Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: NCSLC Double-blind PD-L1 MEDI4736 Durvalumab DFS OS MRD+ MRD- Completely Resected Lung Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 89
Healthy volunteers: no

Brief summary:
This is a Phase III, randomized, parallel-arm, placebo controlled, double blind, multicenter study assessing the efficacy and safety of durvalumab versus placebo following SoC chemotherapy in patients with completely resected stage II-III NSCLC who are MRD+ post surgery

Detailed description:
Patients who have no evidence of disease recurrence confirmed by CT and/or MRI and are confirmed to meet all eligibility criteria will be randomized 1:1 to durvalumab + Standard of care (SoC) chemotherapy or placebo + Standard of care (SoC) chemotherapy arm.

The primary objective of this study is to assess the efficacy of durvalumab +SoC chemotherapy compared to placebo+ SoC chemotherapy as measured by DFS in all patients.

Arms:
arm 1: Intravenous administration of Experimental and Standard of Care Therapy arm 2: Intravenous administration of Placebo and Standard of Care Therapy

Interventions: intervention 1: Durvalumab + SoC chemotherapy intervention 2: Placebo + SoC chemotherapy
Intervention descriptions: intervention 1: Experimental Treatment intervention 2: Placebo Comparator

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol 
Drug Substance
Durvalumab
Study Code
D910LC00001
Version
4.0
Date
02 August 2022
A Phase III, Randomized, Multicenter, Double-blind, Placebo-controlled 
Study to Determine the Efficacy of Adjuvant Durvalumab in Combination 
with Platinum-based Chemotherapy in Completely Resected Stage II-III 
NSCLC (MERMAID-1)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Local Sponsor in Japan: AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, 
Japan
Regulatory Agency Identifying Number(s): IND 120006; EudraCT 2020-000556-35
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Disclosure




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9. Addition of wording to allow telemedicine and/or home nursing for select 
visits, subject to local laws and regulations, and following a discussion with the 
Investigator and Sponsor. Sections updated: 4.1; Table 1; Table 2; Table 3. 
10. Added flexibility to timing of brain scan required for complete staging. 
Sections updated: 5.1.1 (Inclusion criterion #5); Table 1; Table 4.
11. Clarification of post-surgical scan timing. Sections updated: 1.2; 4.1; 5.1.1 
(Inclusion criterion #11); 8.1; Table 1; Table 2; Table 4; Table 5.
12. Clarification that only SAEs related to study procedures must be reported 
during first screening (i.e. after ICF1 is signed but prior to signature of ICF2). 
Sections updated: 6.4; 8.3.2; 8.3.11; 8.4.1; Table 1.
13. Removal of microbiome (stool) sample collection and exploratory endpoint. 
Sections updated: 1.2; 3; 4.2.3.1; Table 2; Table 3. Section removed: 
8.8.2.4.
14. Clarification of disease assessment frequency. Sections updated: 7.1.1; 8.1; 
Table 2; Table 3.
15. Removal of mandatory confirmatory scan post-recurrence. Sections updated: 
1.2; 6.1.4; 7.1.1; 8.1.1.1; Table 2; Table 3.
16. Update of duration of ePRO collection during follow-up. Section updated: 
Table 3.
17. Addition of optional tumor biopsy at recurrence to include follow-up period. 
Section updated: Table 3.
18. Clarification of acceptable EGFR/ALK results. Sections updated: 1.2; 4.1; 5.2 
(Exclusion criterion #2); 8.7.1.1; Table 1; Table 5; Figure 1.
19. Provision of guidance in selecting patients with higher mutational load. 
Sections updated: 1.2; 4.1.
20. Addition of immune cell (IC) PD-L1 expression to exploratory endpoints. 
Sections updated: 1.2; 3; 8.7.2.2.
21. Clarification regarding collection of data following data cut-off and timing of 
overall survival analysis/final overall survival analysis. Sections updated: 1.2; 
4.4; 6.1.4; 6.6.


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22. Extended time to DFS analysis from 3 months to 4 months post-last subject in. 
Sections updated: 1.2; 9.2.
23. Clarification that DFS will be determined using the RECIST 1.1 definition of 
new lesions. Sections updated: 4.2.3; 8.1; Appendix G.
24. Rationale for fixed dosing. Section updated: 4.3.3.
25. Update to and clarification of acceptable pre-surgical imaging modalities and 
timing. Sections updated: 5.1.1 (Inclusion criterion #5).
26. Clarification and definition of complete resection. Section updated: 5.1.1 
(Inclusion criterion #6).
27. Clarification regarding window for randomization. Section updated: 5.1.2 
(Inclusion criterion #12).
28. Clarification of non-leukocyte depleted blood transfusions. Section updated: 
5.2 (Exclusion criterion #7).
29. Clarification regarding prohibited prior radiotherapy. Sections updated: 5.2 
(Exclusion criterion #17); Table 5.
30. Update to "Lifestyle Restrictions" section (regarding birth control and 
pregnancy). Section updated: 5.3. Sections added: Table 18; Appendix H.
31. Addition of re-screening criteria. Section updated: 5.4.
32. Addition of Table 7 – Minimum data entry requirements. Section updated: 
Table 1. Section added: Table 7. 
33. Clarification of why and when a patient may be screen-failed. Sections 
updated: 5.4; 6.2.1.
34. Combined handling instructions for durvalumab and placebo as both are "IP" in 
this double-blinded study. Section updated: 6.1.2.1; Table 8. Section 
removed: 6.1.2.3.
35. Update to guidance regarding post-operative radiotherapy (PORT). Sections 
updated: 6.4; 6.4.1; Table 10; Figure 2.
36. Removal of text related stopping treatment due to rapid tumor progression. 
Section updated: 6.1.4.


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37. Clarified that PD-L1 results will be blinded; unblinding will occur should the 
Investigator request to be unblinded to treatment. Sections updated: 6.2.4 and 
6.2.5.
38. Additional guidance on steroids prior to chemotherapy. Section updated: 
Table 9.
39. Update to guidance regarding antibiotic use prior to randomization. Section 
updated: Table 9. 
40. Removal of Toxicity Management Guidelines webportal as webportal has been 
decommissioned. Sections updated: 6.5; 8.3.12; 8.3.13; 8.4.5.1.
41. Additional guidance regarding treatment post-primary DFS analysis and post-
recurrence. Section updated: 6.6; 7.1.
42. Additional guidance regarding dating disease recurrence. Section updated: 
8.1.1.2.
43. Removal of ePRO completion threshold. Section updated: 8.1.4.5.
44. Allowance for HIV and hepatitis to be tested during first screening; if negative, 
not necessary to test low-risk patients again during second screening. Sections 
updated: 8.2.1; Table 1; Table 2.
45. Updated section "Optional Genomics Initiative genetic sample". Section 
updated: 8.6.2.
46. Update to publication policy. Section updated: Appendix A9.
47. Update to exome coverage description. Section updated: Appendix E.
48. Update to Appendix G to reflect the primary endpoint of disease-free survival 
and to provide additional guidance regarding RECIST 1.1 definition of new 
lesions. Sections updated: Appendix G; Table 17. Sections removed: Table 
18, Table 19.
49. Appendix H is now Appendix I; Appendix I is now Appendix J. 
50. Added references Abbosh et al 2020; Moding et al 2020; Nagashi et al 2018; 
Offin et al 2019; Papadimitrakopoulou et al 2018; Nishio et al 2020; Rolia et al 
2016; Pinato et al 2019. Section updated: 10. 




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8. Removed collection of PROs. Sections updated: 1.1 (Table 2 and Table 3)
and 8.1.4
9. Collection and analysis of health care resource use removed. Sections
updated: 1.1 (Table 2 and Table 3), 1.2, 3, 8.8, 9.4.3.4, and 9.5.1.5
10. Analysis of EORTC QLQ-30 and EORTC-QLQ-LC13 moved from secondary 
to exploratory analysis. Section updated: 1.2 and 3
11. Removed statement that health care resource use will be used to support 
assessment of durvalumab by health technology agencies. Section updated: 
4.2.3.1
12. Addition of text indicating decision to close study enrollment, updated number 
of enrolled patients following study enrollment closure, and indicating final 
number of study centers. Sections updated: 1.2, 4.1, and 5
13. Reference to “primary DFS analysis” removed from table heading in SoA and 
updated assessment duration. Section updated: 1.1 (Table 3)
14. Addition of text that enrollment to the study has now closed. Sections 
updated: 1.2, 1.3, 2.1, 4.1, and 5
15. Update of first patient enrolled and estimated last patient completion. Section
updated: 1.2
16. Removal of text for long-term survival follow up. Sections updated: 1.2, 
6.1.4, 6.6
17. Removal of text for long-term OS collection and study roll over. Sections 
updated: 1.2, 4.4, 6.1.4 and 6.6
18. End of study definition updated to account for early closure of study 
enrollment. Sections updated: 1.2 and 4.4
19. Text added to clarify that the DCO for primary DFS analysis will follow last 
patient last visit. Sections updated: 4.4 and 6.1.4
20. Clarification that  the primary DFS analysis will be performed due to closure
of study enrollment. Sections updated: 1.2, 6.6, and 9.1
21. Statistical methods, analyses, and efficacy outcomes were updated to account 
for AstraZeneca’s decision to close study enrollment early leading to revision 


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of objectives and endpoints based on the revised sample size. Sections 
updated: 1.2, 2.1, 3, 4.2.3, and 9
22. Study schema Figure 2 was added with revised ample size to account for 
AstraZeneca’s decision to close study enrollment early. Sections updated: 1.3
and 4.1
23. New section added to clarify rationale for AstraZeneca’s decision to close 
study enrollment early. Section added: 4.1.1
24. A new section was added for a rationale to continue using placebo in this 
version of the CSP. Section added: 4.3.5
25. Guidance for post data cut-off evaluation was removed. Section updated: 
6.1.4
26. Clarification added that the patient’s MRD status will not be unblinded at the 
time of treatment unblinding. Section updated: 6.2.5
27. Further guidance added for Investigators regarding patients who withdraw 
from the study. Section updated: 7.3
28. Update of procedures for the collection of safety data following the final DCO.
Section updated: 8.3.13
29. Removed sensitivity analysis of DFS, using Investigator assessments according 
to RECIST 1.1, as they may no longer be required due to the exploratory 
nature of analyses. Section updated: 9.5.1.1
30. Minor administrative/editorial changes were made throughout the protocol for 
clarity and consistency
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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TABLE OF CONTENTS
VERSION HISTORY........................................................................................................... 2
TABLE OF CONTENTS...................................................................................................... 9
1
PROTOCOL SUMMARY................................................................................ 15
1.1
Schedule of activities ........................................................................................ 15
1.2
Synopsis ........................................................................................................... 27
1.3
Schema............................................................................................................. 39
2
INTRODUCTION............................................................................................ 44
2.1
Study rationale.................................................................................................. 44
2.2
Background ...................................................................................................... 45
2.2.1
Immunotherapies .............................................................................................. 46
2.2.2
Durvalumab...................................................................................................... 47
2.2.3
Non-small cell lung cancer and unmet need ...................................................... 48
2.2.3.1
Value of mono- and combination immunotherapy in NSCLC ........................... 48
2.2.3.2
Detection of minimal residual disease in NSCLC.............................................. 49
2.2.3.3
Rationale for early interception studies predicated on MRD.............................. 50
2.2.3.4
Monotherapy in advanced NSCLC.................................................................... 50
2.2.3.5
Combination IO therapy and chemotherapy in NSCLC..................................... 51
2.2.4
Durvalumab in combination with chemotherapy ............................................... 52
2.3
Benefit/risk assessment..................................................................................... 53
2.3.1
Potential benefits of durvalumab....................................................................... 53
2.3.2
Overall risks ..................................................................................................... 54
2.3.2.1
Durvalumab...................................................................................................... 54
2.3.2.2
Durvalumab in combination with chemotherapy ............................................... 55
2.3.3
Overall benefit/risk ........................................................................................... 56
3
OBJECTIVES AND ENDPOINTS................................................................... 57
4
STUDY DESIGN ............................................................................................. 59
4.1
Overall design................................................................................................... 59
4.1.1
Early Study Enrollment Closure........................................................................ 62
4.2
Scientific rationale for study design .................................................................. 62
4.2.1
Overall rationale and study population.............................................................. 62
4.2.2
Study design ..................................................................................................... 63
4.2.3
Primary and secondary outcome measures ........................................................ 63
4.2.3.1
Rationale for exploratory endpoints .................................................................. 64
4.3
Justification for durvalumab dose...................................................................... 64
4.3.1
PK/Pharmacodynamic data ............................................................................... 65
4.3.2
Clinical data...................................................................................................... 65
4.3.3
Rationale for fixed dosing................................................................................. 66
4.3.4
Rationale for standard of care adjuvant chemotherapy regimens ....................... 67
4.3.5
Rationale for Placebo........................................................................................ 67
4.4
End of study definition...................................................................................... 67


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5
STUDY POPULATION ................................................................................... 68
5.1
Inclusion criteria............................................................................................... 68
5.1.1
Criteria and procedures initiated with the signing of ICF1................................. 69
5.1.2
Criteria and procedures initiated with the signing of ICF2................................. 72
5.2
Exclusion criteria.............................................................................................. 73
5.3
Lifestyle restrictions ......................................................................................... 76
5.4
Screen failures .................................................................................................. 76
6
STUDY TREATMENTS.................................................................................. 77
6.1
Treatments administered................................................................................... 77
6.1.1
Order of administration..................................................................................... 80
6.1.2
Investigational products.................................................................................... 80
6.1.2.1
Durvalumab/placebo......................................................................................... 80
6.1.2.2
Standard of care chemotherapy ......................................................................... 81
6.1.3
Dosage and treatment regimens......................................................................... 81
6.1.3.1
Durvalumab or placebo..................................................................................... 82
6.1.3.2
Standard of care................................................................................................ 83
6.1.4
Duration of treatment........................................................................................ 83
6.1.5
Storage ............................................................................................................. 83
6.2
Measures to minimize bias: randomization and blinding ................................... 84
6.2.1
Patient enrollment and randomization ............................................................... 84
6.2.2
Procedures for handling incorrectly enrolled or randomized patients................. 85
6.2.3
Methods for assigning treatment groups............................................................ 86
6.2.4
Methods for ensuring blinding .......................................................................... 86
6.2.5
Methods for unblinding..................................................................................... 87
6.3
Treatment compliance....................................................................................... 87
6.4
Concomitant therapy......................................................................................... 88
6.4.1
Postoperative radiotherapy standardized guidance............................................. 90
6.4.2
Other concomitant treatment............................................................................. 91
6.4.3
Durvalumab drug-drug interactions................................................................... 91
6.4.4
Rescue medication............................................................................................ 91
6.5
Dose modification............................................................................................. 91
6.6
Treatment after the end of study........................................................................ 92
7
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL . 92
7.1
Discontinuation of study treatment.................................................................... 92
7.1.1
Procedures for discontinuation of study treatment............................................. 92
7.2
Lost to follow-up .............................................................................................. 93
7.3
Withdrawal from the study................................................................................ 94
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 95
8.1
Efficacy assessments......................................................................................... 96
8.1.1
Disease-free survival......................................................................................... 96
8.1.1.1
Evidence of disease recurrence ......................................................................... 97
8.1.1.2
Dating of recurrence ......................................................................................... 98






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9.4.2.2
Safety assessments.......................................................................................... 132
9.4.3
Calculation or derivation of patient-reported outcome variables...................... 133
9.4.3.1
Calculation or derivation of EORTC QLQ-C30 and EORTC QLQ-LC13 ....... 133
9.4.3.2
Calculation or derivation of 
.......... 134
9.4.3.3
.................................................................................................. 134
9.4.3.4
Calculation or derivation of health economic variables ................................... 135
9.4.4
Calculation or derivation of biomarker variables............................................. 135
9.4.5
Calculation or derivation of pharmacogenetic variables .................................. 135
9.5
Statistical analyses.......................................................................................... 135
9.5.1
Efficacy analyses ............................................................................................ 136
9.5.1.1
Primary endpoint: disease-free survival........................................................... 137
9.5.1.2
Secondary endpoints....................................................................................... 139
9.5.1.3
Exploratory efficacy endpoints........................................................................ 139
9.5.1.4
Patient-reported outcomes............................................................................... 139
9.5.2
Safety analyses ............................................................................................... 140
9.5.3
Biomarker data ............................................................................................... 141
9.5.4
Methods for multiplicity control ..................................................................... 141
9.6
Interim analyses.............................................................................................. 142
9.7
Data monitoring committee............................................................................. 143
10
REFERENCES............................................................................................... 143
11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...................................................................................... 155
LIST OF TABLES
Table 1
Schedule of assessments for first screening (initiated by the signing of 
ICF1)....................................................................................................... 17
Table 2
Schedule of assessments for second screening and 12-month treatment 
period (initiated by the signing of ICF2) .................................................. 21
Table 3
Schedule of assessments for patients who have completed or 
discontinued treatment............................................................................. 25
Table 4
Timing of inclusion criteria assessment relative to screening periods ....... 42
Table 5
Timing of exclusion criteria assessment relative to informed consent....... 43
Table 6
Study objectives and associated endpoints/variables ................................ 57
Table 7
Minimum requirements for data entry for screen-failed patients............... 77
Table 8
Study treatments ...................................................................................... 78
Table 9
Prohibited concomitant medications for all treatment arms ...................... 88
Table 10
Supportive medications............................................................................ 90
Table 11
Clinical chemistry.................................................................................. 103
CCI
CCI


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Table 12
Hematology........................................................................................... 103
Table 13
Urinalysis .............................................................................................. 104
Table 14
Summary of outcome variables and analysis populations ....................... 128
Table 15
Visit responses for symptoms and health-related quality of life.............. 134
Table 16
Pre-planned statistical and sensitivity analyses to be conducted ............. 136
Table 17
Summary of imaging modalities for tumor assessment........................... 181
Table 18
Highly Effective Methods of Contraception (<1% Failure Rate) ............ 189
LIST OF FIGURES
Figure 1
Study schema (original) ........................................................................... 40
Figure 2
Study schema (revised)............................................................................ 41
Figure 3
Dosing scheme ........................................................................................ 82
Figure 4
Multiple testing procedure for controlling the type 1 error rate............... 142
LIST OF APPENDICES
Regulatory, Ethical and Study Oversight Considerations........................ 156
Adverse Event Definitions and Additional Safety Information............... 161
Handling of Human Biological Samples ................................................ 166
Genetics (for Optional Genetic Research Study) .................................... 169
Mandatory Genetic analysis for Minimal Residual Disease.................... 173
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 175
Guidelines for evaluation of new lesions using RECIST 1.1 Criteria 
(Response Evaluation Criteria in Solid Tumors) .................................... 181
Contraception Requirements.................................................................. 187
Patient-Reported Outcomes ................................................................... 190
Study Participant Feedback Questionnaire Template.............................. 200
Abbreviations ........................................................................................ 204


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1
PROTOCOL SUMMARY
1.1
Schedule of activities
This study will employ a 2-tiered consent and screening process that begins prior to surgery in 
patients with histologically confirmed resectable non-small cell lung cancer (NSCLC; World 
Health Organization [WHO] 2015 classification) (stage IIA to select [ie, T3N2 or T4N2] 
stage IIIB; according to Version 8.0 of the International Association for the Study of Lung 
Cancer Staging Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology 
v8.0]). 
Table 1 includes the procedures conducted during the first screening (initiated by the signing 
of Informed Consent Form 1 [ICF1]) for the period before, during, and after surgery but prior 
to final determination of eligibility for randomization in the study. The purpose of this first 
screening period is to collect and analyse tumor and blood samples necessary to determine the 
minimal residual disease (MRD) status of the patient. This is done by performing whole 
exome sequencing (WES) of the patient’s resected tumor tissue and whole blood to identify 
tumor-specific DNA variants. A personalized panel comprised of 50 of the patient’s tumor 
variants is then created and used to identify circulating tumor DNA (ctDNA) extracted from 
the patient’s plasma. The patient is considered MRD-positive (MRD+) if the panel detects 
ctDNA in the patient's plasma. The development of the MRD assay requires mandatory 
genetic testing.
Table 2 includes the procedures conducted during the second screening (initiated by the 
signing of Informed Consent Form 2 [ICF2] once a patient’s MRD status is known) through 
the treatment period. The procedures for the follow-up period are presented in Table 3.
Whenever vital signs and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: vital signs and then blood draws. The timing 
of the vital signs assessments should be such that it allows the blood draw to occur at the 
timepoints indicated in the schedule of activities (SoAs). Whenever electrocardiograms 
(ECGs), vital signs, and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: ECG, vital signs, and then blood draws. The 
timing of the first 2 assessments should be such that it allows the blood draw to occur at the 
timepoints indicated in the SoAs.
For both treatment arms (durvalumab/placebo ± standard of care chemotherapy)
!
One cycle is equal to 21 days (every 3 weeks [q3w]) during the durvalumab plus standard 
of care (SoC) chemotherapy or placebo plus SoC chemotherapy combination portion of 
the study, and 28 days (every 4 weeks [q4w]) during the durvalumab/placebo 
monotherapy portion of the study.


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!
Patients may delay dosing under certain circumstances. 
∀
For durvalumab/placebo:
o
Dosing may be delayed per the Dosing Modification and Toxicity Management 
Guidelines (See Section 8.4.5.1), due to either an immune or a non-immune
related adverse event (AE).
o
If dosing must be delayed for reasons other than treatment-related toxicity, 
dosing will resume as soon as feasible.
∀
Dosing intervals of subsequent cycles may be shortened as clinically feasible in order 
to gradually align treatment cycles with the schedule of disease (Response Evaluation 
Criteria in Solid Tumors [RECIST]) and Patient-reported Outcome (PRO) 
assessments. Subsequent time between 2 consecutive doses cannot be less than 
21 days, based on the half-life of durvalumab (see current Investigator’s Brochure 
[IB] for durvalumab). If there is a dosing delay while on the q3w schedule, all future 
dosing days should be delayed to ensure that the intervals between dosing study 
treatment remain at least 21 days.


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Table 1
Schedule of assessments for first screening (initiated by the signing of ICF1)
Prior to surgerya
Surgerya
Post-surgery
For details, see 
Section
Week
Up to day of 
surgery 
1b
3-5
Prior to 
randomization
Day
Up to 0
0
1-8
21-35
Histologically confirmed NSCLC (WHO 
2015 classification), stage IIA to select (ie, 
T3N2 or T4N2) stage IIIB (according to 
IASLC v8.0)a
X
X
5.1.1
Pre-surgical contrast-enhanced CT/MRI of 
chest and abdomen (including liver and 
adrenals)a,c
X
5.1.1
Brain MRI (preferred) or brain CT with IV 
contrast
Xd
5.1.1
ICF1e
X
5.1, 5.1.1
Study procedures
Eligibilityf
<----------------------------------------X---------------------------------------> 
Table 4, Table 5, 
Table 7, 5.1.1, 5.2, 
5.4
Demography, including initial disease 
characteristics and tobacco useg
X
X
5.1, Table 7
Surgery/confirmation of complete 
resectiona
Complete surgical informationa
X
X
5.1.1
EGFR/ALK testing of tumor tissueh
X
Xi,j
8.7.1.1
Whole blood sample for WESk
X
8.7.1.2
Plasma sample collection for MRD 
evaluation and exploratory analyses
Xl
Xm,n
8.7.1.2, 8.7.2.1


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Table 1
Schedule of assessments for first screening (initiated by the signing of ICF1)
Prior to surgerya
Surgerya
Post-surgery
For details, see 
Section
Week
Up to day of 
surgery 
1b
3-5
Prior to 
randomization
Day
Up to 0
0
1-8
21-35
Resected tumor tissue sample for 
pathology confirmation, WES, and 
development of personalized paneli,j
X
8.7.1.2
Resected tumor tissue collected for 
exploratory analysesi,j
X
8.7.1.2
Resected tumor tissue sample sent for 
prospective PD-L1 testingi,j
Xo
8.7.1.3
SAEs related to study procedures
<----------------------------------------Xp------------------------------------------------------>
8.3
Concomitant medications/medical 
history/concomitant procedures
<----------------------------------------Xp,q --------------------------------------------------->
5.1, 5.2, 6.4, 8.2.2, 
Table 9
Disease assessments (as assessed by 
Investigator using RECIST 1.1)
Xr
a
Stage II or III diagnosis should be confirmed using biopsy or resected tumor tissue results prior to randomization. Confirmation of diagnosis and surgery 
will not be considered study procedures. However, the date of surgery and post-surgical stage must be recorded for every enrolled patient. For every patient   
whose MRD status is determined during first screening, additional study-specific information obtained prior to, during, and after surgery (as outlined in the 
study inclusion criteria, see Section 5.1.1), including pre-surgical imaging details and complete surgical information, must be captured in the appropriate 
eCRFs of the study database (see Table 7 and Section 5.4).
b
The assessments listed in the Week 1 (Day 1-8) post-surgery column should be performed as soon as possible after surgery, but no later than Week 3 (d21) 
post-surgery to allow timely shipment of the samples (i.e. tumor and whole blood) required to develop the personalized MRD panel. Exception: Patients 
identified after Week 3 (d21) post-surgery but prior to Week 5 (d35) post-surgery may be allowed to enrol in the study, depending on the outcome of the 
discussion with the study physician. 
c
Combination FDG-PET/CT is acceptable for pre-operative staging in absence of contrast-enhanced CT of chest and abdomen.
d
The brain MRI (preferred) or brain CT should be performed pre-operatively per standard of care. However, if this scan is not performed prior to surgery, 
this scan must be conducted during first screening (ie, prior to signing ICF2 and entering second screening).


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e
Written informed consent and any locally required privacy act document authorization must be obtained prior to performing any protocol-specific 
procedures, including first screening evaluations. ICF1 can be signed either prior to surgery (preferred) or as soon as possible after surgery (see footnote b
above) and will obtain consent for the mandatory genetic component of this study. Exception: Patients may be allowed to enrol/sign ICF1 after Week 3 
(d21) post-surgery but prior to Week 5 (d35) post-surgery depending on the outcome of the discussion with the study physician. 
f
Eligibility criteria assessed during the first screening period include requirements that must have been met pre-surgery, at surgery, and/or post-surgery as 
summarized in Table 4 and Table 5 and detailed in Section 5.1.1. The reason(s) for screen failure must be captured in the appropriate eCRF for each 
enrolled patient subsequently determined to be ineligible
g
Demographics must be captured in the appropriate eCRFs for every enrolled patient (see Table 7 and Section 5.4).
h
EGFR/ALK testing should be performed on a pre-surgical biopsy wherever possible; however, if a pre-surgical biopsy is not available or evaluable, testing 
will be conducted on the resected tumor tissue while the personalized panel is in development. Testing only needs to be done at one of these timepoints. 
Results from local testing are acceptable, provided testing was performed using a well-validated, local regulatory-approved test; results from testing 
performed during screening for another AstraZeneca study may be used. If local testing and/or previous results are not available, EGFR/ALK testing will be 
performed centrally. Patients will still be allowed to continue study screening procedures and development of the personalized panel would continue while 
testing is ongoing; however, EGFR and ALK status must be known prior to randomization as patients with EGFR mutations or ALK translocations are not 
eligible. Note: Where EGFR/ALK results are obtained from a pre-surgical tissue biopsy as part of standard local practice, the patient must be confirmed as 
EGFR/ALK wild-type prior to signing ICF1 and enrolling in the study.
i
The indicated tumor tissue samples come from the tumor that was removed during surgery. Separate rows indicate that portions of this singular surgical
sample will undergo different tests or analyses performed at different locations.
j
FFPE samples of resected tumor tissue will be collected. 
k
The whole blood sample for germline WES will only be collected at one time, either before or after surgery. For patients who enrol in the study prior to 
surgery, it is preferred that the whole blood sample for germline WES is collected and sent to the diagnostic lab prior to surgery. For patients who do not 
enrol in the study before their surgery, a whole blood sample for germline WES must be sent as soon as possible post-surgery (after they sign ICF1) for 
development of the personalized panel. 
l
All patients who sign ICF1 prior to surgery must have a plasma sample collected before or on the day of surgery (prior to the surgery itself). Patients will 
not be excluded from randomization based on the analysis of this pre-surgical sample. This sample may be collected at the same time as the whole blood 
sample for germline WES.
m
A plasma sample will be collected at Week 3-5 (Day 21-35) post-surgery to determine MRD status. Investigators will not be notified of MRD status and 
eligibility will be managed through the IWRS. 
n
An additional plasma sample will be collected at the same time as the post-surgery sample described in footnote m. This sample will be held as a baseline 
sample for exploratory analyses.
o
Programmed cell death-ligand 1 (PD-L1) tumor cell (TC) expression will be evaluated by a central reference laboratory on the resected tumor tissue 
collected during the first screening period. PD-L1 status is required for randomization. 
p
Only SAEs specifically related to study procedures (ie, study-specific blood draws and [if performed during first screening] the post-surgical scan) should 
be reported during the first screening period (ie, after ICF1 has been signed but prior to signature of ICF2) and recorded in the eCRF. Concomitant 
medications, medical history and concomitant procedures related to this event should only be recorded in the eCRF if such an SAE is reported.
q
Concomitant post-surgery procedures should be captured in the appropriate sections of the eCRF.
r
A CT scan of the chest (including liver and adrenal glands) must be performed within 28 + 7 days (i.e. within 35 days) prior to randomization to confirm 
no evidence of disease and to serve as the patient’s baseline scan. A brain MRI (preferred) or brain CT may be performed if clinically indicated (at the 
discretion of the Investigator). This scan may occur during first or second screening (Table 2). 


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Note: For some visits, telemedicine and/or home visits (at the patient’s home or other appropriate location) may be permitted. Telemedicine and/or home visits 
are permitted only where feasible, allowed by local laws and regulations, and following consultation with the Investigator and the Sponsor.
ALK  Anaplastic lymphoma kinase; d  Day; eCRF  Electronic case report form;  EGFR  Epidermal growth factor receptor; FFPE Formalin-fixed paraffin-
embedded; IASLC  International Association for the Study of Lung Cancer; ICF1 Informed consent form 1; IWRS Interactive web response system; MRD  
Minimal residual disease; MRD-  MRD-negative; MRD+  MRD-positive; NSCLC Non-small cell lung cancer; PD-L1 Programmed cell death-ligand 1; 
SAE Serious adverse event; w Week; WES  Whole exome sequencing; WHO  World Health Organization.  


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Table 2
Schedule of assessments for second screening and 12-month treatment period (initiated by the signing of 
ICF2) 
Screening
C1
C2
C3
C4
C5 to C14 or until RECIST 1.1-
defined disease recurrence
For details, see Section
Week
-4 to -1
0
q3w ±3db unless dosing needs to 
be held for toxicity reasons
q4w ±3db unless dosing needs to 
be held for toxicity reasons
Day
-28 to -1
1a
q21d ±3db unless dosing needs 
to be held for toxicity reasons
q28d±3db unless dosing needs to 
be held for toxicity reasons
ICF2c
X
5.1.2
Informed consent for optional
genetic analysis (Gx)
X
5.1.2
Study procedures
Medical history
X
8.2.2
Physical exam (full) 
X
8.2.3
Targeted physical exam (based 
on symptoms)
X
X
X
X
X
8.2.3
Vital signsd
X
X
X
X
X
X
8.2.4
ECGe
X
As clinically indicated
8.2.5
Concomitant medications
<--------------------------------------------------------------------------------------------------------------->
6.4
Concomitant proceduresf
<--------------------------------------------------------------------------------------------------------------->
6.4.1
Eligibility criteriag
X
Table 4, Table 5, 
Table 7, 5.1, 5.2, 5.4
Laboratory Assessments
Clinical chemistryh
X
Xi
X
X
X
X
Table 11
Hematologyh
X
Xi,j
X
X
X
X
Table 12
TSH, (reflex free T3 or free T4k)
X
Xl
X
X
X
X
Table 11


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Table 2
Schedule of assessments for second screening and 12-month treatment period (initiated by the signing of 
ICF2) 
Screening
C1
C2
C3
C4
C5 to C14 or until RECIST 1.1-
defined disease recurrence
For details, see Section
Week
-4 to -1
0
q3w ±3db unless dosing needs to 
be held for toxicity reasons
q4w ±3db unless dosing needs to 
be held for toxicity reasons
Day
-28 to -1
1a
q21d ±3db unless dosing needs 
to be held for toxicity reasons
q28d±3db unless dosing needs to 
be held for toxicity reasons
Urinalysis
X
As clinically indicated
Table 13
Hepatitis B and C and HIVm
X
8.2.1
Pregnancy testn
X
X
X
X
X
X
8.2.1
Monitoring
WHO/ECOG performance status
X
X
X
X
X
X
8.2.7
AE/SAE assessment
<------------------------------------------------------------------------------------------------------------>
8.3
Patient follow-up contact / 
Patient review for safety
Recommended phone contact 
midway through Cycles 1, 2, 
and 3: days 14 of C1, 2, and 3 
8.2.6
IP administration
Durvalumab/placebon,o,p
X
X
X
X
X
6.1
SoC chemotherapyp,q
X
X
X
X
6.1.2.2
Other assessments and assays
Plasma sample for exploratory 
analysesr
Sample collected on Day 1 of each treatment cycle
8.7.2.1
Whole blood for gene expression 
(PaxGene mRNA)r
X
X
C14 or recurrence
8.7.2.3
Serum for soluble biomarkersr
X
X
C14 or recurrence
8.7.2.1


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Table 2
Schedule of assessments for second screening and 12-month treatment period (initiated by the signing of 
ICF2) 
Screening
C1
C2
C3
C4
C5 to C14 or until RECIST 1.1-
defined disease recurrence
For details, see Section
Week
-4 to -1
0
q3w ±3db unless dosing needs to 
be held for toxicity reasons
q4w ±3db unless dosing needs to 
be held for toxicity reasons
Day
-28 to -1
1a
q21d ±3db unless dosing needs 
to be held for toxicity reasons
q28d±3db unless dosing needs to 
be held for toxicity reasons
Study Participant Feedback 
Questionnaire (SPFQ)
X
C8
8.9
Optional Gx sample (DNA 
element for long-term 
storage/future use)
X
8.6.2
Efficacy evaluations
Disease assessments (as assessed 
by Investigator using 
RECIST 1.1)
Xs
Disease assessments occur q12w ± 1w (relative to the date of randomization) until 
appearance of RECIST 1.1-defined disease recurrence or until primary DFS 
analysis, whichever occurs first.t
8.1, 8.1.1.1, 
Appendix G
Tumor biopsy (optional)
At recurrenceu
8.7
All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated.
a
Every effort should be made to minimize the time between randomization and starting treatment (ie, within 3 days of randomization).
b
The 3-day window applies to these visits, although the time between 2 consecutive doses of durvalumab/placebo cannot be less than 21 days.
c
A patient will be able to sign ICF2 and enter second screening once their MRD result is available in IWRS. Written informed consent and any locally 
required privacy act document authorization must be obtained prior to performing any protocol-specific procedures, including second screening/baseline 
evaluations. The procedures outlined in this table will be initiated by the signing of ICF2.
d
Body weight is recorded at each visit along with vital signs.
e
Any clinically significant abnormalities detected require triplicate ECG results.
f
Concomitant procedures initiated post-treatment, including PORT, will be recorded in the appropriate sections of the eCRF.
g
The reason(s) for screen-failure must be captured in the appropriate eCRF for any patient found to be ineligible for randomization during the second 
screening period (see Table 7 and Section 5.4).
h
Collected prior to dosing of each cycle and as clinically indicated. Serum or plasma clinical chemistry (including LFT monitoring) and hematology may 
be performed more frequently if clinically indicated. 
i
If screening clinical chemistry and hematology assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need to be 
repeated at Day 1. 


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j
For coagulation parameters, activated partial thromboplastin time (APTT; either as a ratio or as an absolute value, in seconds) and international 
normalized ratio (INR) are to be assessed at baseline on Day 1 (unless all screening laboratory hematology assessments are performed within 3 days prior 
to Day 1), and as clinically indicated.
k
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system. 
l
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 1.
m
If negative hepatitis B and C and HIV serology was determined during the first screening period, these tests do not need to be repeated unless the patient 
is at high risk for infection.
n
For women of childbearing potential only. A urine or serum pregnancy test is acceptable. Women of childbearing potential are required to have a 
pregnancy test within 7 days prior to the first dose of IP and then every 3-4 weeks. Pregnancy test may occur on Day 1, but results must be available and 
reviewed by the treating physician or Investigator prior to commencing an infusion 
o
Durvalumab or placebo will be administered on Day 1 of each cycle. During the combination portion of treatment (Cycles 1 through 4), durvalumab will 
be infused first, followed by SoC chemotherapy.  
p
The first day of SoC administration will be Day 1 of each cycle. At these visits, in addition to SoC administration, the following assessments will be 
performed: targeted physical examinations, vital signs, concomitant medications, clinical chemistry, hematology, WHO/ECOG performance status, and 
AE/SAE assessment. Please refer to Table 8.
q
Results for LFTs, electrolytes, full blood count, and creatinine must be available before commencing an infusion (within 3 days) and reviewed by the 
treating physician or Investigator prior to dosing.
r
Samples should be collected pre-dose on Day 1 of each treatment cycle. 
s
A CT scan of the chest (including liver and adrenal glands) must be performed within 28 + 7 days (i.e. within 35 days) prior to randomization to 
confirm no evidence of disease and to serve as the patient’s baseline scan. A brain MRI (preferred) or brain CT may be performed if clinically indicated 
(at the discretion of the Investigator). 
t
The on-study scan schedule of q12w ±1w relative to the date of randomization must be followed regardless of any delays in dosing. Additional scans will 
be completed per standard practice post-recurrence.
u
FFPE samples of recurrent tumor biopsy will be collected from consenting patients.
Note: For some visits, telemedicine and/or home visits (at the patient’s home or other appropriate location) may be permitted. Telemedicine and/or home visits 
are permitted only where feasible, allowed by local laws and regulations, and following consultation with the Investigator and the Sponsor.
AE  Adverse event; C Cycle; C1D1  Cycle 1, Day 1; CT Computed tomography; D  Day; DFS Disease-free survival; ECG Electrocardiogram; 
ECOG Eastern Cooperative Oncology Group; eCRF  Electronic case report form; FFPE  Formalin-fixed paraffin-embedded; Gx Genomics research; 
HIV Human immunodeficiency virus; ICF2 Informed consent form 2; IP Investigational product; LFT Liver function test; mRNA Messenger ribonucleic 
acid; PORT  Post-operative radiation therapy; q3w Every 3 weeks; q4w Every 4 weeks; q12w Every 12 weeks; RECIST  Response Evaluation Criteria in 
Solid Tumors; SAE Serious adverse event; SoC Standard of care; T3 Triiodothyronine; T4 Thyroxine; TSH Thyroid-stimulating hormone; w  Week; WHO  
World Health Organization.


