Background: Retinoic acid receptor–related orphan receptor γ (RORγ) agonists modulate immune cell gene expression to enhance effector function and decrease regulatory T cell formation and expression of checkpoint pathways. RORγ agonists have demonstrated antitumor activity in syngeneic tumor models. Translational and bioinformatic assessments were conducted to support inclusion of patients with non–small-cell lung cancer (NSCLC) in a Phase 2a expansion of clinical trial LYC-55716-1001 (NCT02929862). Methods: The Cancer Genome Atlas (TCGA) NSCLC dataset was evaluated for (a) expression of RORγ and RORγ-inducing cytokines and correlation with survival; (b) genes related to RORγ biology, biomarkers of endogenous RORγ agonists; and (c) tumor microenvironment (TME) immune profiles. RORγ expression and the in vitro effects of a RORγ agonist on peripheral blood mononuclear cells (PBMCs) from lung adenocarcinoma (LA) and squamous cell carcinoma (SCC) patients were assessed. Results: In TCGA, 25% of NSCLC tumors expressed moderate/high levels of RORγ, suggesting infiltration of Type 17 cells. There was a statistically significant correlation between high RORγ expression and improved survival in LA patients. Genes that support Type 17 cell formation (IL1B, IL23A, IL6) were expressed in ~50% of tumors. RORγ expression was confirmed in PBMCs isolated from LA and SCC patients. Analysis of TCGA data and patient samples identified low expression of sterol efflux and uptake genes, suggesting low levels of endogenous RORγ agonist in TME. In TCGA, high mutational burden and high expression of immune-related genes were found in NSCLC tumors. RORγ agonist treatment of PBMCs from LA and SCC patients increased IL-17A and IL-26 (LA and SCC) and decreased PD1 (LA). In Phase 1 clinical testing, LYC-55716 has been well tolerated, demonstrating long-term disease stabilization in heavily pretreated patients. Conclusions: Bioinformatic analyses of RORγ expression/biology, correlation with improved survival, plus in vitro findings support inclusion of NSCLC in an ongoing Phase 2 clinical trial of LYC-55716.