Background: OSE2101 (Tedopi) is an anticancer vaccine increasing overall survival (OS) versus Standard of Care (SoC docetaxel or pemetrexed) in HLA-A2+ NSCLC patients with secondary resistance after sequential Chemo (CT)-IO (ESMO 2021 #47LBA). Here we present the QoL analysis. Methods: EGFR and ALK negative NSCLC patients who failed prior IO, ECOG PS 0-1 were randomized 2:1 to receive either OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was OS; secondary endpoints included time to ECOG PS deterioration and QoL by EORTC QLQ-C30/LC13 questionnaires at baseline and before each treatment administration until the end of treatment (EOT). Changes in QLQ-C30/LC13 scores from baseline to EoT were assessed using mixed-effects model for repeated measures (MMRM). Overall treatment effect and associated p value were estimated using MMRM. Results: 95 out of 118 (81%) patients with secondary resistance to IO completed baseline and ≥ one follow-up questionnaire. Median OS was 11.1 mo for OSE2101 vs 7.5 mo for SoC [HR 0.59; p = 0.02]. Median time to ECOG PS deterioration was 9.0 mo for OSE2101 vs 3.3 mo for SoC [HR: 0.43; p = 0.004]. Global Health Status remained stable with OSE2101 whereas it deteriorated from the 1^st cycle with SoC (p = 0.045). Most pronounced effects were observed in the physical (ability to perform activities that require physical effort; p = 0.07) and the role (ability to work and carry out daily activities; p = 0.03) functioning scores (refer table below). Patients had less mouth soreness (p = 0.01), dysphagia (p = 0.01), peripheral neuropathy (p = 0.03), alopecia (p < 0.001) and fatigue (p = 0.06) with OSE2101 than with SoC. The change from baseline of dyspnea, coughing, hemoptysis, and pain were not significantly different between the 2 groups. Conclusions: In advanced HLA-A2+ NSCLC patients with secondary resistance to IO after sequential CT-IO, OSE2101 improves OS and maintains QoL vs. SoC, especially global health status, physical and role functioning scores. Patients presented fewer symptoms typically related to adverse effects of chemotherapy as compared to SoC. Clinical trial information: NCT02654587.