The main objectives are to explore biomarkers and pharmacodynamic parameters before and after the start of study treatment ( OSE2101 or chemotherapy) in a population of NSCLC patients who progressed after ICI treatment. Blood samples: • Pre-, on-treatment and after treatment collection of peripheric blood mononuclear cells (PBMCs) for: o Immunophenotyping o OSE2101 vaccine antigen -specific T -cell frequency • Pre-, on-treatment and after treatment collection of liquid biopsies (e.g. cell free DNA ( cfDNA) ): o Tumor Mutation al Burden ( TMB ) and/or other mutation of interest (e.g. gene profiling of OSE2101 vaccine TAA ) Blood samples will be taken at baseline, then every 6 weeks until Cycle 7 (e.g. Day 1 of Cycle s 3, 5 and 7), then every 12 weeks (e.g. at time of CT scan) until end of treatment and/or progression in all arms. Tumor samples: • Specimens from archiving tumor biopsies (at first diagnosis and/or at any time before study entry ) will be collected. • If possible, a n ew tumor biopsy will be collected within 35 days prior to the first study treatment administration (during the screening period ). An archiving tumor biopsy collected before the screening period is acceptable, should the biopsy be collected after the end of ICI treatment. A second tumor biopsy ( e.g. in the same tumor site) will be undertaken between cycle 3 and cycle 6 and/or at time of the disease progression . Of note, a blood sample will be collected for Whole -Exome sequencing (WES) for: o Determination of HLA class I expression in tumor (e.g. HLA -A2 and Beta -2 microglobulin ) o Tumor and tumor microenvironment (TME) characterization by multiplex IHC and gene profiling (i.e. CD8 exhausted T cells, TIL infiltration , …) All blood and tumor sample s will be stored in certified biobanks before being submitted to central laboratories for analysis . If the patient agrees, remaining specimens after analysis will be biobanked for future biomarker research and drug development projects, e.g. to identify patients that are more likely to benefit from a treatment or experience an adverse event (AE), or to gain a mechanistic or genetic understanding of drug effects and thereby. OSE2101 Protocol OSE2101C301 Confidential Version n° 6.0 Page 14 of 101 02 February 2022 Statistical methodology Step 1 – Phase II sample size The primary objective of Step 1 is to evaluate the overall survival rate after 12 months in OSE2101 arm. The following statistical hypotheses are considered: - H0 (null): 25% of overall survival rate at 12 months (uninteresting to pursue any further investig ation) - H1 (alternative): 40% of overall survival rate at 12 months ( clinically relevant to discuss the interest of further investigation in a Phase III comparative trial). According to the previous hypotheses and a Fleming one step Phase II design with a 2.5% one -sided type I error and a power of 80%, 84 evaluable patients have to be enrolled in the arm A. Fleming decision rules Amongst the first 84 evaluable patients: To reject H0 we have to observe at least 30 (35.7%) patients alive at 12 months then it will be interesting to run the next step of Phase III comparative trial . If less than 30 patients are alive at 12 months, H0 will not be rejected and it will be considered uninteresting to pursue any further investigation . The probability to conclude for inefficacy whereas the true rate is 40% is β=18.1%. The probability to conclude for efficacy whereas the true rate is 25% is α=1.9%. In order to limit the tot al number of patients needed in Step 1, a 2:1 randomization ratio to receive OSE2101 (Arm A) or pemetrexed or docetaxel (Arm B) has been used for new patients recruited since version 4.0 of the protocol came into effect. A total of 38 patients with previou s ICI treatment have been recruited before protocol version 4.0 , from whom 18 patients randomized in arm A (OSE2101), thus 84 – 18 = 66 new evaluable patients need to be recruited in arm A (OSE2101) . Based on a 2:1 randomization ratio, 66/2 = 33 new patients need to be randomized in arm B, leading to a total of 99 new evaluable patients. With an expected 7% rate of patients not evaluable at 12 months or withdrawn, a total of 108 new patients will be randomized for Step 1. Step 2 – Phase III sample size For Step 2, the same 2:1 randomization ratio will be continued . All the 38 patients randomized before protocol version 4.0 in the subgroup of patients with previous ICI treatment and all new patients included in Step 1 / Phase II will