High Serum Levels of IL-6 Predict Poor Responses in Patients Treated with Pembrolizumab plus Axitinib for Advanced Renal Cell Carcinoma

SIMPLE SUMMARY: Renal cell carcinoma (RCC) is one of the most common types of cancers concerning the kidneys worldwide. Pembrolizumab and axitinib treatment (Pembro/Axi) is amongst the most effective first-line immunotherapies for advanced RCC. However, it remains difficult to predict the effectiveness of Pembro/Axi immunotherapy for the treatment of RCC. Therefore, this prospective study was conducted with the aim of evaluating whether baseline serum interleukin-6 (IL-6) could serve as a predictive biomarker for Pembro/Axi treatment in RCC. Low levels of IL-6 were associated with longer progression-free survival rates, while high IL-6 levels had worse progression-free rates and overall survival. Moreover, high IL-6 levels were related to reduced interferon-γ and tumor necrosis factor-α production. These findings elucidate the clinical and biological implications of IL-6 as a predictive biomarker in RCC patients who received Pembro/Axi as a first-line treatment. ABSTRACT: Renal cell carcinoma (RCC) is the most common type of kidney malignancy worldwide with Pembrolizumab and axitinib treatment (Pembro/Axi) amongst the most effective first-line immunotherapies for advanced RCC. However, it remains difficult to predict treatment response and early resistance. Therefore, we evaluated whether baseline serum interleukin-6 (IL-6) could be a predictive biomarker. Between November 2019 and December 2021, 58 patients with advanced RCC were enrolled, administered first-line Pembro/Axi, and baseline blood samples were analyzed using flow cytometry. The mean baseline serum IL-6 concentration was 8.6 pg/mL in responders and 84.1 pg/mL in patients with progressive disease. The IL-6 cut-off value was set at 6.5 pg/mL using time-dependent receiver operating characteristic curves, with 37.9% of patients having high baseline serum IL-6 levels and 62.1% having low levels. Objective response rates were 58.3% and 36.4% in low and high IL-6 groups, respectively. Overall survival and progression-free survival were longer in patients with low IL-6 levels than in those with high levels. High IL-6 levels were related to reduced interferon-γ and tumor necrosis factor-α production from CD8+ T cells. Overall, high baseline serum IL-6 levels were associated with worse survival outcomes and reduced T-cell responses in Pembro/Axi-treated advanced RCC patients.