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Table 3
Schedule of assessments for patients who have completed or discontinued treatment
Time since last dose of IP (weeks)
For details, see Section
Week
4 (±3d)
12 (±1w)
q12w until disease recurrence (±1w)
Physical examination (full)
X
8.2.3
Vital signs (temperature, 
respiratory rate, blood pressure, 
and pulse)
X
8.2.4
Pregnancy testa
X
As clinically indicated
8.2.1
AE/SAE assessmentb
X
8.3
Concomitant medications
X
6.4
WHO/ECOG performance status
At timepoints consistent with tumor assessments; at 30 and 90 days; and then at 
initiation of subsequent anticancer therapyc
8.2.7
Subsequent anticancer therapyd
and progression assessmente
<-------------------------------------------------------------------------------------------------->
8.1
Survival status
X
Xf
8.1
Hematology
X
X
Table 12
Clinical chemistry
X
X
Table 11
TSH (reflex free T3 or free T4g)
X
X
Table 11
Plasma sample for exploratory 
analyses
q12w ±2w (preferably to coincide with time of scan)
Sample at time of disease recurrence (if applicable)
8.7.2.1
Study Participant Feedback 
Questionnaire (SPFQ)
X
8.9
Disease assessments (as assessed 
by the Investigator using 
RECIST 1.1)
Disease assessments occur q12w ±1w until appearance of RECIST 1.1-defined 
disease recurrence or until completion of the study or until primary DFS analysis, 
whichever occurs first.h
8.1
Tumor biopsy (optional)
At recurrencei
8.7
a
For women of childbearing potential only. A urine or serum pregnancy test is acceptable. 


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b
SAEs that occur after the 90-day safety follow-up period and that the Principal Investigator deems to be significant or related to IP should be reported
(also see Section 8.3.13).
c
WHO/ECOG performance status should also be collected at other site visits that the patient attends, if appropriate site staff are available to collect such 
information. In addition, WHO/ECOG performance status should be provided when information on subsequent anticancer therapy is provided, where 
possible.
d
Details of any treatment for NSCLC (including surgery and/or radiotherapy) post the last dose of IP must be recorded in the eCRF through the completion 
of the study. At minimum, collect the start date and description of the subsequent anticancer therapy. 
e
Post-recurrence progression assessed by Investigator based on scans performed per SoC.
f
Patients may be contacted in the week following data cut-offs to confirm survival status. 
g
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
h
The on-study scan schedule of q12w ±1w relative to the date of randomization must be followed regardless of any delays in dosing. 
i
FFPE samples of recurrent tumor biopsy will be collected from consenting patients.
Note: For some visits, telemedicine and/or home visits (at the patient’s home or other appropriate location) may be permitted. Telemedicine and/or home visits 
are permitted only where feasible, allowed by local laws and regulations, and following consultation with the Investigator and the Sponsor.
AE  Adverse event; D  day; DFS Disease-free survival; ECOG Eastern Cooperative Oncology Group; eCRF  Electronic case report form; IP Investigational 
product; NSCLC Non-small cell lung cancer; OS Overall survival; PFS  Progression-free survival; q4w Every 4 weeks; q12w Every 12 weeks; q21d Every 
21 days; q28d Every 28 days; RECIST  Response Evaluation Criteria in Solid Tumors; SAE  Serious adverse event; SoC Standard of care; 
T3 Triiodothyronine; T4 Thyroxine; TSH Thyroid-stimulating hormone; WHO  World Health Organization; w Week.


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1.2
Synopsis
International Coordinating Investigators:
Protocol Title: A Phase III, Randomized, Multicenter, Double-blind, Placebo-controlled 
Study to Determine the Efficacy of Adjuvant Durvalumab in Combination with 
Platinum-based Chemotherapy in Completely Resected Stage II-III NSCLC
Short Title: MERMAID-1
Rationale: 
Up to 30% of patients with NSCLC present with surgically resectable disease (Molina et al 
2008). For patients with stage II-IIIA and select IIIB disease, surgery and adjuvant SoC 
chemotherapy results in 5-year disease-free survival (DFS) rates of only ~40% (Wakelee et al 
2017). Adjuvant chemotherapy following resection of NSCLC is standard practice to reduce 
risk of disease recurrence. The majority of patients who remain event-free at 5 years are cured 
by surgery alone yet receive adjuvant treatment because there is currently no clear way to 
determine who will benefit from adjuvant chemotherapy.
There is evidence that identification of minimal residual disease (MRD) through detection of 
circulating tumor DNA (ctDNA) post-surgery can accurately predict disease recurrence 
(Abbosh et al 2017, Abbosh et al 2020, Chaudhuri et al 2017). Recent data from the 
TRACERx lung study reported on 78 patients with stage I-III NSCLC had 608 plasma 
samples analysed for ctDNA in pre- and post-operative settings. ctDNA was detectable at or 
before clinical relapse in 37 of the 45 patients who suffered clinical relapse of their disease. 
Conversely, ctDNA was only detected in 1 of 199 timepoints analysed for 23 patients who did 
not suffer relapse of their lung cancer during a median of 1184 days of study follow-up. In 10 
of 10 patients who developed second primary cancers during follow-up no ctDNA was 
detected, reflecting specificity of the MRD assay toward the primary tumor that was excised at 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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surgery. Data from TRACERx also provided evidence that ctDNA detection could occur prior 
to normal surveillance imaging (CT or PET-CT scans), suggesting that detection of ctDNA 
can (in some cases) identify occult metastatic disease in advance of normal radiological 
surveillance (Abbosh et al 2020
Abbosh C, Frankell A, Garnett A, Harrison T, Weichert M, Licon A, et al. Phylogenetic 
tracking and minimal residual disease detection using ctDNA in early-stage NSCLC: A lung 
TRACERx study. Philadelphia, PA: American Association for Cancer Research; 2020; 
CT023.
). An additional study reported that NSCLC patients who were MRD- had excellent outcomes, 
regardless of whether they received immunotherapy as consolidation treatment (Moding et al 
2020). Interestingly, NSCLC patients who were found to be MRD+ after completing 
chemoradiation therapy had better outcomes if they went on to receive consolidation 
immunotherapy treatment compared to those MRD+ patients who did not. These data suggest 
that immunotherapy improves outcomes for NSCLC patients who are MRD+ after completion 
of SoC (Moding et al 2020). 
Taken together, these data demonstrate that detection of MRD at a time when there is no 
radiologic evidence of disease provides an opportunity for earlier therapeutic intervention 
(Abbosh et al 2018). Therefore, MRD+ patients could benefit from earlier intervention and 
escalation of treatment, including immunotherapy alone or in combination with 
chemotherapy; furthermore, MRD- patients (the majority of whom are cured by surgery alone) 
could be spared from more intensive therapy and the resulting unnecessary toxicity. 
Long-term survival can be improved through administration of adjuvant chemotherapy 
immediately following surgery (Pignon et al 2008), yet chemotherapy in the first-line 
metastatic setting results in no long-term survival benefit and progression-free survival (PFS) 
benefits of only a small number of months (Cochrane Review 2000). This contrast 
demonstrates a vulnerability of residual cancer following surgery to systemic therapy and 
provides a rationale to conduct studies to accelerate adoption of novel therapies earlier in the 
disease course. 
Durvalumab can be effective in situations of residual cancer as evidenced by improved PFS 
and overall survival (OS) observed with durvalumab versus placebo following definitive 
concurrent chemoradiation in the PACIFIC study (Antonia et al 2018, Gray et al 2019). 
Intervention with combination chemotherapy and immunotherapy versus chemotherapy alone 
improves PFS and OS in advanced NSCLC (Gandhi et al 2018, Gadgeel et al 2019, Paz-Ares 
et al 2018). These data suggest that the combination of immunotherapy and chemotherapy in 
the adjuvant setting, where patients have undergone a complete resection but may have 
residual disease, would provide additional benefits to single agent immunotherapy and 
improve DFS. However, current immunooncologic (IO) therapy development in the adjuvant 


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setting is based on sequential chemotherapy followed by immunotherapy (eg, BR.31, ANVIL, 
IMpower010, and KEYNOTE-091). This study was originally designed to test the hypothesis 
of an MRD-driven treatment paradigm, wherein MRD status would inform targeted escalation 
of adjuvant therapy only in patients who are MRD+ post-surgery and are thus at high risk for 
disease recurrence while preventing post-surgery overtreatment of MRD- patients, the 
majority of whom have been cured by surgery alone. 
Two Phase III clinical studies have reported positive results for PD-(L)1 inhibitors (used as 
monotherapy) in the adjuvant setting. IMpower010 is a Phase III trial which randomized 
1280 patients with completely resected Stage IB (≥4cm) to Stage IIIA NSCLC (Union for 
International Cancer Control [UICC]/American Joint Committee on Cancer [AJCC] version 7) 
after cisplatin-based chemotherapy to atezolizumab, given every 3 weeks for up to 16 cycles, 
or best supportive care (Felip et al 2021). The primary endpoints tested hierarchically were 
DFS in: (i) the PD-L1 ≥1%, stage II-IIIA population; (ii) the all-randomized stage II-IIIA 
population; (iii) the intent-to-treat population. At interim analysis the first and second of these 
were found to be statistically significant with hazard ratios (HR) of 0.66 (95% confidence 
interval [CIs] 0.50-0.88) and 0.79 (95% CIs 0.64-0.96), respectively. In October 2021, these 
data led to Food and Drug Administration (FDA) approval of atezolizumab for adjuvant 
treatment following resection and platinum-based chemotherapy for adult patients with stage 
II-IIIA NSCLC whose tumors have PD-L1 expression ≥1% (using a Ventana SP263 PD-L1
immunohistochemistry [IHC] assay). PEARLS/KEYNOTE-091 is a Phase III study which 
randomized 1177 patients with completely resected Stage IB (≥4cm) to Stage IIIA NSCLC 
(UICC/AJCC version 7) ± adjuvant chemotherapy to pembrolizumab or placebo (given every
3 weeks for up to 18 cycles) (Paz-Ares et al 2022). The dual primary endpoints were DFS in 
the overall population and DFS in the PD-L1≥50% stage IB-IIIA population. At a second 
interim analysis, the HR for the first of these endpoints was statistically significant (0.76; 95% 
CIs 0.63-0.91). 
One Phase III clinical study has reported positive results for nivolumab (anti-PD-1 
immunotherapy) in the neoadjuvant setting. In the Checkmate816 study, 358 patients with 
Stage IB (≥4cm) to Stage IIIA NSCLC (UICC/AJCC version 7) were randomized to 
neoadjuvant platinum-based chemotherapy with or without open label nivolumab (given every 
3 weeks for up to 3 cycles) (Forde et al 2022). The co-primary endpoints were pathological 
complete response (pCR) rate and event-free survival (EFS). The trial was positive for both 
primary endpoints. The HR for EFS was 0.63 (97.38% CIs 0.43-0.91) at interim analysis. This 
regimen was approved by the FDA in March 2022, for the treatment of patients with 
resectable (tumors ≥4cm or node-positive) NSCLC in the neoadjuvant setting, in combination 
with platinum-doublet chemotherapy.
It is expected that access to (neo)adjuvant PD-(L)1 inhibitors will increase over the coming 
years. Despite this anticipated shift in treatment landscape, it remains unclear if concomitant 


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administration of chemotherapy with PD-(L)1 inhibitors, and if early intervention with this 
combination in post-surgical MRD+ patients, will drive further improvements in treatment 
outcomes. An exploratory analysis of ctDNA in IMpower010 demonstrated worse DFS 
outcomes for the patients whose baseline MRD status was MRD+, highlighting further a 
significant unmet need for MRD+ patients (Zhou et al 2021).
The original research hypothesis for this study was that concurrent durvalumab plus SoC 
chemotherapy would be more effective than placebo plus SoC chemotherapy for the treatment 
of MRD+ patients who have undergone complete resection of stage II-III NSCLC when 
administered in the adjuvant setting. Given the above anticipated changes in treatment 
landscape for patients with resectable NSCLC, enrollment to this study was closed on 
25 May 2022. In order to optimize the ongoing scientific and clinical utility of this study, the 
statistical analyses have been amended to reflect the reduced sample size of the study (see 
Section 9). 
As presented in the objectives and endpoints table below, under CSP V4.0, as a result of the 
decision to close study enrollment early, meaning the intended patient numbers will not be 
reached, the primary objective of this study will now compare the efficacy of durvalumab plus 
SoC chemotherapy to placebo plus SoC chemotherapy in terms of DFS in the FAS rather than 
in the MRD+ analysis set.
Objectives and Endpoints
Primary objective:
Endpoint/variable:
To assess the efficacy of durvalumab + SoC 
chemotherapy compared to placebo + SoC 
chemotherapy as measured by DFS in all patients
DFS in FAS (using Investigator assessments 
according to RECIST 1.1)
Secondary objective:
Endpoint/variable:
To assess the efficacy of durvalumab + SoC 
chemotherapy compared to placebo + SoC 
chemotherapy as measured by DFS in MRD+ patients
DFS in MRD+ analysis set (using Investigator 
assessments according to RECIST 1.1)
To assess the efficacy of durvalumab + SoC 
chemotherapy compared to placebo + SoC 
chemotherapy as measured by OS in MRD+ patients 
and in all patients 
OS in MRD+ analysis set and in FAS
Safety objective:
Endpoint/variable:
To assess the safety and tolerability profile of 
durvalumab + SoC chemotherapy compared to 
placebo + SoC chemotherapy in MRD+ and in all 
patients  
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Objectives and Endpoints
Exploratory objectives:
Endpoint/variable:
To assess the efficacy of durvalumab + SoC 
chemotherapy compared to placebo + SoC 
chemotherapy on post-recurrence outcomes 
PFS (using local standard practice)
To assess the efficacy of durvalumab + SoC 
chemotherapy to clear ctDNA compared to placebo + 
SoC chemotherapy in MRD+ patients 
ctDNA endpoints, as defined by:
•
Best overall clearance rate (number converted at 
any time)
•
Best confirmed clearance rate (as above but 
confirmed at subsequent visit)
•
Time to ctDNA clearance
•
Duration of ctDNA clearance
•
Time to ctDNA recurrence
•
Time to confirmed ctDNA recurrence
•
Changes in variant allele frequencies (VAF) 
following treatment
To assess relationship between treatment effect on 
DFS and treatment effect on ctDNA endpoints
ctDNA endpoints (as defined above) and DFS
To assess prognostic significance of MRD detection 
as determined by ctDNA in NSCLC
Time from randomization to DFS (MRD+ vs MRD-) 
To assess the association of TMB with efficacy of 
durvalumab + SoC chemotherapy compared with 
placebo + SoC chemotherapy
DFS, OS in patients with TMB
To investigate the relationship between a patient’s 
baseline PD-L1 TC and IC expression and efficacy 
outcomes with durvalumab + SoC chemotherapy 
compared with placebo + SoC chemotherapy
IHC analysis of PD-L1 TC and IC expression and 
spatial distribution within the tumor 
microenvironment relative to efficacy outcomes (ie, 
DFS, OS)
To investigate biomarkers in tumor and periphery at 
baseline, on treatment, post-treatment, and/or at 
recurrence wherever feasible to identify markers 
related to disease, mechanism of action of the drug 
and/or their associations with response and clinical 
endpoints  
Exploratory markers, which may include, but are not 
limited to: tumor, immune, and/or stromal cell gene 
and protein expression profiles within the peripheral 
and tumoral compartments.
TMB and somatic mutations in tissue and/or 
blood/plasma.
Changes in RNA, DNA, or protein will be compared 
at baseline, on treatment, post-treatment, and/or at 
recurrence.
Attributes of tumor microenvironment that could be 
assessed using various methods, which may include, 
but are not limited to, high content imaging, 
multiplex RNA/DNA/protein analysis with spatial 
resolution such as Mass Spec or other technologies.
To evaluate patient-reported treatment-related 
symptoms using PRO-CTCAE
To assess the patient´s global impression of 
symptoms severity, and global treatment tolerability 
Prespecified items on the PRO-CTCAE
Patient global assessments
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Objectives and Endpoints
To assess patient-reported symptoms, functioning, 
and HRQoL in MRD+ patients treated with 
durvalumab + SoC chemotherapy compared to 
placebo + SoC chemotherapy 
Change from baseline and time to deterioration in 
EORTC QLQ-C30 and EORTC QLQ-LC13
To explore the impact of treatment and disease on 
health state utility
, descriptor, and VAS
AE Adverse events;  ctDNA Circulating tumor DNA; DFS  Disease-free survival; EORTC  European 
Organisation for Research and Treatment of Cancer; FAS Full analysis set; 
 
; HRQoL Health-related Quality of Life; IC  Immune cell; 
IHC Immunohistochemistry; MRD  Minimal residual disease; MRD+  Minimal residual disease-positive; 
MRD- Minimal residual disease-negative; NSCLC Non-small cell lung cancer; OS Overall survival; 
PD-L1 Programmed cell death-ligand 1; PFS Progression-free survival; PRO-CTCAE Patient-Reported 
Outcomes-Common Terminology Criteria for Adverse Events; QLQ-C30 30-item Core Quality of Life 
Questionnaire; QLQ-LC13 13-item Lung Cancer Quality of Life Questionnaire; RNA  Ribonucleic acid; 
RECIST  Response Evaluation Criteria in Solid Tumors; SoC  Standard of care; TC  Tumor cell; TMB Tumor 
mutational burden; VAS  Visual analog scale. 
Overall design 
This is a Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-arm 
study to evaluate the efficacy and safety of durvalumab plus SoC chemotherapy compared to 
placebo plus SoC chemotherapy in patients with completely resected stage II-III NSCLC who 
are MRD+ post-surgery. 
Prior to CSP V4.0, this study was designed to screen approximately 
 patients and 
randomize approximately 
 patients with stage II-III NSCLC (according to IASLC Staging 
Manual in Thoracic Oncology v8.0) (select stage IIIB patients with T3N2 or T4N2 disease 
may be eligible; see Section 5.1.1), whose tumors are epidermal growth factor receptor 
(EGFR) and anaplastic lymphoma kinase (ALK) wild type, and who have undergone complete 
resection. Eligible patients must be current or former smokers. Randomized patients were 
expected to include approximately 
 MRD+ and 
 MRD- patients. The study has opened 
in 188 centers globally. 
Following a decision to close recruitment on 25 May 2022, a total of 691 patients have been 
enrolled, and a total of approximately 100 patients are now expected to be randomized within 
the study.
The study requires a 2-tiered screening/consent process as described below. Note that 
enrollment has closed for this study.
First screening (initiated by the signing of ICF1)
First screening begins when the patient signs ICF1. It is preferred that patients are identified 
and enrolled prior to surgery (Table 1); however, patients are permitted to sign ICF1 following 
surgery. Surgery is not a study procedure. 
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During first screening, EGFR and ALK will be assessed. A pre-surgical biopsy sample is the 
preferred sample type; however, if a pre-surgery biopsy sample is not available or evaluable, 
testing will be conducted after surgery on the resected tumor tissue. Patients will still be 
allowed to continue with first screening procedures while testing is ongoing but will be 
excluded from second screening and randomization if their tumor sample tests positive for 
EGFR mutations and/or ALK translocations. Local testing must be performed using a 
well-validated, local regulatory approved test; results from testing performed during screening 
for another AstraZeneca study may be used. EGFR/ALK will be tested centrally if results from 
testing either locally or in the context of screening for another AstraZeneca study are not 
available.
Note: Where EGFR/ALK results are obtained from a pre-surgical tissue biopsy as part of 
standard local practice, the patient must be confirmed as EGFR/ALK wild-type prior to 
signing ICF1 and enrolling in the study. 
This study requires mandatory genetic testing. WES of the patient’s tumor is performed on the 
resected tumor tissue and derived tumor-specific DNA variants are identified by removing 
background germline variants, determined by WES of the patient’s whole blood sample. A 
personalized panel is then created, comprised of 50 of the patient’s tumor variants expressed 
at high frequency. This panel is then used to identify the presence of ctDNA extracted from 
the patient’s plasma. The patient is considered MRD+ if the panel detects ctDNA. 
Note: Patients who have higher levels of tumor-specific mutations are more likely to have 
sufficient mutations to satisfy the requirement for a successful panel build. Patients with 
driver mutations and/or non-smokers tend to have a lower mutational burden (Nagahashi et al 
2018, Offin et al 2019). 
Exclusion of never-smokers may decrease the screen -failures due to EGFR mutation or ALK 
translocation positive status that can occur late in the screening process. It may increase the 
probability that patients will be eligible by removing the population of patients who are likely 
to have lower mutational burden and therefore unlikely to satisfy the requirement for a 
successful panel build. 
A pre-surgery plasma sample will be collected from every patient who signs ICF1 prior to 
surgery. These samples will be tested retrospectively using the personalized panel to 
determine if the patient’s tumor is capable of shedding ctDNA prior to surgery for exploratory 
purposes. In addition, a plasma sample will be collected at Week 3-5 (Day 21-35) 
post-surgery and used to determine a patient’s MRD status. Investigators will not be notified 
of MRD status, and eligibility to continue to second screening will be managed through the 
interactive web response system (IWRS).
While it is preferred that patients enrol in the study prior to surgery, ICF1 can be signed after 
surgery. As a plasma sample must still be collected at Week 3-5 (Day 21-35) post-surgery to 


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determine a patient’s MRD status, ICF1 should be signed no later than Week 3 (Day 21) 
post-surgery to ensure the personalized panel is built and MRD result is obtained within the 
screening timeframe. Patients identified after Week 3 (d21) post-surgery but prior to Week 5 
(d35) post-surgery may be allowed to enrol in the study depending on the outcome of the 
discussion with the study physician. A whole blood sample and resected tumor tissue must be 
collected and sent to the diagnostic lab as soon as possible after ICF1 is signed for 
development of the personalized panel. 
Programmed cell death-ligand 1 (PD-L1) tumor cell (TC) expression will be evaluated by a 
central reference laboratory on the resected tumor tissue collected during the first screening 
period. PD-L1 status is required for randomization. 
Second screening (initiated by the signing of ICF2)
Following determination of MRD status during the first screening period, patients will enter 
the second screening period (Table 2) to confirm that they are eligible for randomization to 
treatment. 
Note: If the scan performed after surgery (Table 1 and Table 2) falls outside of the 28 day 
+7 days window prior to randomization, then an additional scan must be performed to 
confirm no evidence of disease.
Prior to CSP V4.0, approximately 
 patients (approximately 
 MRD+ and 
MRD-)
were to be randomized 1:1 to treatment with durvalumab q3w for 4 cycles plus SoC 
chemotherapy q3w for up to 4 cycles or placebo q3w for 4 cycles plus SoC chemotherapy 
q3w for up to 4 cycles followed by durvalumab or placebo monotherapy q4w for up to an 
additional 10 cycles (for a total of 12 months of treatment), until disease recurrence, or until 
other specific treatment discontinuation criteria are met (whichever occurs first).
In addition to blinding to treatment, Investigators will not be notified of the patient’s MRD 
status to limit potential bias upon interpreting the scans. 
Study Period:
Date of first patient enrolled: 17 July 2020
Estimated date of last patient completed: Q3 2023
Number of patients: 
Prior to CSP V4.0, approximately 
 patients were to be screened in order to randomize 
approximately 
 eligible patients in a 1:1 ratio to concurrent durvalumab plus SoC 
chemotherapy or placebo plus SoC chemotherapy. The approximate number of screened 
patients was based on the anticipated prevalence of MRD+ patients at the Week 3-5 
(Day 21-35) post-surgery timepoint based on previously published data (Abbosh et al 2017) 
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and data internal to the Sponsor. Patients will be stratified by disease stage (stage II vs 
stage III), MRD status (MRD+ vs MRD-), and PD-L1 TC expression (<1% vs ≥1%). Of the 
patients randomized into the study, approximately 
patients were expected to be MRD+ as 
determined by the assay results from the personalized panel. At the time of study initiation, 
the number of MRD- patients was originally capped at 
. As the total number of 
randomized patients will not reach 
, the number of MRD- patients will be less than 
. 
MRD- patients will be included in this study to evaluate whether MRD+ is distinct from 
MRD- status as a prognostic marker for disease recurrence and to provide clinical and 
translational data to facilitate the development of an MRD-driven treatment paradigm. 
Under CSP V4.0, the planned number of randomized patients will not be met. This is a result 
of the decision by AstraZeneca to close study enrollment early.
Treatments and treatment duration:
Adjuvant study treatments (durvalumab plus SoC chemotherapy or placebo plus SoC 
chemotherapy) should be initiated by Week 9 post-surgery (once MRD status has been 
determined) but can be delayed up to 12 weeks (+ 7 days) after surgery. Data have shown that 
patients can still benefit from delayed adjuvant chemotherapy started up to 16 weeks after 
surgery (Salazar et al 2017).
Durvalumab or placebo
!
Durvalumab 1500 mg or placebo by intravenous (IV) infusion over 60 minutes in 
combination with chemotherapy (regimens specified below), starting at Week 0, q3w, for 
4 cycles, followed by durvalumab 1500 mg or placebo by IV infusion over 60 minutes 
q4w for up to 10 additional cycles (for a total of 12 months of treatment) unless there is 
unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.  
(Please note, if a patient’s weight falls to 30 kg or below [≤30 kg], then the patient should 
receive weight-based dosing equivalent to 20 mg/kg of durvalumab or placebo q3w or 
q4w after consultation between Investigator and Study Physician, until the weight 
improves to above 30 kg [>30 kg], at which point the patient should start receiving the 
fixed dosing of durvalumab 1500 mg or placebo q3w or q4w). 
SoC chemotherapy
Patients will receive one of the following SoC regimens, based on tumor histology and 
Investigator’s discretion, as adjuvant therapy following complete resection. 
!
Squamous tumor histology: 
∀
Paclitaxel plus carboplatin: paclitaxel 200 mg/m2 and carboplatin area under the 
serum drug concentration-time curve (AUC) 6 via IV infusion on Day 1 of each 
3-week cycle, for 4 cycles. 
!
Non-squamous tumor histology: 
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∀
Pemetrexed plus cisplatin (preferred*): pemetrexed 500 mg/m2 and cisplatin 
75 mg/m2 via IV infusion on Day 1 of each 3-week cycle, for 4 cycles. 
∀
Pemetrexed plus carboplatin: pemetrexed 500 mg/m2 and carboplatin AUC 5 via IV 
infusion on Day 1 of each 3-week cycle, for 4 cycles.
*In the event of unfavorable tolerability, patients can switch from cisplatin to carboplatin 
therapy at any point during the study. However, it is recommended that patients receive at 
least 1 cycle of cisplatin. 
Duration of treatment
Unless specific treatment discontinuation criteria are met, treatment with 4 cycles of 
durvalumab plus SoC chemotherapy or placebo plus SoC chemotherapy (q3w) will be 
administered, followed by treatment with durvalumab or placebo monotherapy for up to 
10 additional cycles (q4w) (for a total of 12 months of treatment) or until evidence of 
RECIST 1.1-defined disease recurrence using Investigator assessments (whichever occurs 
first). 
Post-treatment follow-up period
After completion of 12 months (14 cycles) of treatment, patients will be followed for safety, 
ctDNA, disease recurrence, and survival status at specified intervals until the primary DFS 
analysis.
Patients may not receive retreatment in this study.
Follow up of patients post discontinuation of study drug
Patients who have discontinued treatment due to toxicity or symptomatic deterioration will be 
followed up with disease assessments until disease recurrence, primary DFS analysis, or death 
(whichever comes first). These patients are not eligible for retreatment at any time. 
Survival
All patients randomized in the study should be followed for survival until study completion.  
End of study 
The end of study is defined as the date of the last visit of the last patient in the study, which is 
approximately 12 months following last patient randomized.
Disease assessments
Efficacy assessments of the primary endpoint of DFS will be derived using Investigator 
assessments according to RECIST 1.1 and prespecified definitions of disease recurrence (ie, 
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assessments. All patients will be followed for disease recurrence and survival until the 
primary DFS analysis. OS is a secondary endpoint of the study.
Tumor evaluations utilize images from computed tomography (CT; preferred) or magnetic 
resonance imaging (MRI), each preferably with IV contrast, of the chest and abdomen 
(including liver and adrenal glands) collected during second screening/baseline and at selected 
timepoints during the study duration. Any other areas of disease involvement should be 
additionally imaged based on the signs and symptoms of individual patients. 
Data Monitoring Committee
An independent data monitoring committee (IDMC) comprised of independent experts will 
meet 12 months after the first patient has been dosed with investigational product (IP) or after 
the first 50 patients have received at least 1 dose of IP (whichever occurs first) in order to 
assess the safety and tolerability of durvalumab and report back to the Sponsor. The timing of 
subsequent reviews will be determined by the IDMC but will not occur more frequently than 
every 6 months. The IDMC safety reviews will be conducted in an unblinded manner. 
Full details of the IDMC procedures and processes can be found in the IDMC Charter.
Statistical methods
Prior to CSP V4.0, the primary objective of the study was to compare the efficacy of 
durvalumab plus SoC chemotherapy to placebo plus SoC chemotherapy in terms of DFS, 
defined as time from the date of randomization until the date of disease recurrence (defined 
above) or date of death due to any cause (whichever occurs first) in the MRD+ analysis set. 
DFS in the full analysis set (FAS) was a secondary analysis. Under CSP V4.0, the primary 
analysis is planned to be performed on the FAS and an analysis on the MRD+ analysis set will 
be performed as a secondary objective of the study.
The FAS will include all randomized patients. The MRD+ analysis set will include all patients 
in the FAS who are determined to be MRD+ based on the result from the post-surgical plasma 
sample.
Patients will be stratified at randomisation by disease stage (stage II vs stage III), by MRD 
status (MRD+ vs MRD-), and by PD-L1 status (TC <1% vs TC ≥1%).
DFS will be analyzed using a stratified log-rank test. The treatment effect will be estimated in 
terms of hazard ratio (HR) together with the corresponding 95% confidence interval (CI) from 
a Cox proportional hazard model stratified by disease stage, PD-L1 status, and MRD status. 
For the secondary analysis in the MRD+ analysis set, the MRD status stratification factor will 
not be included. The stratification factor covariates in the statistical modeling will be based on 
the values entered into the IWRS at randomization, even if it is subsequently discovered that 
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secondary endpoints, a plan for reducing the number of strata cells will be included in the 
statistical analysis plan (SAP) in case there are insufficient events in one level of any strata.
The DFS rates at month 6 (DFS-6) and month 12 (DFS-12) will be estimated based on the 
Kaplan-Meier curves along with their 95% CIs and presented by treatment arms.
Prior to CSP V4.0, the study planned to screen approximately 
 patients to randomize 
approximately 
patients with stage II-III NSCLC 1:1 to durvalumab plus SoC 
chemotherapy or placebo plus SoC chemotherapy. Of the patients randomized into the study, 
approximately 
 patients were required to be MRD+, as determined by the result from the 
post-surgical plasma sample. The number of MRD- patients was to be capped at 
 
(Exception: MRD- patients who have signed ICF2 at the time the MRD- cohort cap is met 
could still be randomized). 
Under CSP V4.0, the planned number of randomized patients will not be met. This is a result 
of the decision by AstraZeneca to close study enrollment early. 
Prior to CSP V4.0, the study was sized for the primary endpoint of DFS in the MRD+ analysis 
set and the secondary endpoint of DFS in the FAS. The analysis of the primary endpoint 
(DFS) was planned to occur when approximately 151 DFS events had occurred 
(65% maturity) in the MRD+ analysis set. If the true DFS HR is 0.59 in the MRD+ analysis 
set, the study would have provided at least 90% power to demonstrate a statistically 
significant difference for DFS with overall 2-sided significance level of 5%; this translates to 
a 5.0‑month benefit in median DFS over 7.2 months on placebo plus SoC chemotherapy, or 
16% difference in 2-year DFS rate over 10% on placebo plus SoC chemotherapy, if DFS is 
exponentially distributed. The smallest treatment difference that would be statistically 
significant is an HR of 0.73.
The study was also sized to provide at least 87% power for the DFS endpoint in the FAS. The 
analysis will be performed at the same time as the primary analysis, when it was expected that 
approximately 194 events had occurred (58% maturity) in the FAS. If the true DFS HR is 0.64 
in this population, this would have provided at least 87% power to demonstrate a statistically 
significant difference for DFS, assuming overall 5% 2-sided significance level; this translates 
to a 6.2-month benefit in median DFS over 11.0 months on placebo plus SoC chemotherapy, 
or 16% difference in 2-year DFS rate over 22% on placebo plus SoC chemotherapy, if DFS is 
exponentially distributed. The smallest treatment difference that would be statistically 
significant is an HR of 0.76.
The primary analysis for DFS was planned to occur approximately 51 months after the first 
patient has been randomized, assuming a 3-month lag before the first MRD+ patient was 
randomized, 44‑month recruitment period, and a minimum follow-up of 4 months.  Under 
CSP V4.0 the primary DFS analysis will now occur after the data cut-off (DCO). 
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Prior to CSP V4.0, to provide strong control of the type I error rate, α=5% (2-sided), a 
multiple testing procedure with a gatekeeping strategy was planned across the primary 
endpoint of DFS in the MRD+ analysis set and the secondary endpoint of DFS in the FAS, 
starting with testing the primary endpoint on the MRD+ analysis set. The overall 5% alpha 
was to be allocated to the analysis of DFS in the MRD+ analysis set. If that analysis was 
significant, the 5% alpha was to be recycled to the DFS endpoint in the FAS.
Under CSP V4.0, no methods for multiplicity control will be performed and all analyses will 
be exploratory.
OS will be a secondary efficacy endpoint, defined as the time from the date of randomization 
until death due to any cause. Any patient not known to have died at the time of analysis will 
be censored based on the last recorded date on which the patient was known to be alive. OS 
will analyzed at the time of the DFS analysis. Prior to CSP V4.0, in the MRD+ analysis set, if 
the true HR is 0.62, then it was anticipated that approximately 87 events (38% maturity)
would have occurred. This translates to an 11.5 month benefit in median OS over 18.5 months 
on placebo plus SoC chemotherapy. In the FAS, if the true HR is 0.67, then it was anticipated 
that approximately 112 events (34% maturity) would have occurred. This translates to a 
13.4 month benefit in median OS over 27.3 months on placebo plus SoC chemotherapy. 
OS will be analyzed similarly to DFS.  Under CSP V4.0, these number of events will not be 
observed. This is a result of the decision by AstraZeneca to close study enrollment early.
Prior to CSP V4.0, a further analysis of OS was planned to be performed at approximately 
155 events (67% maturity) in the MRD+ analysis set. At this time there was expected to be 
approximately 190 events (57% maturity) in the FAS. It was anticipated that this analysis 
would occur approximately 72 months after the first patient was randomized. If events were 
accruing slower than expected, then the DCO would have occurred 72 months after the first 
patient was randomized, regardless of number of events accrued. Under CSP V4.0, the further 
analysis of OS at approximately 155 events will not be performed. Safety data will be 
summarized descriptively and will not be formally analyzed.
1.3
Schema
The original general study design is summarized in Figure 1. The inclusion criteria that must 
be met during the periods covered by the first and second screening are briefly summarized in 
Table 4. The timings of assessment of exclusion criteria relative to surgery (pre- and post-) are 
summarized in Table 5.
The revised study design, upon implementation of CSP V4.0, is summarized in Figure 2. All 
enrolled patients were screened and randomized according to the eligibility criteria based on
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Figure 1
Study schema (original)
a
While it is preferred that patients are identified and sign ICF1 prior to surgery, patients will be permitted to 
sign ICF1 after surgery. In this case, whole blood and resected tumor tissue must be collected as soon as 
possible for creation of the personalized panel. A plasma sample must still be collected at Week 3-5 
(Day 21-35) post-surgery, even if creation of the personalized panel is delayed.
b
EGFR/ALK status should be assessed on pre-surgical biopsy. If pre-surgical biopsy is not available or 
evaluable, testing will be conducted on resected tumor tissue while the personalized MRD panel is in 
development. Patients will still be allowed to continue with first screening procedures while testing is 
ongoing but will not be eligible for randomization if their tumor tissue tests positive for EGFR mutations or 
ALK translocations. 
c
PD-L1 status is required for randomization.
d
The plasma sample used to determine MRD status must be collected at Week 3-5 (Day 21-35) post surgery. 
Investigators will not be notified of the patient’s MRD status and eligibility to continue into second 
screening will be managed through the IWRS.
e
A CT scan performed once a patient signs ICF2 (Table 2) can be used as the baseline scan provided this 
scan was performed 28 days + 7 days prior to randomization. 
ALK  Anaplastic lymphoma kinase; CT Computed tomography; d  Day; DFS  Disease-free survival; EGFR  
Epidermal growth factor receptor; FAS Full analysis set; ICF1 Informed consent form 1; ICF2  Informed 
consent form 2; MRD Minimal residual disease; MRD+ MRD-positive; MRD- MRD-negative; NSCLC  
Non-small cell lung cancer; OS Overall survival; PD-L1 Programmed cell death-ligand 1; PD-L1 TC<1%/≥1%  
Expression of PD-L1 on tumor membrane, at any intensity, in<1% or ≥1% of tumor cells; PRO Patient-reported 
outcomes; q3w  Every 3 weeks; q4w  Every 4 weeks; R Randomization; SoC  Standard of care; w  Week; WES  
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Figure 2
Study schema (revised)
a
While it is preferred that patients are identified and sign ICF1 prior to surgery, patients will be permitted to 
sign ICF1 after surgery. In this case, whole blood and resected tumor tissue must be collected as soon as 
possible for creation of the personalized panel. A plasma sample must still be collected at Week 3-5 
(Day 21-35) post-surgery, even if creation of the personalized panel is delayed. Note that enrollment has 
closed for this study.
b
EGFR/ALK status should be assessed on pre-surgical biopsy. If pre-surgical biopsy is not available or 
evaluable, testing will be conducted on resected tumor tissue while the personalized MRD panel is in 
development. Patients will still be allowed to continue with first screening procedures while testing is 
ongoing but will not be eligible for randomization if their tumor tissue tests positive for EGFR mutations or 
ALK translocations. 
c
PD-L1 status is required for randomization.
d
The plasma sample used to determine MRD status must be collected at Week 3-5 (Day 21-35) post surgery. 
Investigators will not be notified of the patient’s MRD status and eligibility to continue into second 
screening will be managed through the IWRS.
e
A CT scan performed once a patient signs ICF2 (Table 2) can be used as the baseline scan provided this 
scan was performed 28 days + 7 days prior to randomization. 
ALK  Anaplastic lymphoma kinase; CT Computed tomography; d  Day; DFS  Disease-free survival; EGFR  
Epidermal growth factor receptor; FAS Full analysis set; ICF1 Informed consent form 1; ICF2  Informed 
consent form 2; MRD Minimal residual disease; MRD+ MRD-positive; MRD- MRD-negative; NSCLC  Non-
small cell lung cancer; OS Overall survival; PD-L1 Programmed cell death-ligand 1; PD-L1 TC<1%/≥1%  
Expression of PD-L1 on tumor membrane, at any intensity, in<1% or ≥1% of tumor cells; PRO Patient-reported 
outcomes; q3w  Every 3 weeks; q4w  Every 4 weeks; R Randomization; SoC  Standard of care; w  Week; WES  
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Table 4
Timing of inclusion criteria assessment relative to screening periods 
First screening (initiated by the signing of ICF1)
(Section 5.1.1)
Second screening (initiated by the signing of ICF2)
(Section 5.1.2)
1
Signature of ICF1 (preferred prior to surgery, but 
allowed up to Week 3 [d21] post-surgery)a
2
Age ≥18 years
3
Male and/or female
4
Diagnosis of histologically confirmed NSCLC with 
resectable (stage IIA to select [ie, T3N2 or T4N2] 
stage IIIB) diseaseb
5
Imaging of chest/abdomen and brainc prior to surgery
6
Complete resection as per protocol definition 
(Section 5.1.1)
7
Collection of pre-surgical plasma sample if enrolled
before surgery
8
Confirmation of resected tumor tissue and whole 
blood sample appropriate for WES for creation of 
personalized MRD panel 
9
Collection of resected tumor tissue for prospective 
PD-L1 testing
10
Collection of post-surgical plasma sample to 
determine MRD status 
11
No evidence of disease recurrence confirmed by CT 
and/or MRId
1
Signature of ICF2 after determination of MRD 
status and prior to second screening and 
randomization
2
No evidence of disease recurrence confirmed by 
CT and/or MRId
3
WHO/ECOG PS 0 or 1
4
Completed postoperative wound healing
5
Able to tolerate 4 cycles of platinum-based 
chemotherapy
6
Adequate organ and marrow function based on 
specified criteria
7
Life expectancy ≥12 weeks
8
Body weight ≥30 kg
a
Exception: Patients may be allowed to enrol/sign ICF1 after Week 3 (d21) post-surgery but prior to Week 5 
(d35) post-surgery depending on the outcome of the discussion with the study physician. Note that 
enrollment has closed for this study.
b
Individuals who have diagnosis of histologically confirmed NSCLC (WHO 2015 classification) with 
resectable (stage II-III) disease (according to IASLC Staging Manual in Thoracic Oncology v8.0). Select 
(ie, T3N2 or T4N2) stage IIIB patients will be eligible, provided that they are upstaged to T3N2 or T4N2 
based on confirmed pathology. Patients who are staged as T3N2 or T4N2 prior to surgery are not eligible.
c
The brain MRI (preferred) or brain CT should be performed pre-operatively per standard of care. However, 
if this scan is not performed prior to surgery, this scan should be conducted during first screening (ie, prior 
to signing ICF2 and entering second screening).
d
The CT scan performed post-surgery during first or second screening (indicated in Table 1 and Table 2) 
may be used as the baseline scan provided this scan was performed 28 days + 7 days prior to 
randomization (Table 1 and Table 2). If this post-operative scan falls outside of the 28 day + 7 days 
window prior to randomization, an additional contrast-enhanced CT scan of the chest and abdomen 
(including liver and adrenal glands) must be performed before the patient is randomized to confirm no 
evidence of disease recurrence. 
For details on each criterion, refer to the full list of inclusion criteria in Sections 5.1.1 (first screening) and 5.1.2
(second screening). All criteria must be assessed prior to randomization.
CT  Computed tomography; ECOG Eastern Cooperative Oncology Group; IASLC  International Association for 
the Study of Lung Cancer; ICF1 Informed consent form 1; ICF2 Informed consent form 2; MRD  Minimal 
residual disease; MRI  Magnetic resonance imaging; NSCLC Non-small cell lung cancer; PD-L1 Programmed 
cell death-ligand 1; PS  Performance status; WES  Whole exome sequencing; WHO  World Health Organization.


