Background: Effective second-line chemotherapeutic treatment options for pts with NSCLC are limited. Pembro, a PD-1–blocking antibody, has demonstrated antitumor activity and proven second-line efficacy in pts with advanced NSCLC. Epigenetic modifying agents can enhance and lengthen responsiveness to subsequent anticancer therapies, including immunotherapeutic agents. The oral azacitidine CC-486 has shown promising activity when combined with cytotoxic chemotherapy in pts with relapsed/refractory solid tumors. This randomized phase II trial will evaluate the safety and efficacy of CC-486 .plus pembro vs pembro plus PBO in the second-line treatment of pts with locally advanced/metastatic NSCLC. Methods:≈ 90 pts will be randomized 1:1 to receive oral CC-486 300 mg/day or PBO on days 1-14 plus pembro 200 mg intravenously (30-minute infusion) on day 1 of a 21-day cycle. Randomization will be stratified by histology (nonsquamous vs squamous). Pts will be treated until disease progression, start of new anticancer therapy, or study withdrawal. Eligibility criteria include stage IIIB/IV NSCLC (any PD-L1 status), 1 prior platinum-containing chemotherapy for advanced disease, Eastern Cooperative Oncology Group performance status ≤ 1, adequate organ function, no known EGFR and/or positive ALK mutation (nonsquamous histology only), and no prior treatment with azacitidine or other checkpoint inhibitor. Safety will be analyzed in the first 10 pts in each arm after the last enrolled pt has completed 1 treatment cycle. The primary endpoint is investigator-assessed progression-free survival (PFS). Secondary endpoints include disease control rate (DCR; stable disease ≥ 18 weeks, complete response, and partial response), overall survival, overall response rate (ORR), safety, and pharmacokinetics. Exploratory endpoints include immune-related efficacy (PFS, DCR, and ORR), tumor PD-L1 expression, tumor-infiltrating lymphocytes, and gene expression and DNA methylation analyses of tumors and/or blood. Twelve pts have been enrolled to date. NCT02546986. Clinical trial information: NCT02546986