IL-8, S100 and IL-10 as indipendent predictors of response and survival in melanoma-patients treated with immune checkpoint inhibitors: preliminary results of an observational prospective study

Background.The identification of factors influencing ICI efficacy in cancer pts and the elaboration of a prognostic score based on circulating biomarkers could optimize treatment selection and outcomes in metastatic melanoma treated with ICI. Matherials and methods. We performed an observational, prospective, translational, multicentric study, which involved 4 Italian centers and two pathologies (melanoma and NSCL) and was approved and, supported by Italian Ministry of Health and, by Veneto Institute of Oncology (RF- 2018-12367604 and IOV-IRCCS BIGID219SILE). The planned accrual was of 160 pts (80 advanced Mel and 80 advanced NSCLC) treated with ICI, according to the Agenzia Italiana del Farmaco (AIFA) authorization and reimbursement. Each patient signed a written informed consent, approved by the local Ethical Committees of all the participating centers. The primary endpoint of the study was to evaluate the association between circulating cytokines (IL-1b, Il-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNFa, GM-CSF) and response to ICI (BOR). Secondary endpoint was the evaluation of the association between the same circulating cytokines and their variations and i) progression free survival (PFS), ii) overall survival (OS) and, iii) toxicity. Pts underwent a blood sample at baseline, before each of first 6 ICI cycles (T1-T6) and at each tumour assessment until disease progression (PD) or for maximum of 2 years. Anti-cancer immunotherapy was administered as per standard of care. Treatment response was evaluated according to RECIST 1.1 criteria and subjects with no progressive disease were considered with disease control (DC). Timing of tumour assessment was performed according to AIFA recommendations. Safety was recorded and graduated according NCI-CTCAE version 5.1. Biomarker levels are assessed by Lumine xMAP based technology using R&D High Sensitivity kits. Results.The results in the first 43 Mel pts enrolled (M:F 20:23, median age 71), showed that IL-6 and IL-8 serum level were significantly higher at baseline and at T2 for PD pts (Kruskal-Wallis test). The median relative increase (RI) from T1 of IL8 was 32% for PD pts and it was significantly higher than for pts with disease control (DC) (decrease of 11%). Likewise, IL-10 median RI was 104% for PD pts and of 41% for DC pts (p=0.002). Multiple logistic analysis confirmed higher T2-IL-8 (>34.22pg/ml) and IL-8-RI (>1%) as independent factors (accuracy 88.6%) associated with a lower probability of DC (odd ratio-OR-=0.02, 95%CI: 0.00─0.18 and OR= 0.06, 95%CI: 0.00─0.65 respectively). In multiple Cox regression: elevated T2-IL-8 (>36.98pg/ml, HR=7.89, 95% CI: 2.66─25.78), T2-IL-10 (>2.66pg/ml, HR=2.99, 95%CI: 1.09─8.49) and IL-8-RI (> 11%, HR=3.61, 95%CI: 1.27─13.81) were significantly associated with a worse PFS. Higher T2-IL-8 (>31.55pg/ml, HR=15.67, 95%CI: 3.54─107.19), IL8-RI (> 30%, HR=5.12, 95%CI: 1.57─19.50), and T2-S100 (>0.15μg/L, HR=14.35, 95%CI: 2.61─170.9) were significantly associated with shorter OS. Conclusions: T2-IL8 and IL8-RI were independently associated to PD, PFS and OS, S100 with OS, and T2-IL-10 with PFS. Conclusions and future perspectives. The accrual of planned patients (166, included NSCLC) has been completed in July 2022.The analyses in all patients are expected to increase the significance level and to allow the evaluation of the impact of all cytokines on activity, efficacy and, safety , The comparison between melanoma and NSCLC will permit to define whether the results are treatment or tumour related or both, and, to analyse if there is or not a gender effect in cytokines behaviour.