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Table 5
Timing of exclusion criteria assessment relative to informed consent
First screening
Second screening
Prior to or immediately following surgery
Pre-randomization
• EGFR/ALK mutant (results of testing either a pre-surgical biopsy [preferred] or 
resected tumor tissue [if biopsy not available/evaluable])a
• Mixed small cell and NSCLC pathology
• Candidates who undergo only wedge resections or deemed unresectable
• Requirement for re-resection 
• History of allogeneic organ or bone marrow transplantation
• Active or prior documented autoimmune or inflammatory disorders 
• History of another primary malignancy (with specified exceptions)
• History of active, primary immunodeficiency
• Known allergy or hypersensitivity to any of the IPs 
• Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample 
collection 
• Prior exposure to durvalumab
• Female patients who are pregnant or breastfeeding
• Judgment by the Investigator that the patient should not participate in the study
• Radiotherapy treatment for NSCLC in the neoadjuvant setting 
•
Evidence of disease recurrence within 28 days (+ 7 days) prior to randomizationb
•
Any concurrent chemotherapy, IP, biologic, or hormonal therapy 
for cancer treatment
•
Received any adjuvant therapy for NSCLC
•
Medical contraindication to platinum-based therapy
•
Evidence of disease recurrence within 28 days (+ 7 days) prior 
to randomizationb
•
Uncontrolled intercurrent illness
•
History of active, primary immunodeficiency
•
Active infection, including tuberculosis, HBV, HCV, or HIV 
•
Receipt of live attenuated vaccine within 30 days of IP dosing
•
Current or prior use of immunosuppressive medication within 14 
days of IP dosing
•
Current enrollment in another clinical study, unless 
observational or during follow-up of interventional study
•
Judgment by the Investigator that the patient should not 
participate in the study 
a
Where EGFR/ALK testing on a pre-surgical tissue biopsy is performed as standard of care, patients should be confirmed EGFR/ALK wild-type prior to 
enrolling in the study. 
b
A CT scan performed after a patient signs ICF2 (Table 2) can be used as the baseline scan provided this scan was performed 28 days + 7 days prior to 
randomization to confirm no evidence of disease recurrence. 
For details, see the full list of exclusion criteria in Section 5.2. Some criteria must be checked at both screenings and therefore appear multiple times. All 
eligibility criteria must be assessed prior to randomization. 
If a patient meets any exclusion criteria during first screening, he/she will not be eligible to continue into second screening. If a patient meets any exclusion 
criteria during second screening, he/she will not be eligible for randomization in the study. 
ALK  Anaplastic lymphoma kinase; CT  Computed tomography; EGFR  Epidermal growth factor receptor; HBV  Hepatitis B; HCV Hepatitis C; HIV  Human 
immunodeficiency virus; IP Investigational product; NSCLC Non-small cell lung cancer.


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2
INTRODUCTION
2.1
Study rationale
Up to 30% of patients with NSCLC present with surgically resectable disease (Molina et al 
2008). For patients with stage II-III disease, surgery and adjuvant SoC chemotherapy results 
in 5-year DFS rates of only ~40% (Wakelee et al 2017). Adjuvant chemotherapy following 
resection of NSCLC is standard practice to reduce risk of disease recurrence. However, it is 
challenging to determine who will benefit from adjuvant chemotherapy. There is evidence that 
identification of MRD through detection of ctDNA post-surgery can accurately predict disease 
recurrence (Abbosh et al 2017, Abbosh et al 2020
Abbosh C, Frankell A, Garnett A, Harrison T, Weichert M, Licon A, et al. Phylogenetic 
tracking and minimal residual disease detection using ctDNA in early-stage NSCLC: A lung 
TRACERx study. Philadelphia, PA: American Association for Cancer Research; 2020; 
CT023.
, Chaudhuri et al 2017). Recent data from the TRACERx lung study, 78 patients with stage I-
III NSCLC had 608 plasma samples analysed for ctDNA in pre- and post-operative settings 
(Abbosh et al 2020
Abbosh C, Frankell A, Garnett A, Harrison T, Weichert M, Licon A, et al. Phylogenetic 
tracking and minimal residual disease detection using ctDNA in early-stage NSCLC: A lung 
TRACERx study. Philadelphia, PA: American Association for Cancer Research; 2020; 
CT023.
). ctDNA was detectable at or before clinical relapse in 37 of the 45 patients who suffered 
clinical relapse of their disease. Conversely, ctDNA was only detected in 1 of 199 timepoints 
analysed for 23 patients who did not suffer relapse of their lung cancer during a median of 
1184 days of study follow-up.
Durvalumab can be effective in situations of residual cancer as evidenced by improved PFS 
and OS observed with durvalumab versus placebo in the PACIFIC study (Antonia et al 2018, 
Gray et al 2019). Intervention with combination chemotherapy and immunotherapy versus 
chemotherapy alone improves PFS and OS in advanced NSCLC (Gandhi et al 2018, Gadgeel 
et al 2019, Paz-Ares et al 2018). These data suggest that the combination of immunotherapy 
and chemotherapy in the adjuvant setting, where patients have undergone a complete resection 
but may have residual disease, may provide additional benefits to single agent immunotherapy 
and improve DFS. However, current IO therapy development in the adjuvant setting is based 
on sequential chemotherapy followed by immunotherapy (eg, BR.31, ANVIL, IMpower010, 
and KEYNOTE-091). On this basis, the Sponsor has opted to exploit the emerging clinical 
value of MRD as an adjuvant biomarker for risk of disease recurrence to inform targeted 
escalation of adjuvant therapy only in patients with evidence of residual disease post-surgery 


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and are thus at high risk for disease recurrence while preventing overtreatment of MRD-
patients, the majority of whom have been cured by surgery alone.
Two Phase III clinical studies have reported positive results for PD-(L)1 inhibitors (used as 
monotherapy) in the adjuvant setting. IMpower010 is a Phase III trial which randomized 
1280 patients with completely resected Stage IB (≥4cm) to Stage IIIA NSCLC (UICC/AJCC 
version 7) after cisplatin-based chemotherapy to atezolizumab, given every 3 weeks for up to 
16 cycles, or best supportive care (Felip et al 2021). The primary endpoints tested 
hierarchically were DFS in: (i) the PD-L1 ≥1%, stage II-IIIA population; (ii) the 
all-randomized stage II-IIIA population; (iii) the intent-to-treat population. At interim analysis 
the first and second of these were found to be statistically significant with HRs of 0.66 (95% 
CIs 0.50-0.88) and 0.79 (95% CIs 0.64-0.96), respectively. In October 2021, these data led to 
FDA approval of atezolizumab for adjuvant treatment following resection and platinum-based 
chemotherapy for adult patients with stage II-IIIA NSCLC whose tumors have PD-L1 
expression ≥1% (using a Ventana SP263 PD-L1 IHC assay). PEARLS/KEYNOTE-091 is a 
Phase III study which randomized 1177 patients with completely resected Stage IB (≥4cm) to 
Stage IIIA NSCLC (UICC/AJCC version 7) ± adjuvant chemotherapy to pembrolizumab or 
placebo (given every 3 weeks for up to 18 cycles) (Paz-Ares et al 2022). The dual primary 
endpoints were DFS in the overall population and DFS in the PD-L1≥50% stage IB-IIIA 
population. At a second interim analysis, the HR for the first of these endpoints was 
statistically significant (0.76; 95% CIs 0.63-0.91). 
One Phase III clinical study has reported positive results for nivolumab (anti-PD-1 
immunotherapy) in the neoadjuvant setting. In the Checkmate816 study, 358 patients with 
Stage IB (≥4cm) to Stage IIIA NSCLC (UICC/AJCC version 7) were randomized to 
neoadjuvant platinum-based chemotherapy with or without open label nivolumab (given every 
3 weeks for up to 3 cycles) (Forde et al 2022). The co-primary endpoints were pathological 
complete response (pCR) rate and event-free survival (EFS). The trial was positive for both 
primary endpoints. The hazard ratio for EFS was 0.63 (97.38% CIs 0.43-0.91) at interim 
analysis. This regimen was approved by the FDA in March 2022, for the treatment of patients 
with resectable (tumors ≥4cm or node-positive) NSCLC in the neoadjuvant setting, in 
combination with platinum-doublet chemotherapy.
It is expected that access to (neo)adjuvant PD-(L)1 inhibitors will increase over the coming 
years. Despite this anticipated shift in treatment landscape, it remains unclear if concomitant 
administration of chemotherapy with PD-(L)1 inhibitors, and if early intervention with this 
combination in post-surgical MRD+ patients, will drive further improvements in treatment 
outcomes. An exploratory analysis of ctDNA in IMpower010 demonstrated worse DFS 
outcomes for the patients whose baseline MRD status was MRD+, highlighting further a 
significant unmet need for MRD+ patients (Felip et al 2021).


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The original research hypothesis for this study was that concurrent durvalumab plus SoC 
chemotherapy would be more effective than placebo plus SoC chemotherapy in treating 
MRD+ patients who have undergone complete resection of stage II-III NSCLC when 
administered in the adjuvant setting. Given the above anticipated changes in treatment 
landscape for patients with resectable NSCLC, enrollment to this study was closed on 
25 May 2022. In order to optimize the ongoing scientific and clinical utility of this study, the 
statistical analyses have been amended to reflect the reduced sample size of the study (see 
Section 9). 
2.2
Background
A detailed description of the chemistry, pharmacology, efficacy, and safety of durvalumab is 
provided in the current durvalumab IB.
2.2.1
Immunotherapies
It is increasingly understood that cancers are recognized by the immune system, and under 
some circumstances, the immune system may control or even eliminate tumors (Dunn et al 
2004). 
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling 
T-cell activation. The programmed cell death 1 (PD-1) receptor (cluster of differentiation 
[CD]279) is expressed on the surface of activated T cells (Keir et al 2008). It has 2 known 
ligands: PD-L1 (B7-H1; CD274) and programmed cell death-ligand 2 (PD-L2) (B7-DC; 
CD273) 
. PD-1 and PD-L1/PD-L2 belong to a family of immune 
checkpoint proteins that act as co-inhibitory factors, which can halt or limit the development 
of T-cell response. When PD-L1 binds to PD-1, an inhibitory signal is transmitted into the 
T cell, which reduces cytokine production and suppresses T-cell proliferation. Tumor cells 
exploit this immune checkpoint pathway as a mechanism to evade detection and inhibit 
immune response.
PD-L1 is constitutively expressed by B cells, dendritic cells, and macrophages (Qin et al 
2016). Importantly, PD-L1 is commonly over-expressed on TCs or on non-transformed cells 
in the tumor microenvironment (Pardoll 2012). PD-L1 expressed on the TCs binds to PD-1 
receptors on the activated T cells, leading to the inhibition of cytotoxic T cells. These 
deactivated T cells remain inhibited in the tumor microenvironment. The PD-1/PD-L1 
pathway represents an adaptive immune resistance mechanism that is exerted by TCs in 
response to endogenous antitumor activity.
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way 
of evading immune detection and elimination. The binding of an anti-PD-L1 agent to the 
PD-L1 receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed 
on immune cells (IC). This activity overcomes PD-L1-mediated inhibition of antitumor 
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immunity. While functional blockade of PD-L1 results in T-cell reactivation, this mechanism 
of action is different from direct agonism of a stimulatory receptor such as CD28.
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti-PD-L1 
antibody could be used therapeutically to enhance antitumor immune responses in patients 
with cancer. Results of nonclinical and clinical studies of monoclonal antibodies (mAbs) 
targeting the PD-L1/PD-1 pathway have shown evidence of clinical activity and a manageable 
safety profile, supporting the hypothesis that an anti-PD-L1 antibody could be used to 
therapeutically enhance antitumor immune response in cancer patients (Brahmer et al 2012, 
Hirano et al 2005, Iwai et al 2002, Okudaira et al 2009, Topalian et al 2012, Zhang et al 2008) 
with responses that tend to be more pronounced in patients with tumors that express PD-L1 
(Powles et al 2014, Rizvi et al 2015, Segal et al 2015). In addition, high mutational burden 
(eg, in bladder carcinoma; Alexandrov et al 2013) may contribute to the responses seen with 
immune therapy.
In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is constitutively 
expressed by regulatory T cells and upregulated on activated T cells. CTLA-4 delivers a 
negative regulatory signal to T cells upon binding of CD80 (B7.1) or CD86 (B7.2) ligands on 
antigen-presenting cells (Fife and Bluestone 2008). Blockade of CTLA-4 binding to CD80/86 
by anti-CTLA-4 antibodies results in markedly enhanced T-cell activation and antitumor 
activity in animal models, including killing of established murine solid tumors and induction 
of protective antitumor immunity. Therefore, it is expected that treatment with an 
anti-CTLA-4 antibody will lead to increased activation of the human immune system, 
increasing antitumor activity in patients with solid tumors.
Nonclinical data have now been added to a wealth of clinical data showing that blockade of 
negative regulatory signals to T cells such as CTLA-4 and PD-L1 has promising clinical 
activity. Ipilimumab was first granted United States Food and Drug Administration approval 
for the treatment of metastatic melanoma and is currently under investigation for several other 
malignancies. Nivolumab and pembrolizumab, 2 anti-PD-1 agents, and atezolizumab, an 
anti-PD-L1 agent, have been granted approvals by agencies for the treatment of a number of 
malignancies, including metastatic melanoma, squamous and non-squamous cell NSCLC, 
squamous cell carcinoma of the head and neck, and urothelial carcinoma. In addition, there are 
data from agents in the anti-PD-1/PD-L1 class showing clinical activity in a wide range of 
tumor types.
2.2.2
Durvalumab
Durvalumab is a human mAb of the immunoglobulin G1 kappa subclass that blocks the 
interaction of PD-L1 (but not PD-L2) with PD-1 on T cells and CD80 (B7.1) on IC. It is being 
developed by AstraZeneca for use in the treatment of cancer. The proposed mechanism of 
action for durvalumab is interference in the interaction of PD-L1 with PD-1 and CD80 (B7.1). 


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Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune 
responses, including those that may result in tumor elimination. In vitro studies demonstrate 
that durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T cells, 
resulting in the restored proliferation of IFN-γ (Stewart et al 2015). In vivo studies have 
shown that durvalumab inhibits tumor growth in xenograft models via a T-cell-dependent 
mechanism (Stewart et al 2015). Based on these data, durvalumab is expected to stimulate the 
patient’s antitumor immune response by binding to PD-L1 and shifting the balance toward an 
antitumor response. Durvalumab has been engineered to reduce antibody-dependent cellular 
cytotoxicity and complement-dependent cytotoxicity. 
To date, durvalumab has been given to more than 
 patients as part of completed and 
ongoing studies either as monotherapy or in combination with other anticancer agents. Refer 
to the current durvalumab IB for a complete summary of nonclinical and clinical information, 
including safety, efficacy, and PK. Details on the safety profile of durvalumab monotherapy 
are summarized in Section 4.3.1 and Section 8.3.12.
2.2.3
Non-small cell lung cancer and unmet need
Lung cancer is the most common cancer and the most common cause of death from cancer in 
the world, with an estimated 2.1 million new cases (11.6% of all new cancers) and 1.8 million 
deaths (18.4% of cancer deaths; GLOBOCAN 2018) in 2018. NSCLC represents 80% to 85% 
of all lung cancers (Pinato et al 2019
Pinato DJ, Howlett S, Ottaviani D, Urus H, Patel A, Mineo T, et al. Association of Prior 
Antibiotic Treatment With Survival and Response to Immune Checkpoint Inhibitor Therapy in 
Patients With Cancer. JAMA Oncol. 2019 Dec 1;5(12):1774-1778. Erratum in: JAMA Oncol. 
2020 Feb 1;6(2):302. 
Pisters and LeChevalier 2005). Up to 30% of patients with NSCLC present with surgically 
resectable disease (Molina et al 2008).
Despite presentation with resectable disease, surgery and adjuvant SoC chemotherapy results 
in 5-year DFS rates of only ~40% in stage II-III NSCLC (Wakelee et al 2017). Following 
disease recurrence, long-term survivorship is rare, ranging from 2% to 13% at 5 years (Wong 
et al 2016, Sekihara et al 2017, McMurry et al 2018). Adjuvant chemotherapy following 
resection of NSCLC is standard practice to reduce risk of disease recurrence. In stage III 
disease, a 5-year OS benefit of up to 15% has been observed with adjuvant cisplatin and 
vinorelbine (Douillard et al 2010). Additional adjuvant chemotherapy regimens have shown 
similar benefits, as reflected in national guidelines (NCCN 2019).
2.2.3.1
Value of mono- and combination immunotherapy in NSCLC
An efficacy plateau has been reached with platinum-based doublet chemotherapy in NSCLC, 
with duration of response and tolerability as additional areas of concern. Therefore, other 
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mechanisms and modalities have been explored to improve upon chemotherapy-based SoC. 
The opportunity to capitalize the anticancer activities of the immune system greatly expanded 
with the identification of checkpoint inhibitor agents. First-line treatment of metastatic 
NSCLC with anti-PD-1 monotherapy demonstrated an OS benefit compared with 
chemotherapy alone in patients whose tumors expressed PD-L1 (Mok et al 2019, Reck et al 
2016). Consolidation therapy with durvalumab following radical treatment of locally 
advanced NSCLC resulted in OS benefit versus placebo (Antonia et al 2018). In addition, 
combination chemotherapy and pembrolizumab conferred OS benefit compared to 
chemotherapy alone in both non-squamous and squamous NSCLC, independent of tumoral 
PD-L1 expression (Gandhi et al 2018, Paz-Ares et al 2018). 
In summary, these agents have demonstrated clinically meaningful responses in metastatic 
NSCLC, with some patients exhibiting durable responses even after discontinuing therapy 
(Martinez et al 2019). As indicated in Section 2.1, (neo)adjuvant treatment options with 
anti-PD-(L)1 therapy are now approved. Ongoing studies are assessing the efficacy of 
adjuvant immunotherapy in NSCLC (eg, BR.31, ANVIL, Impower010, and KEYNOTE-091).
2.2.3.2
Detection of minimal residual disease in NSCLC
MRD, as indicated by detection of ctDNA, may reveal the existence of clinically indiscernible 
residual tumor following curative intent therapy (surgery ± chemotherapy/radiotherapy). 
Detection of MRD at a time when there is no radiologic evidence of disease provides an 
opportunity for earlier therapeutic intervention (Abbosh et al 2018). MRD+ patients 
experience inferior recurrence-free survival compared to MRD- patients. Therefore, MRD+ 
patients may benefit from earlier intervention and escalation of treatment, including 
immunotherapy alone or in combination with chemotherapy; furthermore, MRD- patients (the 
majority of whom are cured by surgery alone) could be spared from more intensive therapy 
and the resulting unnecessary toxicity.
MRD detection in patients with lung cancer has been investigated in 3 independent studies. 
Recent data from the TRACERx lung cancer study, 78 patients with stage I-III NSCLC had 
608 plasma samples analysed for ctDNA in pre- and post-operative settings (Abbosh et al 
2020
Abbosh C, Frankell A, Garnett A, Harrison T, Weichert M, Licon A, et al. Phylogenetic 
tracking and minimal residual disease detection using ctDNA in early-stage NSCLC: A lung 
TRACERx study. Philadelphia, PA: American Association for Cancer Research; 2020; 
CT023.
). ctDNA was detectable at or before clinical relapse in 37 of the 45 patients who suffered 
clinical relapse of their disease. Conversely, ctDNA was only detected in 1 of 199 timepoints 
analysed for 23 patients who did not suffer relapse of their lung cancer during a median of 
1184 days of study follow-up. In a study by Chaudhuri et al, MRD was detectable in 20 of 


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37 lung cancer patients (the majority of whom had undergone curative intent therapy with 
chemotherapy and/or radiotherapy). All 20 MRD+ patients ultimately recurred, whereas the 
17 MRD- patients did not experience a progression event (Chaudhuri et al 2017). Detection of 
MRD preceded radiographic progression in 72% of patients by a median of 5.2 months 
(Chaudhuri et al 2017). An additional study reported that NSCLC patients who were MRD-
had excellent outcomes, regardless of whether they received immunotherapy as consolidation 
treatment (Moding et al 2020).  NSCLC patients who were found to be MRD+ after 
completing chemoradiation therapy had better outcomes if they went on to receive 
consolidation immunotherapy treatment compared to those MRD+ patients who did not. 
These data suggest that immunotherapy improves outcomes for NSCLC patients who are
MRD+ after completion of SoC (Moding et al 2020).
Taken together, these studies demonstrate the potential utility of MRD detection for 
identifying patients who are at high risk of experiencing disease recurrence. 
Detection of MRD is technically challenging due to the ultra-low frequency of ctDNA 
molecules in patient plasma (Abbosh et al 2018). In this study, the Sponsor will leverage an 
advanced, sensitive, personalized assay predicated on sequencing the excised primary tumor 
alongside a whole blood sample to derive a patient-specific MRD signature. This approach 
will lead to optimal capture of MRD+ patients prior to adjuvant SoC therapy.
2.2.3.3
Rationale for early interception studies predicated on MRD
Long-term survival can be improved through administration of chemotherapy in the 
immediate postoperative setting (Douillard et al 2010), yet chemotherapy in the first-line 
metastatic setting results in no long-term survival benefit and PFS benefits of only a small 
number of months (Cochrane Review 2000). This contrast demonstrates a vulnerability of 
post-surgery residual cancer to systemic therapy and provides a rationale to conduct studies to 
accelerate adoption of novel therapies earlier in the disease course. 
Use of MRD as a biomarker has the potential to accelerate adoption of novel therapeutic 
strategies in this setting. For example, the lack of clarity over residual disease status results in 
large recruitment numbers for adjuvant studies to achieve adequate power to investigate a 
novel therapeutic strategy. Consequently, adjuvant trials can take in excess of a decade to read 
out (Wakelee et al 2017). Additionally, escalation of adjuvant therapy in MRD- patients cured 
after surgery would result in unnecessary increased risk of treatment-associated toxicity.
Establishing ctDNA clearance as a novel surrogate of OS or DFS could accelerate the 
adoption of novel therapeutic strategies in the adjuvant NSCLC setting to clear therapeutically 
vulnerable residual disease following SoC curative intent therapy. Two studies conducted in 
patients with either metastatic NSCLC or metastatic urothelial cancer showed that patients 
treated with durvalumab had a reduction in ctDNA at 6 weeks that was associated with tumor 
shrinkage and improved PFS and OS (Raja et al 2018). Similar correlation between ctDNA 


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and outcomes have been reported in studies of agents that target EGFR (Friends of Cancer 
Research White Paper 2018). Recently, exploratory analyses of the IMpower010 study 
demonstrated poorer DFS outcomes for patients with detectable ctDNA post surgery, and a 
numerically improved HR for atezolizumab versus best supportive care for patients who were 
ctDNA+ versus ctDNA- (0.61 [95% CIs 0.39-0.64] versus 0.72 [95% CIs 0.52-1.00], 
respectively (Zhou et al 2021).
2.2.3.4
Monotherapy in advanced NSCLC
Randomized controlled studies of mAbs targeting PD-1 first demonstrated benefit in 
second-line or later metastatic NSCLC setting in 2015, with nivolumab (anti-PD-1 mAb) 
improving survival versus docetaxel in patients with squamous or non-squamous NSCLC 
(Brahmer et al 2015, Borghaei et al 2015, Horn et al 2017). These trials have been followed 
by multiple studies in the first-line setting, demonstrating that pembrolizumab can offer 
survival benefit in patients with PD-L1 tumor proportion scores (TPS) of at least 1% (Reck et 
al 2016, Reck et al 2019). CheckMate 026 did not demonstrate a benefit of nivolumab versus 
platinum-based chemotherapy in patients with advanced untreated NSCLC and at least 1% 
PD-L1 expression; analyses in PD-L1 >5% and >50% populations also failed to show a 
benefit of intervention with nivolumab over platinum-based chemotherapy (Carbone et al 
2017).  
In the monotherapy arms MYSTIC study (Study D419AC00001) of first-line durvalumab in 
patients with advanced metastatic NSCLC, patients with PD-L1 high (≥25% TC) NSCLC, the 
median PFS was 4.7 months for durvalumab monotherapy and 5.4 months for chemotherapy; 
HR 0.87 (99.5% CI: 0.593, 1.285; p=0.324). The median OS was 16.3 months for the 
durvalumab arm and 12.9 months for the chemotherapy arm; the 24-month OS rate was 38.3% 
vs 22.7% and the 12-month PFS rate was 32.3% vs 14.3% for the durvalumab and 
chemotherapy arms, respectively.
2.2.3.5
Combination IO therapy and chemotherapy in NSCLC
Despite improvements in outcome with single agent immune checkpoint inhibition, only a 
minority of NSCLC patients respond to treatment. For example, in KEYNOTE-024 
(pembrolizumab versus chemotherapy for untreated metastatic NSCLC) the objective 
response rate (ORR) to treatment was 44.8%, despite an inclusion criterion mandating PD-L1 
TPS levels of at least 50% (Reck et al 2016). Combining chemotherapy with immunotherapy 
has been demonstrated to improve on these response rates and facilitates more aggressive 
treatment of patients with metastatic disease prior to decline in performance status that 
inexorably occurs with progression of disease (PD).
In the combination therapy arms of MYSTIC in which durvalumab was given as first-line 
therapy in combination with IO agent tremelimumab in patients with advanced metastatic 
NSCLC, patients with PD-L1 high (≥25% TC) NSCLC, median PFS was 3.9 months for 


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durvalumab + tremelimumab and 5.4 months for chemotherapy; HR 1.05 (99.5% CI: 0.722, 
1.534; p=0.705). The median OS was 11.9 months for the durvalumab + tremelimumab arm 
and 12.9 months for the chemotherapy arm. The 24-month OS rate was 35.4% vs 22.7% and 
the 12-month PFS rate was 25.8% vs 14.3% for the durvalumab + tremelimumab and 
chemotherapy arms, respectively.  
In metastatic non-squamous NSCLC, first-line combination checkpoint inhibition and 
chemotherapy has demonstrated efficacy versus chemotherapy alone. KEYNOTE-189 
demonstrated that a combination of pembrolizumab plus a platinum agent and pemetrexed 
improved OS versus platinum agent and pemetrexed alone, regardless of PD-L1 TPS and 
despite significant crossover of the chemotherapy arm to checkpoint inhibitors at progression 
(Gandhi et al 2018, Gadgeel et al 2019). ORR in the PD-L1 >50% TPS group was 61.4% 
(Gandhi et al 2018). IMpower150 evaluated both anti-angiogenic and checkpoint inhibitor 
treatment in combination with chemotherapy in patients with treatment-naïve non-squamous 
NSCLC (Socinski et al 2018). The study demonstrated improved OS in patients treated with 
atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) versus bevacizumab, 
carboplatin, and paclitaxel (BCP) alone (Socinski et al 2018). IMpower130 demonstrated 
improved OS in the intent-to-treat (ITT) EGFR/ALK wild-type population with atezolizumab, 
carboplatin, and nab-paclitaxel versus chemotherapy alone (West et al 2019). IMpower132 
reported an improvement in PFS when atezolizumab was added to pemetrexed plus cisplatin 
or carboplatin for the treatment of chemotherapy-naïve EGFR/ALK wild-type patients with 
stage IV non-squamous NSCLC (Papadimitrakopoulou et al 2018, Nishio et al 2020) 
Combination of chemotherapy and checkpoint inhibition has also shown benefit as a first-line 
treatment for treatment-naïve metastatic squamous NSCLC. KEYNOTE-407 was a 
double-blind, Phase III study that evaluated pembrolizumab plus carboplatin and paclitaxel (or 
nab-paclitaxel) versus carboplatin and paclitaxel (or nab-paclitaxel) alone (Paz-Ares et al 
2018). Combination checkpoint inhibition and chemotherapy resulted in survival benefit 
versus chemotherapy alone, regardless of PD-L1 expression, and occurred despite the 
crossover of 31.7% of the chemotherapy only arm to immunotherapy at progression in the ITT 
population (Paz-Ares et al 2018). ORR in the PD-L1 >50% TPS group was 60.3% (Paz-Ares 
et al 2018). 
IMpower131 evaluated atezolizumab in combination with nab-paclitaxel and carboplatin 
versus nab-paclitaxel and carboplatin alone in treatment-naïve stage IV squamous NSCLC 
(Johnson et al 2021
Johnson M, Cho BC, Luft A, Alatorre-Alexander A, Geater SL, Laktionov K, et al. 
Durvalumab ± tremelimumab + chemotherapy as first-line treatment  for mNSCLC: results 
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Jotte et al 2018). OS benefit was observed in the PD-L1-enriched population (≥50% of TCs or 
≥10% of tumor-infiltrating IC expressing PD-L1). However, this subgroup was not formally 
tested, and in the overall study population, there was no OS benefit with the addition of 
atezolizumab to carboplatin and nab-paclitaxel (Jotte et al 2019).
In summary, published studies suggest benefit of combination chemotherapy and checkpoint 
inhibitor therapy versus chemotherapy alone in NSCLC, and treatment benefit was enriched in 
patients with high PD-L1 TPS scores. These data from the advanced or locally advanced 
NSCLC setting suggest that early interception of MRD with IO therapy following resection of 
early-stage NSCLC could improve survival outcomes versus SoC adjuvant chemotherapy 
alone.
2.2.4
Durvalumab in combination with chemotherapy
The use of combination chemotherapy is a mainstay of oncology therapy. The goal of 
combination chemotherapy is to utilize agents that affect cancer cells by different 
mechanisms, thus reducing the risk of developing resistance. Current studies are now adding 
immunotherapies to chemotherapeutics to broaden antitumor responses. AstraZeneca is the 
Sponsor of several ongoing studies in NSCLC where durvalumab ± tremelimumab is 
administered with standard platinum-based chemotherapy. Regularly scheduled safety IDMC 
reviews have been conducted, and no safety concerns were raised in a Phase Ib study of 
durvalumab ± tremelimumab in patients with advanced solid tumors (Study D419SC00001; 
n=32).
In addition, there is a Phase Ib durvalumab ± tremelimumab in combination with standard 
platinum-based chemotherapy study (NCT02537418) run by the Canadian Cancer Trials 
Group (CCTG; n=118; Daaboul et al 2017). The combinations tested are tolerable and 
toxicities are manageable. Preliminary results from the CCTG study were presented for the 
NSCLC cohorts at the IASLC 2016 meeting; the overall ORR in the NSCLC cohort (n=24) 
was 52.9% (Juergens et al 2017).
In the ongoing Phase III Study D9106C00001 (AEGEAN; n=300 [planned]), durvalumab in 
combination with chemotherapy is administered in the neoadjuvant setting and as 
monotherapy in the adjuvant setting for patients with resectable stage II-III NSCLC.
Another Phase III, randomized, double-blind, placebo-controlled study, in which durvalumab 
is being given concurrently with platinum-based chemoradiotherapy in patients with locally 
advanced, unresectable NSCLC has recently completed recruitment (D933KC00001; 
PACIFIC-2). 
Durvalumab has also demonstrated efficacy when administered in the first-line setting with 
platinum-based chemotherapy in metastatic NSCLC. Study D419MC00004 (POSEIDON; 
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combination with SoC platinum-based chemotherapy vs chemotherapy alone for the first-line 
treatment of patients with metastatic NSCLC (Johnson et al 2021). The study met the primary 
endpoint of PFS by showing a statistically significant and clinically meaningful improvement 
in patients treated with the combination of durvalumab and SoC platinum-based 
chemotherapy vs chemotherapy alone; analysis of the additional primary endpoint of OS in 
the durvalumab + chemotherapy treatment arm is pending. The safety and tolerability of the 
durvalumab ± tremelimumab and chemotherapy combinations were consistent with the known 
safety profile for these agents.
2.3
Benefit/risk assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of durvalumab monotherapy can be found in the durvalumab IB.
See Section 9.7 and Appendix A for information regarding the IDMC.
2.3.1
Potential benefits of durvalumab
The majority of the safety and efficacy data currently available for durvalumab are based on 
the first-in-human, single agent study 
 in 
patients with advanced solid tumors, the study of durvalumab monotherapy in NSCLC 
 
