Nivolumab in Metastatic Clear-cell Renal Cell Carcinoma: An Integrative Biomarker Analysis from the NIVOREN GETUG-AFU...

Area of Science:

• Oncology
• Immunology
• Translational Research

Background:

• Nivolumab demonstrates improved survival in refractory metastatic clear-cell renal cell carcinoma (ccRCC).
• Reliable biomarkers for predicting nivolumab activity in ccRCC are currently lacking.
• Vascular endothelial growth factor (VEGF) receptor-directed therapies are a common first-line treatment.

Purpose of the Study:

• To identify predictive biomarkers for nivolumab activity in ccRCC patients progressing after VEGF-targeted therapy.
• To evaluate the safety and efficacy of nivolumab in a real-world setting.
• To integrate translational research with clinical trial data.

Main Methods:

• A real-world phase 2 clinical trial involving 720 ccRCC patients treated with nivolumab.
• Assessment of candidate tissue and circulating biomarkers using immunoassays and gene expression profiling.
• Analysis of tumor microenvironment features including immune cell infiltration and gene expression signatures.

Main Results:

• Nivolumab activity and safety were consistent with pivotal trial data.
• Tertiary lymphoid structures, CD8+ lymphocytes, and CD163+ macrophages at the invasive margin were marginally associated with longer progression-free survival.
• High expression of VEGF on tumor cells was strongly associated with shorter progression-free and overall survival.
• High tumor lymphocyte infiltration and low neutrophil/stromal cell infiltration correlated with improved nivolumab response.
• Elevated circulating interleukin (IL)-6 and IL-8 levels were independently associated with shorter progression-free and overall survival.

Conclusions:

• Immune and angiogenic features of the tumor microenvironment can inform outcomes for nivolumab treatment in ccRCC.
• Circulating cytokines, specifically IL-6 and IL-8, emerged as the most promising predictors of immunotherapy response in ccRCC.
• Further validation of these biomarkers could personalize ccRCC treatment strategies.