3028Background: Although PD-1/PD-L1 checkpoint blockade has become standard of care for non-small cell lung cancer (NSCLC), some treated patients (pts) do not respond. A deeper understanding of mechanisms of resistance to PD-(L)1 blockade is needed to improve therapeutic decisions. The aim of this study was to identify molecular alterations associated with innate resistance to durvalumab (D) and durvalumab + tremelimumab (D + T) combination therapy in advanced non-squamous (Non-SQ) NSCLC. Methods: CP1108/NCT01693562 and ATLANTIC/NCT02087423 were nonrandomized phase 1/2 and 2 trials of D (10 mg/kg, Q2W). D4190C00006/NCT02000947 was a nonrandomized phase Ib trial of D + T (20 mg/kg + 1 mg/kg, Q4W). Circulating tumor DNA (ctDNA) analysis (Guardant360 70 gene cancer panel) was conducted in pre-treatment plasma samples for 119 and 63 Non-SQ NSCLC pts in CP1108 and ATLANTIC, respectively. Targeted sequencing of pre-treatment tumors (FoundationOne CDx™) was conducted in 120 Non-SQ NSCLC pts in D4190C00006. Assoc...