9.2. Progression -free Survival (PFS) Progression -free survival (PFS) will be defined as time (in months) from randomization to the first documented disease progression (as defined using the RECIST 1.1 criteria and FDA Clinical Trial Endpoints for the Approval of Non -Small Cell Lung Cancer Drugs and Biologics, Guidance for Industry, April 2015) or death whichever occurs first. The PFS derivation rule is as follows (ignoring information collected after the analysis cut -off date) : • Check whether a candidate time p oint (for event or censoring) is more than 14 weeks (2 times 6+1 weeks) after the last available tumor assessment before this time point; apply Table C1 of FDA guidance: o No baseline tumor assessment: censored at randomization (0 days after randomization) o Progression documented in tumor assessment or in Survival Follow -up form or in End of Treatment form : ▪ If previous tumor assessment without progression ≤ 14 weeks before: PD ▪ If previous tumor assessment without progression > 14 weeks before: censored at previous tumor assessment without progression o Death without post -baseline tumor assessment ▪ ≤ 14 weeks after randomization: event at date of death ▪ > 14 weeks after randomization: censored at randomization o Death with at least 1 post -baseline tumor assessme nt ▪ if previous tumor assessment without progression ≤ 14 weeks before: event at date of death ▪ if previous tumor assessment without progression > 14 weeks before: censored at previous tumor assessment without progression ("more than one missed visit”) o new anticancer treatment started without documented progression recorded: censored at previous tumor assessment without progression o no documented progression, no death, no new anticancer treatment started: censored at previous tumor assessment without progression Since the protocol plans for a tumor assessment every 6 weeks (± 1 week) until document ed RECIST 1.1 progression, the 14 weeks (98 days) mentioned above correspond to 'more than one missed visit' used in Table C1 in Appendix C of the FDA guidance 'FDA Clinical Trial Endpoints for the Approval of Non -Small Cell Lung Cancer Drugs and Biologics, Guidance for Industry, April 2015'. Other censoring strategies described in the guidance will be explored in the SAP appendix. As described in Appendix 3 of the FDA guidance 'Clinical Endpoints for the Approval of Cancer Drugs and Biologics, May 2007', cli nical progression is not considered a progression endpoint. OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 37/51 In case of conflicting information between RECIST records indicating no progression of disease and EOT form or survival form reporting a 'documented clinical progression', the worst value (progres sion) will be retained in the PFS derivation. PFS will be summarized using the Kaplan -Meier method and displayed graphically. The median event time for each treatment arm and the corresponding 2 -sided 95% confidence interval will be provided. A 2-sided log -rank test stratified for the randomization stratification factors will be used to compare PFS between the two treatment arms. The Cox regression model, stratified for the same stratification factors, will be fitted, and the estimated hazard ratio and 2 -sided 95% confidence interval will be provided. The hazard ratio, as estimated in this Cox regression model, will be provided with its 2 -sided 95% confidence interval on the Kaplan -Meier plot. The six -month PFS rate will be estimated using the Kaplan -Meier m ethod and a 2 -sided 95% confidence interval for the log [ -log(6 -months survival probability)] will be calculated using a normal approximation and then back transformed to give a confidence interval for the 6 - months PFS rate itself. The 12 -month PFS rate wi ll be estimated similarly. As sensitivity analysis, Clinical Progression -free survival (PFS) analysis will be performed with following definition of progression event: earliest date either of a RECIST tumor assessment with PD status (without consideration for the number of weeks since previous tumor assessment without progression) or of the mention of a documented progression in the Survival Follow -up form or in the End of Treatment form) or death whichever occurs first. 9.3. Overall response Rate (ORR), Diseas e Control rate (DCR) and Duration of response (DR) Assessment of response will be made using RECIST version 1.1 (the protocol does not require confirmation at a subsequent time point for CR and PR) and ignoring assessments performed after the analysis cut -off date. Patients will be considered as without measurable lesions at baseline as soon as (at least) one post-baseline RECIST e -CRF form indicates 'No Target Lesions at Baseline' . The remaining patients will be considered as with measurable lesions at bas eline. Based on the randomized patients, the last available response in patients still alive at the analysis cut -off date will be displayed in the summary of overall survival time (see DMC Table 2.1.1). Based on the randomized patients with measurable lesi ons at baseline, the best response (complete response ( CR), partial response ( PR), stable disease ( SD), progressive disease ( PD), Not evaluable (NE) or no post -baseline assessment ) and the ORR (counting as objective response the patients with CR and PR) will be determined for each patient and will be summarized by treatment arm (see DMC Table 2.2) . The corresponding exact 2 -sided 95% confidence interval of the ORR will be calculated for each treatment arm. The Mantel - Haenszel test will be used to compare OR R between the treatment arms, using the OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 38/51 randomization strata. The corresponding odds -ratio will be provided with its 95% confidence interval. In addition, the difference in ORR between the two treatments will be provided and its 95% confidence interval wil l be calculated based on the normal approximation . DCR at 6 months will be calculated in each treatment arm as the number of patients remaining within CR, PR or SD responses within the considered time period divided by the total number of randomized patients with measurable lesions at baseline. For patients alive at 6 months the last RECIST assessment available up to 183 days (included) after randomization will be retained; a progression declared as 'documented progression' by the site will also be retained and counted as PD. Patients with death within 6 months from randomization will be counted as PD. Patients w ith consent withdrawal before 6 months from randomization will be excluded from this analysis. DCR will then be analyzed as described for ORR. DCR at 12 months will be calculated and analyzed as described for DCR at 6 months. Duration of DCR will be summar ized for the subgroup of patients who have achieved CR, PR, or SD responses. The duration of DCR will be defined as the time (in months) from the date of the first initial occurrence of a CR or PR or SD to the PFS date (corresponding to a PFS event or to a censoring). Duration of DCR will be analyzed as described for the PFS. The rate à 6 months and 12 months will be also estimated as sensitivity analysis. DR will be summarized for the subgroup of patients w ho have achieved objective response. The DR will b e defined as the time (in months) from the date of the first initial occurrence of a CR or PR to the PFS date (corresponding to a PFS event or to a censoring). DR will be analyzed as described for the PFS. Depending on the availability of the data waterfal l plot (to described quantitative data on target lesion) or spider plots (to describe synthetically each patient) will be proposed. 9.4. Time to next lung cancer therapy The date of initiation of a lung cancer therapy will be taken as the date of contact of the first survival follow -up form mentioning that the patient has received a treatment for the disease after stopping the study drug. This date will be censored at the analysis cut -off date for patients having received a lung cancer therapy. This date will be censored at the cut -off date or at the date of death, whichever comes first, for patients having not initiated a lung cancer therapy. The time (in months) from the randomization to this date will be analyzed as described for the PFS. As a sensitivity anal ysis, same analysis will be performed with the time (in months) from the earliest date either of a RECIST tumor assessment with PD status or of the mention of a documented progression in the Survival Follow -up form or in the End of Treatment form to this d ate. The text ‘This date will be censored at the cut -off date or at the date of death, whichever comes first, for patients having not initiated a lung cancer therapy.’ should be changed to ‘This date will be censored at the cut -off date or at the date of d eath (or at the date of last survival information for patients who did not experience death) , whichever comes first, for patients having not initiated a lung cancer therapy’. OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 39/51 Sensitivity analysis using the date of progression (in months) to this date will be analyzed as described for the PFS. The date of progression will be defined as the earliest date either of a RECIST tumor assessment with PD status (without consideration for the number of weeks since previous tumor assessment without progression) o r of the mention of a documented progression in the Survival Follow -up form or in the End of Treatment form. 9.5. Post-progression Survival The date of progression will be defined as the earliest date either of a RECIST tumor assessment with PD status (without consideration for the number of weeks since previous tumor assessment without progression) or of the mention of a documented progression in the Survival Follow -up form or in the End of Treatment form. Post-progression survival of patients having e xperienced a progression will be summarized by treatment arm using the Kaplan -Meier method and displayed graphically. The median event time for each treatment arm and the corresponding 2 -sided 95% confidence interval will be provided. An additional analys is will be performed to explore impact on OS to continue study treatment beyond progression. The number of patients