, and the study of durvalumab monotherapy in NSCLC 
following completion of platinum-based chemotherapy concurrent with radiation therapy 
. Data from these studies have demonstrated clinical 
activity of durvalumab therapy in patients with NSCLC. Details pertaining to these studies are 
provided in the durvalumab IB. Additionally, recent data from 
 
show a benefit of durvalumab plus SoC chemotherapy in patients with metastatic NSCLC 
(Johnson et al 2021). 
2.3.2
Overall risks
Monoclonal antibodies directed against immune checkpoint proteins, such as PD-L1, as well 
as those directed against PD-1 or CTLA-4, aim to boost endogenous immune responses 
directed against TCs. By stimulating the immune system, however, there is the potential for 
adverse effects on normal tissues.
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune-mediated mechanism and that may 
require more frequent monitoring and/or unique interventions such as immunosuppressants 
and/or endocrine therapy. These immune-mediated effects can occur in nearly any organ 
system and are most commonly seen as gastrointestinal AEs such as colitis and diarrhea, 
pneumonitis/interstitial lung disease (ILD), hepatic AEs such as liver enzyme elevations, skin 
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events such as rash and dermatitis, and endocrinopathies, including hypo- and 
hyper-thyroidism.
2.3.2.1
Durvalumab
Risks with durvalumab include, but are not limited to, diarrhea/colitis, pneumonitis/ILD, 
endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypo-thyroidism, Type I diabetes mellitus, and diabetes insipidus), 
hepatitis/increases in transaminases, nephritis/increases in creatinine, rash/dermatitis, 
myocarditis, myositis/polymyositis, infusion-related reactions, hypersensitivity reactions, 
pancreatitis, serious infections, and other rare or less frequent inflammatory events, including 
neuromuscular toxicities (eg, Guillain-Barré syndrome, myasthenia gravis).
For information on all identified and potential risks with durvalumab, please always refer to 
the current version of the durvalumab IB.
In monotherapy clinical studies, AEs at an incidence of ≥20% include events such as fatigue, 
cough, decreased appetite, dyspnea, and nausea. Approximately 10% of patients discontinued 
the drug due to an AE. Please see the current version of the IB for a detailed summary of the 
monotherapy data, including AEs, serious AEs (SAEs), and Common Terminology Criteria 
for Adverse Event (CTCAE) Grade 3 to 5 events reported across the durvalumab program.
The majority of treatment-related AEs were manageable, with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (see Section 8.4.5).
A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab IB.
2.3.2.2
Durvalumab in combination with chemotherapy
As noted in Section 2.2.4, the safety and tolerability of durvalumab in combination with 
chemotherapy is being evaluated in several ongoing studies of NSCLC.
As of 12 July 2018, a total of 22 patients with advanced solid tumors have been treated with 
durvalumab and tremelimumab in combination with chemotherapy in 
. 
All patients had at least 1 AE (regardless of causality). AEs (all grades) reported in >20% of 
patients were nausea (68.2%); neutrophil count decreased (63.6%); decreased appetite 
(50.0%); cough, diarrhea, and rash (36.4% each); anemia and pyrexia (31.8% each); 
constipation, dizziness, insomnia, myalgia, platelet count decreased, and pruritus (27.3% 
each); alanine aminotransferase (ALT) increased, alopecia, dyspepsia, peripheral sensory 
neuropathy, vomiting, and white blood cell count decreased (22.7% each). All patients had 
AEs considered by the Investigator to be related to study treatment. Treatment-related AEs 
reported in >20% of patients were neutrophil count decreased (63.6%); nausea (59.1%); 
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decreased appetite, diarrhea, and rash (31.8% each); platelet count decreased and pruritus 
(27.3% each); and alopecia and peripheral sensory neuropathy (22.7% each). The majority of 
patients (19 [86.4%]) reported ≥Grade 3 AEs; 16 (72.7%) patients reported ≥Grade 3 
treatment-related AEs. SAEs were reported in a total of 10 patients (45.5%). With the 
exception of pneumonia and pyrexia (3 patients each) and diarrhea and neutrophil count 
decreased (2 patients each), all other SAEs were reported in 1 patient each. One patient had a 
fatal AE of lung infection, which was considered treatment-related. A total of 13.6% of 
patients had AEs that led to permanent discontinuation of treatment.
In the CCTG study (NCT02537418), 118 patients were exposed to over 700 cycles of 
treatment, which began with chemotherapy combined with durvalumab ± tremelimumab until 
4 to 6 cycles of chemotherapy ended; afterward, patients received further durvalumab ± 
tremelimumab treatment (Daaboul et al 2017). Recent data from the CCTG study show that 
chemotherapy combined with durvalumab ± tremelimumab did not increase immune-mediated 
AEs (imAEs), giving support to the combination being tolerable and manageable. Overall, 
50% of patients had imAEs of any grade and 10% had ≥Grade 3 imAEs. Differences between 
the chemotherapy combination period and the durvalumab ± tremelimumab alone period were 
not significant, with the exception of biochemistry imAEs (chemotherapy combination 74% 
versus durvalumab ± tremelimumab 48%; p=0.003) and ALT/aspartate aminotransferase 
(AST) changes (41% versus 16% and 38% versus 9%, respectively; p=0.005). The imAEs that 
led to discontinuation of treatment in 15 patients were pneumonitis, hepatitis, nephritis, 
adrenal, myocarditis, gastrointestinal, thrombocytopenia, hyperthyroidism, and encephalitis. 
Pneumonitis and gastrointestinal imAEs were the most common, followed by nephritis. The 
few significant findings are likely due to the nature of combining numerous agents.
Additionally, a Phase III study of durvalumab with or without tremelimumab in combination 
with platinum-based chemotherapy for first-line treatment of patients with metastatic NSCLC 
is currently ongoing 
. Regular scheduled safety IDMC 
reviews have been conducted, and no safety concerns were raised. The study is continuing as 
planned (Johnson et al 2021).
External clinical data also support these findings. In KEYNOTE-189, in patients with NSCLC 
treated with pembrolizumab and chemotherapy or chemotherapy alone, the incidence of Grade 
3 or worse AEs was 67.2% and 65%, respectively. In the pembrolizumab plus chemotherapy 
arm, the most common Grade 3 or worse AEs (AE frequency ≥5%) were anemia (16.3%), 
neutropenia (15.8%), thrombocytopenia (7.9%), asthenia (6.2%), fatigue (5.7%), and diarrhea 
(5.2%). In the chemotherapy alone arm, the most common Grade 3 or worse AEs (AE 
frequency ≥5%) were anemia (15.3%); neutropenia (11.9%); thrombocytopenia (6.9%); 
dyspnea (5.4%); and decreased neutrophil count, pancytopenia, and thrombocytopenia (3% 
each). AEs that led to death occurred in 6.7% of patients in the pembrolizumab plus 
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chemotherapy arm and 5.9% of patients in the placebo plus chemotherapy arm (Gandhi et al 
2018).
For the IMpower150 study, AEs related to any treatment (as determined by the Investigator) 
occurred in 94.4% of patients in the ABCP arm and in 95.4% of patients in the BCP arm. The 
most common Grade 3 or 4 treatment-related AEs were neutropenia, decreased neutrophil 
count, febrile neutropenia, and hypertension (Socinski et al 2018).
For the KEYNOTE-407 and IMpower131 stage IV squamous NSCLC studies, the observed 
AEs were consistent with the known safety profiles of pembrolizumab and chemotherapy and 
atezolizumab and chemotherapy, respectively, with no new safety signals identified (Johnson 
et al 2021
Johnson M, Cho BC, Luft A, Alatorre-Alexander A, Geater SL, Laktionov K, et al. 
Durvalumab ± tremelimumab + chemotherapy as first-line treatment  for mNSCLC: results 
from the phase 3 POSEIDON study [abstract PL02.01]. J Thorac Oncol. 2021;16(10 
Suppl):S844.
Jotte et al 2018, Paz-Ares et al 2018).
Overall, the above data demonstrate that durvalumab in combination with chemotherapy is 
reasonably well tolerated and has an acceptable safety profile.
2.3.3
Overall benefit/risk
Recent progress in immunotherapy for NSCLC has been a substantive advance, although 
further improvement is needed, including predictive biomarkers and application to the 
curative setting. Additional novel treatment approaches are needed to improve the long-term 
prognosis for patients with early-stage NSCLC. Identification of patients who will benefit 
from immunotherapy plus chemotherapy in the adjuvant setting could lead to improved 
outcomes. Therefore, in this Phase III study, the administration of durvalumab plus 
chemotherapy following complete resection in MRD+ patients will be investigated in patients 
with stage II-III NSCLC.
The study design aims to minimize potential risks. For example, a safety evaluation by an 
IDMC will take place to assess whether durvalumab may adversely impact postoperative 
outcomes; the IDMC will report back to the Sponsor.
While neoadjuvant and adjuvant anti-PD-(L)1 treatment options have been approved by the 
FDA, leading to the decision to close this study to further enrollment, their availability 
remains limited globally. Therefore, based upon the available nonclinical and clinical safety 
data and the mitigations designed for this study, the investigation of the potential therapeutic 
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chemotherapy following surgery is acceptable in patients with completely resected NSCLC, 
and the overall benefit/risk assessment supports the proposed study design and the objectives 
and endpoints have been updated. Despite the changes to the study, it is expected that this 
study will retain scientific and clinical utility that will be important to inform future clinical 
studies.
3
OBJECTIVES AND ENDPOINTS
As presented in Table 6, under CSP V4.0, as a result of the decision to close study enrollment 
early, meaning the intended patient numbers will not be reached, the primary objective of this 
study will now compare the efficacy of durvalumab plus SoC chemotherapy to placebo plus 
SoC chemotherapy in terms of DFS in the FAS rather than in the MRD+ analysis set.
Table 6
Study objectives and associated endpoints/variables
Primary objective:
Endpoint/variable:
To assess the efficacy of durvalumab + SoC 
chemotherapy compared to placebo + SoC 
chemotherapy as measured by DFS in all patients 
DFS in FAS (using Investigator assessments 
according to RECIST 1.1)
Secondary objective:
Endpoint/variable:
To assess the efficacy of durvalumab + SoC 
chemotherapy compared to placebo + SoC 
chemotherapy as measured by DFS in MRD+ patients
DFS in MRD+ analysis set (using Investigator 
assessments according to RECIST 1.1)
To assess the efficacy of durvalumab + SoC 
chemotherapy compared to placebo + SoC 
chemotherapy as measured by OS in MRD+ patients 
and in all patients 
OS in MRD+ analysis set and in FAS
Safety objective:
Endpoint/variable:
To assess the safety and tolerability profile of 
durvalumab + SoC chemotherapy compared to 
placebo + SoC chemotherapy in MRD+ patients and 
in all patients  
AEs, physical examinations, vital signs, and 
laboratory findings
Exploratory objectives:
Endpoint/variable:
To assess the efficacy of durvalumab + SoC 
chemotherapy compared to placebo + SoC 
chemotherapy on post-recurrence outcomes 
PFS (using local standard practice)
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Table 6
Study objectives and associated endpoints/variables
To assess the efficacy of durvalumab + SoC 
chemotherapy to clear ctDNA compared to placebo + 
chemotherapy in MRD+ patients 
ctDNA endpoints, as defined by:
•
Best overall clearance rate (number converted at 
any time)
•
Best confirmed clearance rate (as above but 
confirmed at subsequent visit)
•
Time to ctDNA clearance
•
Duration of ctDNA clearance
•
Time to ctDNA recurrence
•
Time to confirmed ctDNA recurrence
•
Changes in variant allele frequencies (VAF) 
following treatment
To assess relationship between treatment effect on 
DFS and treatment effect on ctDNA endpoints
ctDNA endpoints (as defined above) and DFS
To assess prognostic significance of MRD detection 
as determined by ctDNA in NSCLC
Time from randomization to DFS (MRD+ vs MRD-)
To assess the association of TMB with efficacy of 
durvalumab + SoC chemotherapy compared with 
placebo + SoC chemotherapy
DFS, OS in patients with TMB 
To investigate the relationship between a patient’s 
baseline PD-L1 TC and IC expression and efficacy 
outcomes with durvalumab + SoC chemotherapy 
compared with placebo + SoC chemotherapy
IHC analysis of PD-L1 TC and IC expression and 
spatial distribution within the tumor 
microenvironment relative to efficacy outcomes (ie, 
DFS, OS)
To investigate biomarkers in tumor and periphery at 
baseline, on treatment, post-treatment, and/or at 
recurrence wherever feasible to identify markers 
related to disease, mechanism of action of the drug 
and/or their associations with response and clinical 
endpoints  
Exploratory markers, which may include, but are not 
limited to: tumor, immune, and/or stromal cell gene 
and protein expression profiles within the peripheral 
and tumoral compartments.
TMB and somatic mutations in tissue and/or 
blood/plasma.
Changes in RNA, DNA, or protein will be compared 
at baseline, on treatment, post-treatment and/or at 
recurrence.
Attributes of tumor microenvironment that could be 
assessed using various methods which may include, 
but not limited to, high content imaging, multiplex 
RNA/DNA/protein analysis with spatial resolution 
such as Mass Spectroscopy or other technologies.
To evaluate patient-reported treatment-related 
symptoms using PRO-CTCAE
To assess the patient´s global impression of 
symptoms severity, and global treatment tolerability 
Prespecified items on the PRO-CTCAE
Patient global assessments
To assess patient-reported symptoms, functioning, 
and HRQoL in MRD+ patients treated with 
durvalumab + SoC chemotherapy compared to 
placebo + SoC chemotherapy
Change from baseline and time to deterioration in 
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Table 6
Study objectives and associated endpoints/variables
To explore the impact of treatment and disease on 
health state utility
, descriptor, and VAS
AE Adverse events; ctDNA Circulating tumor DNA; DFS  Disease-free survival; EORTC  European 
Organisation for Research and Treatment of Cancer; FAS Full analysis set; 
 
; HRQoL Health-related Quality of Life; IC  Immune cell; 
IHC Immunohistochemistry; MRD  Minimal residual disease; MRD+  Minimal residual disease-positive; 
MRD- Minimal residual disease-negative; NSCLC Non-small cell lung cancer; OS Overall survival; PD-
L1 Programmed cell death-ligand 1; PFS Progression-free survival; PRO-CTCAE Patient-Reported Outcomes-
Common Terminology Criteria for Adverse Events; QLQ-C30 30-item Core Quality of Life Questionnaire; 
QLQ-LC13 13-item Lung Cancer Quality of Life Questionnaire; RECIST  Response Evaluation Criteria in Solid 
Tumors; RNA Ribonucleic acid; SoC  Standard of care; TC  Tumor cell; TMB Tumor mutational burden; VAS  
Visual analog scale. 
4
STUDY DESIGN
4.1
Overall design
For an overview of the study design, see Figure 1 (original study design) and Figure 2 (revised 
study design), Section 1.3. For details on treatments given during the study, see Section 6.1.  
For details on what is included in the efficacy and safety endpoints, see Section 3.  
This is a Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-arm 
study to evaluate the efficacy and safety of durvalumab plus SoC chemotherapy compared to 
placebo plus SoC chemotherapy in patients with completely resected stage II-III NSCLC who 
are MRD+ post-surgery. 
Prior to CSP V4.0, the study was designed to screen approximately 
 patients and 
randomize approximately 
 patients with stage II-III NSCLC (according to IASLC Staging 
Manual in Thoracic Oncology v8.0) (select stage IIIB patients with T3N2 or T4N2 disease 
may be eligible; see Section 5.1.1), whose tumors are EGFR and ALK wild type, and who 
have undergone complete resection. Randomized patients were to include approximately 
 
MRD+ and 
 MRD- patients. The number of MRD- patients was to be capped at 
. As 
the total number of randomized patients will not reach 
, the number of MRD- patients will 
be less than 
. There was expected to be a split of approximately 30%/70% of 
Asian/non-Asian patients within the MRD- randomized population.
Following a decision to close recruitment on 25 May 2022, a total of 691 patients were 
enrolled, and up to approximately 100 patients are expected to be randomized within the 
study. The randomized population is expected to include up to approximately 25 MRD+ and 
75 MRD- patients.
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The study has opened in 188 centers globally. Note that enrollment has closed for this 
study.
First screening (initiated by the signing of ICF1)
First screening begins when the patient signs ICF1. It is preferred that patients are identified 
and enrolled prior to surgery (Table 1); however, patients are permitted to sign ICF1 following 
surgery. Pre-surgical workup and surgery are not considered study procedures.
During first screening, EGFR and ALK will be assessed. A pre-surgical biopsy sample is the 
preferred sample type; however, if a pre-surgery biopsy sample is not available or evaluable, 
testing will be conducted after surgery on the resected tumor tissue. Patients will still be 
allowed to continue with first screening procedures while testing is ongoing but will be 
excluded from second screening and randomization if their tumor sample tests positive for 
EGFR mutations and/or ALK translocations. Local testing must be performed using a 
well-validated, local regulatory approved test; results from testing performed during screening 
for another AstraZeneca study may be used. EGFR/ALK will be tested centrally if results from 
testing either locally or in the context of screening for another study are not available.
Note: Where EGFR/ALK testing of a pre-surgical tissue biopsy is performed locally as 
standard of care, the patient must be confirmed as EGFR/ALK wild-type prior to signing ICF1 
and enrolling in the study. 
This study requires mandatory genetic testing. WES of the patient’s tumor is performed on the 
resected tumor tissue and derived tumor-specific DNA variants are identified by removing 
background germline variants, determined by WES of the patient’s whole blood sample. A 
personalized panel is then created, comprised of 50 of the patient’s tumor variants expressed 
at high frequency. This panel is then used to identify the presence of ctDNA extracted from 
the patient’s plasma. The patient is considered MRD+ if the panel detects ctDNA. 
Note: Patients who have higher levels of tumor-specific mutations are more likely to have 
sufficient mutations for a successful panel build. Patients with driver mutations and/or 
non-smokers tend to have a lower mutational burden (Nagahashi et al 2018, Offin et al 2019). 
A pre-surgery plasma sample will be collected from all patients who sign ICF1 prior to 
surgery. These samples will be tested retrospectively using the personalized panel to 
determine if tumor-specific variants are detectable in the plasma-derived DNA prior to 
surgery for exploratory purposes. In addition, a plasma sample will be collected between 
Week 3-5 (Day 21-35) post-surgery and used to determine a patient’s MRD status. 
While it is preferred that patients sign ICF1 prior to surgery, patients will be permitted to 
enrol in the study after surgery. As a plasma sample must be collected at Week 3-5 
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than Week 3 (Day 21) post-surgery to ensure the personalized panel is built and MRD result is 
obtained within the screening timeframe. Patients identified after Week 3 (d21) post-surgery 
but prior to Week 5 (d35) post-surgery may be allowed to enrol in the study depending on the 
outcome of the discussion with the study physician. A whole blood sample and resected tumor 
tissue must be collected and sent to the diagnostic lab as soon as possible after ICF1 is signed 
for development of the personalized panel. 
Investigators will not be notified of MRD status, and eligibility will be managed through the 
IWRS.
Second screening (initiated by the signing of ICF2)
Following determination of their MRD status during the first screening period, patients will 
enter the second screening period (Table 2) to confirm that they are eligible for randomization 
to treatment. 
Note: If the scan performed after surgery (Table 1 and Table 2) falls outside of the 28 day 
+7 days window prior to randomization, then an additional scan must be performed to 
confirm no evidence of disease.
Prior to CSP V4.0, approximately 
 patients were to be randomized 1:1 to treatment with 
durvalumab q3w for 4 cycles plus SoC chemotherapy q3w for up to 4 cycles or placebo q3w 
for 4 cycles plus SoC chemotherapy q3w for up to 4 cycles followed by durvalumab or 
placebo q4w for up to an additional 10 cycles (for a total of 12 months of treatment), until 
disease recurrence, or until other specific treatment discontinuation criteria are met 
(whichever occurs first). Approximately 100 patients are now expected to be randomized in 
the study.
Efficacy assessments of the primary endpoint of DFS will be derived using Investigator 
assessments according to RECIST 1.1 and prespecified definitions of disease recurrence (ie, 
local or regional recurrence, distant recurrence, second primary NSCLC) and by survival 
assessments. All patients will be followed for disease recurrence and survival until the 
primary DFS analysis. Disease evaluations utilize images from CT (preferred) or MRI, each 
preferably with IV contrast, of the chest and abdomen (including liver and adrenal glands) 
collected during second screening/baseline and at selected timepoints during the study 
duration. Any other areas of disease involvement should be additionally imaged based on the 
signs and symptoms of individual patients. 
Selected visits may be performed via telemedicine or at the patient’s home or other 
appropriate location by a qualified nurse, where feasible, allowed by local laws and 
regulations, and following consultation with the Investigator and Sponsor. These alternatives 
are optional, and all visits could be conducted as on-site visits if this is preferred. The patient 
must consent to have these visits performed at home.
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All patients must be staged according to IASLC Staging Manual in Thoracic Oncology v8.0.
An IDMC comprised of independent experts will meet 12 months after the first patient has 
been dosed with IP or after the first 50 patients have received at least 1 dose of IP (whichever 
occurs first) to assess the safety and tolerability of durvalumab and will report back to the 
Sponsor. The timing of subsequent reviews will be determined by the IDMC but will not 
occur more frequently than every 6 months. Full details of the IDMC procedures will be 
specified within the IDMC Charter. The IDMC safety reviews will be conducted in an 
unblinded manner. 
4.1.1
Early Study Enrollment Closure
On 25 May 2022, AstraZeneca closed study recruitment. This was based on changes in the 
treatment landscape as outlined in Section 2.1. All randomized patients will be followed until 
the primary DCO when no further visits will occur. After the last patient last visit, the 
following are planned: DCO, DBL and primary DFS analysis. This will be followed by DBL 
and then the primary DFS analysis. The study will then be concluded.
4.2
Scientific rationale for study design
4.2.1
Overall rationale and study population
For patients with stage II-III disease, surgery and adjuvant SoC chemotherapy per National 
Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology 
guidelines results in 5-year DFS rates of only ~40% (Wakelee et al 2017). Improvement in 
clinical outcomes may be achieved through the early identification of patients at high risk for 
recurrence and combined treatment of immunotherapy and SoC chemotherapy. Identification 
of high-risk patients may be achieved with detection of MRD after surgery using ctDNA. 
MRD- patients will be included in this study to evaluate whether MRD+ is distinct from 
MRD- status as a prognostic marker for disease recurrence and to provide clinical and 
translational data to facilitate the development of an MRD-driven treatment paradigm. The 
number of MRD- patients was to be capped at 100. 
The stratification factors of stage (II versus III) and MRD status (MRD+ versus MRD-) were 
chosen to mitigate the risk of imbalance across treatment arms based on prognostic differences 
between stages and MRD status. As PD-L1 expression correlates with outcome in clinical 
trials evaluating IO therapy plus chemotherapy (Gadgeel et al 2019, Socinski et al 2018, Jotte 
et al 2019), patients will also be stratified according to PD-L1 status (TC <1% vs TC ≥1%) to 
mitigate the risk of imbalance across treatment arms for this prognostic factor.
In this study, adjuvant treatments should be initiated by Week 9 post-surgery (once MRD 
status has been determined) but can be delayed up to 12 weeks (+ 7 days) after surgery. Data 


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have shown that patients can still benefit from delayed adjuvant chemotherapy started up to 
16 weeks after surgery (Salazar et al 2017).
4.2.2
Study design
In order to avoid bias, the study will be randomized and double-blind. 
The choice of SoC chemotherapy options provided in this study are paclitaxel + carboplatin 
(squamous patients only), pemetrexed + carboplatin (non-squamous patients only), or 
pemetrexed + cisplatin (non-squamous patients only). It is preferred that all non-squamous 
patients receive at least 1 cycle of cisplatin. In the event of unfavorable tolerability of 
cisplatin, non-squamous patients can switch from cisplatin to carboplatin therapy at any point 
during the study. During the first 4 treatment cycles, all patients will receive chemotherapy 
(the exact regimen selected by the Investigator from the SoC chemotherapy options listed 
above). The chemotherapy options provided in this study include agents that are commonly 
used in adjuvant therapy and allow sufficient flexibility for Investigators and patients to select 
the agents that reflect their normal clinical practice and national guidelines (NCCN 2019).
4.2.3
Primary and secondary outcome measures
The primary efficacy endpoint of this study is DFS in the FAS; DFS will be determined using 
the definition of a new lesion per RECIST 1.1. DFS (see Section 8.1.1) represents a direct 
measure of the study drug’s efficacy. Historical data have shown that the DFS benefit seen in 
MRD+ patients treated with adjuvant chemotherapy was consistent with an improvement in 
the OS outcome, which suggests an association between these 2 endpoints in this setting 
(Mauguen et al 2013). DFS has been the primary basis of approval for adjuvant breast cancer 
hormonal therapy, adjuvant colon cancer therapy, and adjuvant cytotoxic breast cancer 
therapy. 
Prior to CSP V4.0, the study was sized on the MRD+ population, since the study was aimed at 
testing the hypothesis that detection of MRD after surgery is a marker of high risk for 
recurrence and can be used to select patients in adjuvant studies. DFS in all patients was to be 
evaluated as a secondary outcome. The study was not sized for the MRD- population. After 
CSP V4.0, the study is not powered to detect statistical significance, and all analyses will be 
performed in an exploratory manner.
OS, which also represents a direct measure of efficacy, is routinely used on oncology trials 
and will also be evaluated as a non-powered, secondary outcome. 
The safety and tolerability of each study treatment will be assessed by the standard safety 
endpoints, including AEs, SAEs, laboratory abnormalities, and vital signs.


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4.2.3.1
Rationale for exploratory endpoints
The potential clinical benefit of durvalumab post disease recurrence will be evaluated by the 
exploratory endpoints of PFS (using local standard practice), 
 
(
), and 
 (
).
Biomarkers to be assessed are justified on the basis that they may identify subpopulations 
most likely to derive clinical benefit from therapy (predictive biomarkers) and to rapidly 
identify patients most likely to experience clinical benefit after treatment has started (early 
efficacy biomarkers), begin to collect data on potential surrogate biomarkers, and to assess 
target engagement and/or mechanism of action (pharmacodynamic biomarkers) to support 
dosing, understanding of the therapeutic index, and/or potential future combination therapies. 
Biomarkers may include, but are not limited to, PD-L1 TC expression, immune and stromal 
cell gene and protein expression profiles, and tumor mutational burden (TMB) analyses. 
Although ctDNA is an emerging biomarker, the endpoint has significant capability for 
diagnosis and has already demonstrated utility at various levels of disease staging and 
management (De Rubis et al 2018, Wills et al 2018). Limitations in using ctDNA as an 
endpoint include detection sensitivity in early cancers, predictability in diseased individuals 
versus healthy individuals, and quality aspects due to processing time (De Rubis et al 2018). 
However, given the supporting literature and regulatory landscape, the proposed primary and 
secondary endpoints are aligned with existing clinical trials and justified by the expected 
clinical benefits, ctDNA will be assessed as an exploratory outcome.
The exploratory objective of disease-related symptoms and overall health-related quality of 
life (HRQoL), assessed using the European Organisation for Research and Treatment of 
Cancer (EORTC) 30-item Core Quality of Life Questionnaire (QLQ-C30), Version 3 
(QLQ-C30 v3), and the complementary 13-item Lung Cancer Quality of Life Questionnaire 
(QLQ-LC13), will show the overall benefits and toxicity of the treatment from the patient’s 
perspective and will aid in understanding the benefit/risk evaluation. These PRO 
questionnaires are well established instruments that have been previously included in cancer 
clinical studies.
 
4.3
Justification for durvalumab dose
A durvalumab dose of 20 mg/kg q4w is supported by in vitro data, nonclinical activity, 
clinical PK/pharmacodynamics, biomarkers, and activity data from Study CD-ON-
MEDI4736-1108 (hereafter referred to as Study 1108) in patients with advanced solid tumors 
CCI
CCI
CCI
CCI
CCI


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and from a Phase I study performed in Japanese patients with advanced solid tumors 
(D4190C00002).
4.3.1
PK/Pharmacodynamic data
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging 
from 0.1 to 10 mg/kg every 2 weeks (q2w) or 15 mg/kg q3w, durvalumab exhibited non-linear 
(dose-dependent) PK consistent with target-mediated drug disposition. The PK approached 
linearity at ≥3 mg/kg q2w, suggesting near complete target saturation (membrane-bound and 
soluble programmed cell death-ligand 1 [sPD-L1]), and further shows that the durvalumab 
dosing frequency can be adapted to a particular regimen given the linearity seen at doses 
higher than 3 mg/kg. The expected half-life with doses ≥3 mg/kg q2w is approximately 
21 days. A dose-dependent suppression in peripheral sPD-L1 was observed over the dose 
range studied, consistent with engagement of durvalumab with PD-L1. A low level of 
immunogenicity has been observed. No patients have experienced immune-complex disease 
following exposure to durvalumab. (For further information on immunogenicity, please see 
the current durvalumab IB).
A population PK model was developed using the data from Study 1108 (doses=0.1 to 
10 mg/kg q2w or 15 mg/kg q3w; Fairman et al 2014). Multiple simulations indicate that a 
similar overall exposure is expected following both 10 mg/kg q2w and 20 mg/kg q4w 
regimens, as represented by AUC at steady state (4 weeks). Median maximum drug 
concentration at steady state is expected to be higher with 20 mg/kg q4w (~1.5 fold) and 
median trough drug concentration at steady state is expected to be higher with 10 mg/kg q2w 
(~1.25 fold). Clinical activity with the 20 mg/kg q4w dosing regimen is anticipated to be 
consistent with 10 mg/kg q2w, with the proposed similar dose of 20 mg/kg q4w expected to 
(a) achieve complete target saturation in the majority of patients; (b) account for anticipated 
variability in PK, pharmacodynamics, and clinical activity in diverse cancer populations; (c) 
maintain sufficient PK exposure in case of antidrug antibody (ADA) impact; and (d) achieve 
PK exposure that yielded maximal antitumor activity in animal models.
Given the similar AUC and modest differences in median peak and trough levels at steady 
state, the observation that both regimens maintain complete sPD-L1 suppression at trough, 
and the available clinical data, the 20 mg/kg q4w and 10 mg/kg q2w regimens are expected to 
have similar efficacy and safety profiles, supporting further development with a dose of 
20 mg/kg q4w for durvalumab monotherapy. This dose has been used in multiple studies 
previously with no safety concerns.
4.3.2
Clinical data
Refer to the current durvalumab IB for a complete summary of clinical information, including 
safety, efficacy, and PK at the 20 mg/kg q4w regimen.


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4.3.3
Rationale for fixed dosing
A population PK model was developed for durvalumab using monotherapy data from 
Study 1108 (N=292; doses=0.1 to 10 mg/kg q2w or 15 mg/kg q3w; solid tumors). Population 
PK analysis indicated only minor impact of body weight on the PK of durvalumab (coefficient 
of ≤0.5). The impact of body weight-based (10 mg/kg q2w) and fixed dosing (750 mg q2w) of 
durvalumab was evaluated by comparing predicted steady state PK concentrations (5th, 
median, and 95th percentiles) using the population PK model. A fixed dose of 750 mg was 
selected to approximate 10 mg/kg (based on median body weight of ~75 kg). A total of 
1000 patients were simulated using body weight distribution of 40 to 120 kg. Simulation 
results demonstrate that body weight-based and fixed dosing regimens yield similar median 
steady state PK concentrations with slightly less overall between-patient variability with a 
fixed dosing regimen. 
Similar findings have been reported by others (Narwal et al 2013, Wang et al 2009, Zhang et 
al 2012). Wang and colleagues investigated 12 mAbs and found that fixed and body 
size-based dosing perform similarly, with fixed dosing being better for 7 of 12 antibodies 
(Wang et al 2009). In addition, they investigated 18 therapeutic proteins and peptides and 
showed that fixed dosing performed better for 12 of 18 in terms of reducing the 
between-patient variability in PK/pharmacodynamic parameters (Zhang et al 2012). 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar PK exposure and variability, AstraZeneca 
considered it feasible to switch to fixed dosing regimens. 
A fixed dose of 1500 mg durvalumab administered q3w or q4w is to be used for all patients
with a body weight greater than 30 kg. Currently, the use of a fixed dose of 1500 mg 
durvalumab, administered both in combination with chemotherapy and as monotherapy, is 
approved for treatment of extensive-stage small-cell lung cancer; additionally, the 1500 mg 
fixed dose is approved in the US as monotherapy for both unresectable stage III non-small cell 
lung cancer (following chemoradiation).
Rationale for proposed every 3 weeks fixed dosing
The proposed dosing schedule is aligned with the standard fixed dosing of 1500 mg 
durvalumab for 4 cycles, which is supported by efficacy and safety as well as tolerability data 
across multiple studies in multiple tumor types. To conform to the chemotherapy schedule in 
the study, the Sponsor proposes to use standard durvalumab dose and ratio at a q3w dosing 
interval for the first 4 cycles rather than the standard q4w schedule.
The safety of a q3w dosing schedule in combination with chemotherapy has been explored in 
the ongoing Study D419SC00001, where durvalumab is administered at 1120 mg q3w in 
combination with 75 mg of the anti-CTLA-4 antibody tremelimumab followed by 1120 mg 


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durvalumab q3w. The combination has been declared tolerable and manageable. The 1120 mg 
dose of durvalumab is the q3w equivalent of the standard 1500 mg q4w dose. The q3w 
regimen is also being administered in the ongoing Study D9106C00001 (AEGEAN), in which 
durvalumab 1500 mg q3w is administered in combination with platinum-based chemotherapy 
regimens as neoadjuvant therapy in patients with resectable NSCLC.
In this study, AstraZeneca proposes to use the Phase III fixed dose of durvalumab, so this 
study will use 1500 mg durvalumab q3w in combination with chemotherapy as adjuvant 
therapy. The relative increase in dose density of durvalumab (ie, 1500 mg q3w instead of 
q4w) is supported by the fact that toxicities attributable to durvalumab do not appear 
dose-dependent, and PK modeling reveals no meaningful differences in drug levels between 
q3w and q4w dosing. After completion of SoC chemotherapy, the dose will be 1500 mg 
durvalumab q4w.
4.3.4
Rationale for standard of care adjuvant chemotherapy regimens
In this study, patients will receive 4 cycles of a SoC platinum-based adjuvant chemotherapy 
regimen, based on squamous or non-squamous histology, either in combination with 
durvalumab or with placebo (specific options are outlined in Table 8). This is in alignment 
with the NCCN guidelines (NCCN 2019), which recommend 4 cycles of chemotherapy in the 
adjuvant setting.
4.3.5
Rationale for Placebo 
In this study patients will receive either durvalumab or placebo in combination with SoC
chemotherapy and then afterwards as monotherapy. The continued use of placebo in this study 
is justified owing to limited global availability of adjuvant anti-PD-(L)1 immunotherapy, to 
determine potential risks and benefits of durvalumab in combination with chemotherapy, rigid 
timescales for commencing anti-PD-(L)1 therapies in Phase III studies leading to approval 
(relevant to patients already established on study treatment), and uncertain risks and benefits 
of anti-PD-(L)1 therapies in MRD- and MRD+ populations. These data are important for 
determining optimal future registrational clinical trial designs aimed at optimising patient 
outcomes. Given potential changes in SoC treatments available to patients, Investigators 
should continue to assess, and discuss with patients, the potential risks and benefits associated 
with ongoing study participation and ensure the nature and outcomes of these discussions are 
recorded in the source documentation.
4.4
End of study definition
The end of study is defined as the date of the last visit of the last patient in the study, which is 
approximately 12 months following last patient randomized. The DCO for primary DFS
analysis will follow last patient last visit. No further visits or assessments will be conducted 


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thereafter.  No additional data will be collected, except for mandatory safety reporting as 
outlined in Section 8.3.13.  
Patients may be withdrawn from the study if the study itself is stopped. The study may be 
stopped if, in the judgment of AstraZeneca, study patients are placed at undue risk because of 
clinically significant findings.
See section 8.3.13 for details regarding data collection on randomized patients (including 
patients in follow-up) and patients in observation following DCO for primary DFS analysis. 
See Appendix A 6 for guidelines for the dissemination of study results.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomized to a study intervention. Under no circumstances can 
there be exceptions to this rule. Patients who do not meet the entry requirements are screen 
failures; refer to Section 5.4.
In this protocol, “enrolled” patients are defined as those who sign ICF1 and enter first 
screening. Note that enrollment has closed for this study. The first screening includes the 
period before, during, and after surgery but before second screening and determination of final 
eligibility for randomization in this study. The primary purpose of the first screening period is 
to determine the patient’s MRD status. 
The procedures during the second screening (initiated by the signing of ICF2) include final 
assessment of eligibility for randomization into the study. “Randomized” patients are defined 
as those who undergo randomization and receive a randomization number.
For procedures for withdrawal of incorrectly enrolled patients, see Section 7.3.
5.1
Inclusion criteria
Patients are eligible to be included in the study only if all of the following inclusion criteria 
and none of the exclusion criteria apply.
Patients must be capable of giving signed informed consent, which includes a mandatory
genetic informed consent and compliance with the requirements and restrictions listed in the 
informed consent forms (ICFs) and in this protocol. Provision of signed and dated, written 
ICFs must occur prior to any mandatory study-specific procedures, sampling, and analyses. 


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This study will use a 2-tiered informed consent and screening process such that initial 
inclusion criteria are assessed during the first screening period (initiated by the signing of 
ICF1; Section 5.1.1) and additional inclusion/exclusion criteria are assessed during the second 
screening period (initiated by the signing of ICF2; Section 5.1.2); all eligibility criteria must 
be assessed prior randomization.
In addition to ICF1 and ICF2, patients will provide signed and dated written optional genetic 
informed consent prior to collection of a sample for optional genetic analysis at the time of 
second screening (Table 2). This is different from the genetic samples and testing covered by 
ICF1, which are mandatory for participation in this study.
The ICF process is described in Appendix A 3. 
See Table 4 for a summary of the timings of inclusion criteria assessments relative to ICF1 
(Section 5.1.1) and ICF2 (Section 5.1.2).
5.1.1
Criteria and procedures initiated with the signing of ICF1
1
ICF1 must be signed and dated prior to any study procedures and prior to the planned 
surgical resection of the primary NSCLC, with the exceptions noted below. This consent 
will cover the study-specific first screening procedures outlined in Table 1.
Exception: Patients will be permitted to sign ICF1 up to Week 3 (Day 21) post-
surgery. Patients identified after Week 3 post-surgery but prior to Week 5 (Day 35) 
post-surgery may be allowed to sign ICF1 depending on the outcome of the 
discussion with the study physician. In these cases, a whole blood sample and 
resected tumor tissue must be collected and sent to the diagnostic lab as soon as 
possible after ICF1 is signed for development of the personalized panel. A plasma 
sample must still be collected at Week 3-5 (Day 21-35) post-surgery, even if creation 
of the personalized panel for MRD detection is delayed. 
Age
2
Age ≥18 years at the time of screening. 
Sex
3
Male and/or female.
Type of patient and disease characteristics
4
Individuals who have diagnosis of histologically confirmed NSCLC (WHO 2015 
classification) with resectable (stage II-III) disease (according to IASLC Staging Manual 
in Thoracic Oncology v8.0). 


