Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 41of 65The l atest versi on of the Medi cal Dict ionary for Regul atory Activit ies (MedDRA) will be used to code the AEs. AEs will be graded by the Invest igator according to the latest version of the National Cancer Inst itute Commo n Termino logy Criteria for AEs (CTCAE). AEs of special or possible interes t Some clinical concepts (including som e selected individual preferred terms [PTs] and higher- level terms [HTLs]) have been considered “AEs of special interest” (AESI) or “AEs of possible interest” (AEPI) to the durvalumab program. AESI /AEPI s represent pre-specified risks that are considered to be of importance to a clinical development program. These AESI /AEPI s have been identified as a list of categories provided by the pat ient safet y team . AESI /AEPI s include but are not limited to events with a potent ial inflammatory or immune - mediated m echanism and which may require more frequent monitoring and/or intervent ions such as steroids, immunosuppressants and/or hormone replacement therapy. These AESI /AEPI s are being closely monitored in clinical studi es wi thdurvalumab monotherapy and co mbinat ion therapy . AESI /AEPI s observed wit h durvalumab ± tremelimumab include but are not limited to : Diarrhea/coli tis and intestinal perforation Pneumo nitis/ interstit ial lung disease Endocrinopathies (i.e. events of hypophysit is/hypopituitarism, adrenal insufficiency, hyper and hypothy roidism and ty pe I diabetes m ellitus) Hepati tis/transaminase increases Nephrit is/blood creatinine increases Pancreat itis/serum lipase and amylase increases Rash/dermat itis Myocardi tis Myositis/polymyosit is Other inflammatory responses that are rare/less frequent with a potential immune- mediated etio logy include, but are not limited to, pericardit is, sarcoidosis, uveit is, and other events invo lving the eye, skin, hematological, and rheumat ologi cal events. In addit ion, infusio n-related reacti ons and hypersensit ivity/anaphylact ic react ions wit h a different underlying pharmaco logical etiology are also considered AESIs. Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 42of 65Other categories may be added as necessary or existing terms may be merged . An AstraZeneca medically qualified expert after consultat ion with the Gl obal Pat ient Safet y Physician has reviewed the AEs o f interest and ident ified which HLTs and which PTs contribute to each AESI /AEPI . Further reviews may take place prior to database lock to ensure any further terms not already included are captured within the categories. Immune -Mediated Adverse Events (imAE) Sponsor will perform medical review of those AESIs and classify them as immune -mediated AEs (imAEs) or not imAEs. Further detai ls are provided in an imAE Charter. 3.3.2 Laboratory data Blood and urine samples for determinat ion of clinical chemistry , hematol ogy, and urinalysis will be taken at the times indicated in the assessment schedules and as clinically indicated Secti ons 1.1 and 8. 2.1 of the CSP. Change from baseline in hematology and clinical chemistry variables will be calculated for each post -dose visit on treatment. CTCAE grades will be defined at each visit according to the CTCAE grade criteria using local ranges as required, a fter conversion o f lab result to corresponding preferred unit. The fo llowing parameters have NCI CTCAE grades defined for both high and low values: Hem oglobin, Leukocy tes, Lymphocy tes, Potassium, Sodium, Magnesium and Corrected calcium so high and low CTC grades will be calculated. Absolute values will be compared to the local laboratory reference ranges and classified as low (below range), normal (within range or on limits of range) and high (above range). The m aximum or minimum on -treatm ent val ue (dependi ng on the di rection of an adverse effect) will be defined for each laboratory param eter as the m aximum (or minimum ) post - baseline value at any time. Corrected calcium product will be derived during creation of the reporting database using the following formula: Corrected calcium (mmo l/L) = Total calcium (mmol/L) + ([40 – albumin (G/L)] × 0.02) Project reference ranges will be used for the primary interpretati on of laboratory data. Local reference ranges will be used for analysing laboratory data at the local laboratory . The deno minator used in laboratory summaries of CTCAE grades will only include evaluable patients, in other words those who had sufficient data to have the possibilit y of an abnorm ality. Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 43of 65For example: If a NCI CTCAE criterion invo lves a change fro m baseline, evaluable pat ients woul d have both a pre -dose and at least 1 post dose value recorded. If a NCI CTCAE criterion does not consider changes from baseline to be evaluable, the patient need only have 1 post dose value recorded. 3.3.3 ECG data ECGs will be recorded at screening and as clinically indicated throughout the study (see Secti on 1.1 of the CSP). 3.3.4 Vital signs Changes in vital signs variables between baseline and each subsequent scheduled visit will be calculated. Body surface area ( BSA) will be calculated from the height (in centi meters) and weight (in kilograms) as fo llows: BSA= √((Weight (kg)*hei ght(cm ))/3600 or (Du Bois formula) = 0.007184 × .× . 3.3.5 Exposure and dose intensity Durati on of exposure is defined as: Total treatm ent durati on (in days) = min (date of last dose>0mg +27 day s, date of death, date of DCO) -date of first dose +1. Actual treatm ent durati on = total treatm ent durati on, excluding the duration of dose delays. Exposure will be defined separately for durval umab m onotherapy , and for combinat ion treatm ent. For the combination therapy, date of first dose refers to first dose of tremelimumab and date of last dose refers to the latest last dose of either durvalumab or tremelimumab, when Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 44of 65durvalumab is no t being received as mo notherapy , and a dose del ay is any day(s) when neit her of these treatm ents was received. If a patient has more than one period of combinat ion therapy, or monotherapy, then each period will be summed when deriving the exposure to durva lumab monotherapy and combinat ion treatment. In addit ion, the total number of dosing occasions will be calculated per patient. The calculat ion of actual exposure makes no adjust ment for any dose reducti ons that m ay have occurred. The rel ative dose intensit y (RDI) will be calculated for each patient for both durvalumab and tremelimumab. RDI i s the percentage of the actual dose delivered relat ive to the intended dose through to treatment discont inuat ion. RDI will be defined as fo llows: RDI (%) = d/D * 100, w here d is the actual cumulative dose delivered up to the actual last day of dosing and D is the intended cumulat ive dose up to the or the actual last day of dosing. D is the total dose that would be delivered if there were no modification to dose or schedu le. The actual cum ulative dose (mg/kg) per patient in a time period is the sum of the actual dose levels that the patient received within that period (i.e. total dose administered mg/kg). Treatment Delays Delays will be derived based on infusio n date and will be based on the deviation o f the actual to the pl anned treatm ent administration day (relative to the previous treatment administration date). A delay is defined as more than 1 day of delay between the actual and the planned treatm ent administration day. For exam ple, if one pati ent receives the study drug on day 1, then the next study drug administrati on date will be on day 29 (Day 1 of next cy cle); however, if the pat ient receives the study drug at day 31 (Day 3 of next cy cle), thi s is considered as a delay of 2 days. For all dosing dates, the total duration of dose delays = Sum of (date of the dose -date of the previous dose –28 day s). Thus, if no del ays were encountered, the duration woul d sum up to 0, since infusio ns were done every 4 weeks. 