continuing study treatment 28 days o r more after progression defined as the earliest date either of a RECIST tumor assessment with PD status or of the mention of a documented progression in the Survival Follow -up form or in the End of Treatment will be presented in each group. Post -progression survival of patients having continuing study treatment 28 days o r more after progression versus patie nts not having continu ed study treatment 28 days o r more after progression (other treatment after progression) will be summarized by treatment arm (4 curves) using the Kaplan -Meier method and displayed graphically. The median event time for each treatment arm and each subgroup and the corresponding 2 -sided 95% confidence interval will be provided. Overall survival of patients having continu ed study treatment 28 days o r more after progression versus patients not having continu ed study treatment 28 days o r more after progression (other treatment after progression) will be summarized by treatment arm (4 curves) using the Kaplan -Meier method and displayed graphically. The median event time for each treatment arm and each subgroup and the corresponding 2 -sided 95 % confidence interval will be provided. A listing of patients continuing treatment after PFS will be provided with following information: date of RECIST progression and PFS in months, date of clinical progression, treatment start date, treatment end date, treatment duration, reason for treatment discontinuation, duration between date of RECIST progression and date of treatment discontinuation, date of death and OS in months . A summary table of number of patients continuing treatment after PFS in each arm ( >=28 days) and overall will be provided . A table of study treatment exposure per cycle beyond 28 days post PFS will be provided in each arm and overall. . OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 40/51 9.6. Quality of life analyses The scores will be derived from the EORTC QLQ -C30 and EORTC QLQ -LC13 questi onnaires items according to the respective scoring manuals , ignoring assessments performed after the analysis cut -off date or after treatment discontinuation . A summary of each total score and sub -score for each dimension, for the EORTC QLQ -C30 will be described by cycle and treatment arm. • Global health status / QoL • Functional scales o Physical functioning o Role functioning o Emotional functioning o Cognitive functioning o Social functioning • Symptom scales / items o Fatigue o Nausea and vomiting o Pain o Dyspnea o Insomnia o Appetite loss o Constipation o Diarrhea o Financial difficulties A summary of each total score and sub -score for each dimension, for the EORTC QLQ -LC13 will be described by cycle and treatment arm. • Symptom scales / items o Dyspnea o Coughing o Hemoptysis o Sore mouth o Dysphagia o Peripheral neuropathy o Alopecia o Pain in chest o Pain in arm or shoulder o Pain in other parts After scoring process, domains score will be from 0 to 100. The higher the value, the higher the quality of life. After scoring process, symptoms score will be from 0 to 100. The lower the value, the poorest the quality of life. OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 41/51 Questionnaire s collected as “end of treatment” visit will be mapped to next protocol visit if they are not duplicate compared to the last non -missi ng visit . Absolute changes from baseline will be summarized as well. Plots representing means and 95%CI for raw data and absolute changes from baseline will be associated to graphically visualized this data. Missing data fractions for quality of life will be reported under different scenarios: - rate of patients completing baseline assessments and the assessments at designated time points over the total number of patients eligible and entered the trial. - rate of patients completing assessments at designated time points while on study treatment over the total number completing assessment at baseline. - rate of patients completing assessments at designated time points over the number of patients still on study, who were expected to complete questionnaires at each of those time points (excluding those who progressed or were dead at that time point). For each domain or symptom, mean changes within arms from baseline to the last cycle with more than 25% of the total nu mber of included patients (Cycle 8) will be reported to provide a complete picture of QoL behavior. Changes in scores from baseline until treatment discontinuation will be assessed using mixed - effects model for repeated measures (MMRM) analysis. Missing da ta are not imputed. The p value will be determined using MMRM analysis, with patient, treatment, visit, and treatment by visit interaction as explanatory variables and baseline score as covariate. Patient will be fitted as a random effect, and compound score covariance structure will be used for all models. The Least Squares M ean differences for each symptom will be reported and plotted with corresponding 95% CIs. Two sensitivity analyses for consistency with those from the main analysis will be conducted only on the quality of