The design of the study needs to consider prognostic factors in the randomization process. Although both patients with squamous and non -squamous NSCLC were included in the Phase II study for OSE2101, histology is a key prognostic factor as reference therapies do not have efficacy over the full range of NSCLC histologic subtypes. Pemetrexed for instance is not approved in squamous NSCLC, survival with docetaxel seems longer in non -squamous than in squamous cancer ( 10, 60) and some treatments ( 64) have positive results in non -squamous and negative in squamous. Best response to chemotherapy is documented as a prognosti c factor ( 59) although patients will only be included in the trial once 1st line chemotherapy failed. Last, previous treatment with checkpoint inhib itors needs to be considered as 2nd or 3rd line therapy patients . They will be selected after failure of checkpoint -inhibitor regimens . Interaction between checkpoints inhibitors and T -specific immunotherapy with OSE2101 will have to be considered, support ing stratification as well on this criterion. Thus, randomization will be stratified by: • histology (squamous vs. non-squamous), • best response to first line treatment (objective response: complete or partial response, vs. no objective response: stabilization or progressive disease), and • before protocol v4.0 only: previous treatment with immune checkpoint inhibitors (yes vs. no). • from protocol v4.0: line rank of previous treatment with immune checkpoint inhibitor (first line vs. second line ). Target endpoints : As recommended in current FDA and EMA ( 18, 21) guidelines the primary endpoint will be overall survival, secondary endpoint will be linked to assessment of tumor response with a cancer vaccine (adding post progression survival and time t o ECOG deterioration as secondary endpoints) but a specific attention will also be paid to quality of life as patient reported outcome and analyzed per EORTC guidelines (https:/ /www.eortc.org/app/uploads/sites/2/2018/02/SCmanual.pdf ) and the FDA Guidance on June 2021 “Core Patient -Reported Outcomes in Cancer Clinical Trials” (https://www.fda.gov/regulatory -information/search -fda-guidance -documents/core -patient - reported -outcomes -cancer -clinical -trials ). 2 STUDY OBJECTIVE S Step 1 (Phase II ): 2:1 randomized non -comparative one stage Fleming Phase II Primary objective OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 38 of 101 02 February 2022 • To evaluate the overall survival (OS) rate at 12 months in HLA -A2 positive patients with advanced NSCLC as 2nd or 3rd line therapy after failure of checkpoint -inhibitor regimens Secondary objectives • To describe secondary measures of clinical efficacy including OS (median), disease control rate (DCR) at 6 and 12 months, Health -related Quality of life (QoL) , progression free survival ( PFS), objective response rate (ORR) and evaluate duration of response (DR ) • To assess the safety and tolerability • To describe patient reported outcomes (PRO) disease/treatment -related symptoms of lung cancer Step 2 (conditional Phase III ): 2:1 comparative randomized Phase III Primary objective • To demonstrate that OSE2101 is superior to control treatment with respect to OS in HLA -A2 positive patients with advanced NSCLC as 2nd or 3rd line therapy after failure of checkpoint - inhibitor regimens ; primary population will be the Population of Interest (PoI) defined as patients with secondary resistance to ICI and ICI 2nd line; sensitivity analysis will be done in all patients Secondary objectives • To compare secondary measures of clinical efficacy including Post Progression Survival (PPS) , Time to worsening ECOG PS deterioration, Health -related QoL, DCR at 6 and 12 months, and PFS • To assess the safety and tolerability of OSE2101 compared to the cont rol treatment Exploratory objectives • To compare other efficacy criteria (ORR, DR) , other QoL criteria , time to next lung cancer therapy and COVID -19 impact in both treatment arms . 3 ETHICAL CONSIDERATIONS 3.1 Ethics and Good Clinical Practice The investigator m ust ensure that this study is conducted in full conformance with the principles of the “Declaration of Helsinki ” and its amendments, and with the laws and regulations of the country in which the clinical research is conducted.