Soluble Immune Checkpoint Molecules as Predictors of Efficacy in Immuno-Oncology Combination Therapy in Advanced Renal Cell Carcinoma.

Immuno-oncology (IO) combination therapy is the first-line treatment for advanced renal cell carcinoma (RCC). However, biomarkers for predicting the response to IO combination therapy are lacking. Here, we investigated the association between the expression of soluble immune checkpoint molecules and the therapeutic efficacy of IO combination therapy in advanced RCC. The expression of soluble programmed cell death-1 (sPD-1), soluble programmed cell death ligand-1 (sPD-L1), soluble PD-L2 (sPD-L2), and lymphocyte activation gene-3 (sLAG-3) was assessed in plasma samples from 42 patients with advanced RCC who received first-line IO combination therapy. All IMDC risk classifications were represented among the patients, including 14.3, 57.1, and 28.6% with favorable, intermediate, and poor risk, respectively. Univariate analysis revealed that prior nephrectomy, sPD-L2 levels, and sLAG-3 levels were significant factors affecting progression-free survival (PFS), whereas multivariate analyses suggested that sPD-L2 and sLAG-3 levels were independent prognostic factors for PFS. In a univariate analysis of the overall survival, prior nephrectomy and sPD-L2 levels were significant factors; no significant differences were observed in the multivariate analysis. No significant correlation was observed between the sPD-L2 and sLAG-3 levels and PD-L2 and LAG-3 expression via immunohistochemistry. In conclusion, sPD-L2 and sLAG-3 expression may serve as a potential biomarker for predicting IO combination therapy efficacy.

Prognostic Value of Absolute Lymphocyte Count in Patients with Advanced Renal Cell Carcinoma Treated with Nivolumab Plus Ipilimumab.

Nivolumab and ipilimumab (NIVO + IPI) is standard therapy for patients with advanced renal cell carcinoma (RCC). Absolute lymphocyte count (ALC) is a valuable prognostic factor in patients with various cancers treated with immune checkpoint inhibitors. Herein, we determined the prognostic value of pretreatment ALC in advanced RCC patients treated with NIVO + IPI as first-line therapy. Data from 46 advanced RCC patients treated with NIVO + IPI between September 2018 and August 2022 were retrospectively reviewed and analyzed. Median progression-free survival (PFS) and overall survival (OS) were significantly shorter in patients with low than high ALC (PFS: p = 0.0095; OS: p = 0.0182). Multivariate analysis suggested that prior nephrectomy [hazard ratio (HR) = 3.854, 95% confidence interval (CI) = 1.433-10.359, p = 0.0075] and pretreatment ALC (HR = 2.513, 95% CI = 1.119-5.648, p = 0.0257) were independent factors for PFS. Our new prognostic ALNx model based on ALC and prior nephrectomy suggested that the poor-risk group was a predictor of significantly worse PFS (p < 0.0001) and OS (p = 0.0016). Collectively, the developed ALNx model may be a novel predictor of response in advanced RCC patients treated with NIVO + IPI.

Early primary renal tumor response predicts clinical outcome in patients with primary unresectable renal cell carcinoma with synchronous distant metastasis receiving molecularly targeted therapies.

The aim of the present study was to investigate the prognostic factors for patients with primary unresectable renal cell carcinoma (RCC) with synchronous distant metastasis receiving molecularly targeted therapies. A total of 26 patients with primary unresectable RCC with synchronous distant metastasis underwent molecularly targeted therapies at the Kurume University Hospital (Kurume, Japan) between March 2008 and March 2016. Early primary renal tumor response was evaluated at 8-12 weeks after the introduction of molecularly targeted therapy and a 10% decrease in the diameter of primary renal tumor was used as the cut-off value. The median overall survival from the initiation of first-line molecularly targeted therapy was 18.3 months. Univariate analyses for various factors identified early primary renal tumor response (P=0.0004) and best response to first-line treatment (P=0.0002) as prognostic variables. Multivariate analyses also identified early primary renal tumor response (P=0.0099) and best response to first-line treatment (P=0.0054) as independent prognostic factors. A comparison of clinical characteristics between the group with ≥10% shrinkage and the group with disease progression or <10% shrinkage revealed that the number of metastatic sites and pretreatment monocyte-to-lymphocyte ratio tended to be predictive factors for primary renal tumor response. These results suggest that early primary renal tumor shrinkage is highly variable for patients with primary unresectable RCC with synchronous distant metastasis receiving molecularly targeted therapies.