CONFIDENTIAL SAP Version: 3.0 Effective Date: 09DEC2020 Page 3 of 27 (PD), or to the da te of de ath, if PD does not occur. Week 8 corresponds to Cycle 3 Day 1 and Week 24 corresponds to Cycle 7 Day 1. • Overall Survival (OS). OS is defi ned as the inte rval between t he date of first dose until the date of death or t he date of last follow-up. • All efficacy analyses will be reported separately for Arm A and Arm B. Pharmacodynamics analyses on biologic activity related to study treatment will be performed for all subjects who receive at least one dose of any study drug. These ana lyses will not be performed by Advanced Clinical but will be conducted by the Sponsor’s designated pharmacodynamics experts/vendors and the results will be summarized separately . 2.3 Trial Design and Trial Procedures This is an open- label multicenter 2-arm study to eval uate the saf ety and preliminary efficacy of the additi on of a vaccine the rapy to 1 or 2 che ckpoint i nhibitors for NS CLC: • Arm A: mRN A Va ccine [BI 1361849 (f ormerly CV9202)] + anti-PD-L1 [du rvalumab]. • Arm B: mRN A Va ccine [BI 1361849] + anti- PD-L1 [du rvalumab ] + anti-CTLA-4 [treme limumab]. For each arm of t he study, there is a dose evalu ation phas e in which t he Re commended Combinati on Dose (RC D) is determined according to a standard 3 + 3 de sign. For A rm A, the RCD of BI 1361849 + durval umab is determined. The st arting dose of durval umab is 1500 mg with pos sible de-escalat ion to 750 mg; the dose fo r BI 1361849 rem ains cons tant at 12 x 80 ug. The 1500 mg Q4W dosi ng of durval umab is recommended only for subje cts with > 30kg body weight. Sub jects w ith a body we ight ≤ 30 kg are not e ligible for enroll ment in the current st udy. If a s ubject’s body weight drops to ≤ 30 kg wh ile on the study, the subje ct will receive wei ght- based dosi ng equivalent to 20 mg/kg of durval umab as long as the body wei ght rem ains ≤ 30 kg. When the wei ght improv es to >30 kg, the s ubject may return to fixed dosi ng of durval umab 1500 mg. For Arm B, the RCD of BI 1361849 + durv alumab from Arm A w ith the addition of tremelimum ab 75 mg is ev aluated. There is no dose escalat ion/de-esc alation for Arm B; if there is unaccepta ble toxici ty in Arm B, the arm w ill be dis continued as presented in Figure 1. The dose eval uation phase is followed by an expan sion phase, in which the cohort at the R CD for each arm is expande d to 20 subje cts (i nclusive of the subje cts from the dose ev aluation cohort i.e., 14 subjects will be added to the 6 treated at the RCD in the dose evaluation phase for each arm (A and B ). Sponsor: Ludwig Institute for Cancer Research. Protocol Number: LUD2014- 012-VAC. CONFIDENTIAL SAP Version: 3.0 Effective Date: 09DEC2020 Page 4 of 27 2.4 Treatments and Assignment to Treatments En rollment w ill sta rt in the A rm A dose eval uation cohorts in a sequen tial fas hion. A fter the RCD is determined for Arm A, enrollment w ill start for the dose evaluation of Arm B and for the Arm A Expansi on Cohor t, whereby no randomiz ations w ill be pe rformed. Any new subje ct will be assi gned to the A rm B dose ev aluation cohort, unle ss no slot is availa ble, in which ca se the subje ct will be assi gned to the Arm A Ex pansion C ohort. Afte r the dose eval uation and safe ty review for A rm B is comple te, enrollment in to the A rm B Ex pansi on Co hort Group w ill be prioritized ove r Arm A. Figure 1: Enrollment Schema for Arms A and B * A fter the dose evaluation and safety review for Arm B is complete, enrollment into the Arm B Expansion Cohort will be prioritized over Arm A. 2.5 Determination of Sample Size The dose evaluation pha se will utilize a standard 3 + 3 de sign for Arms A and B, which w ill result in the enrollment of 6 to 18 subjec ts. In the expan sion pha se, 20 subje cts per arm are thought to provide suffic ient dat a to adequat ely identify essential safety and pre liminary efficacy signals. Therefore, up to 14 additional s ubjects will be added to the 6 s ubjects treated at the RCD in each arm (A and B). The sample size n=20 for the expansion phase is deemed to provide suffi cient pre cision for t he estimation of inci dence of adve rse events as estimated by the Cloppe r Pearson confi dence intervals (CI) for i ncidence of a dverse events. Overall, approximately 56 subjec ts will be enrolled in up to 8 sites in the US. The enrollment period will take approximately 24 months. Sponsor: Ludwig Institute for Cancer Research. Protocol Number: LUD2014- 012-VAC. CONFIDENTIAL SAP Version: 3.0 Effective Date: 09DEC2020 Page 5 of 27 3.0 GENERAL ANALYSIS CONVENTIONS 3.1 General Conventions Data collected in this study will be documented using summary tables and subject data listings. Continuous endpoints will be summarized using descriptive statistics, e.g. number of subjects , mean, median, standard deviation, minimum and maximum values. The mean and median will be reported to 1 decimal place more than the level of precision of the data being reported and the SD will be reported to 2 decimal places more than the level of precision of the data being reported, unless otherwise noted. Categorical endpoints will be presented in frequency tables with number and percentage of observations for each level. All efficacy analyses will be presented separately for Arm A and Arm B. Tumor Response will be summarized and analyzed descriptively. A 95% Confidence Interval based on the binomial distribution will be constructed for the estimated PFS rate and ORR at 8 and 24 weeks and DCR. The number and percentage of subjects who died or had a confirmed progression, who survived without a confirmed progression, and who were lost to follow up (unknown survival and/or progression status) will be summarized. PFS rate at 8 and 24 weeks and the corresponding 95% CIs will be calculated based on Kaplan-Meier product limit estimates and will be displayed along with the corresponding number of subjects at risk. (Note – this may include OS as well) PFS and OS will be summarized using the 25th percentile, Median, and 75th percentile as well as the minimum and maximum survival time, calculated by Kaplan -Meier method, and will be displayed graphically. The ORR, DCR and DOR will be summarized descriptively and a 95% Confi dence Interv al based on binom ial distri bution w ill be presented. 3.2 Trial Periods The overall length of study per subject is up to 15 months; comprising of 12 months for treatment and three months for on study follow-up. The screening period is up to one month prior to first drug administration. Study drug w ill be admin istered ove r 12 cycl es with a cy cle le ngth of 28 days. The st udy dr ugs used in this study w ill be administ ered per cycle as shown in Appendix B. The overall length of the study is 39 months. However the length of the surviaval post study follow- up is up to five years from initiation of treatment. Sponsor: Ludwig Institute for Cancer Research.