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Select (ie, T3N2 or T4N2) stage IIIB patients will be eligible, provided that they are 
upstaged to T3N2 or T4N2 based on confirmed pathology. Patients who are staged as 
T3N2 or T4N2 prior to surgery are not eligible. 
5
A contrast-enhanced CT or MRI scan of the chest must have been done for surgical 
planning prior to surgery. It is recommended that patients undergo combined FDG-PET 
(18F-Fluoro-deoxyglucose positron emission tomography) and CT scan (contrast-
enhanced or low-dose CT component) in order to rule out detectable extrathoracic, 
extracranial metastasis and to assess for potential mediastinal lymph node involvement 
prior to surgery. In the absence of pre-operative FDG-PET CT imaging, pre-operative 
contrast-enhanced CT imaging or MRI scan must cover liver and adrenal glands. If only 
CT is available, or FDG-PET reveals suspicious lymph node mediastinal involvement, it 
is recommended that invasive pre-operative mediastinal staging is performed according to 
the algorithm of the European Society of Thoracic Surgeons guidelines (algorithm to 
follow for primary mediastinal staging if only pre-operative CT is available [De Leyn et 
al 2007], algorithm to follow for primary mediastinal staging when PET-CT is available 
[De Leyn et al 2014]). It is preferred that imaging occurs within 6 weeks prior to surgery. 
Brain MRI (preferred) or brain CT with IV contrast is required for complete staging of the 
tumor. 
6
Complete resection of the primary NSCLC is mandatory. The primary tumor must be 
deemed resectable by a multidisciplinary evaluation that must include a thoracic surgeon 
certified or trained according to local standards and who performs lung cancer surgery as 
a significant part of their practice. Surgical resection of the primary NSCLC can occur by 
open thoracotomy or by video-assisted thoracic surgery (VATS) and resection can be 
achieved by segmentectomy, lobectomy, sleeve resection, bilobectomy, or 
pneumonectomy. Patients undergoing wedge resection are not eligible for this study. 
Note: Patients undergoing segmentectomy must have tumors less than 2 cm in maximum 
diameter. Where a resection has been extended by means of a wedge resection of an 
adjacent lobe to ensure complete resection of a tumor at or crossing a fissure between 
lobes, this is acceptable if surgical margins are clear of disease. Where the resection of a 
second tumor nodule (eg, a T4 lesion) is undertaken by means of a wedge resection of a 
separate lobe, then the patient is not eligible.
At a minimum, the following parameters should be met for a tumor to be declared 
completely resected:
(a) The surgeon performing the resection should remove all gross disease by the end of 
surgery. All surgical margins of resection must be macroscopically negative for 
tumor. 


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(b) Pathology and/or operative reports must include the examination of at least 2 
different mediastinal lymph node (N2) levels, one of which is the subcarinal 
node-group (level 7) and the second of which is lobe-specific (defined below). 
Note: In the uncommon clinical situation where the surgeon thoroughly examines a 
mediastinal lymph node level and does not find any lymph nodes, that mediastinal 
lymph node level may be counted among the minimum 2 required levels. However, 
the surgeon must clearly document in the operative report or in a separate written 
statement that the lymph node level was explored and no lymph nodes were present. 
Normal appearing lymph nodes, if present, must be biopsied or removed. Exploration 
of nodes must clearly be documented in medical file if not recorded in operative 
report.
Note: Lobe-specific lymph node stations are classified based on the location of the 
primary tumor as follows (based on IASLC 2009 lymph node map terminology 
[Rusch et al 2009]): Stations 2R and 4R for right upper lobe or middle lobe tumors, 
stations 4L, 5, and 6 for left upper lobe tumors, stations 8 and 9 for lower lobe tumors 
of both sides (Adachi et al 2017, Rami-Porta et al 2005). 
(c) No extracapsular nodal extension of the tumor is observed in resected mediastinal N2 
lymph nodes.
Note: Extracapsular nodal extension in resected N1 nodes is permitted.
Note: The highest mediastinal node resected can be positive for malignancy.
Note: Carcinoma-in-situ can be present at the bronchial margin.
7
All patients who enrol in the study prior to surgery must have a pre-surgical plasma 
sample collected for MRD evaluation. Patients will not be excluded from randomization 
based on the results of analysing the pre-surgical plasma samples. 
The following criteria must be met prior to signing ICF2:
8
Confirmation of suitable samples of resected tumor tissue and whole blood for WES of 
tumor and germline DNA, respectively, and creation of Sponsor-approved personalized 
panel for MRD detection. Tumor tissue and whole blood samples must be provided to the 
diagnostic laboratory for development of the personalized panel as soon as possible. 
Germline sequencing of whole blood is mandatory. 
Note: If a patient’s tumor has less than the requisite 50 tumor-specific variants, a 
panel cannot be built and the patient will no longer be able to participate in the study.
9
Established MRD status (MRD+ or MRD-) based on Sponsor-approved personalized 
assay of a plasma sample collected at Week 3-5 (Day 21-35) post-surgery. 
10 Known tumor PD-L1 status determined at a central reference laboratory testing service 
using a validated Ventana SP263 PD-L1 immunohistochemistry (IHC) assay prior 
randomization. Patients with unknown PD-L1 status are not eligible for the study. 


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5.1.2
Criteria and procedures initiated with the signing of ICF2 
11 Post-operative CT scan of the chest (including liver and adrenal glands) performed within 
28 days + 7 days prior to randomization. If clinically indicated, additional scans (such 
as brain MRI [preferred] or brain CT with IV contrast) should be performed to confirm no 
evidence of metastasis.
12 ICF2 must be signed and dated after MRD status is determined and prior to initiation of 
any study-specific procedures, sampling, and analyses outlined in SoAs in Table 2 and 
Table 3. Randomization must occur within the 12 weeks (+ 7 days) following surgery.
13 WHO/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
14 Complete postoperative wound healing must have occurred prior to randomization; 
patients must have recovered from all acute, reversible toxic effects from prior treatments 
(excluding alopecia) that could potentially adversely impact further administration of 
durvalumab/placebo or chemotherapy according to the Investigator’s judgment.
15 Eligible to tolerate 4 cycles of platinum-based adjuvant chemotherapy
16 Adequate organ and marrow function as defined below:
∀
Hemoglobin ≥9.0 g/dL
∀
Absolute neutrophil count ≥1.5 × 109/L
∀
Platelet count ≥100 × 109/L
∀
Serum bilirubin ≤1.5 × the upper limit of normal (ULN). This will not apply to 
patients with confirmed Gilbert’s syndrome, who will be allowed in consultation with 
their physician.
∀
ALT and AST ≤2.5 × ULN
∀
Measured creatinine clearance (CL) ≥40 mL/min or Calculated creatinine CL 
≥40 mL/min as determined by Cockcroft-Gault (using actual body weight)
Males:
Creatinine CL = Weight (kg) × (140 - Age)
(mL/min)
72 × serum creatinine (mg/dL)
Females:
Creatinine CL = Weight (kg) × (140 - Age) × 0.85
(mL/min)
72 × serum creatinine (mg/dL)
17 Must have a life expectancy of at least 12 weeks
Weight
18 Body weight >30 kg


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5.2
Exclusion criteria 
All exclusion criteria must be checked prior to randomization. If a patient meets an exclusion 
criterion, the patient is ineligible to continue in the study.
Diagnostic assessments
1
Post-operative imaging demonstrating unequivocal evidence of disease recurrence or 
tissue biopsy-proven disease recurrence. In the event of lymphadenopathy on imaging 
that would lead to exclusion, histopathological confirmation of lymph node metastasis 
should be obtained prior to excluding a patient from the study. If pathological 
confirmation of lymph-node metastasis is not technically feasible and imaging appearance 
are deemed unequivocal for relapse, the patient will be excluded.
2
EGFR-mutant and/or ALK-translocation-positive, as assessed either from a pre-surgical 
biopsy sample (preferred) or the resected tumor tissue (if biopsy was not evaluable or 
available). Any of the following scenarios are acceptable for this study:
Where EGFR/ALK results are obtained from a pre-surgical tissue biopsy as part of 
standard local practice, the patient must be confirmed EGFR/ALK wild-type prior to 
enrolling in the study.
Results obtained from testing the patient’s primary tumor tissue during screening for 
another AstraZeneca study may be used in this study.
Results from local testing of a pre-surgical biopsy. 
All local EGFR/ALK testing performed locally must be performed using a 
well-validated, local regulatory-approved test.
EGFR/ALK may be tested centrally if local testing is unavailable. Patients will still be 
allowed to continue with first screening procedures while testing is ongoing but will 
not be able to continue into second screening if their tumor tests positive for EGFR
mutations and/or ALK translocations.
3
Mixed small cell and NSCLC histology.
4
Require re-resection or are deemed to have unresectable NSCLC by a multidisciplinary 
evaluation that must include a thoracic surgeon who performs lung cancer surgery as a 
significant part of their practice.
5
Patients who are candidates to undergo only wedge resections.
Medical conditions
6
History of allogeneic organ or bone marrow transplantation.
7
Non-leukocyte-depleted whole blood transfusion within 120 days of genetic sample 
collection. Note: This exclusion criterion only relates to whole blood and does not 
include other blood products (eg, packed red blood cells).


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8
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
∀
Patients with vitiligo or alopecia
∀
Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement 
∀
Any chronic skin condition that does not require systemic therapy
∀
Patients without active disease in the last 5 years may be included but only after 
consultation with the Study Physician
∀
Patients with celiac disease controlled by diet alone
9
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina 
pectoris, uncontrolled cardiac arrhythmia, active ILD, serious chronic gastrointestinal 
conditions associated with diarrhea, or psychiatric illness/social situations that would 
limit compliance with study requirements, substantially increase risk of incurring AEs, or 
compromise the ability of the patient to give written informed consent.
10 History of another primary malignancy, except for
∀
Malignancy treated with curative intent and with no known active disease ≥5 years 
before the first dose of IP and of low potential risk for recurrence
∀
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease
∀
Adequately treated carcinoma-in-situ without evidence of disease
11 History of active primary immunodeficiency 
12 Active infection, including tuberculosis (clinical evaluation that includes clinical history, 
physical examination, and radiographic findings, and tuberculosis testing in line with 
local practice), hepatitis B (HBV; known positive HBV surface antigen [HBsAg] result), 
hepatitis C (HCV), or human immunodeficiency virus infection (positive HIV 1/2 
antibodies). Patients with a past or resolved HBV infection (defined as the presence of 
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients 
positive for HCV antibody are eligible only if polymerase chain reaction is negative for 
HCV RNA.
13 Known allergy or hypersensitivity to any of the IPs or any of the IP excipients.
14 Any medical contraindication to treatment with platinum-based doublet chemotherapy as 
listed in the local labeling.


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Prior/concomitant therapy
15 Received any prior adjuvant therapy for NSCLC or any prior exposure to durvalumab.
16 Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. 
Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone 
replacement therapy) is acceptable. 
17 Radiotherapy treatment for NSCLC in the neoadjuvant setting. Radiotherapy treatment to 
more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the 
first dose of IP.
18 Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: 
Patients, if enrolled, should not receive live vaccine while receiving IP and up to 30 days 
after the last dose of IP. 
19 Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of IP. 
20 Current or prior use of immunosuppressive medication within 14 days before the first 
dose of durvalumab/placebo. The following are exceptions to this criterion:
∀
Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection)
∀
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or its equivalent
∀
Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
Prior/concurrent clinical study experience
21 Participation in another clinical study with an IP administered since completion of 
surgery.
22 Previous IP assignment in the present study.
23 Concurrent enrollment in another clinical study, unless it is an observational 
(noninterventional) clinical study, or during the follow-up period of an interventional 
study.
24 Prior randomization or treatment in a previous durvalumab clinical study regardless of 
treatment group assignment.
Other exclusions
25 Patients who are never-smokers; defined as no more than 100 cigarettes or its equivalent 
in his/her lifetime.
26 Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 90 days after the last dose of durvalumab/placebo.


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27 Judgment by the Investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions, and requirements.
5.3
Lifestyle restrictions
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after:
1
Patients must follow the contraception requirements outlined in Appendix H.
2
All patients: Patients should not donate blood or blood components while participating in 
this study and through 90 days after receipt of the final dose of durvalumab/placebo or 
until alternate anticancer therapy is started. 
3
Restrictions relating to concomitant medications are described in Section 6.4.
5.4
Screen failures
Screen failures are patients who do not fulfill the eligibility criteria for the study, and therefore 
must not be randomized. Screen failed patients should be recorded in the IWRS as soon as 
possible.  These patients should have the reason for study withdrawal recorded as “eligibility 
criteria not fulfilled” (ie, patient does not meet the required eligibility criteria). “Eligibility 
criteria not fulfilled” as a reason for study withdrawal is only valid for screen failures (ie, not 
randomized patients). The reason for screen failures will be captured in the appropriate section 
of the electronic case report form (eCRF).  
Please note that the patient may screen fail during either first or second screening. Screen 
failure may occur before a patient’s MRD status can be determined. If a patient’s tumor is 
found to have less than 50 tumor-specific variants required to build the MRD personalized 
panel, then the panel cannot be created, the MRD status will not be determined and the patient 
will not be able to continue to participate in the study.
Patients may be rescreened, following discussion with the study team and provided adjuvant 
therapy can be initiated within 12 weeks (+ 7 days) from surgery. Patients cannot be 
re-randomized in this study.
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure patients to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE
(Table 7). 


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Table 7
Minimum requirements for data entry for screen-failed patients
All patients
Patients with MRD result
!
Demographics (age, gender, ethnicity, race, region)a
!
Pre-surgical details (including imaging, if available)
!
Smoking history
!
Histology, pre- and post-surgery
!
Stage (post-surgery)
!
Surgical details, including:
o Extent of resection
o Pleural invasion status
o Nodal disease/Confirmation of node-negative 
disease
o Extracapsular disease
o Medistinal lymph node examination/dissection
o Confirmation of complete resection 
!
Post-surgical scan datab
!
Local EGFR/ALK statusb
!
Central EGFR/ALK and PD-L1 resultsb
!
Date of surgeryb
!
Date(s) of sample collectionb
!
Reason(s) for screen failure (if applicable)
!
Any SAE related to study procedures
a
Where allowed by local laws and regulations.
b
If available.
6
STUDY TREATMENTS
Study treatment is defined as any IP(s) (including marketed product comparator and placebo) 
or medical device(s) intended to be administered to a study participant according to the 
clinical study protocol (CSP). Study treatment in this study refers to durvalumab plus SoC 
chemotherapy or placebo plus SoC chemotherapy.
6.1
Treatments administered
AstraZeneca will supply durvalumab and placebo. SoC chemotherapy will be supplied locally. 
Under certain circumstances when local sourcing is not feasible, SoC chemotherapy may be 
supplied centrally through AstraZeneca. Study treatments are described in Table 8. 


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Table 8
Study treatments
Study treatment 
name
Durvalumab
Placebo
Standard of Carea
Squamous histology
Non-squamous histology
Carboplatin/Paclitaxel
Cisplatinb,c/ Pemetrexed 
Carboplatinc/ Pemetrexed
Dosage formulation
500-mg vial solution for 
infusion after dilution, 
50 mg/mL
Vial solution for infusion after 
dilution 
As sourced locallya
As sourced locallya
As sourced locallya
Route of 
administration 
IV
IV
IV
IV
IV
Dosing instructionsd
1500 mginfusion over 60 
min q3w x 4 cycles 
followed by 1500 mg over 
60 min q4w x 10 cycles 
up to a total of 12 months 
(14 cycles) of treatmentd,e
Infusion over 60 min q3w x 4 
cycles followed by infusion 
over 60 min q4w x 10 cycles 
up to a total of 12 months (14 
cycles) of treatmentd,e
Paclitaxel (200 mg/m2) 
and carboplatin (AUC 6)
Day 1 of each 3-week 
cycle for 4 cycles
Pemetrexed (500 mg/m2) 
and cisplatin (75 mg/m2)
Day 1 of each 3-week 
cycle for 4 cyclesf
Pemetrexed (500 mg/m2) 
with carboplatin (AUC 5)
Day 1 of each 3-week cycle 
for 4 cyclesf
Packaging and 
labeling
Study treatment will be 
provided in 500 mg vials. 
Each 500 mg vial will be 
labeled in accordance with 
Good Manufacturing 
Practice (GMP) Annex 13 
and per country regulatory 
requirement.e,g
Study treatment will be 
provided in vials. Each vial 
will be labeled in accordance 
with Good Manufacturing 
Practice (GMP) Annex 13 and 
per country regulatory 
requirement.e
Sourced locally by sitea
Sourced locally by sitea
Sourced locally by sitea
Provider
AstraZeneca
AstraZeneca
Sourced locally by sitea
Sourced locally by sitea
Sourced locally by sitea
a
Patients will receive one of the specified SoC regimens, depending on histology and per Investigator’s decision. Regimens listed are according to NCCN 
guidelines (NCCN 2019, Version 3.2019). Under certain circumstances when local sourcing is not feasible, a chemotherapy treatment may be supplied 
centrally through AstraZeneca.
b
In the event of unfavorable tolerability, non-squamous patients can switch from cisplatin to carboplatin therapy at any point during the study. However, it is 
preferred that all non-squamous patients receive at least 1 cycle of cisplatin. 
c
Patients with non-squamous NSCLC only: Administer vitamin B12 and folic acid in line with local practice.
d
See Sections 6.1.2.1for specific instructions for preparing and storing durvalumab and placebo.


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e
If a patient’s weight falls to 30 kg or below, the patient should receive weight-based dosing equivalent to 20 mg/kg of durvalumab q3w or q4w after 
consultation between Investigator and Study Physician until the weight improves to >30 kg, at which point the patient should start receiving the fixed 
dosing of durvalumab 1500 mg q3w or q4w. Durvalumab will be administered q3w in combination with SoC chemotherapy for the first 4 cycles of the 
study and q4w as monotherapy for an additional 10 cycles.
f
Prepared in accordance with local labeling.
g
Label text prepared for durvalumab (MEDI4736) will show the product name as “MEDI4736” or “durvalumab (MEDI4736)” depending upon the agreed 
product name used in the approved study master label document. All naming conventions are correct during this transitional period.
AUC  Area under the serum drug concentration-time curve; IV  Intravenous; min  Minutes; NCCN  National Comprehensive Cancer Network; NSCLC  Non-
small cell lung cancer; q3w  Every 3 weeks; q4w  Every 4 weeks; SoC  Standard of care.


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6.1.1
Order of administration
On Day 1 of each cycle, patients will receive durvalumab 1500 mg or placebo via IV infusion 
over 1 hour. For the combination portion of the study, SoC chemotherapy via IV infusion will 
start approximately 1 hour (maximum 2 hours) after the end of the durvalumab or placebo 
infusion. The time between administration of durvalumab/placebo and SoC chemotherapy 
should be as short as possible.
If there are no clinically significant concerns after the first cycle, reducing the observation 
period after durvalumab administration to 30 minutes is recommended, at the Investigator’s 
discretion.
6.1.2
Investigational products
6.1.2.1
Durvalumab/placebo
Durvalumab and placebo will be supplied by AstraZeneca as vial solutions for infusion after 
dilution.  Durvalumab will be supplied as a 500 mg vial containing 50 mg/mL durvalumab, 
 histidine/histidine hydrochloride, 
 trehalose dihydrate, and 
 
 polysorbate 80; it has a pH of 6.0 and density of 1.054 g/mL.  Placebo 
will be supplied as a vial containing 
 histidine/histidine hydrochloride, 
 
trehalose dihydrate, and 
 polysorbate 80; it has a pH of 6.0. The nominal fill 
volume for durvalumab and placebo is 10.0 mL.
Durvalumab is a sterile, clear to opalescent, colorless to slightly yellow solution, free from 
visible particles.
Durvalumab and placebo vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Durvalumab and placebo should be kept in original packaging until use to prevent prolonged 
light exposure.
Preparation of durvalumab/placebo doses for administration with an IV bag
The dose of durvalumab/ placebo for administration must be prepared by the Investigator’s or 
site’s designated IP manager using aseptic technique.  Total time from needle puncture of the 
durvalumab/ placebo vial to the start of administration should not exceed: 
!
24 hours at 2°C to 8°C (36°F to 46°F)
!
4 hours at room temperature
!
If the final product is stored at both refrigerated and ambient temperatures, the total time 
should not exceed 24 hours. 
CCI
CCI
CCI
CCI
CCI
CCI


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A dose of 1500 mg (for patients >30 kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab concentration 
ranging from 1 to 15 mg/mL and delivered through an IV administration set with a 0.2- or 
0.22-μm filter. Add 30 mL (ie, 1500 mg) of investigational product to the IV bag. The IV bag 
size should be selected such that the final concentration is within 1 to 15 mg/mL. Mix the bag 
by gently inverting to ensure homogeneity of the dose in the bag.
If participant weight falls to ≤30 kg weight-based dosing at 20 mg/kg will be administered 
using an IV bag size selected such that the final concentration is within 1 to 15 mg/mL.
Standard infusion time is one hour, however if there are interruptions, the total allowed time 
should not exceed 8 hours at room temperature.  
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed according to local practices to ensure the full dose is administered.  
Infusion time does not include the final flush time.
If either preparation time or infusion time exceeds the time limits, a new dose must be 
prepared from new vials. Durvalumab and placebo do not contain preservatives, and any 
unused portion must be discarded.
6.1.2.2
Standard of care chemotherapy
The SoC agent(s) will either be locally sourced or centrally supplied by AstraZeneca and will 
be administered according to prescribing information or treatment guidance in general use by 
the investigating site. Under certain circumstances when local sourcing is not feasible, 
AstraZeneca will centrally supply the drug and it will be labeled with local language 
translated text in accordance with regulatory guidelines.
6.1.3
Dosage and treatment regimens
The full dosing scheme by treatment arm throughout the 12-month treatment period is shown 
in Figure 3 and described in the following sections.


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Figure 3
Dosing scheme
q3w x 4 cycles
q4w x 10 cyclesa
a
At the discretion of the Investigator, eligible patients may receive PORT during the durvalumab/placebo 
monotherapy phase (see Section 6.4.1).
Note: Each treatment will be administered on Day 1 of each cycle, as indicated by the arrows. 
IP  Investigational product; PORT  Postoperative radiation therapy; q3w  Every 3 weeks; q4w  Every 4 weeks; 
SoC  Standard of care.
6.1.3.1
Durvalumab or placebo
Patients in the durvalumab or placebo arm will receive 1500 mg durvalumab or placebo via IV 
infusion q3w for 4 cycles then q4w for 10 cycles (for a total of 12 months of treatment) with 
the last administration on Week 48 or until disease recurrence (whichever occurs first) unless 


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there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is 
met. See Figure 3. (Please note, if a patient’s weight falls to 30 kg or below [≤30 kg], the 
patient should receive weight-based dosing equivalent to 20 mg/kg of durvalumab or placebo 
q3w or q4w after consultation between Investigator and Study Physician, until the weight 
improves to >30 kg, at which point the patient should start receiving the fixed dosing of 
durvalumab 1500 mg or placebo q3w or q4w). 
6.1.3.2
Standard of care
SoC chemotherapy will consist of 4 cycles of carboplatin + paclitaxel or cisplatin/carboplatin 
+ pemetrexed administered q3w, depending on tumor histology (per NCCN guidelines; 
NCCN 2019) and Investigator’s discretion, as summarized in Table 8 and Figure 3. 
6.1.4
Duration of treatment 
All treatment will be administered beginning on Day 1 for up to 4 cycles (q3w) of durvalumab 
or placebo plus SoC chemotherapy, then continuing q4w for up to 10 additional cycles (for a 
total of 12 months of treatment) of durvalumab monotherapy or placebo, unless there is 
unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. 
Treatment will be stopped when a patient has received a total of 12 months of therapy 
(14 cycles of treatment) or upon evidence of RECIST 1.1-defined disease recurrence, 
whichever occurs first. 
Crossover within the study will not be permitted.
Patients who AstraZeneca and/or the Investigator determine may not continue treatment after 
RECIST 1.1-defined disease recurrence will be followed up for survival until completion of 
the study. Patients who have discontinued treatment due to toxicity or symptomatic 
deterioration, or who have commenced subsequent anticancer therapy, will be followed up 
with tumor assessments until RECIST 1.1-defined disease recurrence, until death, or until 
DCO (whichever occurs first). The DCO for the primary DFS analysis will follow last patient 
last visit. See Section 4.1.1 for the order of events following last patient last visit.
Patients may not receive retreatment in this study.
6.1.5
Storage
The Investigator, or an approved representative (eg, pharmacist), will ensure that all IP is 
stored in a secured area, in refrigerated temperatures (2°C to 8°C), and in accordance with 
applicable regulatory requirements. A temperature log will be used to record the temperature 
of the storage area. Temperature excursions outside the permissible range listed in the clinical 
supply packaging are to be reported to the monitor upon detection. A calibrated temperature 


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monitoring device will be used to record the temperature conditions in the drug storage 
facility. Storage conditions stated in the IB may be superseded by the label storage.
The IP label on the pack/bottle/carton for SoC specifies the appropriate storage for these 
agents.  
6.2
Measures to minimize bias: randomization and blinding
6.2.1
Patient enrollment and randomization
All patients will be centrally assigned to randomized study treatment using an IWRS. Before 
the study is initiated, the log-in information and directions for the IWRS will be provided to 
each site. 
If a patient withdraws from the study, then his/her enrollment/randomization code cannot be 
reused. Withdrawn patients will not be replaced.
Investigators should keep a record (ie, the patient screening log) of patients who entered 
screening. 
This study will use a 2-tiered consent process. The signing of ICF1 will initiate the first 
screening, which includes procedures conducted prior to surgery and/or post-surgery through 
determination of MRD status, as outlined in Table 1. The signing of ICF2 will initiate the 
second screening procedures required for randomization and will also include the treatment 
and follow-up periods, as outlined in Table 2 and Table 3. 
After confirmation of NSCLC diagnosis and prior to surgery, the Investigators or suitably 
trained delegate will:
!
Obtain signed ICF1 before any study-specific first screening procedures are performed.  
!
Obtain a unique 7-digit enrollment number (E-code), via the IWRS in the following 
format: ECCNNXXX (with CC being the country code, NN being the center number, and 
XXX being the patient enrollment code at the center). This number is the patient’s unique 
identifier and is used to identify the patient on the eCRFs. 
!
Determine eligibility based on the criteria outlined in the SoAs in Table 1, Table 4, and 
Table 5, and Sections 5.1 and 5.2. 
∀
This will include EGFR/ALK and PD-L1 testing, obtaining a whole blood sample and 
resected tumor tissue for development of the personalized panel, and obtaining a 
post-surgical plasma sample to assess MRD status. 
∀
NOTE: Surgery is not a study-specific procedure. However, patients will need to 
sign ICF1 to give the Sponsor access to complete surgical information and obtain 
resected tumor tissue for this study.


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After determination of MRD status, patients will sign ICF2 and enter the second screening 
period (Days -28 to 0 relative to randomization). Randomization is allowed up to 12 weeks 
(+7 days) following surgery. If randomization cannot occur within this timeframe, the patient 
is ineligible for the study. During the second screening, the Investigator or suitably trained 
delegate will: 
!
Obtain signed ICF2 before any study-specific procedures outlined in the SoAs in Table 2
are performed. If laboratory or imaging procedures were performed for alternate reasons 
prior to signing consent, these can be used for screening purposes with consent of the 
patient. However, all second screening laboratory and imaging results required for final 
eligibility (specified in Table 2) must have been obtained within 28 days (+7 days) prior 
to randomization. 
!
Determine patient eligibility based on study procedures conducted during second 
screening (see Table 2 and Sections 5.1 and 5.2)
!
Obtain signed informed consent for optional genetic research study (optional) 
At randomization, once the patient is confirmed to be eligible, the Investigator or suitably 
trained delegate will:
!
Randomize the patient in IWRS. Numbers will be assigned strictly sequentially by IWRS 
as patients are eligible for entry into the study. The system will randomize the eligible 
patient to 1 of the 2 treatment groups. 
If the patient is ineligible and not randomized, the IWRS should be contacted as soon as 
possible to screen fail the patient and terminate the patient in the system. Screen failures can 
occur at any time during first or second screening, including prior to determination of a 
patient’s MRD status (see Section 5.4).
Patients will begin treatment on Day 1. Treatment should start no more than 3 days after being 
randomized. Patients must not be randomized and treated unless all eligibility criteria have 
been met. 
6.2.2
Procedures for handling incorrectly enrolled or randomized patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Patients who are 
enrolled, but subsequently found not to meet all the eligibility criteria must not be randomized 
or initiated on treatment, and must be withdrawn (ie, screen-failed) from the study.
Where a patient does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the Study Physician 
immediately, and a discussion should occur between the Physician and the Investigator 
regarding whether to continue or discontinue the patient from treatment. The Study Physician 


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must ensure all decisions are appropriately documented and that the potential benefit:risk 
profile remains positive for the patient.
Patients may not be re-randomized into the study.
6.2.3
Methods for assigning treatment groups
The actual treatment given to patients will be determined by the randomization scheme in the 
IWRS. The randomization scheme will be produced by a computer software program that 
incorporates a standard procedure for generating randomization numbers. One randomization 
list will be produced for each of the randomization strata. A blocked randomization will be 
generated, and all centers will use the same list in order to minimize any imbalance in the 
number of patients assigned to each treatment group. 
Patients will be identified to the IWRS per country regulations. Randomization codes will be 
assigned strictly sequentially, within each stratum, as patients become eligible for 
randomization. The IWRS will provide the kit identification number to be allocated to the 
patient at the randomization visit and subsequent treatment visits. 
6.2.4
Methods for ensuring blinding
The study is being conducted in a double-blind fashion. Investigator, study team, and Sponsor 
will be fully blinded to all treatment.
The IWRS will provide to the Investigator(s) or pharmacist(s) (or a trained delegate) the kit 
identification number to be allocated to the patient at the dispensing visit.
Routines for this will be described in the IWRS user manual that will be provided to each 
center.
The randomization code should not be broken except in medical emergencies and/or when the 
appropriate management of the patient requires knowledge of the treatment randomization. 
The Investigator documents and reports the action to AstraZeneca, without revealing the 
treatment given to the patient to AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities. Randomization codes will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual patient have been 
made and documented.
The IWRS will provide to the Investigator and pharmacist(s) or a trained delegate the kit 
identification number to be allocated to the patient at the dispensing visit. Blinded access and 


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notifications will be controlled using the IWRS. Investigators will remain blinded to each 
patient’s assigned study treatment throughout the course of the study. 
In the event that the treatment allocation for a patient becomes known to the Investigator or 
other study staff involved in the management of study patients, or needs to be known to treat 
an individual patient for an AE, the Sponsor must be notified promptly by the Investigator 
and, if possible, before unblinding. In addition to blinding to treatment, Investigators will be 
blinded to the patient’s PD-L1 status. 
Please note that Investigators will not be notified of the patient’s MRD status to limit potential 
bias upon interpreting the scans. If an Investigator becomes unblinded to treatment allocation, 
it is not necessary to also notify the Investigator regarding the patient’s MRD status, as this 
information is not necessary to inform treatment decisions.
6.2.5
Methods for unblinding
The IWRS will be programmed with blind-breaking instructions. The blind may be broken if, 
in the opinion of the Investigator, it is in the patient’s best interest for the Investigator to know 
the study treatment assignment. The Sponsor must be notified before the blind is broken 
unless identification of the study treatment is required for a medical emergency in which the 
knowledge of the specific blinded study treatment will affect the immediate management of 
the patient’s condition (eg, antidote available). In this case, the Sponsor must be notified 
within 24 hours after breaking the blind. The date and reason that the blind was broken must 
be recorded in the source documentation and eCRF. 
If the Investigator requests to be unblinded to the patient’s study treatment assignment, they 
will also be automatically unblinded to the patient’s PD-L1 status. The patient’s MRD status 
will not be unblinded at the time of treatment unblinding.
If the blind is broken, a patient should continue to be followed up per the schedule of 
assessments outlined in Table 3.
Study unblinding should not occur until DBL and all decisions on the evaluability of the data 
from each individual patient have been made and documented.
6.3
Treatment compliance
The administration of IP should be recorded in the appropriate sections of the eCRF. 
Any dose reductions (applicable for SoC chemotherapy only), change from the dosing 
schedule, dose delays/interruptions, and dose discontinuations should be recorded in the 
eCRF.
Treatment compliance will be ensured by reconciliation of site drug accountability logs. 


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The Investigational Product Storage Manager is responsible for managing the IP from receipt 
by the study site until the destruction or return of all unused IP.
6.4
Concomitant therapy
Concomitant medications should only be recorded during the first screening period in the 
eCRF if an SAE has been reported (Table 1). Note: During first screening, only SAEs related 
to study procedures (ie, blood draws and [if performed during first screening] the post-surgical 
scan) must be reported. 
The Investigator must be informed as soon as possible about any medication taken from the 
time of the second screening until the end of the clinical treatment phase of the study, 
including the 90-day follow-up period following the last dose of IP (Table 2 and Table 3). 
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements, that the patient is receiving at the time of enrollment or receives 
during the study, must be recorded along with:
!
Reason for use
!
Dates of administration, including start and end dates
!
Dosage information, including dose and frequency
Patients must be instructed not to take any medications, including herbal medication and 
over-the-counter products, without first consulting with the Investigator.
Restricted, prohibited, and permitted concomitant medications are described in Table 9 and 
Table 10. Refer also to the Dosing Modification and Toxicity Management Guidelines (see 
Section 8.4.5). For agents in the SoC chemotherapy group, please refer to the local prescribing 
information with regard to warnings, precautions, and contraindications.
Table 9
Prohibited concomitant medications for all treatment arms
Prohibited medication/class of drug:
Usage:
Any investigational anticancer therapy other than 
those under investigation in this study
Should not be given concomitantly whilst the patient is on 
study treatment
mAbs against CTLA-4, PD-1, or PD-L1 other than 
those under investigation in this study
Should not be given concomitantly whilst the patient is on 
study treatment
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal therapy 
for cancer treatment other than those under 
investigation in this study
Should not be given concomitantly whilst the patient is on 
study treatment. Concurrent use of hormones for 
non-cancer-related conditions (eg, insulin for diabetes and 
hormone replacement therapy) is acceptable. 
Exception is made for patients who are eligible for PORT 
therapy, provided the radiotherapy is given after 
chemotherapy has been completed (Section 6.4.1)


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Table 9
Prohibited concomitant medications for all treatment arms
Prohibited medication/class of drug:
Usage:
Live attenuated vaccines 
Should not be given through 30 days after the last dose of 
IP
Immunosuppressive medications including, but not 
limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or equivalent 
methotrexate, azathioprine, and tumor necrosis 
factor – alpha blockers
Should not be given concomitantly or used for 
premedication prior to the IO infusions. The following are 
allowed exceptions:
•
Use of immunosuppressive medications for the 
management of IP-related AEs
•
Short-term premedication for patients receiving 
chemotherapya where the prescribing information for 
the agent requires the use of steroids for documented 
hypersensitivity reactions
•
Use in patients with contrast allergies
•
Use of inhaled, topical, and intranasal corticosteroids 
is permitted.
A temporary period of steroids will be allowed if clinically 
indicated and considered to be essential for the 
management of non-immunotherapy-related events 
experienced by the patient (eg, chronic obstructive 
pulmonary disease, radiation, nausea, etc).
Drugs with laxative properties and herbal or natural 
remedies for constipation
Should be used with caution through to 30 days after the 
last dose of IP
EGFR TKIs
Should not be given concomitantly while the patient is on 
study treatment
Should be used with caution in the 90 days post last dose 
of durvalumab
Increased incidences of pneumonitis (with third generation 
EGFR TKIs) and increased incidence of transaminase 
increases (with first generation EGFR TKIs) has been 
reported when durvalumab has been given concomitantly.
Herbal and natural remedies, which may have 
immune-modulating effects
Should not be given concomitantly unless agreed by the 
Sponsor
Antibiotics 
Should not be used within 30 days prior to randomizationb
a
Note: Alternative anti-emetic pre-medication should be prioritised in place of steroids (eg, 5-HT3 
inhibitors, neurokinin inhibitors). Where steroid pre-medication is utilised, steroid doses should be 
administered in line with the Multinational Association of Supportive Care in Cancer (MASCC) 
guidelines (Rolia et al 2016).
b
Pinato et al 2019
AE  Adverse event; CTLA-4 Cytotoxic T-lymphocyte-associated antigen 4; IO Immuno-oncologic therapy; IP  
Investigational product; mAbs  Monoclonal antibodies; PD-1  Programmed cell death 1; PD-L1  Programmed 
cell death-ligand 1; PORT Postoperative radiation therapy; TKI Tyrosine kinase inhibitor.


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Table 10
Supportive medications
Supportive medication/class of drug:
Usage:
Post-operative radiation therapy (PORT) for 
pathologically confirmed N2 lesions following 
adjuvant chemotherapy; concurrent chemo-
radiation is not permitted
To be administered at the discretion of the Investigator, 
only after chemotherapy has been completed, but permitted 
during durvalumab/placebo maintenance.
Please refer to Section 6.4.1
Concomitant medications or treatments (eg, 
acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications 
identified as “prohibited,” as listed above 
To be administered as prescribed by the Investigator
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy to 
non-target lesions, etc])
Should be used, when necessary, for all patients
Please note restrictions in Table 9 regarding antibiotic 
usage prior to randomization 
Inactivated viruses, such as those in the influenza 
vaccine
Permitted
6.4.1
Postoperative radiotherapy standardized guidance
Patients with pathologically confirmed N2 disease or positive pleural margins may receive 
adjuvant postoperative radiation therapy (PORT) at the discretion of the Investigator, provided 
that PORT is given sequential to chemotherapy (ie, during durvalumab or placebo 
monotherapy) but not concurrent to chemotherapy. 
Either intensity-modulated radiation therapy (IMRT) or 3D-conformal radiotherapy is 
allowed, though IMRT is preferred.
Motion assessment is required, with motion management depending on the results of the 
motion assessment. Four-dimensional CT simulation is the preferred method for motion 
assessment. Motion management acceptable forms require that the motion management 
method employed by the participating institution reduces the effective motion of the target to 
≤10 mm. 
Daily image-guided radiotherapy is strongly recommended.
Some form of immobilization is required, with attention to patient comfort to prevent 
intra-fraction motion. Patients must be immobilized in a stable position using the participating 
institution’s standard of practice. 
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6.4.2
Other concomitant treatment
Medication other than that described above, which is considered necessary for the patient’s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the eCRF.
Note: For all patients with non-squamous tumor histology scheduled to receive pemetrexed, 
folic acid and vitamin B12 should commence prior to treatment initiation for up to 7 days, in 
line with local practice. This is to ensure treatment can begin on Day 1.
6.4.3
Durvalumab drug-drug interactions
There is no information to date on drug-drug interactions with durvalumab, either 
nonclinically or in patients. As durvalumab is a mAb and therefore a protein, it will be 
degraded to small peptides and amino acids and will be eliminated by reticuloendothelial 
clearance. It is therefore not expected that durvalumab will induce or inhibit the major drug 
metabolizing cytochrome P450 pathways. As a result, there are no expected PK drug-drug 
interactions. The mechanism of action of durvalumab involves binding to PD-L1, and 
therefore significant pharmacodynamic drug interactions with the commonly administered 
concomitant medications are not expected. Despite this, appropriate clinical monitoring in all 
of the planned clinical studies will be conducted to evaluate any potential drug-drug 
interactions.
6.4.4
Rescue medication
As a result of imAEs that could potentially be experienced by patients on durvalumab, steroids 
and other immunosuppressant rescue medication has to be made available to this patient 
population. The 2 products that fall into the category of immunosuppressants are infliximab 
(eg, for colitis) and mycophenolate (eg, for hepatitis). AstraZeneca supply chain will be 
responsible for sourcing these 2 rescue medications to the sites if local regulations prevent the 
use of infliximab and mycophenolate in this indication, as they are considered off-label for 
management of immunotherapy-related toxicities. These rescue medications must be 
receipted, controlled, and dispensed by the pharmacist and stored according to the labeled 
storage conditions, with temperature excursions reported accordingly by the pharmacist. If 
required for use as a result of an imAE, the IWRS will provide to the pharmacists the kit 
identification number to be allocated to the patient at the time. Blinded and unblinded access 
and notifications will be controlled using the IWRS.
6.5
Dose modification
Dose delays are permitted for durvalumab (see Section 8.4.5.1). The patient should receive up 
to 14 cycles of therapy, even if a dose delay causes the treatment period to extend beyond 12 
months. 
However, dose reduction is not permitted for IO therapy.  


