General Study Design and Plan As background for the statistical methods presented below, this section provides an overview of the study design and plan of study execution. This is an open -label, multicenter, controlled, randomized, parallel group, two-stage design phase II/III trial of OSE2101 (Arm A – experimental treatment) versus docetaxel or pemetrexed (Arm B – control treatments) as 2nd or 3rd line treatment in HLA -A2 positive patients with advanced NSCLC with progressive disease after last treatment with ICI . Randomization to Arms A and B was stratified according to histology (squamous vs. non - squamous), initial response to first line treatment (objective response: complete or partial response, vs. no objective response: stabilization or progressive disease), and - from version 4.1 of the protocol - previous treatment with immune checkpoint inhibitors (used in 1st line vs. used in 2nd line). Before this amendment, the 3rd randomization stratification factor was previous treatment with immune checkpoint inhibitor (yes vs. no). The schedule for assessments and timing of events is presented in Tables 1 and 2 (Arm A and Arm B respectively) . OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 15/51 Table 1 Schedule of Time and Events for A rm A OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 16/51 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 discontin uation 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 tu mor tissue: if these results are not available, they have to be done in local or central laboratories during the screening period. EGFR/ALK alterations is mandatory before randomization in patients with non -squamous cancer or never/light smokers with squam ous 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 da ys 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 C ycle 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 with HIV status unknown. 7 Tumor assessments (CT scan of thorax, abdomen and brain CT or brain MRI) to be don e 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 cli nical 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 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 du ring the treatment period. 9 OSE2101 treatment will continue until unequivocal RECIS T 1.1 -defined disease progression as determined by the investigator, unacceptable toxicity, or consent withdrawal. Should pseudo progression or delayed response 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 remai ning 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 translational 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 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. OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 17/51 Table 2 Schedule of Time and Events for Arm B OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 18/51 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 during 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 C ycle 6, then every 8 weeks (less than 4 days before study administration) unt il Cycle 9, then every 12 weeks (less than 8 days before each subsequent administration. 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 ev ery 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 cli nical 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 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 du ring the treatment period. 9 Docetaxel and pemetrexed treatment will continue until unequivocal RECIST 1.1 -defined disease progre ssion as determined by the investigator, unacceptable toxicity, or consent withdrawal. Premedication is required with docetaxel and pemetrexed. 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 bio banking of the remaining samples to be used for future biomarker research and drug development projects. Patie nt can agree to participate in all and/or some parts of the translational study. Patient can refuse to participate in the translational study without 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 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 scr eening 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. OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 19/51 5.2. Inclusion – Exclusion Criteria and General Study Population The inclusion and exclusion criteria defined in the protocol apply to a ll subjects and are not repeated herein the SAP. 5.3. Randomization and Blinding All eligible and consented subjects will receive OSE2101 (Arm A) or docetaxel or pemetrexed (according to histology and previous treatment) (Arm B). The final analysis of step-2 will include a combination of patients recruited before amendment (ratio= 1:1; 38 patients ) and after amendment in 2017 (ratio= 2:1, 181 patients ). 5.4. Analysis Variables Variables to be analyzed include demographics and baseline characteristics, safety variables (adverse events, concomitant medications, clinical laboratory investigations, vital signs, ECOG and ECG ), efficacy variables (tumor assessments and survival status) , and quality of life va riables . 6. SAMPLE SIZE Step 2 – Phase III sample size for all ICI population The i nitial hypotheses in the protocol version 4.0 were: “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 (HR=0.70) . If the new patients are uniformly included over an accrual period of 36 months followed by a follow -up of 6 months after the last inclusion, observi ng 278 events would require a total of 363 new patients.” The Phase 3 sample size consists in 219 patients. With this final sample size of 219 patients, the power decrease to 62% with the same hypotheses (HR=0.70) . Considering Step 1 results, statistical h ypotheses have been revised to address the PoI as follow: Assuming a HR of 0.55 consistent with that observed in Step -1 (HR stratified =0.67, HR unstratified = 0.52) with a 7 months OS in the SoC group (unchanged as initially planned in the protocol), a to tal 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 . OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 20/51 7. GENERAL CONSIDERAT IONS 7.1. Analysis Sets Six different analysis sets are defined in the post ICI population (N=219) . The 3 analysis sets will be duplicate d in the population of interest and in the overall p ost ICI population. For safety analyses, baseline is the first dose of s tudy treatment and for « baseline characteristics » section, baseline is defined as last value before randomization. 7.1.1. Safety Set PoI This analysis set includes all patients included in the PoI who were randomized and received at least one dose of randomized study treatment. Patients will be analyzed in the group according to the treatment they received . All safety data analyses will be analyzed using the safety set. 7.1.2. Intent -to-Treat Set PoI (ITT _PoI) This analysis set includes all patients included in the PoI and randomized. Patients will be analyzed in the group as randomized. All efficacy data analyses will be analyzed using the ITT_PoI set. 7.1.3. Per-Protocol Set PoI (PP_PoI) This analysis set includes all patients of the ITT _PoI set who did not violate the protocol in a way that might affect the evaluation of the effect of the study drugs on the overall survival . The patients to be excluded from the PP _PoI set will be identified before performing the analysis. Selected sensitivity efficacy data analyses will be performed using the PP_PoI set. 7.1.4. Safety Set This analysis set includes all patients included who were randomized and received at least one dose of randomized study treatment. Patients will be analyzed in the group according to the treatment they re ceived. All safety data analyses will be analyzed using the safety set. 7.1.5. Intent -to-Treat Set (ITT) This analysis set includes all patients included and randomized. Patients will be analyzed in the group as randomized. All efficacy data analyses will be analyzed using the ITT set. OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 21/51 7.1.6. Per-Protocol Set (PP) This analysis set includes all patients of the ITT set who did not violate the protocol in a way that might affect the evaluation of the effect of the study drugs on the overall survival. The patients to be excluded from the PP set will be identified before performing the analysis. Selected sensitivity efficacy data analyses will be performed using the PP set. The exclusion of patients from the PP _PoI and PP sets was prepared using the minutes and the deviations report of the blind review meeting that was held on 08 April 2021 . 7.2. Subgroups The following variables will be used to define subgroups: Stratification criteria - Histology (squamous vs. non-squamous), - Best response to 1st line treatment ( CR/PR vs. SD/PD ) - Line rank of ICI therapy (2nd line vs. 1st line) * Other criteria - Gender (male vs. female) - Age (< 75 vs. ≥ 75) - Age (< 65 vs. ≥ 65) - Smoking status: never, former, or current smoker - Baseline ECOG score (0 vs. 1) - Best response to 1st line treatment (CR/PR/SD vs. PD) - Best response to 1st line treatment (CR/PR vs SD vs. PD) - Best response to ICI therapy (CR/PR vs. SD vs PD) - Best response to ICI therapy (CR/PR/SD vs. PD) - Duration of previous ICI therapy ( weeks: 0 -12, > 12-24, > 24 weeks )* - Duration of previous ICI therapy ( weeks: 0 -12, > 12 weeks )* - Time from end of ICI to study treatment initiation (weeks: 0 -6, 6-12, > 12 weeks ) - Time from end of chemotherapy to study treatment initiation (weeks: 0 -24, 24 -48, > 48 weeks ) - Duration of previous ICI therapy (>12 weeks) and Line rank of ICI therapy (2nd line) * - Duration of previous ICI therapy (>12 weeks) and Line rank of ICI therapy (1st line)* - Liver metastases at study entry (presence vs. absence) - Brain metastases at study entry (presence vs.