life secondary endpoints (QLQ -C30 Global health status, QLQ -C30 Physical and Role functioning score s): - using only patients with complete data from cycle 1 to the median number of cycle s - imputing the worst value to next protocol visi t after the last non -missing visit of patients discontinued treatment for death Best QoL response from baseline will be derived for each domain or symptom as follows: a change score of at least 10 points from baselin e will be defined as clinically relevant. Patients will be considered improved if they reported a score of 10 points or more better than baseline at any time a nd will be considered worsened if they reported a score 10 or more points worse than baseline (without improvement). Patients whose scores change less than 10 points from baseline will be considered stable. Only patients who had completed the baseline and at least one follow -up questionnaire w ill be included. An exact linear rank test will be used to test whether the two study arms had the same underlying multinomial distribution of the ordered QoL response OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 42/51 9.7. ECOG The time to worsening of ECOG will be defined as the time from randomization to the earliest time when the ECOG becomes greater than 1 ignoring all assessments performed after the analysis cut -off date. P atients who die without having record ed an ECOG >1 will be assigned an ECOG = 5 (Dead) at the tim e of death . Patients without worsening will be censored at the last time when an ECOG value was recorded. The endpoint will be analyzed as described for the PFS. By protocol, ECOG is not collected anymore when a subject discontinues study treatment while t he time between study treatment discontinuation and death can be quite long. The analysis described above assigns an ECOG 5 at the time of death. This imputation may seem exaggerated as, for most of the imputed patients, a condition corresponding to a (unr ecorded) Grade 2 or worse is likely to have occurred markedly earlier than the date of death imputed as Grade 5. In that situation the imputation artificial ly extends the TTD -free period. For this reason, an additional analysis without imputation for death will be performed . This analysis will exclude patients without any post -baseline ECOG assessment and censor patients without observed ECOG worsening at their last ECOG assessment. 10. SAFETY ANALYSES All Safety analyses will be conducted using the Safety sets. An overall treatment summary will be included. All safety analyses will be completed using the actual treatment a subject received. For laboratory safety parameters, vital signs and ECGs, the ba seline will be the last available value up to the date of first study drug administration included. 10.1. Adverse Events All AEs and SAEs will be coded using the MedDRA dictionary for System Organ Class (SOC) and Preferred Term (PT), with the creation of an ad h oc SOC 'Injection site reactions' grouping all PTs with High Level Term 'Administration site reactions' . Level of intensity was graded according to the CTCAE v5.0 grading. Treatment -emergent adverse events (TEAEs) are defined as any adverse event or worsen ing of an existing condition after the date of the first administration of the study treatment (included) and up to 28 days after the date of the last administration of the study treatment (included) or up to the analysis cut -off date (whichever comes firs t). Immune -related TEAEs (irAEs) are defined as any TEAE that has been specifically flagged as immune -related on the e-CRF. OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 43/51 Serious adverse events w ere recorded from the date of informed consent, throughout the clinical trial, and for up to 28 days after the final administration of study drug. The number of emergent events and the number and percent age of subjects with TEAEs will be summarized by SOC and PT by treatment arm for different categories of TEAEs . At each level of tabulation ( e.g., at the PT level) patients will be counted only once if they had more than one such event reported during the AE collection period. The following summary tables wi ll be presented for TEAE data: • Treatment -Emergent Adverse Events Overview • Treatment -Emergent Adverse Events, by Severity and Grade • Treatment -Emergent Adverse Events, by SOC and PT • Treatment -Emergent Severe Adverse Events, by SOC and PT • Treatment -Emerge nt Serious Adverse Events, by SOC and PT • Treatment -Emergent Adverse Events with Fatal Outcome, by SOC and PT • Treatment -Emergent Adverse Events leading to Withdrawal from the Study, by SOC and PT • Treatment -Emergent Drug Related Adverse Events, by SOC and PT • Treatment -Emergent Severe Drug Related Adverse Events, by SOC and PT • Treatment -Emergent Serious Drug Related Adverse Events, by SOC and PT • Treatment -Emergent Drug Related Adverse Events with Fatal Outcome, by SOC and PT • Treatment -Emergent Drug Relat ed Adverse Events leading to Withdrawal from the Study, by SOC and PT The Treatment -Emergent Adverse Events Overview table will display by treatment arm the number of