3.3.6 Dose Limiting Toxicities (DLTs) Dose -limit ing toxicit ies will be determined during Cycles 1 and 2 of the dose- finding phase using CTCAE versio n 5. Toxi cities that occur during the first 28 -day cycle and meet the criteria below will be assessed for attribut ion to durvalumab monotherapy. Any of the below listed AEs encountered between Cycle 1 Day 1 and Cy cle 2 Day 28 (i e, 56 day DLT monitoring peri od for combinat ion therapy ) and in the opi nion of the Invest igator is thought to Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 45of 65be attributable to durvalumab or/a nd tremelimumab, given a reasonable possibilit y based on temporal exposure to IP and for which an alternate etiology does not exist or cannot be ident ified, will be classified as DLTs: Grade 5 toxicit y Hem atological toxi city: Any Grade ≥3 (including febri le neutropenia Grade ≥3) except for the fo llowing: oGrade 3 thrombocy topeni a that does not result in a bleeding event or does not requi re platelet transfusio n oGrade 3 neutropenia that resolves to Grade ≤2 within 7 days. Non-hematol ogical toxicity: oAny Grade 4 immune -related AE (i rAE) oAny ≥ Grade 3 colit is oAny Grade 3 or 4 noninfect ious pneumo nitis oAny Grade 2 pneumo nitis that does not resolve within 5 days to ≤ Grade 1 after initiation of maximal supportive care (including use of steroids) oAny Grade 3 irAE, excluding co litis or pneumonit is, that does not downgrade to Grade 2 within 3 days after onset of the event despite optimal medical management including systemic corticosteroids and does not downgrade to ≤ Grade 1 or baseline within 14 days of onset oLiver transaminase elevation >5 × ULN or total bilirubin >3 × ULN. For patients with liver metastases at baseline, transaminase elevat ion >8 × ULN will const itute a DLT oGrade 4 vomit ing, di arrhea, electroly te abnorm ality, or sy stemic react ion oGrade 3 toxicit y lasing >7 days despite optimal supportive care oAny ≥ Grade 3 non -irAE, except for the exclusio ns listed below oAny Grade 3 immune -mediated peri pheral neuropathy or other immune -mediated neurotoxi city oGrade ≥3 inflammatory reacti ons. The definit ion of DLTs excludes the fo llowing condi tions: Grade 3 fat igue lasting ≤7 days. Grade 3 endocrine disorder (pituitary and/or adrenal insufficiency ) that i s managed with or wi thout systemic corticosteroid therapy and/or horm one repl acement therapy and the patient is a symptom atic. Grade 4 hy pothy roidism adequately treatm ent wi th horm one replacement. Grade 3 inflammatory react ion attributed to a local antitumor response (eg, inflammatory react ion at sites of metastatic disease, lymph nodes, etc.). Statistical Analysis Plan Study Code D419EC00001 Edition Number 4.0 Date 19Apr2023 CONFIDENTIAL AND PROPRIETARY 46of 65Concurrent vit iligo or alopeci a of any AE grade. Grade 3 infusio n-related reaction (first occurrence and in the absence of steroid prophylaxis) that resolves wit hin 6 hours with appropriate clinical management. Grade 3 fever (fever greater than 40ºF for ≤24h in duration). Any grade lymphopenia. Isolated Grade 3 el ectroly te abnorm alities that are not associated with clinical signs or symptoms and are reversed with appropriate maximal medical intervent ion (including supplementati on) wi thin 7 days of init iating supplementatio n. irAEs are defined as AEs of immune nature (ie, inflammatory ) in the absence of a clear alternat ive etio logy. In the absence of clinical abnormalit y, repeat l aboratory testing must be conducted to confirm significant laboratory findings prior to designat ion as a DLT. Guiding principles: 1. While the rules outlined above dictate the classification of AEs as DLTs, any other AEs that are observed during the observation perio d may be defined as a DLT in consultation wit h the DRC; after having taken into conside ration the emerging safet y profile of durvalumab and tremelimumab. 2.The NCI CTCAE (versio n 5.0) will be used for AEs reporting and its severit y will be graded on a scale from 1 to 5 provided for each AE term. 3.An immune -mediated AE is defined as an AE that is associated with exposure to durvalumab or/and tremelimumab and is consistent with an immune -mediated mechanism o f action after al ternate eti ologies have been considered and excluded. 4.In the absence of clinical findings, repeat laboratory test ing must be conducted to confirm the clinical significance o f abnorm al laboratory test resul t before it is classified as a DLT. For reporting purposes, the DLTs are as approved and documented at the DRC meet ings. 3.4 Pharmacokinetic and Immunogenicity Variables 3.4.1 PK pa rameters PK parameters (including C max, Cmin, AUC, and others) is primary endpoint of dose -finding phase and will be used to facilitate the determinat ion of the RP2D. 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.