...... 17 LIST OF FIGURES Figure 1 SDTM, ADaM, and TFL Development and Validation ................................ ................ 24 OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 6/51 2. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS Only abbreviations and terms relevant to the SAP are repeated herein. The reader is referred to the protocol for the complete and comprehensive list of abbreviations and definitions of terms for the study . Abbreviation/Term Definition ADaM Analysis data Model AE Adverse Event ALK Anaplastic Lymphoma Kinase ATC Anatomic Therapeutic Chemical BMI Body Mass Index CDISC Clinical Data Interchange Standards Consortium CR Complete Response CSR Clinical Study Report dNLR derived Neutrophils/(Leukocyte minus neutrophils Ratio) DCR Disease Control Rate DR Duration of Response ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group eCRF Electronic Case Report Form EGFR Epidermal Growth Factor HLA -A2 Human Leukocyte Antigen - A2 ICI Immune Checkpoint Inhibitor IDMC Independent Data Monitoring Committee irAE Immune -related Adverse Event ITT Intention to Treat LDH Lactate Dehydrogenase MedDRA Medical Dictionary for Regulatory Activities mITT Modified Intention to Treat mPP Modified Per Protocol ORR Objective Response Rate OS Overall Survival PD Progressive Disease PD-L1 Programmed Death -Ligand 1 OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 7/51 Abbreviation/Term Definition PFS Progression Free Survival PoI Population Of Interest PP Per Protocol PR Partial Response PT Preferred Term SAE Serious Adverse Event SAP Statistical Analysis Plan SD Stable Disease SDTM Study Data Tabulation Model SOC System Organ Class TEAE Treatment Emergent Adverse Event TFL Tables, Figures, and Listings TTD Time to Deterioration ULN Upper Limit of Normal Range WHO -DD World Health Organization Drug Dictionary OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 8/51 3. INTRODUCTION 3.1. Preface This document presents the final statistical analysis plan (SAP) for OSE Immunotherapeutics (A randomized parallel group Phase III trial of OSE2101 as 2nd or 3rd line compared with standard treatment (docetaxel or pemetrexed) in HLA -A2 positive patients with advanced Non -Small -Cell Lung Cancer with progressive disease after last treatment with immune checkpoint inhibitors (ICI [OSE2101C301 – ATALANTE 1 ]). The pres ent SAP is intended to plan the analyses to be presented in the final CSR (update of the step 1 CSR) . Reference materials for this statistical plan include the Protocol (Version 5.0 29MAR2019 ) and Annotated Case Report Form (Version 18.4 10DEC 2019 ). The pr esent SAP is an exten sion of the I DMC SAP (Planned s tep 1 analysis version 1.0 signed the 5 February 2021 – N=103 patients ) and describe s the SAP for the discontinued step-2 part of this Phase 3 trial. On March 25, 2020, t he step -2 part was ongoing when the IDMC met to review the final Step - 1 results and concluded that the predefined thresholds of survival rate at 12 months in OSE2101 arm was achieved (cut -off date of February 26, 2020 (n=103)). This analysis was blinded from the investigators and th e Sponsor. A t this time, the IDMC was concerned about the impact of the COVID -19 pandemic on the primary endpoint of the study (O verall Survival ) and the risk on data integrity. Despite step -1 positive results, the IDMC and the Steering Committee (SC) recommended to halt patients screening and accrual and to continue the treatment of patients enrolled before April 2020. So, the trial was stopped in April 2020. At that date, 219 patients post ICI have been enrolled and followed for survival up to 15 January 2021 (cutoff date for final analysis) . The present SAP is describing the final analysis on overall post ICI population (N=219 patients). 3.2. Purpose of Analyses The purposes of the planned analyses described in this SAP are to assess the safety and efficacy of OSE2101 in comparison with standard treatment (docetaxel or pemetrexed) . Results from the analyses will be included in the final clinical study report for OSE2101C301 , and may also be utilized for regulatory submissions, manuscripts, or other clinical development activities. The Step -1 results in 103 patients showed a 12 -month OS rate of 46 .0% [95% CI 33.4%, 59.1%] , and the step -1 objectives on 1 -year OS rate (H0: OS rate at 12 months >25% and H1 > 40%) were achieved. OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 9/51 An outstanding beneficial effect of OSE2101 in patients with secondary resistance to ICI given as last treatment was observed in step 1 . It is proposed to confirm the efficacy and safety of OSE210 1 in th is population of interest ( PoI) as primary analysis from the 219 randomized patients . Considering that the total number of randomized patients is 219 and that the initial hypotheses were 278 events (deaths) in 363 anticipated patients , statistical hypotheses were revised in this SAP for PoI. 3.3. Summary of Statistical Analysis Changes to the Protocol The SAP update Version 2.0 reflects a major improvement to the SAP in clarity, detailedness, organization and coherence. The SAP update is completed after last patient last visit of this phase 3 trial was done on January 15th, 2021 , and database cleaning up to June 2021 . Database lock is anticipated in July 2021 , after FDA ’ meeting occu rred July 1st, 2021 . The aim of the update is to provide sufficient details to ensure accurate and correct execution of statistical programming of tables, figures, and listings in implementing this plan, improve clarity