Background: Anti-PD-1(L1) therapies appear to be less efficacious in NSCLC patients whose tumors have EGFR activating mutations, but the underlying mechanism is poorly understood. We investigated the relationship between Methods: Flow cytometry and/or quantitative PCR were used to evaluate genes and proteins in five NSCLC EGFR mt cell lines and 6 wt lines. Anti-EGFR TKIs gefitinib and osimertinib were used at concentrations ranging from 0.001-100uM; EGF was used at 50 ng/mL. CP1108/NCT01693562 was a nonrandomized phase 1/2 trial evaluating durvalumab (10 mg/kg Q2W) in advanced NSCLC. As of 24OCT16, 304 previously treated patients in CP1108 were enrolled. RNA sequencing was conducted on available tumor specimens from 97 patients in CP1108. CP1108 and TCGA were separated by EGFR status for genomic comparisons. Results: Median CD73 expression was increased 10-fold in EGFR mt NSCLC cell lines (n = 5) compared to wt cell lines (n = 6). EGF induced CD73 protein levels 5-40-fold in 3/6 EGFR wt lines. There was dose-dependent inhibition of CD73 expression (45-70 fold maximum) following treatment with gefitinib or osimertinib in 3/5 mt cell lines and 4/6 wt lines, suggesting a causal relationship between the EGFR pathway and CD73 expression. Consistent with these observations, EGFR mutant tumors had ≥2 fold increased expression of CD73 compared to wt (p < 0.05) in TCGA and CP1108 NSCLC adenocarcinoma patients. These EGFR mutants had significantly lower levels of IFNg signature, previously reported to be associated with enhanced benefit from durvalumab. Conclusions: Our findings identify a novel relationship in NSCLC between EGFR pathway activation, expression of the immunosuppressive molecule CD73 and reduced expression of IFNg mRNA signature. These results prompt the hypothesis that over-expression of CD73 in EGFR-mt NSCLC may explain, at least in part, the reduced benefit from anti-PD-1(L1) in this subset of NSCLC, and suggest evaluating anti-CD73 in combination with EGFR TKIs or anti-PD-L1 in EGFR-mt NSCLC.