be follo wed during Step 2 /Phase III . However , the final analysis of Phase II /Phase III will exclude the 38 patients with previous ICI treatment randomized before the recruitment hold . In order to reach a power of 80% for the two-sided log rank test at the 5% significance level when assuming a median OS of 7 months for the control and 10 months for the experimental arm , a total of 278 events is required. If the new patients are uniformly included over an accrual period of 36 months followed by OSE2101 Protocol OSE2101C301 Confidential Version n° 6.0 Page 15 of 101 02 February 2022 a follow -up of 6 mont hs after the last inclusion , observing 278 events would require a total of 363 new patients . The actual number of new patients may be reduced if the 278 events are observed earlier (this is an event -driven study). Both counts exclud e the 38 patients enrolled before protocol 4.0. Due to early study discontinuation due to COVID -19 (219 patients included instead of 363 patients ), the power decrease d to 62% with the same hypotheses (HR=0.70). Considering Step 1 results in the PoI , the following hypotheses have been proposed for final analysis : Assuming a HR of 0.55 observed in PoI in Step-1 and a median OS of 7 months in SoC (unchanged as initially planned), a total of 90 events in the PoI will provide a power of 80% and a 2 -sided logrank test at a 5% two-sided level, if the patients are included over an accrual period of 48 months followed by a follow -up of 6 months after the last inclusion . Steering Committee A Steering Committee including representatives from the investigators, the Sponsor and other experts will be responsible of the study supervision. Independent Data Monitoring Committee An independent Data Monitoring Committee (IDMC) will review the safet y and tolerability data and assess the risk/benefit ratio of the investigational drug on a regular basis. The IDMC membership, role and responsibilities will be detailed in a specific IDMC charter. OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 16 of 101 02 February 2022 Table 1: Visits and assessments schedule (Arm A: OSE2101) Period Pre-screening Screening Treatment End of treatment Visit Screening and randomization Cycle 1 (3 week -cycle) Cycles 2 to 6 (3 week -cycle) Cycles 7 to 9 (8 week -cycle) Cycles ≥ 10 or EOT (12-week cycle) End of treatment1 Post- treatment Follow -up2 Cycle day -35 Day/ -1 Day Day 1 (±2) Day 15 (±2) Day 1 (±2) Day 1 (±4) Day 1 (±8) Informed consent for HLA -A2 determination and biobanking X HLA -A2 determination3 X Informed consent X Medical/ Oncological history X Previous medications X EGFR /ALK alterations, PD -L14 X Body height X Body weight X X X X X X Physical examination X X X X X X Vital signs (Body temperature, BP/PR, oxygen saturation) X X X X X X 12-lead ECG X X X X X ECOG Performance status X X X X X X Hematology/ Biochemistry5 X X X X X X X Coagulation/ HIV test6 X Pregnancy test (as appropriate) X X Tumor assessments (including scans) X every 6 (± 1) weeks until documented RECIST 1.1 progression7 (X)8 Randomization X OSE2101 administration9 X X X X EORTC QLQ -C30, QLQ -LC13 X X X X X Survival follow -up X Concomitant medications X X X X X X X Adverse Events X X X X X X X Serious Adverse Events X X X X X X X Hospitalizations X X X X X X X Informed consent for translational study and biobanking (optional)10 X Blood samples for biomarkers (optional)11 X every 6 (± 3) weeks (e.g. at D1 of Cycles 3, 5 & 7) every 12 (± 3) weeks (e.g. at time of imaging) until EOT and/or progression Tumor samples for biomarkers (optional)12 X X (e.g. between Cycles 3 & 6) X (e.g. at tumor progression) OSE2101 Protocol OSE2101C301 Confidential Version n° 6.0 Page 17 of 101 02 February 2022 1 End of treatment: visit to obtain last assessments after the study drug stop from the 4 previous weeks. 2 Post-treatment follow -up: data collection on survival status and any subsequent cancer therapy (if any) every 2 months after study drug discontinuation unti l death. 3 HLA -A2 testing can be done at any time during patient management before inclusion. A pre -screening consent is available to test patients for instance during 1st or 2nd line therapy. 