Background: CD73 is a rate-limiting enzyme in adenosine pathway promoting immune suppression in tumor microenvironment. The role of CD73 as a novel target in cancer immune therapy is further supported by correlation between its high expression in tumors and poor prognosis in cancer pts. Here we evaluate safety and efficacy of uliledlimab, a differentiated CD73 antibody, in combination with toripalimab, a PD-1 antibody, in treatment naive NSCLC pts. In particular, we investigate the correlation between clinical response and tumor CD73 expression to assess its value as a potential predictive biomarker, following a previous study where a correlation was indicated (Robert F, et al. ASCO 2021). Methods: Pts with treatment naïve advanced NSCLC (EGFR/ALK wild type) were enrolled in a dose-expansion cohort and received uliledlimab (20mg/kg or 30mg/kg Q3W) in combination with toripalimab 240mg Q3W. Safety, the primary endpoint, and clinical efficacy including ORR, determined by iRECIST, were evaluated. Baseline CD73 and PD-L1 expression in tumor specimens were measured by IHC. The cut-off value for CD73^High expression was assessed by ROC analysis for correlation with ORR. Results: As of 12/2/22, 66 pts were enrolled (median age 62.5 years, ECOG PS 0 40.6%, male 84.8% and never smokers 22.7%) and received at least one dose. Treatment-related adverse events (TRAEs) occurred in 86.4% of pts (Gr≥3, 15.2%) with no grade 5 TRAE. One patient was discontinued due to TRAE (1.5%). Efficacy was analyzed in 48 pts who were enrolled at least 90 days prior to data cut-off, allowing for two assessments. Baseline PD-L1 and CD73 expression was available in 45 pts. 40% of tumor or immune cells with ≥1+ staining intensity by IHC was determined as a preliminary cut-off for CD73^High (the area under ROC curve =0.72, p = 0.02). While ORR and DCR were 31.3% (15/48) and 79.2% (38/48) respectively in all pts, ORR appeared higher in CD73^High pts (50%, 9/18) and much lower in CD73^Low pts (14.8%, 4/27). Highest ORR was found in a cohort with CD73^High and PD-L1 TPS≥1% (57.1%, 8/14). Conclusions: Uliledlimab and toripalimab combination therapy was well-tolerated in treatment naïve advanced NSCLC pts. Clinical response of the therapy seems to correlate with high tumor CD73 expression, indicating a potential value of CD73 as a predictive biomarker. The study warrants a biomarker-guided randomized clinical trial that is currently in preparation. Clinical trial information: NCT04322006.