emergent events and the number and percentage of subjects with TEAEs for each of the foll owing TEAE categories: • Treatment -Emergent Adverse Events • Treatment -Emergent Drug Related Adverse Events • Treatment -Emergent Severe Adverse Events • Treatment -Emergent Severe Drug Related Adverse Events • Treatment -Emergent Serious Adverse Events • Treatment -Emergent Serious Drug Related Adverse Events • Treatment -Emergent Adverse Events with Fatal Outcome • Treatment -Emergent Drug Related Adverse Events with Fatal Outcome • Treatment -Emergent Adverse Events leading to Withdrawal from the Study • Treatment -Emergent Drug Related Adverse Events leading to Withdrawal from the Study For each row of the overview table, the chi -square test comparing the two treatment arms on the proportion of patients with the considered TEAE category will be used as a flagging dev ice. The same presentation will be repeated for the irAEs. OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 44/51 All the tables listed above will be repeated on the following subgroups: • Age (< 65 years vs. ≥ 65 years) • Sex (Male, Female • Age and sex ( Male < 65 years, Male. ≥ 65 years, Female < 65 years, Female ≥ 65 years) • Region (US, non -US). Race is not retained for defining subgroups since the number of patients of non -white patients is very limited (1 Asian and 1 Black or African American within the treated patients ). 'Severe' will be defined as Grade 3 or above. A missing severity will be consider ed Grade 3. 'Drug Related' will be defined as 'Definitely Related', 'Probably related' or 'Possibly Related', excluding 'Unlikely Related' and 'Not Related'. A missing relationship will be considered as 'Definitely Related'. TEAEs 'leading to Wi thdrawal from the Study' are defined as TEAEs where the AE data 'Withdrawn from Study?' is ticked Yes. The list of summary tables for TEAE data will include a table for 'Treatment -Emergent Drug Related Adverse Events by Severity and Grade'. The irAEs will be described by 2 tables: 'Treatment -Emergent Adverse Events Overview' and 'Treatment -Emergent Adverse Events by SOC and PT'. No subgroup tables will be prepared for the irAEs. Since the number of patients in US is limited (7 within the treated ICI patients randomized before 26 February 2019, 16 within the ICI patients randomized and treated as of 26 February 2020), the subgroup variable Region (US, non US) will not be retained for the CSR . The ad hoc SOC 'Administration site reactions' will be created by gr ouping all PTs with High Level Group 'Administration site reactions'. AEs not coded for patients 1514021 and 2202009 (respectively: 'Right arm inflammation' and 'Increase of cholestasis' ) will be displayed in the summary tables by their reported term (in place of PT) within the ad hoc SOC 'Not coded' . 10.2. Deaths, Serious Adverse Events and Other Significant Adverse Events 10.2.1. Deaths All deaths occurring up to the analysis cut -off date, regardless of causality, will be summarized by cause of death. OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 45/51 10.2.2. Serious Adverse Events A listing of Serious Adverse Events (SAEs) occurring up to the analysis cut -off date will be provided. SAEs occurring before study drug initiation will be listed separately . 10.2.3. Adverse Events Leading to Discontinuation of Study Drug or Withdrawal from Study A listing of all AEs occurring up to the analysis cut -off date and leading to discontinuation of study drug or withdrawal from study will be presented. 10.3. Clinical Laboratory Evaluations Clinical laboratory values will be analyzed after conversion into standard international units. International units will be used in all listings and tables. The results will be graded according to the CTCAE v5.0, when applicable. The n umber and percentage of pa tients with laboratory abnormalities (all grades and by grade) using the worst grade between the date of the first administration of the study treatment (excluded) and up to 28 days after the date of the last administration of the study treatment (included) or up to the analysis cut -off date (whichev er comes first) will be displayed by treatment arm in a shift table stratifying the patients according to the grade observed at baseline . For safety laboratory parameters where the CTCAE v5.0 grading scale is not applicable, the number and percentage of patients with a value below the normal range and the number and percentage of patients with a value above the normal range will be displayed by treatment arm in a shift table stratifying the patients according to their situation at baseline (below the lower limit of normal range, within normal range, above the upper limit of normal range) . A same patient may be present in both counts . For each parameter, and among each grade observed at baseline the percentages will be based on the number of subjects having a t least one post -baseline value no later than the analysis cut - off date. 10.4. Vital Signs The number and percentage of patients with marked abnormalities between the date of the first administration of the study treatment (excluded) and up