4 EGFR/ALK alterations and PD -L1 expression on tumor tissue: if these results are not available, they have to be done in local or central laboratories duri ng the screening period. EGFR/A LK alterations is mandatory before randomization in patients with non -squamous cancer or never/light smokers with squamous cancer. If PD -L1 expression is not documented and no tumor tissue available to perform the testing, then the PD -L1 status can be omit ted. 5 Hematology and biochemistry tests: to be done at Day 1 Cycle 1 only if screening assessment done more than 7 days before. The reafter at Day 1 of each subsequent cycle, local laboratory tests will be done every 3 weeks (less than 72 hours (3 days) befo re study treatment administration) until Cycle 6, then every 8 weeks (less than 4 days before study administration) until Cycle 9, then every 12 weeks (less than 8 days before each subsequent administration. 6 HIV test: to be done for all eligible patients w ith HIV status unknown. 7 Tumor assessments (CT scan of thorax, abdomen and brain CT or brain MRI) to be done every 6 weeks (± 1 -week allowance) after Day 1 Cycle 1, meaning it could be between 2 treatment visits; CT scan of the pelvis will be performed only upon request according to clinical suspicion. In case of clinical suspicion of bone metastasis out of the area reported by CT scan, imaging test will be performed under discretion of the investigator and will be repeated eve ry 12 weeks. For Germany , with respect to brain metastases, MRI should be the privileged imaging technic and CT should only be considered when there are contra -indications to MRI. 8 Tumor assessments should be continued until documented RECIST 1.1 disease progression for patients who have not progressed during the treatment period. 9 OSE2101 treatment will continue until unequivocal RECIST 1.1 -defined disease progression as determined by the investigator, unacceptable toxicity, or consent withdrawal. Should pseudo progression or delayed resp onse to treatment suspected in arm A, investigator may continue treatment beyond the time of RECIST -defined progression, if the patient is perceived to be experiencing clinical benefit. 10 Separate informed consent (optional) will be obtained from the patient who agreed to participate in a translational study and authorizing the bio banking of the remaining samples to be used for future biomarker research and drug development projects. Patient can agree to participate in all and/o r some parts of the translatio nal study. Patient can refuse to participate in the translational study without compromising his/her participation in the main study. 11 Blood samples for biomarkers will be taken at baseline (during the screening period), then every 6 (± 3) weeks until Cycle 7 (e.g. at D1 of Cycles 3, 5 and 7), then every 12 (± 3) weeks (e.g. at time of imaging) until end of treatment and/or progression. 12 Specimens from archiving tumor biopsies (at first diagnosis and/or at any time during previous treatment) will be collected . As possible, a new tumor biopsy will be collected within 35 days prior to the first study treatment administration (during the screening period). An archiving tumor biopsy collected before the screening period is acceptable, should the biopsy be collecte d after the end of ICI treatment. A second tumor biopsy (e.g. in the same tumor site) will be undertaken between Cycle 3 and Cycle 6 and/or at time of the disease progression. A blood sample will be collected for Whole -Exome sequencing (WES) at screening. OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 18 of 101 02 February 2022 Table 2: Visits and assessments schedule (Arm B: Docetaxel or Pemetrexed) Period Pre-screening Screening Treatment End of treatment Visit Screening and randomization Cycle 1 (3 week -cycle) Cycle 2 (3 week -cycle) Cycles ≥3 (3 week -cycle) End of treatment1 Post-treatment Follow -up2 Study day -35 Day/ -1 Day Day 1 (±2) Day 15 (±2) Day 1 (±2) Day 1 (±2) Informed consent for HLA -A2 determination and biobanking X HLA -A2 determination3 X Informed consent X Medical/ Oncological history X Previous medications X EGFR/ALK alterations, PD -L14 X Body height X Body weight X X X X X Physical examination X X X X X Vital signs (Body temperature, BP/PR, oxygen saturation) X X X X X 12-lead ECG X X X X ECOG Performance status X X X X X Hematology/ Biochemistry5 X X X X X X Coagulation/ HIV tes t6 X Pregnancy test (as appropriate) X X Tumor assessments (including scans) X every 6 (± 1) weeks until documented RECIST 1.1 progression7 (X)8 Randomization X Docetaxel or Pemetrexed9 X X X EORTC QLQ -C30, QLQ -LC13 X X X X Survival follow -up X Concomitant medications X X X X X X Adverse Events X X X X X X Serious Adverse Events X X X X X X Hospitalizations X X X X X X Informed consent for translational study and biobanking (optional)10 X Blood samples for biomarkers (optional)11 X every 6 (± 3) weeks (e.g. at D1 of Cycles 3, 5 & 7), then every 12 (± 3) weeks (e.g. at time of imaging) until EOT and/or progression Tumor samples for biomarkers (optional)12 X X (e.g. between Cycles 3 & 6) X (e.g. at tumor progression) OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 19 of 101 02 February 2022 1 End of treatment: visit to obtain last assessments after the study drug stop from the 4 previous weeks. 