and coherence of the d ocument to both internal and external stakeholders, as well as correcting some apparent errors and inconsistencies. Some new analyses were also added to ensure comprehensive and robust data analyses and interpretation. To this end, text was significantly a dded, revised, consolidated, or reorganized in appropriate sections. However, the specifics of study critical details such as those concerning definitions of primary endpoint, significance levels for testing OS are not changed. Notable changes are delineated below : - Primary analysis: The primary population of this analysis will be the PoI. PoI is defined as patients with secondary resistance to ICI (ICI ≥ 2nd line administered for > 12 weeks). - Sensitivity analyses on primary endp oint (O S) (described in an ancillary SAP) : o Additional subgroups ( e.g., ICI as maintenance therapy in 1st line, OS with or without anti-cancer treatment after study treatment discontinuation , post- progression survival with or without anti -cancer treatment , duration of stable disease, duration of OSE2101 treatment …) o OS according to Best Response to study treatment o OS for patients continuing study treatment beyond progression - Sequential analysis of secondary criteria: The secondary endpoints will focus on the clinical benefit provided by treatments: they will be Post progression Survival, Time to worsening of ECOG, QLQ -C30 Global health status score change from baseline, QLQ - C30 Functional total score s change from baseline, QLQ -C30 total symptom score s chan ge from baseline, QLQ -LC13 total score change from baseline, DCR at 6 and 12 months, and Progression Free Survival . OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 10/51 Consequently, the order of secondary endpoints was updated (see 4.2.4 ). The hierarchical method in the ordering sequence of secondary endpoints to control the overall type I error remains unchanged. Once the primary objective is established, each of the secondary efficacy endpoints wil l be tested at 5% significance level using a further hierarchical order in the ordering sequence of the list described above to control the overall type I error. If the primary objective is not established, these endpoints will still be analyzed but interp reted as exploratory endpoints . Similarly if one secondary endpoint in the sequence is not significant, the lower rank secondary endpoint(s) will be considered exploratory. - Time to ECOG deterioration will be evaluated. It is an accepted endpoint for clinic ians who use it to propose treatment strategy in clinical practice. It could be used later in development as a validated secondary endpoint. Complementary analyses will be described in the ancillary SAP. - Quality of Life analyses were updated and more detai led in this SAP. A complete analysis according to EORTC guidelines (https://www.eortc.org/app/uploads/sites/2/2018/02/SCmanual.pdf ) and the FDA Guidance “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 ) is considered instead of the previous approach replacing the time to deterioration of the 3 selected symptoms . QLQ -C30 Global health status/QoL score change from baseline, QLQ -C30 Functional score s change from baseline and QLQ -C30 Symptom score s change from baseline , and QLQ - LC13 Symptom score s change from baseline were added in the analysis a s secondary endpoints per EORTC guidance . As exploratory, quality of life items will be analyzed per FDA guidance to elaborate an instrument to measure the PRO (described in an ancillary SAP). As an example, summary score for the EORTC QLQ -C30 as described in the paper from Giesinger , Journal of Clinical Epidemiology 2015 “Replication and validation of higher order models demonstrated that a summary score for the EORTC QLQ -C30 is robust” will be explored. - Sensitivity analyses on PFS (described in an ancillary SAP) as described in FDA guidance ( https://www.fda.gov/regulatory -information/ search -fda-guidance - documents/clinical -trial-endpoints -approval -non-small -cell-lung-cancer -drugs -and- biologics ) - COVID -19 Impact: In the OSE2101C301 study, 110 patients out of the 219 (50.2%) were potentially impacted by the pandemic. Out of these 110 patients, 87 (79.1%) were included in France, Italy , Spain, or US . Following FDA Guidance on “Conduct of Clinical Trials of Medical Products During COVID -19 Public Health Emergency: Guidance for Industry, Investig ators, and Institutional Review Boards. ” and “Statistical Considerations for Clinical Trials During the COVID -19 Public Health OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 11/51 Emergency: Guidance for Industry ”, it is proposed to test COVID -19 impact in the ITT population using : o Time -dependent OS surviva l analyses to test the heterogeneity of the periods of randomization with or without COVID -19. o OS analysis using different cut -off dates for censored data as previously proposed (www.ema.europa.eu/en/implications -coronavirus -disease -covid -19- methodological -aspects -ongoing -clinical -trials; (Degtyarev et al., 2020; Meyer et al., 2020) - Baseline data of first line ICI population versus second line ICI and PoI population versus non-PoI population (described in an ancillary SAP). OSE Immunotherapeutics v2.2 Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 2021 -07-23 IND#: BB-IND 10802 CONFIDENTIAL P a g e | 12/51 4. STUDY OBJECTIVES AND ENDPOINTS Study objectives and endpoints defined in the protocol include safety and efficacy endpoints . Objectives and pre -specified e ndpoints are as follows . 4.1.