See further details in the imAE Charter with respect to derivat ion rules. In ad dition, the fo llowing analyses regarding systemic steroid use for imAE will be provided by imAE group. See further details in the imAE Charter with respect to derivat ion rules associ ated wi th durati on and time to systemic steroid use for imAE. The duration of steroi d use will be produced by imAE group for both all systemic steroids and high dose sy stemic steroi ds. 4.2.3.3 Clinical laboratory variables (clinical chemistry, hematology and urinalysis) All laboratory safet y data will be listed for each patient and summ arized where appropriate. Clinical chemistry and hematol ogy values outsi de the reference ranges will be highlighted in the list ings. Data summaries will be provided in preferred units. Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 58of 65For continuous laboratory data absol ute and change from baseline will b e summari zed by visit. Box pl ots of change fro m baseline will be presented for haematology and clinical chemistry variables. Shift tables for laboratory values by worst CTCAE grade will be produced, and for specific param eters separate shift tables indicat ing hyper -and hypo -directionali ty of change will be produced. The laboratory parameters for which CTCAE grade shift outputs will be produced are: -Hem atology: Hem oglobin (low and high), Leukocy tes(low and high), Lymphocy tes(low and high –absolute count ), Neutrophils (low –absolute count ), Platelets. -Clinical chemistry : ALT (high) , AST (high) , ALP (high) , Total bilirubin (high), Albumin (low), Magnesium (hypo and hyper ), Sodium (hypo and hyper ), Potassi um (hypo and hyper ), Corrected calci um (hypo and hyper ), Glucose (low), Creatinine (high) . For uri nalysis a shift table co mpar ing baseline to the maximum on -treatm ent value will be presented. Hy's law The fo llowing summaries will include the number (%) of pat ients who have: Elevated ALT, AS T, and Total bilirubin during the study ALT ≥3× -≤5×, > 5× - ≤8×, >8× - ≤10×, >10× - ≤20×, and >20× Upper Limit of Norm al (ULN) during the study AST ≥3× -≤5×, >5× - ≤8×, >8× - ≤10×, >10× - ≤20×, and >20× ULN during the study Total bilirubin ≥2× -≤3×, >3× -≤5×, >5× ULN during the study ALT or AST ≥3× -≤5×, >5× -≤8×, >8× -≤10×, >10× -≤20× and >20× ULN during the study ALT or AST ≥3× ULN and Total bilirubin ≥2× ULN during the study (potential Hy’s law). Note: Note: The onset date of ALT or AST elevat ion shoul d be pri or to or on the date of total bilirubin elevat ion. Narratives will be provided in the CSR for patients who have ALT ≥3× ULN plus Total bilirubin ≥2× ULN or AST ≥3× ULN plus Total bilirubin ≥2× ULN at any visit. Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr202 3 CONFIDENTIAL AND PROPRIETARY 59of 65Liver biochemistry test results over time for patients with elevated ALT (i.e. ≥3× ULN) or AST (i.e. ≥3× ULN), and elevated Total bilirubin (i.e. ≥2× ULN) (at any time) will be plotted. Individual pat ient data where ALT or AST (i.e. ≥3× ULN) plus Total bilirubin (i.e. ≥2× ULN) are elevated at any time will be listed also. Plots of ALT and AST versus total bilirubin by cohort will also be produced with reference lines at 3×ULN for ALT, AST, and 2×ULN for total bilirubin. In each plot, total bilirubin will be in the vertical axis. 4.2.3.4 Vital signs Height, wei ght, BMI, Pulse rate, respiratory rate, systolic and diastolic blood pressure, peripheral oxygen saturati on and tem perature will be listed by pat ient and summarized for the absolute value at each visit. Box pl ots for abso lute values and change fro m baseline by visit may be presented for certain vital signs parameters if warranted after data review. 4.2.3.5 Physical examination Physical examinat ion findings will be reported as adverse events. 4.2.3.6 Electrocardiogram ECG details will be listed indiv idually by pati ent. The overall ECG evaluat ions, cl assified as norm al, borderline, abnorm al not clinically significant and abnorm al clinically significant will be summarized using shift tables summarising the change fro m baseline to last on -treatm ent obser vation, a shift table of baseline evaluat ion to worst evaluat ion on-treatm ent will be produced if sufficient assessments are recorded to allow this. 4.2.3.7 Exposure and compliance Study treatm ent exposure data will be listed for each pat ient. The total and actua l durati on of durvalumab monotherapy and combinat ion treatment exposure will be summarized. Number of patients with at least one delay (and reason for delay), the number of pat ients with no del ay, the number of dosing occasions and the RDI will also be su mmarized. Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 60of 654.2.3.8 Other safety data Other safet y data will be listed and/or summarized: Tanner stage Perform ance status ( Karnofsky or Lansky –the scale appropriate to the patient at the time of screening will be used through the study ) 4.2.4 Pharmacokinetic and Immunogenicity analysis 4.2.4.1 Pharmacokinetics -PK parameters PK data will be summarized and analyzed based on the PK analysis set. PK concentration data will be listed for each patient and each dosing day, and a summary will be provided for all evaluable patients at each planned time point. Serum concentrati ons at each time point will be summarized using the following summary statist ics: The geometric mean (gmean), calculated as exp [μ], where μ is the mean of the data on a logarithmic scale. CV, cal culated as 100 √ [exp(s2)-1], where s is the STD of the data on a log scale Arithmetic mean calculated using untransformed data STD calculated using untransformed data Minimum Median Maximum Number of observat ions The fo llowing summary statist ics will be presented for Cmax(μg/m L), C min(μg/m L), time to Cmax, and AUC after the first dose, if the data allo w Gmean, calculated as exp[μ], where μ is the mean of the data on a logarithmic scale CV, cal culated as 100 √ [exp(s2) -1], where s is the STD of the data on a log scale Arithmetic mean calculated using untransformed data STD calculated using untransformed data Minimum Median Maximum Number