2 Post treatment follow -up: data collection on survival status and any subsequent cancer therapy (if any) every 2 months after study drug discontinua tion until death. 3 HLA -A2 testing can be done at any time during patient management before inclusion. A pre -screening consent is available to test patients for instance during 1st or 2nd line therapy. 4 EGFR/ALK alterations and PD -L1 expression on tumor tissue: if these results are not available, they have to be done in local or central laboratories duri ng the screening period. EGFR/ALK alterations is mandatory before randomization in patients with non -squamous cancer or never/light smokers with squamous cancer. If PD-L1 expression is not documented and no tumor tissue available to perform the testing, then the PD -L1 status can be omitted. 5 Hematology and biochemistry tests: to be done at Day 1 Cycle 1 only if screening assessment done more than 7 days before. Thereafter at Day 1 of each subsequent cycle, local laboratory tests will be done every 3 weeks (less than 72 hours (3 days) before study treatment administration) until Cycle 6, then every 8 weeks (le ss than 4 days before study administration) until Cycle 9, then every 12 weeks (less than 8 days before each subsequent administ ration. 6 HIV test: to be done for all eligible patients with HIV status unknown. 7 Tumor assessments (CT scan of thorax, abdomen and brain CT or brain MRI) to be done every 6 weeks (± 1 -week allowance) after Day 1 Cycle 1 meaning it could be between 2 treatment visits; CT scan of the pelvis will be performed only upon request according t o clinical suspicion. In case of clinical suspicion of bone metastasis out of the area reported by CT scan, imaging test will be performed under discretion of the investigator and will be repeated every 12 weeks. For Germany , with respect to brain metastas es, MRI should be the privileged imaging technic and CT should only be considered when there are contra -indications to MRI. 8 Tumor assessments should be continued until documented RECIST 1.1 disease progression for patients who have not progressed du ring th e treatment period. 9 Docetaxel and pemetrexed treatment will continue until unequivocal RECIST 1.1 -defined disease progression as determined by the investigator, unacceptable toxicity, or consent withdrawal. Premedication is required with docetaxel and peme trexed. Premedication will occur before Day 1 (i.e. Day 1 of each cycle will be injection day for chemotherapy). 10 Separate informed consent (optional) will be obtained from the patient who agreed participating in a translational study and authorizing the bi o banking of the remaining samples to be used for future biomarker research and drug development projects. Patient can agree to participate in all and/or some parts of the translational study. Patient can refuse to participate in the translational study wi thout compromising his/her participation in the main study. 11 Blood samples will be taken at baseline (during the screening period), then every 6 (± 3) weeks until Cycle 7 (i.e. at D1 of Cycles 3, 5 and 7), then every 12 (± 3) weeks (e.g. at time of CT imagi ng) until end of treatment and/or progression. 12 Specimens from archiving tumor biopsies (at first diagnosis and/or at any time during previous treatment) will be collected. As possible, a new tumor biopsy will be collected within 35 days prior to the first study treatment administration (during the screening period). An archiving tumor biopsy collected before the screening period is acceptable, should the biopsy be collected after the end of ICI treatment. A second tumor biopsy (e.g. in the same tumor site) will be undertaken between Cycle 3 and Cycle 6 and/or at time of the disease progression. A blood sample will be collected for Whole -Exome sequencing (WES) at screening. OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 20 of 101 02 February 2022 TABLE OF CONTENTS 1 BACKGROUND AND RATIONALE ................................