to 28 days after the date of the last administration of the study treatment (included) or up to the analysis cut -off date (whichever comes first) will be displayed for each type of abnormality by treatment arm in a shift table stratifying the patients according to their situat ion at baseline (with/without the considered marked abnormality at baseline) . Marked abnormalities are classified as high or low based on values occurring above the higher limit or below the lower limit, respectively. It is possible OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 46/51 that, for a given param eter, the same subject is counted as a high marked abnormality for an observed value and as a low marked abnormality for a different observed value. Variable Abnormality Weight (kg) decrease from baseline > 10% increase from baseline > 10% Body temperature (°C) < 36 > 39 Systolic blood pressure (mm Hg) < 90 > 140 Diastolic blood pressure (mm Hg) < 60 > 90 Heart Rate (bpm) < 50 > 100 Respiratory rate (breaths/minute) < 10 > 20 Oxygen saturation (%) <95% For each parameter, the percentages will be based on the number of subjects having at least one post -baseline value no later than the analysis cut -off date. ---- Addition or change after 04 June 2020 -------- For the weight, the percentages will be based on the number of subjects having a baseline value and at least one post -baseline value no later than the analysis cut -off date. [Reference: e -mail of 18 August 2020]. 10.5. 12-Lead ECG The number and percentage of patients with clinically significant abnormal ECG between the date of the first administration of the study treatment (excluded) and up to 28 days after the date of the last administration of the study treatment (included) or u p to the analysis cut -off date (whichever comes first) will be displayed by treatment arm in a shift table stratifying the patients according to their situation at baseline (with/without clinically significant abnormal ECG at baseline) . The percentages will be based on the number of subjects having at least one post-baseline ECG no later than the analysis cut -off date . 11. ADDITIONAL SAFETY ANALYSES The population of all ICI treated patients randomized until the analysis cut -off date will be described by treatment arm for the following items: • Demographics • Baseline characteristics OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 47/51 • Previous ICI treatment • History of immune -related AEs • Medical history • Concomitant medications • Medications received for the disease after stopping study drug All safety a nalyses described in the previous section will be repeated on this population. 12. COVID -19 IMPACT According to the following guidance’s • European Medicines Agency (2020a), “Guidance on the Management of Clinical Trials During the COVID -19 (Coronavirus) Pandemi c,” Version 3. • European Medicines Agency (2020b), “ PoInts to Consider on Implications of Coronavirus disease (COVID -19) on Methodological Aspects of Ongoing Clinical Trials .” • “FDA Guidance on Conduct of Clinical Trials of Medical Products During COVID -19 Public Health Emergency: Guidance for Industry, Investigators, and Institutional Review Boards.” • Statistical Considerations for Clinical Trials During the COVID -19 Public Health Emergency: Guidance for Industry and considering that 110 patients out of the 219 are potentially impacted by the pandemic on the 01JAN2020: • 60 patients untreated in follow -up for survival • 24 patients treated • 26 patients randomized between the 01JAN2020 and 30APR2020 During the data review committee, protocol deviation s related to COVID -19 (visits or infusions cancelled or delay, COVID -19 events, death related to COVID, follow -up visits delayed, …) will be reviewed . If some major deviations are decided related to COVID -19 patients will be excluded from PP population. Num ber of deviations will be presented overall and per category of deviation ( DVCAT in the ADDV database) and protocol deviation coded term (DV.DVDCOD) using 2 different periods of randomization with or without COVID -19 (Period without COVID -19: First inclusion to 31DEC2019 , then COVID -19 period: 01JAN 2020 to last inclusion) using following table OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 48/51 Arm A (N=XX) Arm B (N=XX) Total (N=XX) Number of deviations Number of patients % Number of deviations Number of patients % Number of deviations Number of patients % At least one deviation DVCAT: EXCLUSION DVCAT: CRITERION protocol deviation coded term 1 protocol deviation coded term 2 … DVCAT: NOT MET protocol deviation coded term 1 protocol deviation coded term 2 … DVCAT: INCLUSION DVCAT: CRITERION NOT MET protocol deviation coded term 1 protocol deviation coded term 2 … DVCAT: NFORMED CONSENT protocol devia tion coded term 1 protocol deviation coded term 2 … DVCAT: PROCEDURES/ TESTS protocol deviation coded term 1 protocol deviation coded term 2 … DVCAT: RANDOMIZATION protocol deviation coded term 1 protocol deviation coded term 2 … DVCAT: SERIOUS ADVERSE EVENTS protocol deviation coded term 1 protocol deviation coded term 2 … DVCAT: STUDY