Background:Ιmmune checkpoint inhibitors (ICIs) have tremendously changed the daily clinical practice on the treatment of advanced non-small cell lung cancer (aNSCLC). However, clinical useful biomarkers remain an unmet need. Recently, a new score, Patras Immunotherapy Score (PIOS), has been proposed by our group proving its prognostic value in aNSCLC patients treated with ICIs monotherapy. The objective of the current study was to assess the clinical significance of PIOS formula in aNSCLC patients treated with combination of immunotherapy with chemotherapy. Methods: PIOS is a baseline formula derived by combining the following non-interventional clinical parameters, Performance Status (PS), Body Mass Index (BMI), age and Line Of Treatment (LOT) and it is calculated as PIOS = (PS×BMI)/(LOT×AGE). In the current study, 159 aNSCLC patients, treated with combination of immunotherapy with chemotherapy, were retrospectively selected, blindly to the clinical outcome, and enrolled. In addition, a second subcohort with 444 aNSCLC patients, who had been treated with chemotherapy alone, were also retrospectively included. The primary endpoint of this study was to investigate the prognostic value of PIOS in terms of progression free survival (PFS) and overall survival (OS). Results: Patients with higher PIOS score had longer PFS compared to patients with lower PIOS score (ΗR 0.575, 95% CI 0.364-0.908, p= 0.016), while multivariate analysis for PFS, adjusted for PD-L1, confirmed the clinical value of PIOS score (HR 0.561, 95% CI 0.352-0.893, p= 0.015). Moreover, PIOS score was also associated with prognosis (p= 0.003). The median OS for the favorable group was 1067 days compared to 528 days for the unfavorable group with low PIOS score (HR 0.487, 95% CI 0.302-0.787, p< 0.001) at univariate analysis. This association remained statistically significant (HR 0.468, 95% CI 0.286-0.764, p= 0.002) after adjusting for PD-L1 expression. Specificity of PIOS formula was also confirmed in the second cohort (n = 444) of patients with metastatic disease who had been treated with chemotherapy alone, in which no prognostic significance for PIOS was observed. Conclusions: This study for the first time documents the prognostic significance of PIOS model in aNSCLC patients treated with immunotherapy/chemotherapy combination and provides adequate evidence regarding the specificity of this association, since no similar finding was observed in the patients treated with chemotherapy alone.