of observat ions Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 61of 65The fo llowing convent ions will be applied to values below the lower limit of quant itation (LLOQ) for summarising PK data: If, at a gi ven time point, 50% or less o f the blood concentrations are non -quant ifiable (NQ), the gmean, CV, geometric standard deviat ion (geoSD), arithmetic mean and STD are cal culated by substi tuting the limit of quant ification (LOQ) for values whi ch are NQ. If more than 50%, but not all, o f the concentrations are NQ, the gmean, CV, geoSD, arithmetic m ean and STD are reported as not calculable (NC) If all the concentrations are NQ, the gmean and arithmet ic mean are reported as NQ and the CV, geoSD a nd STD as NC The number of values above LLOQ are reported for each time point along with the total number of collected values Samples below the lower limit of quant ificat ion will be treated as zero in predose samples and as missing subsequent ly in the analyses. The PK data for after a single -dose and separately will also be displayed graphically . Displays will include serum concentration pat ient profiles (on the linear and log -scale) versus time and gmean concentration (±STD) versus time, stratified b y dose. 4.2.4.2 Pharmacokinetic relationships If the data are suitable, the relationship between PK exposure and efficacy/safety parameters may be invest igated. A population PK model will be developed using a non -linear mixed -effects m odeling approach. The impact of physio logically -relevant pati ent characteri stics (covariates) and disease on PK will be evaluated. The relat ionship between the PK exposure and the effect on safet y and efficacy endpo ints will be evaluated if the data allow. The results of such an analysis will be reported in a separate report. The PK, demographic, safet y, and efficacy data collected in this study may also be combined wit h similar data from other studies and explored using popul ation PK and/or PK -pharmacodynamic methods. 4.2.4.3 Immunogenicity - ADAs A summary will be provi ded of number and percentage of patients who develop detectable ADAs. The immunogenicit y titer and neutralizing ADA data will be listed for samples confirmed posit ive for the presence of ant i-durvalumab and ant i-tremelimumab antibodies. Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 62of 65The summaries will consider durvalumab and tremelimumab evaluabilit y of ADA sam ples separately . For instance, summaries considering ADA+ to durvalumab and tremelimumab will need to first consider if a pat ient was both evaluable to durvalumab an d evaluable to tremelimumab. Subsequent ly, if summarizing for ADA+ to durvalumab only, we only consider if a pat ient was evaluable to durvalumab. The effect of immunogenicit y as well as the effect of its neutralizing properties on PK, efficacy , and safet y will be evaluated, if the data allow. A detailed plan will be written by the AstraZeneca Clinical Pharmaco logy group or designee. 4.2.5 Demographic, patient disposition and baseline characteristics data The fo llowing will be summarized for all pat ients in the F AS. Disposition of patients A summary will be provi ded for the number of patients enro lled, who received treatment, who completed the study , and who terminated prematurely. Reasons for premature terminat ion will be summarized. The number of pat ients in e ach analysis set, by country and centre will also be summarized. Demographic data Descript ive statistics will be presented for age, height, weight and BMI. In addit ion, frequencies and percentage of patients will be tabulated for the categorical variables age group (0-<6, 6 -<12, 12- <18), sex, race and ethnic group. Other baseline data Other demographic and baseline data will be listed and/or summarized: Medical and surgical history Nicotine use categori zed (never, current, former) Extent of disease at baseline Pregnancy informat ion Important protocol deviat ions (both overall, and separate summaries for those related and unrelated to the Coronavirus Disease 2019 (COVID -19) pandemic) COVID -19 study disrupti ons (number and percentage of patients with the f ollowing: visits impacted, study drug impacted and conco mitant medicat ions not started) Inclusio n in analysis populations. Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 63of 65Any COVID- 19 rel ated summaries will only be produced if there are a minimum of 5 patients with data to present. 4.2.6 Concomitant and ot her treatm ent All medications will be coded using the latest AstraZeneca Drug Dict ionary at the time of database lock. Prior medicat ion is defined as medicat ion with a stop date before the date of the first dose of study treatm ent A medicat ion will b e regarded as concomitant if the start date is on or after the date of first dose, or if it started prior to the date of first dose and was ongo ing after the date of first dose. Separate tables will be presented according to whether the medicat ion is allow ed or disallowed. Di sallowed medicat ions are detailed in section 6.4 of the CSP and will ident ified by the physician throughout the study and m erged into the reporting database by IQVIA programming. Start and stop dates for all conco mitant medicat ions are collected on the eCRF. However, in case of missing or partial informat ion in these dates, the fo llowing rules will be used: If start date is missing or partial: if month is missing, use January (01) if day is missing, use the 1st (01) if year is missing, use y ear of the consent date if ent ire date i s missing, use consent date If stop date is missing, partial or “continuing:” if month is missing, use December (12) if day is missing, use the last day of the m onth under considerat ion if year or the entire date is missing or if “cont inuing”, set to missing. A pat ient is only counted once if receiving the medicat ion more than once. 4.2.7 Biomarker data 4.2.7.1 Antibody titer measurements before and after routine immunization Vaccine ant ibody titer da ta will be listed by pat ient. Statistical A nal ysis Pla n St u d y C o de D 4 1 9 E C 0 0 0 0 1 E diti o n N u m ber 4.