Background: First line combination of chemotherapy and immune checkpoint inhibitors (ICIs) improves overall survival (OS) compared with chemotherapy alone in non-small cell lung cancer (NSCLC) patients. However, only few options are available at chemoimmunotherapy failure, with docetaxel representing the standard of care. Tedopi is a cancer vaccine which stimulates killer T cells, currently under development for the therapy of HLA-A2+ lung cancer. In the ATALANTE-1 Phase III trial (EudraCT no. 2015-003183-36), Tedopi provided clinical benefits in patients with advanced NSCLC who failed to respond to checkpoint inhibitors. Given the need for new therapeutic options in patients failing first-line chemo-immunotherapy and the encouraging preliminary data with Tedopi, there is a strong rationale for investigating the activity of Tedopi plus nivolumab or Tedopi plus docetaxel in patients with metastatic NSCLC failing standard first-line therapy. Methods: This is a phase II, non-comparative, randomized multicenter study assessing the combination of Tedopi with docetaxel or nivolumab in NSCLC patients failing after first-line chemoimmunotherapy (EudraCT no. 2020-005170-10). All NSCLC patient candidates for second-line therapy are considered eligible for the study if they are HLA-A2+, with no evidence of EGFR mutations or ALK/ROS1 rearrangement and if they progressed after at least 4 cycles of previous first-line chemo-immunotherapy. Patients are randomly assigned to Tedopi plus docetaxel, Tedopi plus nivolumab (treatment arms) or docetaxel monotherapy (standard arm). The primary endpoint is 1-year OS rate. Secondary endpoints include OS, 2-year OS rate, progression-free survival (PFS), objective response rate (ORR), and safety. An explorative analysis of the correlation of efficacy with several tumor or blood biomarkers (PD-L1 expression, tumor mutational burden, Tedopi neoantigen expression, T cell infiltration), is also performed. Sample size was calculated assuming a 1-year OS rate in the standard arm of 20%. According to the single-stage design, in both treatment arms a 1-year OS rate of 20% would imply that treatment does not warrant further investigation and a 1-year OS rate of 40%, would imply that treatment has a sufficient activity. With a one-sided significance level of 5% and a power of 80%, a total number of 105 patients (35 per treatment arm) need to be enrolled. At the drafting of this abstract, 7 patients have already been enrolled. Total follow-up will be 24 months from last enrolment, for an approximate duration of 48 months. Clinical trial information: NCT04884282.