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Investigators should follow local standard clinical practice regarding dose modifications (dose 
delay and/or dose reductions) for the SoC treatments (chemotherapy).
6.6
Treatment after the end of study 
No further treatment will be offered after the end of study.
7
DISCONTINUATION OF TREATMENT AND SUBJECT 
WITHDRAWAL 
7.1
Discontinuation of study treatment 
An individual patient will not receive any further IP (durvalumab, placebo, and/or 
chemotherapy [SoC]) if any of the following occur in the patient in question:
!
Withdrawal of consent from further treatment with IP. The patient is, at any time, free to 
discontinue treatment, without prejudice to further treatment. A patient who discontinues 
treatment is normally expected to continue to participate in the study (eg, for safety and 
survival follow-up) unless they specifically withdraw their consent to all further 
participation in any study procedures and assessments (see Section 7.3). 
!
An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates further 
dosing
!
Any AE that meets criteria for discontinuation as defined in the Dosing Modification and 
Toxicity Management Guidelines (see Section 8.4.5.1) or as defined in the local 
prescribing information for the SoC agents
!
Pregnancy or intent to become pregnant
!
Non-compliance with the CSP that, in the opinion of the Investigator or AstraZeneca, 
warrants withdrawal from treatment with IP (eg, refusal to adhere to scheduled visits)
!
Initiation of alternative anticancer therapy, including another investigational agent
!
Documented disease recurrence (refer to Section 8.1.1.1 and Appendix G) and 
Investigator determination that the patient is no longer benefiting from treatment with IP
!
Completion of 12 months (14 cycles) of treatment
In the event that durvalumab/placebo is permanently discontinued due to treatment-related 
toxicity, chemotherapy may still be administered as scheduled. In the event that chemotherapy 
is permanently discontinued due to treatment-related toxicity, durvalumab/placebo may still 
be administered as scheduled. Treatment decisions should be made at the Investigator’s 
discretion and AstraZeneca should be consulted.
7.1.1
Procedures for discontinuation of study treatment
At any time, patients are free to discontinue treatment, without prejudice to further treatment.


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Patients can discontinue durvalumab/placebo and continue with SoC chemotherapy through 
the planned 4 cycles. Patients can discontinue SoC chemotherapy and still continue with 
durvalumab/placebo. In both cases, patients will still be considered on study treatment while 
they receive either SoC chemotherapy or durvalumab/placebo. 
Discontinuation of study treatment, for any reason, does not impact the patient’s participation 
in the study. A patient who decides to discontinue IP will always be asked about the reason(s) 
for discontinuation and the presence of any AE. The patient should continue attending 
subsequent study visits, and data collection should continue according to the CSP. If the 
patient does not agree to continue in-person study visits, a modified follow-up must be 
arranged to ensure the collection of endpoints and safety information. This follow-up could be 
a telephone contact with the patient, a contact with a relative or treating physician, or 
information from medical records. The approach taken should be recorded in the medical 
records. A patient who agrees to modified follow-up is not considered to have withdrawn 
consent or to have withdrawn from the study.
Patients who are permanently discontinued from further receipt of any IP, regardless of the 
reason, will be identified as having permanently discontinued treatment. Patients who are 
permanently discontinued will enter follow-up (see the SoAs, Table 3). 
Patients who prematurely permanently discontinue IP prior to completing 12 months 
(14 cycles) of treatment for reasons other than disease recurrence should continue to have 
scans performed every 12 weeks (q12w) ± 1week (relative to the date of randomization) until 
primary DFS analysis or until RECIST 1.1-defined disease recurrence or death (whichever 
occurs first) as defined in the SoAs.
All patients will be followed for survival until the end of the study. 
Patients who decline to return to the site for evaluations should be contacted by telephone, as 
indicated in the SoAs as an alternative. 
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IWRS. 
7.2
Lost to follow-up
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (see Section 4.4), such that there is insufficient information to 
determine the patient’s status at that time. Patients who refuse to continue participation in the 
study, including telephone contact, should be documented as “withdrawal of consent” rather 
than “lost to follow-up.” Investigators should document attempts to re-establish contact with 
missing patients throughout the study period. If contact with a missing patient is 


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re-established, the patient should not be considered lost to follow-up and evaluations should 
resume according to the protocol.
The survival status of all patients in the FAS and the safety analysis set (SAS) should be 
re-checked; this includes those patients who withdrew consent or are classified as “lost to 
follow-up.”
!
Potentially lost to follow-up – site personnel should check hospital records, the patient’s 
current physician, and a publicly available death registry (if available) to obtain a current 
survival status. (The applicable eCRF modules will be updated.)
!
In the event that the patient has actively withdrawn consent to the processing of their 
personal data, the survival status of the patient can be obtained by site personnel from 
publicly available death registries (if available) where it is possible to do so under 
applicable local laws to obtain a current survival status. (The applicable eCRF modules 
will be updated.)
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
!
The site must attempt to contact the patient and reschedule the missed visit as soon as
possible and counsel the patient on the importance of maintaining the assigned visit
schedule.
!
Before a patient is deemed lost to follow-up, the Investigator or designee must make
every effort to regain contact with the patient or next of kin by, for example, repeat
telephone calls, certified letter to the patient’s last known mailing address, or local
equivalent methods. These contact attempts should be documented in the patient’s
medical record.
!
Efforts to reach the patient should continue until the end of the study. Should the patient 
be unreachable at the end of the study, the patient should be considered to be lost to 
follow-up with unknown vital status at the end of the study and censored at the latest 
follow-up contact.
7.3
Withdrawal from the study
Patients are free to withdraw from the study at any time (IP and assessments) without 
prejudice to further treatment.
Patients who withdraw consent for further participation in the study will not receive any 
further IP or further study observation, with the exception of follow-up for survival, which 
will continue until the end of the study unless the patient has expressly withdrawn their 
consent to survival follow-up. Note that the patient may be offered additional tests or tapering 
of treatment to withdraw safely.


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A patient who withdraws consent will always be asked about the reason(s) for withdrawal and 
the presence of any AE. The Investigator will follow up AEs outside of the clinical study. 
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent 
to:
!
All further participation in the study, including any further follow up (eg, survival contact 
telephone calls)
!
Withdrawal to the use of any samples (see Section 8.7.3).
Given potential changes in SoC treatments available to patients, Investigators should continue 
to assess, and discuss with patients, the potential risks and benefits associated with ongoing 
study participation and ensure the nature and outcomes of these discussions are recorded in 
the source documentation. 
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoAs (Table 1, Table 2, and 
Table 3).  
The Investigator will ensure that data are recorded on the eCRFs. The RAVE Web Based Data 
Capture (WBDC) system will be used for data collection and query handling.  
The Investigator ensures the accuracy, completeness, legibility, and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement. The Investigator will sign the completed eCRFs. A copy of the completed eCRFs 
will be archived at the study site.
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
treatment.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  
Procedures conducted as part of the patient’s routine clinical management (eg, blood count) 
and obtained before signing of ICF1 and/or ICF2 may be utilized for screening or baseline 


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purposes provided the procedures met the protocol-specified criteria and were performed 
within the timeframe defined in the SoAs.
8.1
Efficacy assessments 
The primary endpoint of DFS in the FAS will be derived using Investigator assessments 
according to the RECIST 1.1 definition of new lesions. 
Secondary efficacy endpoints will include DFS in the MRD+ analysis set, also using 
Investigator assessments according to RECIST 1.1; DFS in both MRD+ patients and the FAS; 
and OS in MRD+ analysis set and the FAS. See Section 8.1.1 for details on assessment of 
DFS. In addition, PFS, 
, and 
 are included as exploratory endpoints.
Radiological assessment of scans will be according to RECIST 1.1 guidelines for new lesions 
(Appendix G). To limit potential bias in reading the scans, Investigators will not be notified of 
the patient’s MRD status.
A “baseline” scan must be performed within 28 days + 7 days prior to randomization (Table 
2). Subsequent scans are to be performed q12w ± 1 week (relative to the date of 
randomization) until disease recurrence is recorded or until primary DFS analysis (whichever 
occurs first). If an unscheduled assessment is performed and the patient has not had disease 
recurrence, every attempt should be made to resume subsequent assessments according to the 
original imaging visit schedule. For patients who discontinue treatment due to toxicity or other 
reasons in the absence of radiological disease recurrence, disease assessments should continue 
according to the SoAs. 
8.1.1
Disease-free survival
DFS is the primary endpoint in this study and is defined as the time from the date of 
randomization until any one of the following events:
!
Disease recurrence
∀
Local, regional, or distant disease recurrence,
∀
Diagnosis of a second primary NSCLC, 
OR
!
Death from any cause
As DFS is the primary endpoint in this study, it is vital that it be adequately and precisely 
documented. 
The imaging modalities used for radiological assessments will be CT scans of the chest and 
abdomen (including liver and adrenal glands) with contrast. In the rare case where a patient is 
contrast intolerant, the preferred imaging would be CT chest without contrast and MRI 
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abdomen with contrast. Further details of the CT and MRI acquisition parameters are 
documented in the Image Acquisition Guidelines; however, a non-contrast abdominal CT will 
also be accepted. The methods used at baseline (CT or MRI) must be used at each subsequent 
follow-up assessment. 
The “baseline” scan must be performed within 28 days + 7 days prior to randomization
(Table 2). It is also required that the scan is collected before PORT, as applicable. Subsequent 
assessments are to be performed q12w until RECIST 1.1-defined disease recurrence is 
recorded or until primary DFS analysis (whichever occurs first). If a patient discontinues 
treatment prior to disease recurrence or receives other anticancer treatment, the patient should 
continue to be imaged in accordance with this schedule until disease recurrence is recorded. It 
is important to follow the assessment schedule as closely as possible. If scans are performed 
outside of the scheduled visit (±7 days window interval; unscheduled assessment) and the 
patient has not recurred, every attempt should be made to perform the subsequent scans at 
their scheduled timepoints. Any other sites at which a new disease is suspected should also be 
appropriately imaged during the study.
8.1.1.1
Evidence of disease recurrence
Disease recurrence is defined as evidence of disease recurrence on CT or MRI scan (which 
may or may not be confirmed as pathological disease on biopsy by investigational site 
assessment).
NOTE: The finding of a new lesion should be unequivocal. If a new lesion is equivocal, for 
example, because of its small size, continued therapy and follow-up evaluation will clarify if it 
truly represents new disease. If repeat scans (scheduled or unscheduled per Investigator 
discretion [if unscheduled, a minimum of 6 weeks between scans is recommended]) 
definitively confirm there is a new lesion, then recurrence should be declared using the date of 
the initial scan where the equivocal new lesion was first identified.
NOTE: Please refer to Appendix G for further guidance on defining disease recurrence.
NOTE: Invasive biopsy is recommended for all cases of disease recurrence.
Recurrence will be categorized as local/regional, distant, or second primary NSCLC. When 
recurrence is first documented at any site, complete restaging is required to identify all sites of 
recurrence.
Local or regional recurrence
Local or regional recurrence is defined as recurrence in the area of the tumor bed, hilum, or 
mediastinal lymph nodes. Loco-regional recurrence of the disease should be 
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Distant recurrence
Distant recurrence is defined as spread of disease beyond the area of the tumor bed, hilum, or 
mediastinal lymph nodes and can describe extrathoracic disease, metastasis to the contralateral 
lung, pleural metastasis, pleural effusion, or pericardial effusion. Distant recurrence should be 
diagnosed by radiological examination and/or histopathological confirmation when the 
metastatic lesion is easily accessible for biopsy.
Second primary NSCLC 
Second primary NSCLC is defined as diagnosis of a new primary invasive NSCLC and should 
be pathologically or molecularly defined. A new cancer other than NSCLC is defined as 
diagnosis of a new malignancy excluding second primary NSCLC or recurrent NSCLC and 
should be pathologically defined as well. 
If the site is unsure whether a new lesion represents NSCLC recurrence, a second primary 
NSCLC, or a new malignancy, a tissue biopsy should be performed to characterize the nature 
of the new lesion. If a new lesion cannot be unequivocally confirmed as a second primary 
NSCLC or a new malignancy other than NSCLC by tissue analysis, the new lesion should be 
considered a NSCLC recurrence and documented as such. 
The development of a new cancer other than NSCLC should be regarded as an SAE (see 
Section 8.3.10). 
8.1.1.2
Dating of recurrence
Dating of recurrence should always be based on the first onset of a sign but never on the onset 
of a symptom. The date of first detection of a palpable lesion is acceptable only when the 
diagnosis of tumor involvement is subsequently established. The diagnosis of recurrent 
disease by radiographs or scans should be dated from the date of the first positive record (ie, 
the first time the lesion was observed, even if it was marked as equivocal at the initial 
observation), even if this is determined in retrospect or tissue confirmation occurs subsequent 
to the initial appearance of a suspicious area/lesion on a scan (see Appendix G for additional 
details).
If there is equivocal progression, and the site is unsure whether to consider this a DFS event, 
the medical monitor/Study Physician should be contacted. 
8.1.1.3
Post-recurrence
Following recurrence, patient management is at the discretion of the Investigator, and tumor 
assessments will be in accordance with local policy. Date of the first subsequent progression 
as indicated in the SoAs (Table 2 and Table 3) will be collected per local practice, assessed by 
the Investigator, and entered into the database.


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8.1.2
Computed tomography and magnetic resonance imaging
Efficacy evaluation of DFS will be derived using Investigator assessments according to 
RECIST 1.1. The management of patients will be based solely upon the results of the 
RECIST 1.1 assessment conducted by the Investigator. 
8.1.2.1
Central reading of scans
Images, including unscheduled visit scans, may be collected on an ongoing basis and sent to 
an AstraZeneca-appointed imaging Contract Research Organization (iCRO) for quality 
control, storage, and for BICR. Guidelines for image acquisition, de-identification, storage of 
digital copies at the investigative site (as source documents), and transfer to the iCRO will be 
provided in a separate document. Electronic image transfer from the sites to the iCRO is 
strongly encouraged. Image collection will occur for all patients until the last patient last visit. 
A BICR of images may be performed at the discretion of AstraZeneca. Results of these 
independent reviews will not be communicated to Investigators, and results of Investigator 
RECIST 1.1 assessments will not be shared with the central reviewers. The management of 
patients will be based in part upon the results of the RECIST 1.1 assessment conducted by the 
Investigator. Further details of the BICR will be documented in the Independent Review 
Charter.
8.1.3
Survival assessments
Survival assessments must be made according to the schedule in Table 3 following treatment 
discontinuation. Survival information may be obtained via telephone contact with the patient 
or the patient’s family, or by contact with the patient’s current physician. 
The details of first and subsequent therapies for cancer, after discontinuation of treatment, will 
be collected. 
In addition, patients on treatment or in survival follow-up will be contacted following the 
DCO for the primary analysis and all subsequent survival analyses to provide complete 
survival data. These contacts should generally occur within 7 days of the DCO.
8.1.4
Clinical outcome assessments
A Clinical Outcome Assessment (COA) is any assessment that may be influenced by human 
choices, judgment, or motivation and may support either direct or indirect evidence of 
treatment benefit. PROs are a type of COA. PRO, an umbrella term referring to all outcomes 
and symptoms, is directly reported by the patient. PRO has become a significant endpoint 
when evaluating effectiveness of treatments in clinical studies. The following PROs have been 
administered in this study: EORTC QLQ-C30; EORTC QLQ-LC13, 
,
, 
, and 
 (see Appendix I). Each is described below.
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PRO assessments will no longer be performed under CSP V4.0. Analyses of PRO data will be 
performed on data collected up to and including CSP V3.0.
8.1.4.1
EORTC QLQ-C30 and EORTC QLQ-LC13 
The EORTC QLQ-C30 was developed by the EORTC Quality of Life Group in 1993. It 
consists of 30 items and measures symptoms, functioning, and global health status/quality of 
life (GHS/QoL) (Aaronson et al 1993) for all cancer types. Questions are grouped into 
5 multi-item functional scales (physical, role, emotional, cognitive, and social); 3 multi-item 
symptom scales (fatigue, pain, and nausea and vomiting); a 2-item GHS/QoL scale; 5 single 
items assessing additional symptoms commonly reported by cancer patients (dyspnea, loss of 
appetite, insomnia, constipation, and diarrhea); and 1 item on the financial impact of the 
disease. The EORTC QLQ C30 is a valid and reliable PRO instrument in this patient 
population (see Appendix I).
The EORTC QLQ-LC13 is a well-validated complementary module measuring lung 
cancer-associated symptoms (Bergman et al 1994). The EORTC QLQ-LC13 includes 
questions assessing cough, hemoptysis, dyspnea, site-specific pain, sore mouth, dysphagia, 
peripheral neuropathy, alopecia, and pain medication (see Appendix I).
8.1.4.2
 
The 
 will be used to explore the impact of treatment and disease state on health 
state utility.
The 
, developed by the 
, is a generic questionnaire that provides a 
simple descriptive profile of health and a single index value for health status for economic 
appraisal (
). The 
 questionnaire comprises  questions that 
cover  dimensions of health 
 
 
 
8.1.4.3
 
 
 
 
 
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8.1.4.4
 
 
 
 
 
 
 
 
 
 
 
 
8.1.4.5
Administration of patient-reported outcome questionnaires (not applicable 
from CSP V4.0)
The PRO instruments will be self-administered by the patients using a handheld electronic 
device. Patients will start to report PROs on Cycle 1 Day 1 before dosing (baseline 
assessments), to ensure that the device is correctly set up and working properly. 
Thereafter, PRO assessments should be completed by the patients at home according to the 
SoAs in Table 2 and Table 3. Multiple PRO assessments scheduled for the same time do not 
have to be completed on the same day, but should be completed within a window of ±3 days.
The instructions below should be followed when collecting PRO data via an electronic device:
!
The research nurse or appointed site staff must explain to patients the value and relevance 
of electronic patient-reported outcomes (ePRO) participation so they are motivated to 
comply with questionnaire completion and inform the patient that these questions are 
being asked to find out, directly from them, how they feel.
!
PRO questionnaires must be completed prior to treatment administration and before 
discussion of health status to avoid biasing the patient’s responses to the questions.
!
Each site must allocate the responsibility for the administration of the ePRO instruments 
to a specific individual (eg, a research nurse or study coordinator) and, if possible, assign 
a back-up person to cover if that individual is absent.
!
The research nurse or appointed site staff should stress that the information is not 
routinely shared with study staff. Therefore, if the patient has any medical problems, they 
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should discuss them with the doctor or research nurse separately from the ePRO 
assessment. 
!
The research nurse or appointed site staff must remind patients that there are no right or 
wrong answers and avoid introducing bias by not clarifying items. The patient should not 
receive help from relatives, friends, or clinic staff to answer the PRO questionnaires. The 
patients should be given sufficient time to complete the PRO questionnaires at their own 
speed.
!
The research nurse or appointed site staff must train the patient on how to use the ePRO 
device using the materials and training provided with the ePRO device.
!
The research nurse or appointed site staff must provide guidance on whom to call if there 
are problems with the device if the patient is completing the ePRO at home. 
!
All questionnaires must be completed using the ePRO device. If technical or other 
device-related issues prohibit completion on the device, an appropriate back-up option 
may be considered with prior approval from AstraZeneca.
!
If the patient is unable to read the questionnaire (eg, is blind or illiterate), that patient 
should be exempted from completing PRO questionnaires but may still participate in the 
study. Patients exempted in this regard should be flagged appropriately by the site staff in 
the source documents and in the eCRF.
A key aspect of study success is to have high PRO compliance. To minimize missing data, 
compliance must be checked and discussed with the patient at each site visit, and the reason(s) 
why the patient could not complete assessments should be documented in source documents 
and in the eCRF. 
8.2
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoAs (Table 2 and Table 3).
8.2.1
Clinical safety laboratory assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken at the times indicated in the assessment schedules and as clinically indicated (see 
the SoAs [Table 2 and Table 3]). 
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a 
licensed clinical laboratory according to local standard procedures. Sample tubes and sample 
sizes may vary depending on the laboratory method used and routine practice at the site. 
Pregnancy tests may be performed at the site using a licensed test (urine or serum pregnancy
test). Abnormal clinically significant laboratory results should be repeated as soon as possible 
(preferably within 24 to 48 hours).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection, and results (values, units, and reference ranges) will 
be recorded on the appropriate eCRF.


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The laboratory variables to be measured are presented in Table 11 (clinical chemistry), 
Table 12 (hematology), and Table 13 (urinalysis).
Other safety tests to be performed at screening include assessment for HBsAg, HCV 
antibodies, and HIV antibodies.  If negative HIV and hepatitis serology was determined 
during the first screening period, re-testing during the second screening period is not 
necessary, provided the patient is not at high risk for infection.
The following laboratory variables will be measured:
Table 11
Clinical chemistry
Albumin
Lipaseb
Alkaline phosphatase
Magnesiumc
ALTa
Potassium
Amylaseb
Sodium
ASTa
Total bilirubina
Bicarbonatec
Total protein
Calcium 
TSHe
Chloridec
T3 freef (reflex)
Creatinined
T4 freef (reflex)
Gamma glutamyltransferasec
Urea or blood urea nitrogen, depending on local practice
Glucose
Lactate dehydrogenase
a
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently. 
If total bilirubin is ≥2 × upper limit of normal (and no evidence of Gilbert’s syndrome), then fractionate into 
direct and indirect bilirubin.
b
It is preferable that both amylase and lipase parameters are assessed. For sites where only 1 of these 
parameters is routinely measured, either lipase or amylase is acceptable.
c
Bicarbonate (where available), chloride, creatinine clearance, gamma glutamyltransferase, and magnesium 
testing are to be performed at baseline, on Day 1 (unless all screening laboratory clinical chemistry 
assessments are performed within 3 days prior to Day 1), and if clinically indicated.
d
Creatinine clearance will be calculated by data management using Cockcroft-Gault (using actual body 
weight). 
e
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at 
Day 1.
f
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE 
related to the endocrine system.
AE  Adverse event; ALT Alanine aminotransferase; AST Aspartate aminotransferase, TSH Thyroid-stimulating 
hormone.
Table 12
Hematology
Absolute neutrophil counta
Absolute lymphocyte counta
Hemoglobin
Platelet count
Total white cell count


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a
Can be recorded as absolute counts or as percentages. Absolute counts will be calculated by Data 
Management if entered as percentage. Total white cell count therefore has to be provided.
Note: For coagulation parameters, activated partial thromboplastin time (either as a ratio or as an absolute value, 
in seconds) and international normalized ratio are to be assessed at baseline on Day 1 (unless all screening 
laboratory hematology assessments are performed within 3 days prior to Day 1), and as clinically indicated.
Table 13
Urinalysis
Bilirubin
Ketones
Blood
pH
Color and appearance
Protein
Glucose
Specific gravity
Note: Urinalysis should be done at baseline (screening) and then as clinically indicated.
Note: Microscopy is preferred to investigate white blood cells with the use of high-power field for red and white 
blood cells; dipstick can be used as well. 
If a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, refer to 
Appendix F for further instructions on cases of increases in liver biochemistry and evaluation 
of Hy’s Law. These cases should be reported as SAEs if, after evaluation, they meet the 
criteria for a Hy’s Law case or if any of the individual liver test parameters fulfill any of the 
SAE criteria. 
All patients should have further chemistry profiles performed at 30 days (±3 days), 2 months 
(±1 week), and 3 months (±1 week) after permanent discontinuation of IP (see the SoAs in 
Table 3).
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF. Situations in which laboratory safety results should be 
reported as AEs are described in Section 8.3.7.
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from IP must have further tests performed until the laboratory values have returned to Grade 1 
or 2, unless these values are not likely to improve because of the underlying disease.
8.2.2
Medical history
Medical history information will be obtained only in the event of a reported SAE during the 
first screening period (Table 1).
A complete medical history will be obtained at the second screening (Table 2); findings from 
current medical history will be assigned a baseline grade according to NCI CTCAE 
Version 5.0 guidelines, whenever applicable. As a result, increases in severity of pre-existing 
conditions during the study will be considered AEs, with resolution occurring when the grade 
returns to the baseline grade or below.


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8.2.3
Physical examinations
No physical examination will be performed during the first screening (initiated by the signing 
of ICF1).
Physical examinations will be performed according to the assessment schedules (see the SoAs 
[Table 2 and Table 3]). Full physical examinations will include assessments of the head, eyes, 
ears, nose, and throat and the respiratory, cardiovascular, gastrointestinal, urogenital, 
musculoskeletal, neurological, dermatological, hematologic/lymphatic, and endocrine 
systems. Height will be measured at the second screening only (initiated by the signing of 
ICF2). Targeted physical examinations are to be utilized by the Investigator on the basis of 
clinical observations and symptomatology. Situations in which physical examination results 
should be reported as AEs are described in Section 8.3.7. 
8.2.4
Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the SoAs (Table 2 and Table 3). Body weight is also recorded at each visit along 
with vital signs.
First infusion of durvalumab/placebo
On the first infusion day, patients in the durvalumab/placebo group will be monitored and 
vital signs collected/recorded in the eCRF prior to, during, and after infusion of IP as 
presented in the bulleted list below. 
BP and pulse will be collected from patients before, during, and after each infusion at the 
following times (based on a 60-minute infusion):
!
Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minutes [ie, the beginning of the infusion])
!
Approximately 30 minutes (±5 minutes) during the infusion (halfway through infusion) 
!
At the end of the infusion (approximately 60 minutes ±5 minutes)
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow 
the principles as described above or be taken more frequently if clinically indicated. A 1-hour 
observation period is recommended after the first infusion of durvalumab. If there are no 
clinically significant concerns after the first cycle, reducing the observation period after 
durvalumab administration to 30 minutes is recommended, at the Investigator’s discretion.
Subsequent infusions of durvalumab/placebo
BP, pulse, and other vital signs should be measured, collected/recorded in the eCRF 
≤30 minutes prior to the start of the infusion. Patients should be carefully monitored and BP 
and other vital signs should be measured during and post infusion as per institution standard 


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and as clinically indicated. Any clinically significant changes in vital signs should be entered 
onto an unscheduled vital signs eCRF page. 
Infusion of SoC agents
During administration of SoC agents, patients should be monitored predose and as clinically 
indicated before every infusion or administration. SoC agents should always be administered 
after completion of the observation period following the durvalumab/placebo infusions. 
Situations in which vital signs results should be reported as AEs are described in 
Section 8.3.7. For any AEs of infusion reactions, the vital signs values should be entered into 
the eCRF.
8.2.5
Electrocardiograms
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study (see the SoAs, Table 2 and Table 3). ECGs should be obtained after the patient has been 
in a supine position for 5 minutes and recorded while the patient remains in that position.
In case of clinically significant ECG abnormalities, including a QT interval corrected for heart 
rate using Fridericia’s formula (QTcF) value >470 ms, 2 additional 12-lead ECGs should be 
obtained over a brief period (eg, 30 minutes) to confirm the finding. 
Situations in which ECG results should be reported as AEs are described in Section 8.3.7.
8.2.6
Early patient review for safety
It is recommended that patients are contacted 2 weeks after receiving the first 3 cycles of 
durvalumab (Cycle 1 Day 14, Cycle 2 Day 14, and Cycle 3 Day 14) IP(s) to ensure early 
identification and management of toxicities (Table 2).
8.2.7
WHO/ECOG performance status
WHO/ECOG performance status will be assessed at the times specified in the assessment 
schedules (see the SoAs, Table 2 and Table 3) based on the following:
0
Fully active; able to carry out all usual activities without restrictions
1
Restricted in strenuous activity, but ambulatory and able to carry out light work or work 
of a sedentary nature (eg, light housework or office work)
2
Ambulatory and capable of self-care, but unable to carry out any work activities; up and 
about more than 50% of waking hours.
3
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours
4
Completely disabled; unable to carry out any self-care and totally confined to bed or chair


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5
Dead 
Any significant change from baseline or screening must be reported as an AE.
8.2.8
Other safety assessments
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormality 
suggestive of pneumonitis/ILD is observed, toxicity management as described in detail in the 
Dosing Modification and Toxicity Management Guidelines (see Section 8.4.5) will be applied. 
The results of the full diagnostic workup (including high-resolution computed tomography 
[HRCT], blood and sputum culture, hematological parameters, etc) will be captured in the 
eCRF. It is strongly recommended to perform a full diagnostic workup, to exclude alternative 
causes such as lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or 
pulmonary hemorrhage. In the presence of confirmatory HRCT scans where other causes of 
respiratory symptoms have been excluded, a diagnosis of pneumonitis (ILD) should be 
considered and the Dosing Modification and Toxicity Management Guidelines should be 
followed. 
Pneumonitis (ILD) investigation
The following assessments, and additional assessments if required, will be performed to 
enhance the investigation and diagnosis of potential cases of pneumonitis. The results of the 
assessment will be collected.
!
Physical examination
∀
Signs and symptoms (cough, shortness of breath, pyrexia, etc), including auscultation 
for lung field will be assessed.
!
Saturation of peripheral oxygen
!
Other items
∀
When pneumonitis (ILD) is suspected during study treatment, the following markers 
should be measured where possible:
o
ILD markers (KL-6, SP-D) and β-D-glucan
o
Tumor markers: Particular tumor markers that are related to disease progression 
o
Additional Clinical chemistry: C-reactive protein, lactate dehydrogenase 
8.3
Collection of adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.  


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AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legally authorized representative).  
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow up AEs, 
see Section 8.3.3.  
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.  
8.3.2
Time period and frequency for collecting AE and SAE information 
During the first screening period (ie, from the time the patient signs ICF1 but before signing 
ICF2), only SAEs related to study procedures (ie, study-specific blood draws and [if 
performed during first screening] the post-surgical scan) will be collected. All AEs and SAEs 
will be collected from the time that the patient signed ICF2 until the follow-up period is 
completed (90 days after the last dose of IP) (see Table 1 and Sections 6.4 and 8.2.2). If an 
event that starts post the defined safety follow-up period noted above is considered to be due 
to a late onset toxicity to IP, then it should be reported as an AE or SAE as applicable.
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix B. The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available.
Investigators are not obligated to actively seek AEs or SAEs in former study patients.
However, if the Investigator learns of any SAE, including a death, at any time after a patient’s 
last visit and he/she considers the event to be reasonably related to IP treatment or study 
participation, the Investigator may notify the Sponsor.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow up of adverse events and serious adverse events
After the initial AE/SAE report, the Investigator is required to proactively follow each patient 
at subsequent visits/contacts. All events will be followed until resolution, stabilization, the 
event is otherwise explained, or the patient is lost to follow-up. 
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated (this may be beyond the 90 days after last dose 


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of IP). AstraZeneca retains the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
8.3.4
Adverse event data collection
The following variables will be collected for each AE:
!
AE (verbatim)
!
The date when the AE started and stopped
!
The maximum CTCAE grade reported
!
Changes in CTCAE grade (report only the maximum CTCAE grade for a calendar day)
!
Whether the AE is serious or not
!
Investigator causality rating against the IPs (yes or no)
!
Action taken with regard to IPs
!
Administration of treatment for the AE
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for SAE
!
Date Investigator became aware of SAE
!
Seriousness criteria
!
Date of hospitalization
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Whether an autopsy was performed
!
Causality assessment in relation to study procedure(s)
!
Causality assessment to other medication, as explained in Section 8.3.5
!
Description of SAE
The grading scales found in the revised NCI CTCAE Version 5.0 will be utilized for all events 
with an assigned CTCAE grading. For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate, and severe events into 
CTCAE grades should be used. A copy of the CTCAE Version 5.0 can be downloaded from 
the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).


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8.3.5
Causality collection
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the IP?’
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure, the causal relationship 
is implied as ‘yes’.
A guide to the interpretation of the causality question can be found in Appendix B.
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the CRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.7
Adverse events based on examinations and tests
The results from the CSP-mandated laboratory tests and vital signs will be summarized in the 
Clinical Study Report (CSR). Deterioration as compared to baseline in protocol-mandated 
laboratory values and vital signs should therefore only be reported as AEs if they fulfill any of 
the SAE criteria or are the reason for discontinuation of treatment with the IP.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible, the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease recurrence, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE, unless unequivocally 
related to the disease under study (see Sections 8.3.9 and 8.3.10).


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8.3.8
Hy’s law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need 
to be reported as SAEs. Please refer to Appendix F for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law
8.3.9
Disease recurrence
Events, which are unequivocally due to disease recurrence, should not be reported as AEs 
during the study.
8.3.10
New cancers
The development of a new cancer (new non-NSCLC malignancy) should be regarded as an 
SAE. New primary cancers are those that are not the primary reason for the administration of 
the IP and have been identified after the patient’s inclusion in this study.
8.3.11
Deaths
During first screening (that is, from the time a patient signs ICF1 until they sign ICF2), only 
deaths related to study procedures (i.e. study-specific blood draws and [if performed during 
first screening] the post-surgery scan) must be reported. 
All deaths that occur after the patient has signed ICF2, including during the study treatment 
period, or within the protocol-defined follow-up period after the administration of the last 
dose of IP, must be reported as follows:
!
Death clearly resulting from disease recurrence or progression should be reported to the 
Study Monitor/Physician at the next monitoring visit and should be documented in the 
eCRF in the Statement of Death page. It should not be reported as an SAE.
!
Where death is not due (or not clearly due) to disease recurrence/progression of the 
disease under study, the AE causing the death must be reported to the Study 
Monitor/Physician as an SAE within 24 hours. It should also be documented in the 
Statement of Death page in the eCRF. The report should contain a comment regarding the 
co-involvement of PD, if appropriate, and should assign main and contributory causes of 
death.
!
Deaths with an unknown cause should always be reported as an SAE. It should also be 
documented in the Statement of Death page in the eCRF. A post mortem may be helpful 
in the assessment of the cause of death, and if performed, a copy of the post mortem 
results should be forwarded to AstraZeneca Patient Safety or its representative within the 
usual timeframes.
Deaths occurring after the protocol-defined safety follow-up period after the administration of 
the last dose of IP should be documented in the Statement of Death page in the eCRF. If the 
death occurred as a result of an event that started post the defined safety follow-up period and 


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the event is considered to be due to a late onset toxicity to IP, then it should also be reported 
as an SAE.
8.3.12
Adverse events of special interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the IP and may require close monitoring. An AESI may be serious or 
nonserious. The rapid reporting of AESIs allows ongoing surveillance of these events in order 
to characterize and understand them in association with the use of this IP.
AESIs for durvalumab include, but are not limited to, events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants, and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with durvalumab and combination 
therapy. An imAE is defined as an AESI that is associated with drug exposure and is 
consistent with an immune-mediated mechanism of action and where there is no clear 
alternative etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, 
should be used to support an imAE diagnosis. Appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. 
If the Investigator has any questions with regard to an event being an imAE, the Investigator 
should promptly contact the Study Physician.
AESIs/imAEs observed with PD-L/PD-L1 agents such as durvalumab include pneumonitis, 
hepatitis, diarrhea/colitis, intestinal perforation, endocrinopathies (hypo- and 
hyper-thyroidism, adrenal insufficiency, hypophysitis/hypopituitarism, and Type I diabetes 
mellitus), nephritis, rash/dermatitis, myocarditis, myositis/polymyositis, pancreatitis, and 
rare/less frequent imAEs, including neuromuscular toxicities such as myasthenia gravis and 
Guillain-Barré syndrome.
Other inflammatory responses that are rare/less frequent with a potential immune-mediated 
etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and other events 
involving the eye, skin, hematological, rheumatological events, vasculitis, non-infectious 
meningitis, and non-infectious encephalitis. It is possible that events with an inflammatory or 
immune-mediated mechanism could occur in nearly all organs.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology are also considered AESIs.
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the durvalumab IB. More specific guidelines for their evaluation and treatment are 
described in detail in the Dose Modification and Toxicity Management Guidelines (see 
Section 8.4.5.1). These guidelines have been prepared by the Sponsor to assist the Investigator 


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in the exercise of his/her clinical judgment in treating these types of toxicities. These 
guidelines apply to AEs considered causally related to the IP/study regimen by the reporting 
Investigator.
8.3.13
Safety data to be collected following the final DCO of the study
For patients who received the last dose of study treatment <90 days prior to the final DCO, 
AEs and SAEs will be collected at least 90 days after the last dose, but only SAEs will be 
reported. In addition, it is recommended that Investigators monitor the patient’s safety 
laboratory results periodically for at least 90 days after the last dose of study treatment in 
order to manage AEs consistent with the durvalumab Dose Modification and Toxicity 
Management Guidelines (see Section  8.4.5.1). 
All data post the final DCO and database closure will be recorded in the patient notes but, 
with the exception of SAEs, will not otherwise be reported for the purposes of this study.
All SAEs that occur in patients still receiving durvalumab treatment (or within the 90 days 
following the last dose of durvalumab treatment) post the final DCO and database closure 
must be reported as detailed in Section 8.4.1.
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
During first screening (ie, after a patient has signed ICF1 but before they have signed ICF2), 
only SAEs related to study procedures (ie, study-specific blood draws and [if performed 
during first screening] the post-surgical scan) must be reported. 
Following the signature of ICF2, all SAEs have to be reported, whether or not considered 
causally related to the IP, or to the study procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow up is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day, ie, immediately but no later than 24 hours of when he or she becomes aware of it.


