolumab, including ECOG performance status 2, brain metastases, renal function impairment, or more highly pretreated disease. With a long-term median follow-up ≥4.5 years, activity and safety were in line with the CheckMate-025 trial. Grade 3 or 4 nivolumab-related adverse events occurred in 143 patients (19.9%; 95% CI: 17.0%–23.0%). Median progression-free survival (PFS) was 3.3 months (95% CI: 2.8–4.4), and median overall survival (OS) was 24.5 months (95% CI: 22.1–28.1).
Tissue analyses included evaluation of the immune infiltrate by immunohistochemistry, the presence of tertiary lymphoid structures, expression of immune checkpoints, and transcriptomic profiling. Circulating factors included proteins involved in myeloid inflammation, B-cell-related factors, immune checkpoints, soluble adhesion molecules, and hypoxia markers. These ancillary analyses were performed among 353 (circulating biomarkers) and 323 patients (tissue-based biomarkers).
The detection of tertiary lymphoid structures within the tumor was positively associated with response. Checkpoint immunostainings were of more limited predictive value: PD-1 expression on immune cells, but not PD-L1 expression on tumor cells, was associated with marginally longer PFS. However, expression of the hypoxia-related marker VEGF on tumor cells was strongly and inversely associated with PFS. Transcriptomic analysis of the tumor microenvironment revealed that patients with predominant T-cell and NK-cell infiltration, together with a low proportion of neutrophils and non-immune stroma, had a significantly higher response rate to nivolumab and a trend toward longer PFS.
Analysis of soluble factors showed that circulating cytokines associated with pro-tumoral myeloid inflammation, IL-6 and IL-8, were independently associated with shorter PFS and OS, as was the hypoxia marker VEGF. These soluble factors demonstrated stronger predictive value than tissue-based factors. Moreover, circulating IL-6 and IL-8 levels predicted PFS and OS more accurately than the IMDC classification. We further demonstrated the interplay between circulating and tissue-based features in this population.4
Our study supports the broader use of immune checkpoint inhibitors in patients with metastatic renal cell carcinoma, including patients with adverse baseline features. Our comprehensive ancillary program demonstrated an interplay between adverse hypoxia-related features and markers of myeloid inflammation, which could be recapitulated through circulating-based assessments. In the first-line setting, where treatment strategies based on immune checkpoint inhibition and antiangiogenics are both available, our translational findings open the way to more relevant biology-driven approaches to improve patient selection.
Implementation of easily available circulating candidate biomarkers could allow for a more dynamic evaluation of primary and acquired resistance to immune checkpoint inhibitor-based strategies.
Written by:
- Ronan Flippot, MD, PhD, Medical Oncology Department, Gustave Roussy, Immunomonitoring laboratory, INSERM US23, Université Paris Saclay, Orsay, France
- Laurence Albigès, MD, PhD, Medical Oncology Department, Gustave Roussy, Université Paris Saclay, France
- Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015;373:1803–13. https://doi.org/10.1056/NEJMoa1510665.
- Braun DA, Hou Y, Bakouny Z, Ficial M, Angelo MS, Forman J, et al. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med 2020;26:909–18. https://doi.org/10.1038/s41591-020-0839-y.
- Flippot R, Vano Y-A, Dalban C, Beuselinck B, Fléchon A, Meylan M, et al. Nivolumab in Metastatic Clear-cell Renal Cell Carcinoma: An Integrative Biomarker Analysis from the NIVOREN GETUG-AFU 26 Phase 2 Study. Eur Urol 2025:S0302-2838(25)04730-X. https://doi.org/10.1016/j.eururo.2025.09.4169.
- Carril-Ajuria L, Flippot R, Naigeon M, Dalban C, Desnoyer A, Rioux-Leclercq N, et al. High Circulating IL-6/IL-8 Is Associated with Intratumoral Myeloid Contexture and Poor Outcomes in Patients with Advanced Renal Cell Carcinoma Treated with PD-1 Blockade. Clin Cancer Res Off J Am Assoc Cancer Res 2025;31:4150–8. https://doi.org/10.1158/1078-0432.CCR-24-0902.