DRUG protocol deviation coded term 1 protocol deviation coded term 2 … DVCAT: VISIT SCHEDULE protocol deviation coded term 1 protocol deviation coded term 2 … Same table will be presented for patients excluded from PP. Analysis described in 8.11.1 Time Intervals between Cycles , 8.11.3 Time Intervals between RECIST Assessments , and 8.11.4 Time Intervals between Quality of Life Assessments will be OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 49/51 repeated for the 2 different periods of randomization with or without COVID -19 (Period without COVID -19: First inclusion to 31DEC2019 , then COVID -19 period: 01JAN 2020 to last inclusion) . This analysis will be performed at a patient level and at visit level and will be added in the ancillary SAP . Analysis desc ribed in 8.11.1 Time Intervals between Cycles , 8.11.3 Time Intervals between RECIST Assessments , and 8.11.4 Time Intervals between Quality of Life Assessments will be repeated for the 2 different periods of randomization with or without COVID -19 (Period without COVID -19: First inclusion to 31DEC2019 , then COVID -19 period: 01JAN 2020 to last inclusion) . This analysis will be performed at a patient level and at visit level a nd will be added in the ancillary SAP. The number of deaths any cause will be summarized by treatment arm for the 2 different periods of randomization with or without COVID -19 (Period without COVID -19: First inclusion to 31DEC2019 , then COVID -19 period: 01 JAN2020 to last inclusion) . This analysis will be performed at a patient level and using the patient year unit during the 2 periods. These analyses will be added in the ancillary SAP. The number of emergent events and the number and percentage of subjects with TEAEs will be summarized by SOC and PT by treatment arm for different categories of TEAEs for the 2 different periods of randomization with or without COVID -19 (Period without COVID -19: First inclusion to 31DEC2019 , then COVID -19 period: 01JA N2020 to last inclusion) . This analysis will be performed at event level and at patient level . This analysis will be repeated using the patient year unit during the 2 periods for the denominator . These analyses will be added in the ancillary SAP. • Death any cause • Treatment -Emergent Adverse Events Overview • Treatment -Emergent Adverse Events, by SOC and PT • Treatment -Emergent Drug Related Adverse Events, by SOC and PT • Treatment -Emergent Severe Drug Related Adverse Events, by SOC and PT Same analyses will be performed using the same 2 periods (without COVID -19, with COVID - 19) but considering start date of AE for the tables. In this analysis patients with AEs in the 2 periods will be counted in the 2 periods. For patient without any AE during study, da te of randomization will be considered for the denominator of the percentages. - Period1: AE which start between f irst inclusion and 31DEC2019 - Period2: AE which start between 01JAN 2020 and 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 | 50/51 12.1. Disposition Status of the population before and after pandemic will be summarized using following table: N (%) Arm A (n=XX) Arm B (n=XX) Total (n=219) Randomized until 31 DEC19 Na Nb Na+Nb Alive on 01JAN20 or randomized after the 31DEC 19 In Follow -up after the 01JAN20 Treated after the 01JAN20 Included after the 01JAN20 12.2. Sensitivity analysis on censor date Same analysis for OS as described in 9.1 will be repeated with a censor date a t 3 following cut-offs: 31DEC20 19, 31JAN2020 and 26FEB2020 (cut off for Step 1 analysis) . 12.3. Time -dependent covariate analyses Time -dependent covariates are t hose that may change in value over the course of observation. For a model with one time -invariant covariate and one time-dependent covariate, we have log h(t)= α(t)+β1X1 + β2X2(t) For example, if we want a model in which the hazard of OS depends on COVID -19 status, we could specify COVID as whether the person is currently COVID exposed in week t . Cox model s taking into account COVID time dependent will be presented using - 3 different periods of randomization with or without COVID -19 (Period 1: Step1: First inclusion to 26FEB2019, then post step 1: 26FEB2019 to 31DEC2019 , then COVID -19 period: 01JAN 2020 to last inclusion). - 2 different periods of randomization with or without COVID -19 (Step1: First inclusion to 26FEB2019, then post step 1: 26FEB2019 to last inclusion). - 2 different periods of randomization with or without COVID -19 (Step1: First inclusion 31DEC 2019, then : 01JAN2020 to last inclusion). Using AIC criterion, the best model will b e chosen. OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 51/51 • One simple model with overall population to test COVID impact proc phreg data = XX; class COVIDIMPACT / ref = last; model (before, after) * censored( 1) = COVIDIMPACT / ties = EFRON rl;run; • One simple model for each treatment arm • One model with overall population to test COVID impact with treatment arm in the model with or without interaction proc phreg data = XX; class COVIDIMPACT ARMGR/ ref = last; model (before, after) * censored( 1) = COVIDIMPACT ARMGR / ties = EFRON rl;run;