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Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site staff reports an 
SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff on how to proceed.  
For further guidance on the definition of an SAE, refer to Appendix B.
8.4.1.1
Regulatory reporting requirements for SAEs
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of patients and the safety of a study 
intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRBs)/Independent Ethics 
Committees (IECs), and Investigators.
For all studies except those utilizing medical devices, Investigator safety reports must be
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to Investigators as necessary.
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then 
file it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except if the 
pregnancy is discovered before the study patient has received any IP.
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.4.2.1
Maternal exposure
If a patient becomes pregnant during the course of the study, IP should be discontinued 
immediately.


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Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day (ie, immediately but no 
later than 24 hours of when he or she becomes aware of it).
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy.
8.4.2.2
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
90 days after the last dose of IP. Please follow the local prescribing information relating to 
contraception and the time limit for such precautions for SoC agents.
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) occurring from the date of the first dose until 90 days after the last 
dose of IP should, if possible, be followed up and documented.
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the patient’s partner. Therefore, the local study 
team should adopt the generic ICF template in line with local procedures and submit it to the 
relevant IECs/IRBs prior to use.
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment and will enter follow-up (see 
the SoAs [Table 3]).


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8.4.3
Overdose
8.4.3.1
Durvalumab
Use of durvalumab in doses in excess of that specified in the protocol is considered to be an 
overdose. There is currently no specific treatment in the event of overdose of durvalumab, and 
possible symptoms of overdose are not established. 
!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.
!
An overdose without associated symptoms is only reported on the Overdose CRF module.
If an overdose on an AstraZeneca IP occurs in the course of the study, then the Investigator or 
other site personnel inform appropriate AstraZeneca representatives immediately, or no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply (Section 8.3.2). 
For other overdoses, reporting must occur within 30 days.
8.4.3.2
Standard of care
For SoC, please refer to the local prescribing information for treatment of cases of overdose. If 
any overdose is associated with an AE or SAE, please record the AE/SAE diagnosis or 
symptoms only in the relevant AE modules of the eCRF.
8.4.4
Medication error
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.2) and within 30 days for all other 
medication errors.
The definition of a medication error can be found in Appendix B.
8.4.5
Specific toxicity management and dose modification information 
The following general guidance should be followed for management of toxicities.


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!
Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity if required).
!
If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of the assigned IP along with appropriate continuing supportive 
care. If medically appropriate, dose modifications are permitted. 
!
All dose modifications should be documented with clear reasoning and documentation of 
the approach taken.
All toxicities will be graded according to NCI CTCAE, Version 5.0. 
8.4.5.1
Specific toxicity management and dose modification information for 
durvalumab 
Comprehensive toxicity management guidelines (TMG) have been developed to assist 
Investigators with the recognition and management of toxicities associated with the use of the 
immune checkpoint inhibitor durvalumab (PD-L1 inhibitor). These guidelines are applicable 
when durvalumab is used alone or in combination (concurrently or sequentially) with other 
anticancer drugs (ie, antineoplastic chemotherapy, targeted agents), as part of a 
protocol-specific treatment regimen. The TMGs provide information for the management of 
immune-mediated reactions, infusion-related reactions, and non-immune-mediated reactions 
that may be observed with checkpoint inhibitor monotherapy or combination checkpoint 
inhibitor regimens, with specific instructions for dose modifications (including 
discontinuations) and treatment interventions. Investigators are advised, however, to use local 
practice guidelines and consult local references for the management of toxicities observed 
with the SoC chemotherapy regimen(s) administered. The most current version of the TMGs
entitled “Dosing Modification and Toxicity Management Guidelines for Immune-Mediated,
Infusion-Related, and Non-Immune Mediated Reactions (MEDI4736) Monotherapy or
Combination Therapy with Tremelimumab or Tremelimumab Monotherapy” is provided to
the investigative site as an Annex document and is maintained within the Site Master File. 
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered 
potentially immune-related. In addition, there are certain circumstances in which durvalumab 
should be permanently discontinued (see Section 7.1 of this protocol and refer to the Dosing 
Modification and Toxicity Management Guidelines). Following the first dose of IP, 
subsequent administration of durvalumab can be modified based on toxicities observed as 
described in the Dosing Modification and Toxicity Management Guidelines. These guidelines 
have been prepared by the Sponsor to assist the Investigator in the exercise of his/her clinical 
judgment in treating these types of toxicities. These guidelines apply to AEs considered 
causally related to the durvalumab regimen by the reporting Investigator.


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Dose reductions are not permitted. In case of doubt, the Investigator should consult with the 
Study Physician.
Dose Delays: In the event that durvalumab/placebo is delayed due to a treatment-related 
toxicity during the first 4 cycles of treatment, SoC chemotherapy should still be administered 
as scheduled; every effort should be made to ensure patients receive all scheduled cycles of 
SoC chemotherapy across all arms in the study, if conditions allow.
When it is feasible to restart durvalumab/placebo treatment, durvalumab/placebo should be 
administered with SoC chemotherapy on Day 1 of the next cycle to ensure treatment visits 
continue to coincide.
The patient should still receive up to 14 cycles of therapy, even if a dose delay causes the 
treatment period to extend beyond 12 months.
If unsure of how to manage a patient, please contact the Study Physician at AstraZeneca to 
discuss individual cases. 
8.4.5.2
Specific toxicity management and dose modification information – standard 
of care 
Chemotherapies are associated with a number of unwanted effects. SoC chemotherapy-related 
toxicity management and/or dose adjustments (including dose delays and reductions) should 
be performed as indicated in the local prescribing information for the relevant agent. In the 
event of unfavorable tolerability, patients can switch from cisplatin to carboplatin at any point 
in the study. Note: It is preferred that patients begin the chemotherapy regimen with cisplatin 
and receive at least 1 cycle of cisplatin. 
Dose reduction is permitted for chemotherapy. 
Dose Delays: SoC chemotherapy-related toxicity management, dose adjustment, including 
dose delays and reductions should be performed as indicated in the local prescribing 
information for the relevant agent. In the event of unfavorable tolerability, patients can switch 
between cisplatin and carboplatin therapy at any point on study (at the discretion of the 
Investigator). 
If toxicities can reasonably be attributed to SoC chemotherapy, dose adjustment should be 
attempted before modifying the administration of durvalumab. In the event that SoC 
chemotherapy is delayed, durvalumab/placebo should also be delayed and should resume as 
soon as feasible. Every effort should be made to ensure patients receive all scheduled cycles 
of SoC chemotherapy across all treatment arms in the study, if conditions allow. If unsure of 
how to manage a patient, please contact the Study Physician at AstraZeneca to discuss 
individual cases. 


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8.5
Pharmacodynamics
Plasma ctDNA will be evaluated during and after study treatment as a pharmacodynamic 
parameter. See Section 8.7.2.1 for information on methods related to on-study evaluation of 
plasma samples for ctDNA. No other pharmacodynamic parameters will be evaluated in this 
study.
8.6
Genetics
8.6.1
Collection of mandatory genetic samples
The patient’s consent to participate in the genetic MRD testing components of the study is 
mandatory and will be obtained via signature of ICF1. See Section 8.7.1.2 for details on 
sample collection, analysis performed, and data storage. This mandatory genetic testing is 
conducted for detection of MRD. As part of this mandatory genetic testing, germline and 
tumor DNA (exome only) is analyzed to enable the design of the personalized panel for MRD 
determination and subsequent testing for ctDNA.
See Section 8.7.1 and Appendix E for additional information on collection of mandatory 
genetic samples. 
8.6.2
 
 
 
 
 
8.6.3
Storage and destruction of genetic samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality. Samples may be stored for a maximum of 
15 years or as per local regulations from the date of the last patient, last visit, after which they 
will be destroyed. DNA is a finite resource that may be used up during analyses. The results of 
any further analyses will be reported either in the CSR itself or as an addendum, or separately 
in a scientific report or publication.
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No personal details identifying the individual will be available to AstraZeneca or designated 
organizations working with the DNA.
8.7
Biomarkers
By participating in this study, the patient consents to the mandatory collection and use of 
donated biological samples as described here. Samples will be obtained from all screened 
patients.
All samples collected for biomarker analyses will be stored at the study site, a reference 
laboratory, or at AstraZeneca facilities and may be used for subsequent research relevant to 
evaluating biological and/or clinical response to therapy as described in the exploratory 
analyses section.
The results may be pooled with biomarker data from other durvalumab studies to evaluate 
biological responses across indications.
Details for collection, volumes, storage, and shipment of biologic samples are presented in a 
separate Laboratory Manual.
8.7.1
Mandatory biomarkers
8.7.1.1
Assessment of EGFR/ALK status
A sample of a pre-surgical tumor biopsy (preferred) or resected tumor tissue is required for 
assessing EGFR mutation and ALK translocation status. EGFR/ALK wild-type patients will be 
eligible for the study. If a pre-surgery biopsy is not available or evaluable, testing will be 
conducted as soon as possible on the resected tumor tissue while the personalized panel is in 
development; patients will still be allowed to continue with first screening procedures while 
testing is ongoing, but will be ineligible to enter second screening if their tumor tissue tests 
positive for EGFR mutations and/or ALK translocations. 
Testing must be performed using a well-validated, local regulatory approved kit. EGFR/ALK
may be tested centrally if local testing is unavailable.
Note: Where EGFR/ALK results are obtained from pre-surgical tissue biopsy as part of 
standard local practice, the patient should be confirmed as EGFR/ALK wild-type prior to 
signing ICF1 and enrolling in the study.
8.7.1.2
Minimal residual disease
Tumor and whole blood samples for whole exome sequencing and development of 
personalized panel
This study requires comparison of genetic data from a patient’s tumor and blood cells to 
identify tumor-specific mutations for MRD determination (see Section 8.6.1). Countries, 


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centers, or patients that do not permit or consent to such analyses will not be able to 
participate in the study.
Detection of MRD in solid tumors requires a complex multi-step assay. Firstly, WES is 
performed on DNA extracted from the patient’s resected tumor tissue and controlled for 
germline mutations by WES of the patient’s whole blood (as indicated in the SoAs, Table 1). 
A Sponsor-approved personalized panel is then developed, comprised of 50 of the patient’s 
tumor variants expressed at high frequency (see Appendix E for more detail). This panel is 
then used to identify the presence of these variants on ctDNA extracted from the patient’s 
plasma and the patient is considered MRD+ if the panel detects tumor variants. This 
personalized approach allows detection of the patient’s tumor variants in DNA extracted from 
their plasma at high sensitivity. Tumor and whole blood samples, as well as WES data, will be 
used for diagnostic development and exploratory research. 
The buffy coat layers obtained from a separate baseline whole blood sample will be retained 
and may be analyzed for germline mutations for future diagnostic development.
Details on tumor and whole blood sample collection, processing, storage, and shipment are 
provided in the Laboratory Manual.
Plasma samples for determination of MRD status based on ctDNA
Once plasma has been drawn, cell-free DNA is extracted and a polymerase chain reaction is 
performed using primers from the patient-specific panel designed based on the WES data 
(generation of which is described above). The resulting amplicons are then sequenced and 
analyzed by the proprietary Analysis MRD bioinformatics pipeline at the designated 
organization, which reports on the presence or absence of ctDNA and detection of MRD.
A plasma sample will be collected between Week 3-5 (Day 21-35) post-surgery for 
determination of MRD status using the personalized assay, as described in the SoAs (Table 1). 
A pre-surgical plasma sample will be collected from all patients who sign ICF1 prior to 
surgery. Patients will not be excluded from randomization based on the results from analysing 
the pre-surgical sample. 
Pre-surgical, on-treatment, and post-treatment plasma samples will be collected longitudinally 
for exploratory evaluations of ctDNA and to support exploratory endpoints (see 
Section 8.7.2.1). Plasma samples, including derived DNA, will be used for diagnostic 
development and exploratory research. No treatment decisions will be made based on the 
results from these samples. 


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All samples submitted for ctDNA analysis will be coded to prevent patient identification. 
Sequencing data and variant calls from ctDNA analysis will be stored in a secure system at 
designated organizations and/or at AstraZeneca to analyze the sample.
Details on plasma collection, processing, storage, and shipment are provided in the Laboratory 
Manual.
8.7.1.3
Tissue samples for PD-L1 TC expression assessment and biomarker research
PD-L1 TC expression will be evaluated prospectively on resected tumor tissue collected 
during surgical resection. PD-L1 TC expression must be known for randomization. Data will 
be compared between arms to determine if baseline PD-L1 status is prognostic and/or 
predictive of outcomes associated with durvalumab plus SoC chemotherapy versus placebo 
plus SoC chemotherapy. Baseline tumor requirements are described in Section 5.1. 
Based on availability of tissue, additional exploratory biomarkers may be evaluated as 
described in Section 8.7.2. Also, descriptions of exploratory, peripheral measures are 
described in this section. Samples will be obtained according to the assessment schedules 
provided in the SoAs (Table 1 and Table 2).
MANDATORY: Provision of tumor tissue from the primary resection, formalin fixed and 
embedded in paraffin, for the purpose of PD-L1 TC expression analysis (and for enabling 
exploratory analyses as described in Section 8.7.2). 
Details for collection, volumes, storage, and shipment of biologic samples are presented in a 
separate Laboratory Manual.
PD-L1 TC expression analysis will be performed by at a central reference laboratory testing 
service using the Ventana SP263 PD-L1 IHC assay. 
A brief description of exploratory tumor markers to be explored is provided in Section 8.7.2. 
8.7.2
Exploratory biomarkers
WES data generated during the development of the personalized panel (described above in 
section 8.7.1.2) may also be used for exploratory purposes to better understand NSCLC and/or 
to identify biomarkers (eg, tissue TMB) which may correlate with patient outcomes.
Blood and tumor samples for exploratory biomarker analyses will be obtained according to the 
schedules presented in the SoAs (Table 1, Table 2, and Table 3). Details for collection, 
volumes, storage, and shipment of biologic samples are presented in a separate Laboratory 
Manual. 
Measurements at baseline, on treatment, and/or at recurrence may be correlated with 
outcomes. Note that samples will be obtained from patients randomized to each treatment 


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group. Comparisons may be made between baseline measures to determine if biomarkers (or 
combination of markers) are prognostic or predictive of outcomes associated with durvalumab 
plus SoC chemotherapy versus placebo plus SoC chemotherapy, subgrouped by histology. 
Additional sample collections and analyses may be completed at select study sites by 
site-specific amendment. All samples collected for such exploratory analyses will be stored at 
site, a reference laboratory, or at AstraZeneca’s facilities and may be used for subsequent 
research relevant to evaluating response to immunotherapy.
The exploratory biomarker plan is described by sample type below.
8.7.2.1
Plasma and serum
Plasma samples will be collected throughout the course of the study to assess the relationship 
between treatment effect on ctDNA clearance and DFS endpoint. 
Plasma analyses may also include evaluating baseline mutations to treatment, changes in 
ctDNA levels on treatment, TMB, and correlations with clinical outcome. Overall mutational 
burden, or somatic mutations/genomic alterations, RNA, and/or protein markers in plasma 
may be assessed using state-of-the-art methodologies. 
Serum samples will be collected for potential analysis of circulating soluble prognostic and 
pharmacodynamic biomarkers, including, but not limited to, proinflammatory, regulatory, and 
chemotactic cytokines and chemokines. 
8.7.2.2
Tumor markers
Tissue obtained as part of screening procedures and for establishing PD-L1 status may be 
analyzed for additional markers, including PD-L1 immune cell (IC) expression. TMB may
also be assessed in tumor tissue. Based on availability of tissue, a panel of immune-relevant 
markers expressed on tumor-infiltrating lymphocytes or on tumor cells may be assessed. 
Attributes of tumor microenvironment that could be assessed using various methods, which 
may include, but are not limited to, high content imaging, multiplex RNA/DNA/protein 
analysis with spatial resolution such as Mass Spec, in-situ hybridization, or other technologies 
may be correlated with response and clinical outcome.
Exploratory analysis of RNA (mRNA/miRNA/lncRNA), DNA, or protein using 
state-of-the-art technologies including, but not limited to, RNAseq, WES, and QRT-PCR may 
be conducted to evaluate study association with response and clinical outcome.
OPTIONAL: Provision of tumor tissue upon recurrence, formalin fixed and embedded in 
paraffin, for exploratory analyses to compare biomarker changes compared to baseline/surgery 
and to identify mechanisms of recurrence. If the patient refuses to provide this sample, the 
reason for this refusal must be captured. 


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8.7.2.3
Whole blood gene expression (PaxGene RNA)
Whole blood samples will be collected in PaxGene RNA tubes and stored frozen for nucleic 
acid preparation. Total RNA may be prepared for quantification of RNA, micro-RNA, and/or
non-coding RNA using reverse transcription quantitative polymerase chain reaction, 
microarray, sequencing, or other technology. The focus will be on genes linked to target 
expression, mechanism of action, and immunomodulatory genes linked to pharmacodynamic 
activity. RNA expression signatures may be defined, before and after treatment, and correlated 
with other exploratory biomarkers and clinical outcomes.
8.7.2.4
Management of biomarker data
The biomarker data will have unknown clinical significance. AstraZeneca will not provide 
biomarker research results other than MRD status for eligibility to patients, their family 
members, any insurance company, an employer, clinical study Investigator, general physician, 
or any other third party, unless required to do so by law. The patient’s samples will not be 
used for any purpose other than those described in the CSP.
Individual patients will not be identified in any report or publication resulting from this work. 
The data and results of this research may be reviewed with collaborators and published, but 
neither the patient’s name nor any other personal identifiers will appear in any publication or 
report.
8.7.2.5
Optional Genomic Initiative samples
Details on the optional genetic research study can be found in Section 8.6.2 and in 
Appendix D.
8.7.3
Storage, re-use, and destruction of biomarker samples 
Samples will be stored for a maximum of 15 years from the end of study, after which they will 
be destroyed. Summaries and analyses for exploratory biomarkers will be documented in a 
separate analysis plan and will be reported outside the CSR in a separate report. The results of 
this biomarker research may be pooled with biomarker data from other studies involving 
durvalumab or other IO therapies to generate hypotheses to be tested in future research.
8.7.4
Labeling and shipment of biological samples
The Principal Investigator will ensure that samples are labeled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B, Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria); 
see Appendix C 3 “International Airline Transportation Association 6.2 Guidance Document”.
Any samples identified as Infectious Category A materials will not be shipped, and no further 
samples will be taken from the involved patients unless agreed upon with AstraZeneca and 
appropriate labeling, shipment, and containment provisions are approved.


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8.7.5
Chain of custody of biological samples
A full chain of custody will be maintained for all samples throughout their life cycle.
The Principal Investigator at each center will keep full traceability of collected biological 
samples from the patients while in storage at the center until shipment or disposal (where 
appropriate) and will keep documentation of shipments.
The sample receiver will keep full traceability of the samples while in storage and during use 
until used or disposed of or until further shipment and will keep documentation of receipt of 
arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers.
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks and will 
be registered with the AstraZeneca Biobank Team during the entire life cycle.
8.7.6
Withdrawal of informed consent for donated biological samples
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of or destroyed and the action documented. If samples have already been analyzed, 
AstraZeneca is not obliged to destroy the results of this research.
The Principal Investigator will:
!
Ensure that AstraZeneca is immediately notified of the patient’s withdrawal of informed 
consent to the use of donated samples
!
Ensure that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of or destroyed, and the action documented
!
Ensure that the organization(s) holding the samples is/are immediately informed about the 
withdrawn consent and that samples are disposed of or destroyed, the action is 
documented, and the signed document is returned to the study site
!
Ensure that the patient and AstraZeneca are informed about the sample disposal
8.8
Medical resource utilization and health economics
Medical resource utilization and health economics will not be evaluated in this study.
8.9
Study Participant Feedback Questionnaire (SPFQ)
This study will include an option for patients to complete an anonymized questionnaire, 
‘Study Participant Feedback Questionnaire’ for patients to provide feedback on their clinical 
trial experience (Appendix J). Individual patient level responses will not be reviewed by 


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investigators. Responses would be used by the Sponsor to understand where improvements 
can be made in the clinical trial process. This questionnaire does not collect data about the 
patient's disease, symptoms, treatment effect, or AEs and therefore would not be study data.
9
STATISTICAL CONSIDERATIONS 
The primary objective of the study is to compare the efficacy and safety of durvalumab plus 
SoC chemotherapy to placebo plus SoC chemotherapy in terms of DFS (using Investigator 
assessments according to RECIST 1.1), in all patients with a diagnosis of stage II-III NSCLC 
with complete resection. 
!
All personnel involved with the analysis of the study will remain blinded until DBL and 
CSP deviations are identified.  
!
Analyses will be performed by AstraZeneca or its representatives. 
!
A SAP will be written to provide further details and will be finalized in advance of 
database lock.
9.1
Statistical hypotheses
Prior to CSP V4.0, a formal statistical analysis was to be performed to test the main 
hypotheses: 
!
H0: No difference between durvalumab plus SoC chemotherapy and placebo plus SoC 
chemotherapy
!
H1: Difference between durvalumab plus SoC chemotherapy and placebo plus SoC 
chemotherapy
Under CSP V4.0 no formal statistical analyses will be performed, and all analyses will be 
exploratory. Further details will be included in the SAP.
Prior to CSP V4.0, the primary objective of this study was to compare the efficacy of 
durvalumab plus SoC chemotherapy to placebo plus SoC chemotherapy in terms of DFS in 
the MRD+ analysis set. A secondary objective was to compare the efficacy of durvalumab 
plus SoC chemotherapy to placebo plus SoC chemotherapy in terms of DFS in the FAS. 
Under CSP V4.0 as a result of the decision to close study enrollment, the intended patient 
numbers will not be reached. The primary objective of this study will now compare the 
efficacy of durvalumab plus SoC chemotherapy to placebo plus SoC chemotherapy in terms of 
DFS in the FAS rather than in the MRD+ analysis set. A secondary objective will compare the 
efficacy of durvalumab plus SoC chemotherapy to placebo plus SoC chemotherapy in terms of 
DFS in the MRD+ analysis set. The details on the multiple testing procedure for controlling 
the type I error rate can be found in Section 9.5.4.


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9.2
Sample size determination 
Prior to CSP V4.0, approximately 
patients with stage II-III NSCLC were planned to be 
randomized 1:1 to durvalumab plus SoC chemotherapy or placebo plus SoC chemotherapy. Of 
the patients randomized into the study, approximately 
 patients were required to be 
MRD+, as determined by the result from their post-surgical plasma sample. The number of 
MRD- patients was to be capped at 100 (See Section 4.2.1 for the caveat to this cap). 
The study was sized for the primary endpoint of DFS in the MRD+ analysis set and for the 
secondary endpoint of DFS in the 
.
The analysis of the primary endpoint (DFS) was to occur when approximately 
DFS events 
had occurred (
% maturity) in the MRD+ analysis set. If the true DFS HR is 
 in the 
MRD+ analysis set, the study would have provided at least 
 power to demonstrate a 
statistically significant difference for DFS with an overall 2-sided significance level of 
; 
this translates to a 
‑month benefit in median DFS over 
 months on placebo plus SoC 
chemotherapy, or 
 difference in -year DFS rate over 
 on placebo plus SoC 
chemotherapy, if DFS is exponentially distributed. The smallest treatment difference that 
would be statistically significant is an HR of
. It was estimated that this analysis would 
occur approximately 51 months after the first patient has been randomized, assuming a 
3-month lag before the first MRD+ patient is randomized, 44‑month recruitment period, and a 
minimum follow-up of 4-months.
The study was also sized to provide at least
 power for the DFS endpoint in the 
. The 
analysis will be performed at the same time as the primary analysis, when it was expected that 
approximately 
 events had occurred (
) in the FAS. If the true DFS HR is 
 
in this population, this would have provided at least 
 power to demonstrate a statistically 
significant difference for DFS, assuming an overall 
 2-sided significance level; this 
translates to a 
‑month benefit in median DFS over 
 months on placebo plus SoC 
chemotherapy, or 
 difference in 
year DFS rate over 
 on placebo plus SoC 
chemotherapy, if DFS is exponentially distributed.  
Under CSP v4.0, the planned number of randomized patients will not be met. This is a result 
of the decision by AstraZeneca to close study enrollment early. There will be one analysis (i.e. 
primary DFS analysis) which will occur after DCO (see Section 4.4). 
OS will also be analyzed in the MRD+ analysis set and in the 
 at the time of the DFS 
analysis. Prior to CSP V4.0, in the MRD+ analysis set, if the true HR is 
, then it was 
anticipated that approximately 
 events 
 maturity) would have occurred. This translates 
to an 
month benefit in median OS over 
 months on placebo plus SoC chemotherapy. 
In the 
, if the true HR is 
, then it was anticipated that approximately 
 events (
 
maturity) would have occurred. This translates to a 
 month benefit in median OS over 
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 months on placebo plus SoC chemotherapy. Under CSP V4.0 these events will not be 
reached.
Prior to CSP V4.0, a further analysis of OS was to be performed at approximately
 events 
(
 maturity) in the MRD+ analysis set. At this time there was also expected to be 
approximately 
 events (
 maturity) in the 
. It was anticipated that this analysis 
would occur approximately 
 months after the first patient was randomized. If events were 
accruing slower than expected, then the DCO would have occurred 
 months after the first 
patient was randomized, regardless of number of events accrued.  Under CSP V4.0 this further 
analysis will not be performed and the primary DFS analysis will be the final analysis.
9.3
Populations for analyses
The populations for analyses are summarized in Table 14 per outcome variable.
Table 14
Summary of outcome variables and analysis populations
Outcome
Population
Efficacy data
DFS
MRD+ analysis set
Full analysis set
OS
MRD+ analysis set
Full analysis set
PROs
MRD+ analysis set
Full analysis set
Demography
Full analysis set
MRD+ analysis set
Safety data
Exposure
Safety analysis set
AEs
Safety analysis set
Laboratory measurements
Safety analysis set
Vital signs
Safety analysis set
AEs  Adverse events; DFS  Disease-free survival; MRD+  Minimal residual disease-positive; OS  Overall 
survival; PROs  Patient-reported outcomes.
9.3.1
Full analysis set
The FAS will include all randomized patients. The FAS will be used for all efficacy analyses, 
including PROs. Treatment groups will be compared on the basis of randomized study 
treatment, regardless of the treatment actually received. Patients who were randomized but did 
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not subsequently go on to receive study treatment are included in the analysis in the treatment 
group to which they were randomized.
9.3.2
MRD+ analysis set
The MRD+ analysis set will include all patients in the FAS who are MRD+, as determined by 
results from the post-surgical plasma sample. 
9.3.3
Safety analysis set
The SAS will consist of all randomized patients who received at least 1 dose of study 
treatment (durvalumab/placebo and/or SoC chemotherapy). Safety data will not be formally 
analyzed but summarized using the SAS according to the treatment received If a patient 
receives any amount of durvalumab, with or without SoC chemotherapy, they will be 
summarized in the durvalumab plus SoC chemotherapy treatment group. If a patient only 
receives placebo, with or without SoC chemotherapy, they will be summarized in the placebo 
plus SoC chemotherapy treatment group.  Patients who only received SoC chemotherapy and 
did not receive any doses of either the durvalumab or placebo will be summarized in the 
placebo treatment group.
9.4
Outcome measures for analyses
9.4.1
Calculation or derivation of efficacy variables
9.4.1.1
RECIST 1.1-based endpoints
The analysis of the primary endpoint, DFS, will be based on the Investigator assessments 
using RECIST 1.1.
Investigator RECIST 1.1-based assessments
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations. This is also regardless of whether a patient discontinues study treatment or 
receives another anticancer therapy.
Please refer to Appendix G for further details.
Blinded Independent Central Review
An analysis of DFS may be performed based on data assessed by a BICR for all patients. 
Where BICR is performed, the imaging scans will be reviewed by 2 independent radiologists 
using RECIST 1.1 and will be adjudicated, if required. For each patient, the BICR will define 
the overall visit response data and the relevant scan dates for each timepoint (ie, for visits 
where recurrence is/is not identified). 
Further details of the BICR will be documented in the Imaging Charter.


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9.4.1.2
Primary and secondary endpoints: disease-free survival
DFS is defined as the time from the date of randomization until the date of disease recurrence 
(local, regional, or distant disease recurrence or second primary NSCLC) using Investigator 
RECIST 1.1 assessments or date of death due to any cause, whichever occurs first.
Patients who are disease-free, ie, have not experienced disease recurrence and are alive at the 
time of analysis, will be censored at the latest date of assessment from their last evaluable 
RECIST 1.1 assessment. However, if the patient experiences disease recurrence or dies after 2 
or more missed visits, the patient will be censored at the latest evaluable RECIST 1.1 
assessment prior to the 2 missed visits. If the patient has no evaluable assessments or does not 
have baseline data, they will be censored at Day 1 unless they die within 2 visits of baseline, 
then they will be treated as an event with the date of death as the event date. The primary 
endpoint analysis of DFS will be based on Investigator RECIST 1.1 assessments. 
The DFS time will always be derived based on scan/assessment dates and not visit dates.
RECIST 1.1 assessments/scans contributing toward a particular visit may be performed on 
different dates. The following rules will be applied:
!
For Investigator assessments, the date of disease recurrence will be determined based on 
the earliest of the RECIST assessment/scan dates of the component that indicates disease 
recurrence.
!
Where BICR assessments are performed, date of recurrence will be determined based on 
the earliest of the dates of the component that triggered the recurrence on the first set of 
scans that indicates recurrence for the adjudicated reviewer selecting recurrence, or of 
either reviewer where both reviewers select recurrence as a timepoint response, and there 
is no adjudication for central review (BICR) data.
!
When censoring a patient for DFS, the patient will be censored at the latest of the scan 
dates contributing to a particular overall visit assessment.
DFS rate at 6 and 12 months is defined as the proportion of patients alive and disease free at 6 
and 12 months respectively, estimated from Kaplan-Meier plots of the primary endpoint of 
DFS.
9.4.1.3
Secondary efficacy endpoint: overall survival
OS is defined as the time from the date of randomization until death due to any cause. Any 
patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the patient was known to be alive. 
Note: Survival calls (if agreed to by the patient and in compliance with local data privacy 
laws/practices) will be made following the date of DCO for the analysis (these contacts should 
generally occur within 7 days of the DCO). If patients are confirmed to be alive or if the death 


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date is post the DCO date, these patients will be censored at the date of DCO. Death dates 
may be found by checking publicly available death registries.
9.4.1.4
Exploratory efficacy endpoint: progression-free survival
PFS is defined as the time from the date of randomization to the date of post-recurrence 
disease progression (using local standard practice) or death. Patients alive and for whom a 
disease progression has not been observed should be censored at the last time they are known 
to be alive and without a disease progression; ie, censored at the last progression assessment 
date if the patient has not had a progression or died.
9.4.1.5
Exploratory efficacy endpoint: 
 
 
 
9.4.1.6
Exploratory efficacy endpoint: 
 
 
 
 
 
 
9.4.1.7
Exploratory efficacy endpoint: ctDNA clearance or changes
The efficacy of durvalumab treatment on ctDNA clearance will be evaluated as an exploratory 
objective, and endpoints will include:
!
Best overall clearance rate (number converted at any time)
!
Best confirmed clearance rate (as above, but confirmed at subsequent visit)
!
Time to ctDNA clearance
!
Duration of ctDNA clearance
!
Time to ctDNA recurrence
!
Time to confirmed ctDNA recurrence
!
Changes in variant allele frequencies following treatment
The relationship between treatment effect on DFS and on ctDNA endpoints will also be 
evaluated. 
Details on these exploratory analyses will be presented in a SAP.
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9.4.2
Calculation or derivation of safety variables
9.4.2.1
Adverse events
Safety and tolerability will be assessed in terms of AEs (including SAEs), deaths, laboratory 
data, vital signs, ECGs, and exposure. These will be collected for all patients. Data from all 
cycles of treatment will be combined in the presentation of safety data. “On treatment” will be 
defined as assessments between the date of start dose and 90 days following discontinuation of 
IP (ie, the last dose of durvalumab/placebo or SoC agents). For AEs, on treatment (or 
treatment-emergent AEs) will be defined as any AEs that started after dosing or prior to 
dosing and which worsen following exposure to the treatment. 
The SAS will be used for reporting of safety data.
Adverse events observed up until 90 days following discontinuation of IP (ie, the last dose of 
durvalumab/placebo/SoC agent) or until the initiation of the first subsequent therapy following 
discontinuation of treatment (whichever occurs first) will be used for the reporting of the AE 
summary tables. This will more accurately depict AEs attributable to study treatment only, as 
a number of AEs up to 90 days following discontinuation of durvalumab/placebo/SoC agent 
are likely to be attributable to subsequent therapy. However, to assess the longer-term toxicity 
profile, AE summaries will also be produced containing AEs observed up until 90 days 
following discontinuation of durvalumab/placebo/SoC agent (ie, without taking subsequent 
therapy into account). Any events in this period that occur after a patient has received further 
therapy for cancer (following discontinuation of study treatment) will be flagged in the data 
listings. 
A separate data listing of AEs occurring more than 90 days after discontinuation of IP will be 
produced. These events will not be included in AE summaries.  
9.4.2.2
Safety assessments
For the change from baseline summaries for vital signs, laboratory data, ECGs (to be 
administered at baseline and as clinically indicated), and physical examinations, the baseline 
value will be the latest result obtained prior to the start of study treatment. 
QTcF will be derived during creation of the reporting database using the reported ECG values 
(RR and QT) using the following formula:
QTcF=QT/RR^ (1/3) where RR is in seconds
Corrected calcium product will be derived during creation of the reporting database using the 
following formula:
Corrected calcium (mmol/L)=Total calcium (mmol/L) + ([40 – albumin (G/L)] × 0.02)


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The denominator used in laboratory summaries will only include evaluable patients, ie, those 
who had sufficient data to have the possibility of an abnormality.
For example:
!
If a CTCAE criterion involves a change from baseline, evaluable patients would have 
both a predose and at least 1 postdose value recorded.
!
If a CTCAE criterion does not consider changes from baseline to be evaluable, the patient 
need only have 1 postdose value recorded.
The denominator in vital signs data should include only those patients with recorded data.
9.4.3
Calculation or derivation of patient-reported outcome variables
Symptoms and overall QoL will be assessed using the EORTC QLQ-C30 and QLQ-LC13 
modules (secondary endpoints). Questionnaires will be scored according to published scoring 
guidelines or the developer’s guidelines, if published guidelines are not available. 
All PRO analyses will be conducted on the FAS and MRD+ analysis sets.
9.4.3.1
Calculation or derivation of EORTC QLQ-C30 and EORTC QLQ-LC13
The EORTC QLQ-C30 consists of 30 questions that can be combined to produce 5 functional 
scales (physical, role, cognitive, emotional, and social) and 3 symptom scales (fatigue, pain, 
and nausea and vomiting), 5 individual items (dyspnea, insomnia, appetite loss, constipation, 
and diarrhea), and a global measure of health status. The EORTC QLQ-LC13 is a lung 
cancer-specific module from the EORTC for lung cancer comprising 13 items/questions 
(cough, hemoptysis, dyspnea, site-specific pain, sore mouth, dysphagia, peripheral 
neuropathy, alopecia, and pain medication). With the exception of a multi-item scale for 
dyspnea, all are single items. The dyspnea scale will only be used if all 3 items have been 
scored; otherwise, the items are treated as single-item measures.
An outcome variable consisting of a score from 0 to 100 will be derived for each of the 
symptom scales/symptom items, the functional scales, and the GHS/QoL scale according to 
the EORTC QLQ-C30 Scoring Manual 
 and EORTC QLQ-LC13 
instructions.
Higher scores on the GHS/QoL and functioning scales indicate better health status/function, 
but higher scores on symptom scales/items represent greater symptom severity.
Changes in score compared with baseline will be evaluated. For each subscale, if <50% of the 
subscale items are missing, then the subscale score will be divided by the number of 
non-missing items and multiplied by the total number of items on the subscales 
 
. If at least 50% of the items are missing, then that subscale will be treated as missing. 
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Missing single items are treated as missing. The reason for any missing questionnaire will be 
identified and recorded. If there is evidence that the missing data are systematic, missing 
values will be handled to ensure that any possible bias is minimized.
Definition of clinically meaningful changes
Changes in score compared with baseline will be evaluated. A minimum clinically relevant 
change is defined as a change in the score from baseline of ≥10 for scales/items from the 
QLQ-C30 and the QLQ-LC13 (Osoba et al 1998). For example, a clinically relevant 
deterioration or worsening in chest pain (as assessed by QLQ-LC13) is defined as an increase 
in the score from baseline (defined as Day 1, predose) of ≥10. A clinically relevant 
improvement in fatigue (as assessed by QLQ-C30) is defined as a decrease in the score from 
baseline of ≥10. At each post-baseline assessment, change in symptoms/functioning from 
baseline will be categorized as improved, stable, or worsening, as shown in Table 15. 
Table 15
Visit responses for symptoms and health-related quality of life
Score
Change from baseline
Visit response
QLQ-C30/QLQ-LC13 symptom 
scales/items
≥+10
≤-10
Otherwise
Worsened
Improved
Stable
QLQ-C30 functional scales and 
global health status/QoL
≥+10
≤-10
Otherwise
Improved
Worsened
Stable
QLQ-C30  30-Item core quality-of-life questionnaire; QLQ-LC13  13-Item lung cancer quality-of-life 
questionnaire; QoL  Quality of life.
Time to deterioration in symptom and functional scales/items and GHS/QoL, based on the 
clinically meaningful cut-offs, will be evaluated.
See SAP for further details.
9.4.3.2
Calculation or derivation of 
 data will be presented using summaries and descriptive statistics. 
Additionally, 
 data may be further explored. Further details will be 
provided in the SAP.
9.4.3.3
The 
 data will be presented using summaries and descriptive statistics. 
Additionally, data may be further explored. Further details will be provided in the SAP.
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9.4.3.4
Calculation or derivation of health economic variables
 index 
The 
 index comprises
 
