Background: Vaccine therapies stimulate the immune system to attack cancer cells (active immunotherapy), whereas checkpoint inhibitors block immune inhibition (passive immunotherapy). Several PD-1 and PD-L1 blocking antibodies are approved for NSCLC. This study combines active and passive immunotherapies to determine if the addition of a mRNA vaccine can enhance the activity of checkpoint blockade. The vaccine BI 1361849 (comprising 6 mRNAs encoding for selected tumor-associated antigens: MUC1, survivin, NY-ESO-1, 5T4, MAGE-C2 and MAGE-C1) is combined with 1 or 2 checkpoint inhibitors (durva [anti-PD-L1] ± treme [anti-CTLA-4]). Methods: This ongoing Phase 1/2, open-label study (NCT03164772) evaluates the safety and efficacy of BI 1361849 when administered with durva (Arm A) or durva + treme (Arm B) in NSCLC patients. In arm A, an initial dose-evaluation phase follows a 3+3 design to determine the dose of durva (1500 or 750 mg) to be given with the vaccine. Arm B uses the durva dose from Arm A, with the addition of 75 mg treme. In the expansion phase, 20 patients are treated in each arm. To aid in the evaluation of immune responses, there is an additional control group (n = 10), which receives the checkpoint inhibitors only. Study treatment is administered over 12 (28-day) cycles. Durva (x 12 doses) and treme (x 4 doses) are administered intravenously every 28 days. The vaccine is administered on 1 to 3 days over each of the 12 cycles using a device that provides a needle-free intradermal administration. The primary endpoint is safety/tolerability per CTCAE, including dose-limiting toxicity during dose evaluation. Secondary endpoints are progression-free survival and objective response rate at 8 and 24 weeks, disease control rate, response duration, and overall survival, with tumor response evaluated by RECIST and immune-related RECIST. Exploratory objectives include effects on tumor microenvironment and evaluation of immune responses. Enrollment opened 20Dec2017. Clinical trial information: NCT03164772