............ 23 17.0 APPENDICES ................................ ................................ ...................... 24 17.1 Appendix A: Study Flowchart ............................................................. 24 17.2 Appendix B: Drug Administrative Schedules per Cycle ......................... 27 ACRONYMS Below is the list of acronyms that will be used throughout this document. Abbreviation Definition AE adverse event AESI adverse event of special i nterest CI confidence intervals CR Complete response CTC AE V.4.03 Common Terminology Criteria for Adverse Events v. 4.03 CTLA-4 Cytotoxic T lymphocyte-associated antigen 4 DNA Deoxy ribonucleic Acid DCR Disease Control Rate DLT Dose limiting toxicity DoR Duration of response ECG electrocardiogram ECOG Eastern Cooperative Oncology Group FFPE Formalin-fixed paraffin -embedded GCP Good Clinical Practice ICH International Conference on Harmonization ILD Interstitial l ung disease irRECI ST Immune-related Response Evaluation Cri teria in Solid Tumors MedDRA Medical Dictionary for Regulatory Activities NCI CTCAE National Ca ncer Institute Common Terminology Criteria for d NSCLC Non-small cell lung cancer ORR Objective Response Rate OS Overall survival PBMC Peripheral blood mononuclear c ell PD Progressive disease PD-L1 Programmed death li gand 1 PFS Progression free survival PR Partial response Q4W Every 4 weeks RECI ST Response Evaluation Cri teria in Solid T umors RCD Recommended combination dose RNA Ribonucleic Acid SAE Serious Adverse Event SD Stable disease TEAE Treatment Emergent Adverse Event TIL tumor-infiltra ting lymphocyte TME Tumor microenvironment Sponsor: Ludwig Institute for Cancer Research. Protocol Number: LUD2014- 012-VAC. CONFIDENTIAL SAP Version: 3.0 Effective Date: 09 DEC2020 Page 1 of 27 1.0 PURPOSE This SAP describes the methods to be used in the analysis of trial data from clinical protocol “ A Phase 1/2 Study of Combinati on Immunothe rapy and mRN A Va ccine in Subje cts with Non- small Ce ll Lung Cancer (NSCLC)” in order to answer the trial objective(s), and is based on Amendment 9.1 of the trial protocol ( LUD2014-012- VAC) , dated 01 September 2020. Populations for analysis, data handling rules, statistical methods, and formats for data presentation are described within this document. The statistical analyses and summary tabulations described in this SAP will provide the basis for the results sections of the CSR for this trial. The SAP outlines any differences in data analysis methods relative to those planned in the trial protocol. Any changes to the data analysis methods after the SAP is finalized will be described in the CSR. 2.0 OVERALL STUDY DESIGN AND OBJECTIVE S 2.1 Trial Objectives This study w ill eval uate the safety and e fficacy of the add ition of a v accine the rapy (BI 1361849, previously known as CV9202) to 1 or 2 che ckpoint inhibitors (durval umab and tre melimumab) for NS CLC. The study has two phases; the dose evaluation phase and the dose expansion phase. In the dose expansion phase, there are two cohorts as follows: Arm A: mRNA Vaccine [BI 1361849 (formerly CV9202)] + anti- PD-L1 [durvalumab] Arm B: mRNA Vaccine [BI 1361849] + anti- PD-L1 [durva lumab] + anti -CTLA -4 [tremelimumab]. The p rimary trial objectives are: • Dose evaluation Phase: To evaluate s afety an d toler ability, including Dose Limiting Toxicities ( DLTs) and Recommended Combination Dose ( RCD) of a combination immunotherapy with durval umab or durvalumab and tr emelimum ab together with an RNA vaccine BI 1361849. • E xpansion Phase: To e valuate s afety an d toler ability of a combination immunotherapy with durval umab or durvalumab and tr emelimumab together with an RNA vaccine BI 1361849. The secondary trial objective is: • To evaluate the clinical efficacy of the combination immunotherapy for all subjects in both the dose evaluation and the dose expansion phases. The exploratory trial objective is: Sponsor: Ludwig Institute for Cancer Research. Protocol Number: LUD2014- 012-VAC. CONFIDENTIAL SAP Version: 3.0 Effective Date: 09DEC2020 Page 2 of 27 • To evaluate Bi ologic Ac tivity and the e ffects on t umor microenvironment, and i mmune response for all subjects in both the dose evaluation and the dose expansion phases. 2.2 Study Endpoints Primary Endpoints The primary endpoint of the combination therapy of durval umab and tremelimumab are: • Dose- Lim iting Toxici ties (DL Ts). DLTs are de fined as any ad verse events that are possibly, probably, or de finitely related to the administra tion of durval umab, tremelimumab, or BI 1361849 components. This applies to Dose Evaluation subject s during the DLT Evaluation period. • Safety and tolerability evaluated using CTCAE 4.03. • Recommended Combination Dose (RCD) determined in Dose Evaluation Phase. The safety endpoints for this study include: • Treat ment-emergent adv erse events (TEA Es) and serious AEs ( SAEs) • Clinical la boratory te sts (hematology and chemistry) • Vital signs and we ight me asurements • ECG • ECOG pe rformance status eval uation • An y other medically indicated assessments, incl uding s ubject intervi ews • All safety analyses will be reported separately for Arm A and Arm B The Clinical efficacy endpoints will be assessed by ir RECI ST and RECI ST 1.1 and will include: • Objective Response rate (ORR) at 8 and 24 weeks. ORR is defined as the pe rcentage of subjects meeting c riteria of Complete Respon se (CR) or P artial Response (PR) over a period of at least 4 weeks.