Background: Plinabulin (Plin) is a microtubule-destabilizing agent (MDA) that inhibits the polymerization of tubulin monomers and leads to disruption of the tumor vasculature. It has been shown in clinical studies of advanced NSCLC to produce a significantly longer duration of response when combined with docetaxel versus docetaxel alone (NCT00630110). MDAs were also shown to trigger the maturation of dendritic cells and the production of pro-inflammatory cytokines, thereby enhancing T-cell proliferation. Pre-clinical studies have shown that MDAs in combination with immune checkpoint inhibitors (ICI) demonstrated a superior response rate and survival when compared to ICI alone. Nivolumab is an anti-PD-1 antibody that is FDA approved for previously treated metastatic NSCLC regardless of PD-L1 expression. We hypothesized that the combination of Plin and Nivolumab will enhance the immune response, resulting in a higher response rate and longer overall survival. Methods: This is an open label single center phase I trial. The Dose Escalation Portion (Part 1) employs a 3+3 design with dose escalation of Plin starting at 13.5mg/m² (biologically effective dose as single agent), combined with the FDA approved dose of Nivolumab 240mg. Plin is given on days 1,8, and 15 of 28- day cycles and Nivolumab is given on days 1 and 15. The dose of Plin will be escalated to 20mg/m², 30 mg/m², and 40mg/m² until the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) is determined. The Expansion Cohort (Part 2) will enroll 20 patients with NSCLC to be treated at the RP2D, including the patients who will have received this dose in Part 1. Treatment will continue until disease progression, development of unacceptable toxicity, or a protocol-defined reason for discontinuation. Eligible patients include metastatic NSCLC who have failed platinum-based doublet and regardless of prior anti-PD-1/PD-L1 antibody treatment. Part 1 is enrolling in an expanded cohort 2 due to one dose-limiting toxicity (DLT) in this group. Clinical trial information: NCT02812667