Baseline circulating soluble factors as predictors of immune-related adverse events (irAEs) in patients (pts) with metastatic clear cell renal carcinoma (mRCC) treated with nivolumab: A translational NIVOREN GETUG-AFU 26 study.

724 Background: The NIVOREN GETUG-AFU 26 study launched a translational research program to quantify baseline circulating soluble factors levels and correlate them with outcomes and irAEs in mRCC pts treated with nivolumab. We previously identified (training-set = 80 pts, validation-set= 233 pts) several soluble factors associated with overall survival (IL-6, IL-8, VEGF, BAFF, and CXCL13) (Carril-Ajuria et al. ASCO. 2022). Our aim was to evaluate the association between baseline levels of circulating soluble factors and the presence of all grade and severe irAEs. Methods: 720 patients treated with nivolumab within the NIVOREN study and with available safety data were included in the study. The association between baseline levels of seven different circulating soluble factors (VEGF, VCAM-1, IL-6, IL-7, IL-8, BAFF, CXCL13) and the development of all grade and severe irAEs was evaluated in those pts who had previously undergone soluble factors quantification within the translational program. The association between other systemic inflammatory markers (the lung immune prognostic index (LIPI), LDH and the derived neutrophil to lymphocyte ratio (dNLR)) and irAEs was also evaluated. Results: Out of 720 pts, 456 (63%) and 143 (20%) pts presented all grade and severe irAEs respectively. Soluble factors quantification at baseline was available for 353 pts. Baseline characteristics were similar to the overall trial population. Lower levels of circulating IL-6 (cut-off: 8.7 pg/ml) at baseline were significantly associated with a higher risk of all grade irAEs (p=0.025). Lower dNLR levels (<3, p=0.003) at baseline and a good LIPI score (p=0.014) were also associated with a higher risk of all grade AEs. No other significant associations were found between circulating soluble factors and all grade irAEs. No significant associations were found between circulating solubles factors/systemic inflammatory markers and the presence of severe irAEs Conclusions: Using the cut-off values previously identified, we observed that lower baseline levels of circulating IL-6 were associated with an increased risk of all grade irAEs. Good LIPI patients and those with a lower dNLR also presented a higher risk of all grade irAEs. Baseline circulating soluble factors and systemic inflammatory markers failed to demonstrate a significant association with the development of severe irAEs.