 (see Section 8.1.4.2). For each dimension, 
respondents will select which statement best describes their health on that day from a possible 
5 options of increasing levels of severity (no problems, slight problems, moderate problems, 
severe problems, and extreme problems). A unique 
 health state is referred to by a 
5-digit code allowing for a total of 3125 health states. For example, state 11111 indicates no 
problems on any of the 
. These data will be converted into a weighted health 
state index by applying scores from 
 value sets elicited from general population 
samples (the base case will be the United Kingdom valuation set, with other country value sets 
applied in scenario analyses). Where value sets are not available, the 
 to 
 
crosswalk will be applied (
). In addition to the descriptive system, 
respondents also assess their health on the day of assessment on a visual analog scale, ranging 
from 0 (worst imaginable health) to 100 (best imaginable health). This score is reported 
separately.
9.4.4
Calculation or derivation of biomarker variables
Biomarker status, as defined in the exploratory objectives, will be assessed for evaluable 
patients in each cohort according to prespecified criteria that will be detailed in a SAP. 
9.4.5
Calculation or derivation of pharmacogenetic variables
In the case of optional genetic data, only the date that the patient gave consent to participation 
in the genetic research and the date the blood sample was taken from the patient will be 
recorded in the eCRF and database. The optional genetic data generated from the study will be 
stored in the AstraZeneca Laboratory Information Management System (LIMS) database or 
other appropriate system. This database is a secure database, which is separate from the 
database used for the main study. Some or all of the dataset from the mandatory main study 
may be duplicated within the AstraZeneca LIMS database for exploratory genetic analysis. 
Data will be reported outside the CSR (please see Appendix D).
9.5
Statistical analyses
All personnel involved with the analysis of the study will remain blinded until database lock 
and CSP deviations are identified.
Analyses will be performed by AstraZeneca or its representatives. A comprehensive SAP will
be developed and finalized before database lock and will describe the patient populations to be 
included in the analyses, and procedures for accounting for missing, unused, and spurious 
data. This section is a summary of the planned statistical analyses of the primary and 
secondary endpoints. Any deviations from this plan will be reported in the CSR.
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Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment group. Continuous variables will be summarized by the number of observations, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized by frequency counts and percentages for each category. Unless otherwise stated, 
percentages will be calculated out of the population total for the corresponding treatment 
group.  
Baseline will be the last assessment of the variable under consideration prior to the intake of 
the first dose of IP, except for efficacy variables. For efficacy variables, baseline is defined as 
the last visit prior to randomization.
All data collected will be listed. Efficacy and PRO data will be summarized and analyzed 
based on the MRD+ analysis set and FAS. Safety data will be summarized on the SAS. 
All outputs will be summarized by treatment group for all randomized patients (FAS), and all 
randomized patients in the MRD+ analysis set.  
Results of all statistical analysis will be presented using a 95% CI and 2-sided p-value, unless 
otherwise stated. 
9.5.1
Efficacy analyses
The primary aim of the study is to assess the efficacy of durvalumab plus SoC chemotherapy 
versus placebo plus SoC chemotherapy in terms of DFS, using Investigator assessments 
according to RECIST 1.1, in the FAS. DFS, using Investigator assessments according to 
RECIST 1.1, in the MRD+ analysis set is a secondary endpoint. 
Under CSP V4.0, all analyses will be exploratory.
Table 16 details the statistical analysis planned for each endpoint, together with pre-planned 
sensitivity analyses, making it clear which analysis is regarded as primary for that endpoint. 
Note: All endpoints compare durvalumab plus SoC chemotherapy versus placebo plus SoC 
chemotherapy in the MRD+ analysis set and all randomized patients (FAS), unless otherwise 
indicated. Results of all statistical analysis will be presented using a 95% CI and 2-sided 
p-value, unless otherwise stated. 
Table 16
Pre-planned statistical and sensitivity analyses to be conducted
Endpoints analyzed
Notes
Disease-free survival
Primary analysis using stratified log-rank test using Investigator 
assessments (RECIST 1.1) for FAS.
Secondary analysis using stratified log-rank test using Investigator 
assessments (RECIST 1.1) for MRD+ analysis set
Estimate of DFS rates at 6 and 12 months based on the Kaplan-Meier curve


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Table 16
Pre-planned statistical and sensitivity analyses to be conducted
Endpoints analyzed
Notes
Overall survival
Stratified log-rank test, Kaplan-Meier plots
Change from baseline (EORTC 
QLQ-C30 and QLQ-LC13)
Summary statistics, change from baseline, including mixed model repeated 
measures (MMRM)
Time to deterioration (EORTC 
QLQ-C30 and QLQ-LC13)
Stratified log-rank test, Kaplan-Meier plots
DFS  Disease-free survival; EORTC-QLQ-C30  European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire – Core 30 items; EORTC QLQ-LC13  European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire – Lung Cancer 13 items; FAS  Full analysis set; MRD+  
Minimal residual disease-positive; RECIST  Response Evaluation Criteria in Solid Tumors. 
9.5.1.1
Primary endpoint: disease-free survival
DFS, using Investigator assessment according to RECIST 1.1, will be analyzed using the 
log-rank test stratified by disease stage (stage II or III), PD-L1 TC expression (<1% versus 
≥1%) and MRD status (MRD+ or MRD-) on the FAS.  
The treatment effect will be estimated in terms of the HR and its associated 95% CI from a 
Cox proportional hazards model (Cox 1972) stratified by disease stage and PD-L1 TC 
expression.  
The stratification factor covariates in the statistical modeling will be based on the values 
entered into IWRS at randomization, even if it is subsequently discovered that these values 
were incorrect.  
For the purpose of statistical analysis of the primary and relevant secondary endpoints, a plan 
for reducing the number of strata cells will be included in the SAP in case there are 
insufficient events in one level of any strata.
Kaplan-Meier plots of DFS will be presented by treatment group. Summaries of the number 
and percentage of patients experiencing a DFS event will be provided along with median time 
to DFS with 95% CI for each treatment estimated based on the Kaplan-Meier curves.
The DFS rates at month 6 (DFS-6) and month 12 (DFS-12) will be estimated based on the 
Kaplan-Meier curves along with their 95% CIs and presented by treatment arms. 
The assumption of proportionality will be assessed firstly by examining plots of 
complementary log-log (event times) versus log (time) and, if these raise concerns, by fitting a 
time-dependent covariate to assess the extent to which this represents random variation. If a 
lack of proportionality is evident, the variation in treatment effect will be described by 
presenting piecewise HR calculated over distinct timeperiods. In such circumstances, the HR 
can still be meaningfully interpreted as an average HR over time unless there is extensive 
crossing of the survival curves. If lack of proportionality is found, this may be a result of 


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treatment-by-covariate interactions, which will be investigated. In addition, the Kaplan-Meier
curve along with landmark analyses (eg, 1-year DFS rate) will also help in understanding the 
treatment benefit.
Subgroup analyses may be conducted comparing DFS between durvalumab plus SoC 
chemotherapy versus placebo plus SoC chemotherapy in the following subgroups of the FAS 
(but not limited to):  
!
PD-L1 status (TC <1% versus ≥1%)
!
PD-L1 status (TC <25% and ≥25%)
!
TMB (high, low)
!
Histology (squamous versus non-squamous)
!
Sex (male versus female)
!
Age at randomization (<65 versus ≥65 years of age)
!
Smoking status (current smoker versus former non-smoker vs never smoker)
!
Race (Asian versus non-Asian)
Other baseline variables may also be assessed if there is clinical justification or an imbalance 
is observed between the treatment groups. The purpose of the subgroup analyses is to assess 
the consistency of treatment effect across expected prognostic and/or predictive factors. 
No adjustment to the significance level for subgroup and sensitivity analyses will be made 
since all these analyses will be considered supportive of the analysis of DFS.
Cox proportional hazards modeling will be employed to assess the effect of covariates on the 
HR estimate. A model will be constructed, containing treatment and the stratification factors, 
to ensure that any output from the Cox modeling is likely to be consistent with the results of 
the stratified log-rank test. Interactions between treatment and stratification factors will also 
be tested to rule out any qualitative interaction using the approach of Gail and Simon (Gail 
and Simon 1985).
Additionally, for each subgroup, the HR (durvalumab plus SoC chemotherapy:placebo plus 
SoC chemotherapy) and 95% CI will be calculated from a Cox proportional hazards model 
with treatment as the only covariate. These will be presented on a forest plot and will include 
the HR and 95% CI. 
If there are too few events available for a meaningful analysis of a particular subgroup (it is 
not considered appropriate to present analyses where there are less than 20 events in a 
subgroup), the relationship between that subgroup and DFS will not be formally analyzed. In 
this case, only descriptive summaries will be provided.




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In addition, physical and role functioning and overall GHS/QoL domains of the 
EORTC-CT30 are further prespecified endpoints of interest.
Summaries of original and change from baseline values of each symptom scale/item, the
GHS/QoL score, and each functional domain will be reported by assessment timepoint for 
each treatment group. Graphical presentations may also be produced as appropriate. 
Summaries of the number and percentage of patients in each response category at each 
assessment timepoint for each ordinal item (in terms of the proportion of patients in the 
categories of improved, stable, and worsened as defined in Table 15) will also be produced for 
each treatment group.
Changes from baseline will be analyzed using a linear mixed model for repeated measures 
analysis for each assessment timepoint (for primary PRO measures only).
Time to deterioration will be analyzed for each of the symptom scales/items, function scales, 
and GHS/QoL using a stratified log-rank test as described for the primary analysis of DFS. 
The HR and 95% CI for each scale/item will be presented graphically on a forest plot. 
For each of the symptom scales/items, functional scales, and GHS/QoL, time to deterioration 
will be presented using a Kaplan-Meier plot. Summaries of the number and percentage of 
patients experiencing a clinically relevant deterioration as well as who are censored will also 
be provided along with the medians for each treatment group.
Additional analyses and data visualizations may be considered. Further details will be 
provided in the SAP.
 data will be presented using summaries and descriptive statistics. 
Further details will be provided in the SAP.
 
 data will be presented using summaries and descriptive statistics. Further 
details will be provided in the SAP. 
9.5.2
Safety analyses
All safety and tolerability data will be presented by treatment group using the SAS. 
Data from all cycles of treatment will be combined in the presentation of safety data. AEs 
(both in terms of Medical Dictionary for Regulatory Activities [MedDRA] preferred terms 
and CTCAE grade) will be listed individually by patient. The number of patients experiencing 
each AE will be summarized by treatment group and CTCAE grade. Additionally, data 
presentations of the rate of AEs per person-years at risk may be produced. 
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Other safety data will be assessed in terms of physical examination, clinical chemistry, 
hematology, vital signs, and ECGs (conducted at baseline and as clinically indicated). 
Exposure to durvalumab plus SoC chemotherapy and placebo plus SoC chemotherapy will be 
summarized. Time on study, time on durvalumab, and SoC dose delays and dose reductions 
for the SoC regimen will also be summarized. At the time of the analysis, appropriate 
summaries of all safety data will be produced, as defined in the SAP.
9.5.3
Biomarker data
The relationship of PD-L1 TC expression and, if applicable, of exploratory biomarkers to 
clinical outcomes (including, but not restricted to DFS and OS) will be presented. 
PD-L1 TC expression determined by IHC will be reported in the CSR. Summaries and 
analyses for exploratory biomarkers, including the correlation between ctDNA and DFS, will 
be documented in a separate analysis plan and will be reported outside the CSR in a separate 
report.
9.5.4
Methods for multiplicity control
Prior to CSP V4.0, in order to provide strong control of the type I error rate, α=5% (2-sided), a 
multiple testing procedure with gatekeeping strategy was to be used across the primary 
endpoint of DFS in the MRD+ analysis set and the secondary endpoint of DFS in the FAS. 
The first 2 layers of the multiple testing procedure are shown in Figure 4. If DFS was 
significant in the FAS, the alpha was to be recycled to other endpoints. The recycle scheme of 
these additional endpoints, if included in the multiple testing procedure, was to be specified in 
the SAP prior to database lock.
The overall 5% type I error rate was to be allocated to the DFS analysis on the MRD+ analysis 
set. If this analysis was statistically significant, 5% alpha (2-sided) was to be allocated to the 
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9.7
Data monitoring committee 
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to Investigators.
An IDMC comprised of independent experts will meet to assess the safety and tolerability 
of durvalumab and report back to the Sponsor. The first data cutoff for the IDMC will 
be 12 months after the first subject has received IP or after the first 50 subjects have received 
IP, whichever occurs first.  The frequency of subsequent reviews will be determined by the 
IDMC, but will be no more frequent than every 6 months. The IDMC safety reviews will be 
conducted in an unblinded manner.
Full details of the IDMC procedures and processes can be found in the IDMC Charter. 
10
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11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


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Regulatory, Ethical and Study Oversight Considerations
A 1
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with the following:
!
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines
!
Applicable ICH Good Clinical Practice (GCP) Guidelines
!
Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients.  
The investigator will be responsible for the following:
!
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC
!
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
!
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples.
A 2
Financial disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.


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A 3
Informed consent process
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study. 
Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center. 
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative. 
If a patient declines to participate in any voluntary exploratory genetic research component of 
the study, there will be no penalty or loss of benefit to the patient and he/she will not be 
excluded from other aspects of the study. This does not apply to the mandatory genetic testing
required to generate the personalized panel required for MRD assay.
If a patient’s partner becomes pregnant during within 90 days after the last dose of 
durvalumab/placebo, the partner is asked to sign the "Adult Study Informed Consent Form for 
Pregnant Partners of Study Patients" and provide information about the pregnancy 
accordingly.
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The Investigator or authorized designee will 
explain to each patient the objectives of the exploratory research. Patients will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. The patient will give a separate agreement to allow any 
remaining specimens to be used for exploratory research. Patients who decline to participate 
in this optional research will indicate this in the ICF. If a patient withdraws consent to the use 
of donated biological samples, the samples will be disposed of/destroyed, and the action 
documented. If samples already have been analyzed at the time of the request, AstraZeneca 
will not be obliged to destroy the results of this research.


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A 4
Data protection
The ICF will incorporate wording that complies with relevant data protection and privacy 
legislation. In some cases, such wording will be in a separate accompanying document. 
AstraZeneca will not provide individual genotype results to patients, their family members, 
their general physician, any insurance company, any employer, or any other third party, unless 
required to do so by law.
Precautions are taken to preserve confidentiality and prevent genetic data from being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and might also have access to his or her genetic data. Also, regulatory authorities may 
require access to the relevant files. Even so, the patient’s medical information and the genetic 
files would remain physically separate.
Each patient will be assigned a unique identifier by the Sponsor. Any patient records or data 
sets transferred to the Sponsor will contain only the identifier; patient names or any 
information which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient. 
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance this could involve amendments to the Clinical Study Protocol and 
letters to Investigators.
A 6
Dissemination of clinical study data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com
and http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical study and/or summary of main study results may also be available on 
other websites according to the regulations of the countries in which the main study is 
conducted.


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A 7
Data quality assurance
All patient data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor. 
A 8
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.
All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the reconstruction and 
evaluation of the study are defined as source documents. Source data are contained in source 
documents (original records or certified copies).


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A 9
Publication policy
The results of this study may be published or presented at scientific meetings once the primary 
analysis is completed and the study is unblinded. No other publications prior to that timepoint 
is allowed.
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee  
of Medical Journal Editors authorship requirements. 
Subsequent to the primary publication, if an Investigator plans to publish any subset of data, 
or case report, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to provide 
comments.


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Adverse Event Definitions and Additional Safety 
Information
B 1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence (other than 
recurrence of malignancy under evaluation) in a patient or clinical study patient administered 
a medicinal product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (eg, an abnormal 
laboratory finding), symptom (for example nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no Study treatment has been administered.
B 2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-patient hospitalisation or prolongation of existing hospitalisation 
!
Results in persistent or significant disability or incapacity.  
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardise the patient or may require medical 
treatment to prevent one of the outcomes listed above.
!
Adverse Events (AEs) for malignant tumors reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical 
Event’ criterion should be used. In certain situations, however, medical judgment on an 
individual event basis should be applied to clarify that the malignant tumour event should 
be assessed and reported as a Non-Serious AE. For example, if the tumour is included as 
medical history and progression occurs during the study, but the progression does not 
change treatment and/or prognosis of the malignant tumor, the AE may not fulfill the 
attributes for being assessed as serious, although reporting of the progression of the 
malignant tumor as an AE is valid and should occur. Also, some types of malignant 
tumours, which do not spread remotely after a routine treatment that does not require 
hospitalization, may be assessed as Non-Serious; examples include Stage 1 basal cell 
carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.
!
Malignant tumors that – as part of normal, if rare, progression – undergo transformation 
(eg, Richter's transformation of B cell chronic lymphocytic leukemia into diffuse large B 
cell lymphoma) should not be considered a new malignant tumor


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B 3
Life threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (eg, hepatitis that resolved without hepatic failure).
B 4
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
B 5
Important medical event or medical treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the patient or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious.  These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse
B 6
CTCAE grade
The grading scales found in the revised National Cancer Institute CTCAE latest version will 
be utilized for all events with an assigned CTCAE grading. For those events without assigned 
CTCAE grades, the criteria recommended in the CTCAE manual that converts severity levels 
into CTCAE grades should be used. A copy of the CTCAE can be downloaded from the 


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Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable version 
of CTCAE should be described clearly.
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Appendix B 2.
B 7
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.
!
Time Course.  Exposure to suspect drug.  Has the patient actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?
!
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
!
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.


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The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca IP that either causes harm to the participant or has 
the potential to cause harm to the participant.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error.  
!
occurred
!
was identified and intercepted before the participant received the drug
!
did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Drug name confusion
!
Dispensing error eg,  medication prepared incorrectly, even if it was not actually given to 
the participant
!
Drug not administered as indicated, for example, wrong route or wrong site of 
administration
!
Drug not taken as indicated eg,  tablet dissolved in water when it should be taken as a 
solid tablet 
!
Drug not stored as instructed eg,  kept in the fridge when it should be at room temperature 
!
Wrong participant received the medication (excluding IVRS/IWRS errors)
!
Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IVRS/IWRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error 
!
Participant accidentally missed drug dose(s) eg,  forgot to take medication
!
Accidental overdose (will be captured as an overdose)
!
Participant failed to return unused medication or empty packaging


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!
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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Handling of Human Biological Samples
C 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each center keeps full traceability of collected biological samples from the 
patients while in storage at the centre until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers
Samples retained for further use will be stored in the AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for donated biological samples 
AstraZeneca ensures that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the informed consent.
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analyzed, 
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological sample(s) is an integral part of the study, then the patient is 
withdrawn from further study participation. 
The Investigator:
!
Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca
!
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented
!
Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented, 
and the signed document returned to the study site
!
Ensures that the patient and AstraZeneca are informed about the sample disposal.


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AstraZeneca ensures the organizations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories. For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations in the 46th edition (2005). 
Infectious substances are now classified either as Category A, Category B or Exempt. There is 
no direct relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. Category A pathogens are eg, Ebola, Lassa fever virus:
!
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number 
and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
!
Clinical trial samples will fall into Category B or exempt under IATA regulations
!
Clinical trial samples will routinely be packed and transported at ambient
!
temperature in IATA 650 compliant packaging 
!
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content
!
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable
!
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to contain 
any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 


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containment standards are encouraged wherever possible when road or rail transport is 
used.


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Genetics (for Optional Genetic Research Study)
This appendix relates to the optional genetic research study only. This is separate from the 
mandatory genetic components of this study. Details pertaining to the mandatory genetic 
samples and analyses that are required in this study are addressed in the Laboratory Manual.
D 1
Use/analysis of DNA
Genetic variation may impact a patient’s response to therapy, susceptibility to, and severity 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, 
and excretion; mechanism of action of the drug; disease etiology; and/or molecular subtype of 
the disease being treated. Therefore, where local regulations and IRB/IEC allow, a blood 
sample will be collected for DNA analysis from consenting patients.
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications. Genetic research may lead to better understanding of diseases, better diagnosis of 
diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications. 
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical studies 
and, possibly, to genetically guided treatment strategies.
Genetic research may consist of the analysis of the structure of the patient´s DNA (ie, the 
entire genome). 
The results of genetic analyses may be reported in the CSR or in a separate study summary.
The Sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be retained while research on durvalumab continues but no longer than 15 
years or other period as per local requirements.
D 2
Genetic research plan and procedures
Selection of genetic research population
Study selection record
All patients will be asked to participate in this genetic research. Participation is voluntary and 
if a patient declines to participate there will be no penalty or loss of benefit. The patient will 
not be excluded from any aspect of the main study.


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Inclusion criteria
!
For inclusion in this genetic research, patients must fulfill all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and: Provide informed consent 
for the genetic sampling and analyses.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:
!
Previous allogeneic bone marrow transplant
!
Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection
Withdrawal of consent for genetic research:  
Patients may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study.  Voluntary withdrawal will not 
prejudice further treatment.  Procedures for withdrawal are outlined in  Appendix C 2.
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the patients pre-dose at the first
dosing visit. Although DNA is stable, early sample collection is preferred to avoid introducing 
bias through excluding patients who may withdraw due to an adverse event (AE), such 
patients would be important to include in any genetic analysis. If for any reason the sample is 
not drawn at the first dosing visit, it may be taken at any visit until the last study visit. Only 
one sample should be collected per patient for genetics during the study. Samples will be 
collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality. Samples will be stored for a maximum of 15 
years, from the date of last patient last visit, after which they will be destroyed. DNA is a 
finite resource that is used up during analyses. Samples will be stored and used until no further 
analyses are possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube. Thereafter, the sample will be 
identifiable only by the second, unique number. This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organization. No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organizations working with the DNA).


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The link between the patient enrollment/randomization code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organizations. The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit, 
and permit tracing of samples for destruction in the case of withdrawal of consent.
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix B.
Informed consent
The Genomics Initiative component of this study is optional and the patient may participate in 
other components of the main study without participating in the genetic component. To 
participate in the genetic component of the study the patient must sign and date both the 
consent form for the main study and the Genomics Initiative subsection of the main consent 
form for the study. Copies of both signed and dated consent forms must be given to the patient 
and the original filed at the study center. The Principal Investigator(s) is responsible for 
ensuring that consent is given freely and that the patient understands that they may freely 
withdrawal from the genetic aspect of the study at any time.
Patient data protection
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and also have access to his or her genetic data. In addition, Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyses the samples.
AstraZeneca and its designated organizations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as hospitals, academic organizations or health insurance companies. This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease. The researchers can 


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only use this information for health related research purposes. Researchers may see summary 
results but they will not be able to see individual patient data or any personal identifiers. 
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Statistical methods and determination of sample size
The number of patients that will agree to participate in the genetic research is unknown. It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A Statistical
Analysis Plan may be prepared where appropriate.


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Mandatory Genetic analysis for Minimal Residual 
Disease
This appendix relates to the mandatory genetic component of this study. 
Use/analysis of DNA in mandatory genetic study
Minimal residual disease (MRD) will be detected using a Sponsor-approved, complex 
personalized multi-step assay. Firstly, whole exome sequencing (WES) of the patient’s tumor 
is performed on primary resection sample and controlled for germline mutations by WES of 
whole blood (as indicated in the Schedule of Activities [Table 1]), using 
. 
Germline exome sequencing will be performed at a depth of 90% of targeted bases covered at 
20X or greater, whereas tumour exome sequencing will have a mean sample coverage of 
 
 
 
 
 
 
 This personalized approach allows detection of the patient’s tumor variants in 
circulating tumor DNA (ctDNA) at high sensitivity. Tumor and whole blood samples, 
including DNA derived from those samples, as well as WES data, will be used for diagnostic 
development and exploratory research.
Sample coding and storage
All samples submitted for MRD will be coded to prevent patient identification. Sequencing 
data and variant calls from MRD analysis will be stored in a secure system at designated 
organizations to analyze the sample and/or at AstraZeneca. Germline data analysis will be 
conducted for the purpose of identifying tumor-specific variants not present in the patient’s 
non-cancerous cells.
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this mandatory 
genetics research component, are outlined in Appendix B.
Informed consent
Patients must sign Informed Consent Form 1 (ICF1) of the overall study to participate in this 
mandatory genetic component of the study.
Patient data protection
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
CCI
CCI


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Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and also have access to his or her genetic data. In addition, Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyze the samples.


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Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
F 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases.  It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a patient meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The Investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Serious Adverse Events (SAEs) and Adverse Events (AEs) according to the 
outcome of the review and assessment in line with standard safety reporting processes.
F 2
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).


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Hy’s Law (HL)
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, e.g., elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
F 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:
!
ALT ≥ 3xULN
!
AST ≥ 3xULN
!
TBL ≥ 2xULN
Central laboratories being used:
When a patient meets any of the PHL identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the Investigator will:
!
Notify the AstraZeneca representative 
!
Request a repeat of the test (new blood draw) by the central laboratory without delay
!
Complete the appropriate unscheduled laboratory CRF module(s) with the original local 
laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:
!
Determine whether the patient meets PHL criteria (see Section F 2 within this Appendix 
for definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results)


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Local laboratories being used:
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Notify the AstraZeneca representative 
!
Determine whether the patient meets PHL criteria (see Section 2 Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits
!
Promptly enter the laboratory data into the laboratory CRF
F 4
Follow-up
F 4.1
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:
!
Inform the AstraZeneca representative that the patient has not met PHL criteria.
!
Perform follow up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol.
F 4.2
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:
!
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment
!
Notify the AstraZeneca representative who will then inform the central Study Team 
!
Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting.
!
For patients that met PHL criteria prior to starting IMP, the investigator is not required to 
submit a PHL SAE unless there is a significant change# in the patient’s condition
!
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up (including any further laboratory testing) and 
the continuous review of data
!
Subsequent to this contact the Investigator will:
∀
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.
∀
Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which the tests available 
in the Hy’s law lab kit should be used 


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∀
Complete the three Liver CRF Modules as information becomes available 
# A ‘significant’ change in the patient’s condition refers to a clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST or total 
bilirubin) in isolation or in combination, or a clinically relevant change in associated 
symptoms.  The determination of whether there has been a significant change will be at 
the discretion of the Investigator, this may be in consultation with the Study Physician if 
there is any uncertainty.
F 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from date PHL criteria was met.  The AstraZeneca Global Clinical Lead or equivalent and 
Global Safety Physician will also be involved in this review together with other subject matter 
experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for an SAE:
!
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF
!
If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE CRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AZ standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:
!
Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 
∀
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply


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∀
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:
!
Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE reporting.
!
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
F 6
Laboratory tests
Hy’s Law laboratory kit for central laboratories 
Additional standard chemistry and 
coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA
IgG anti-HCV
HCV RNA* 
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-
transferrin)**
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-
LKM)
Anti-Smooth Muscle Ab (ASMA)


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Hy’s Law laboratory kit for central laboratories 
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
* HCV RNA is only tested when IgG anti-HCV is positive or inconclusive
** Carbohydrate deficient transferrin (CD-transferrin) is not available in China. Study teams should amend this 
list accordingly
REFERENCES
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf


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Guidelines for evaluation of new lesions using RECIST 1.1 
Criteria (Response Evaluation Criteria in Solid Tumors)
Introduction
The RECIST 1.1 guidelines are typically used in the context of patients who have measurable 
and/or non-measurable disease at baseline. However in thist study, patients will be 
randomized once there is confirmation that there are no lesions at baseline.  In the setting of 
early stage disease, new lesions may be difficult to detect. This appendix details the 
implementation of (RECIST 1.1) guidelines (Eisenhauer et al 2009) for the assessment of new 
lesions  Additional special guidance is provided for evaluation of scans collected after 
equivocal radiological progression.
Imaging modalities and acquisition specifications for RECIST 1.1
The preferred imaging modality and coverage for radiological assessments of disease 
recurrence (new lesions, NLs) is contrast CT of the chest and abdomen including liver and 
adrenal glands. A summary of all the imaging modalities that can be used (under specific 
circumstances) for assessment of new lesions Table 17 and detailed in the paragraphs below.
Table 17
Summary of imaging modalities for tumor assessment
New Lesions
CT
MRI
Plain X-ray
Chest X-ray
Bone scan (Scintigraphy)
FDG-PET/CT
CT Computed tomography; FDG-PET/CT 18F-Fluoro-deoxyglucose positron emission tomography/CT; 
MRI Magnetic resonance imaging.
CT and MRI 
Computed tomography (CT) with intravenous (IV) contrast is the preferred imaging modality 
(although magnetic resonance imaging [MRI] with IV contrast is acceptable if CT is 
contraindicated) to generate reproducible anatomical images for identification of NLs.  It is 
essential that the same correct imaging modality, image acquisition parameters (eg, anatomic 
coverage, imaging sequences, etc), imaging facility, tumor assessor (eg, radiologist), and 
method of tumor assessment (eg, RECIST 1.1) are used consistently for each patient 
throughout the study.  The use of the same scanner for serial scans is recommended, if 
possible.  It is important to follow the image collection/tumor assessment schedule as closely 
as possible (refer to the Schedule of Activities [SoA; Table 2]), and this on-study imaging 
schedule MUST be followed regardless of any delays in dosing or missed imaging visits.  If 
an unscheduled assessment is performed (eg, to investigate clinical signs/symptoms of 


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progression) and the patient has not progressed, every attempt should be made to perform the 
subsequent scan acquisitions at the next scheduled imaging visit.
Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice.  Body 
scans should be performed with breath-hold scanning techniques, if possible.  Therefore, CT 
of the chest is recommended over MRI due to significant motion artifacts (eg, heart, major 
blood vessels, breathing) associated with MRI.  MRI has excellent contrast and spatial and 
temporal resolutions; however, there are many image acquisition variables involved in MRI, 
which greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  The modality used at follow-up should be the same 
as was used at baseline, and the lesions should be assessed on the same pulse sequence.  In 
general, local oncology diagnostic imaging parameters are applied for scan acquisition.  It is 
beyond the scope of this appendix to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.
The most critical CT and MRI image acquisition parameters for optimal tumor evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval.
a.  Anatomic coverage: Optimal anatomic coverage for most solid tumors is the 
chest-abdomen.  Coverage should encompass all areas of known predilection for metastases in 
the disease under evaluation and should additionally investigate areas that may be involved 
based on signs and symptoms of individual patients.  Because a lesion later identified in a 
body part not scanned at baseline would be considered as a new lesion representing disease 
progression, careful consideration should be given to the extent of imaging coverage at 
baseline and at subsequent follow-up timepoints.  This will enable better consistency not only 
of tumor measurements but also identification of new disease.
Required anatomical regions to be imaged for assessment of tumor burden at the pre-surgery 
baseline (screening) and follow-up visits the timepoints are specified in the SoA (Table 2).  
Examples of the preferred modalities include the following:
!
IV contrast-enhanced CT of chest and abdomen (including liver and adrenal glands) 
!
Non-contrast CT of chest and IV contrast-enhanced abdomen (including liver and adrenal 
glands) 
!
IV contrast-enhanced CT or MRI of the head and neck
!
IV contrast-enhanced MRI (preferred) or CT of the brain
For chest-abdomen imaging, the following are scanning options in decreasing order of 
preference, with additional options for consideration when patients have sensitivity to IV 
contrast or have compromised renal function:
!
Chest-abdomen CT with IV CT contrast (most preferred)


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!
Chest CT without IV contrast + abdomen MRI with IV MRI contrast, if CT IV contrast 
(iodine based) is medically contraindicated at any time during the study
!
Chest-abdomen MRI with IV MRI contrast, if CT cannot be performed at any time during 
the study
b.  IV contrast administration: Optimal visualization and measurement of metastases in 
solid tumors require consistent administration (dose and rate) of IV contrast as well as timing 
of scanning.  An adequate volume of a suitable contrast agent should be given so that the 
tumor lesions are demonstrated to best effect and a consistent method is used on subsequent 
examinations for any given patient.  Oral contrast is recommended to help visualize and 
differentiate structures in the abdomen.  
c.  Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) slices with ≤5-mm thickness throughout the 
entire anatomic region of interest for optimal lesion measurements.  
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered.  
Chest X-ray
  Chest X-ray can, be used to identify the presence of NLs.  However, there is preference that 
a higher resolution modality, such as CT, be used to confirm the presence of NLs.
Plain X-ray 
Plain X-ray may be used as a method of assessment to identify the presence of new bone 
lesions.  
Isotopic bone scan 
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits.  NLs may be recorded in case positive hot-spots appear on a 
bone scan that were not present on a previous bone scan; however, a newly observed 
equivocal hot-spot on a bone scan that cannot be verified with correlative imaging (CT, MRI, 
or X-ray) of the same anatomical region shall not be the only trigger for a progressive disease 
(PD) assessment at that timepoint.  
FDG-PET/CT
18F-Fluoro-deoxyglucose positron emission tomography/computed tomography/CT 
(FDG-PET/CT) scans may be used as a method for identifying new extrahepatic lesions (but 
not intrahepatic lesions) for RECIST 1.1 assessments according to the following algorithm: 


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NLs will be recorded where there is positive 18F-Fluoro-deoxyglucose uptake1 not present on 
baseline or prior FDG-PET scan or in a location corresponding to a NL on a companion 
CT/MRI collected close in time to the FDG-PET scan.  The PET portion of the PET/CT 
introduces additional data that may bias an Investigator if it is not routinely or serially 
performed.  Therefore, if there is no baseline or prior FDG-PET scan available for 
comparison, and no evidence of NLs on companion CT/MRI scans, then follow-up CT/MRI 
assessments should continue as per the regular imaging schedule to verify the unequivocal 
presence of NLs.
The low-dose or attenuation correction CT portions of a combined FDG-PET/CT scan may be 
of limited use in anatomically based efficacy assessments, and it is therefore suggested that 
they should not substitute for dedicated diagnostic contrast-enhanced CT scans for tumor 
measurements by RECIST 1.1.  In exceptional situations, if a site can document that the CT 
performed, as part of a PET/CT examination, is of identical diagnostic quality (with IV 
contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT can be used 
for RECIST 1.1 tumor assessments.  Caution that this is not recommended because the PET 
portion of the CT introduces additional (PET) data that may bias an Investigator if it is not 
routinely or serially performed.
Ultrasound 
Tumors identified by ultrasound will need to be assessed by correlative CT or MRI anatomical 
scan.
Other tumor assessments
Clinical examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for RECIST 1.1 assessments.  Tumors identified by clinical examination will need 
to be assessed by correlative CT or MRI anatomical scans.
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated 
in the context of tumor assessment.
Histology and cytology
Histology or tumor markers on tumor biopsy samples will not be used as part of the tumor 
response assessment as per RECIST 1.1.  
                                               
1
A positive FDG-PET scan lesion should be reported only when an uptake (eg, SUV) greater than twice that of the surrounding tissue or liver is observed.


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Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, and pleural effusion) that appears or worsens during the study will not be 
used as part of the tumor response assessment as per RECIST 1.1.  
RECIST 1.1 NL identification at follow-up
Details, including the imaging modality, the date of scan, and the location of any NLs will 
also be recorded in the case report form.  The presence of 1 or more NLs is assessed as 
progression.  The finding of a NL should be unequivocal, ie, not attributable to differences in 
scanning technique, change in imaging modality, or findings thought to represent something 
other than tumor (e.g. pseudoprogression related to edema or infiltration of immune cells).  If 
a NL is equivocal, for example because of its small size, the treatment and tumor assessments 
should be continued until the previously (pre-existing) new lesion has been assessed as 
unequivocal at a follow-up visit, and then the progression date should be declared using the 
date of the initial scan when the NL first appeared.
If equivocal lesions are present at baseline, they will not be documented on the baseline CRF. 
Therefore, such lesions would not be recorded as new until the timepoint they are determined 
to be unequivocal, if applicable, and will not be backdated to baseline. However, they can be 
backdated to post-baseline follow-up scans in instances where the equivocal lesion converts to 
unequivocal without an intervening period of lesion absence.  
Pleural effusions, when present at baseline, should not be recorded at baseline and therefore 
would not be recorded as new lesions until the timepoint they are determined to be 
unequivocal, if applicable. 
New or pleural enlarging effusions will be considered new equivocal lesions unless there are 
corresponding soft tissue changes suggestive of metastatic disease in which case they will be 
documented as new unequivocal lesions. Only significant and unequivocally new pleural 
effusions will be recorded as new unequivocal lesions and be indicative of disease relapse.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate disease progression.
If the site is unsure whether a new lesion represents NSCLC recurrence, a second primary
NSCLC, or a new malignancy, a tissue biopsy should be performed to characterize the nature 
of the new lesion. If a new lesion cannot be unequivocally confirmed as a second primary 
NSCLC or a new malignancy other than NSCLC by tissue analysis, the new lesion should be 
considered a NSCLC recurrence and documented as such.   


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Central imaging
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed Contract Research Organization (CRO) for QC and storage. 
Guidelines for image acquisition, de-identification, storage at the investigative site as source 
data, and transfer to the imaging CRO will be provided in a separate document. A blinded 
independent central review (BICR) of images will be performed at the discretion of 
AstraZeneca. Results of these independent reviews will not be communicated to Investigators, 
and results of Investigator RECIST 1.1 assessments will not be shared with the central 
reviewers. The management of patients will not be based upon the results of theBICR. 
Further details of the BICR will be documented in the Independent Review Charter.
References
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47.


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Contraception Requirements
Contraception requirements for this study are as follows.
H 1
Female Pateints
Women not of childbearing potential are defined as those who are surgically sterile (ie, 
bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or who are 
post-menopausal.
Women will be considered post-menopausal if they have been amenorrhoeic for 12 months 
without an alternative medical cause. The following age-specific requirements apply:
!
Women <50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy and if they have luteinizing hormone and follicle-stimulating hormone levels in 
the post-menopausal range for the institution.
!
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy, or had radiation-induced menopause with last menses >1 year ago, or had 
chemotherapy-induced menopause with last menses >1 year ago.
Women of childbearing potential who are not totally sexually abstinent (ie, refraining from 
heterosexual intercourse during the entire period of risk associated with study interventions) 
and intend to be sexually active with a non-sterilized male partner must use at least 1 highly 
effective method of contraception (Table 18). They should have been stable on their chosen 
method of birth control for a minimum of 3 months before entering the study and continue to 
use it throughout the total duration of the drug treatment and the drug washout period (90 days 
after the last dose of durvalumab/placebo or 180 days after the last dose of chemotherapy, 
whichever is longer). 
Non-sterilized male partners of a woman of childbearing potential must use a male condom 
plus spermicide (condom alone in countries where spermicides are not approved) throughout 
this period. Cessation of birth control after this point should be discussed with a responsible 
physician. Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. Total sexual abstinence is an acceptable method 
provided it is the usual lifestyle of the participant. Female patients should refrain from 
breastfeeding throughout this period.
H 2
Male Pateints with a Female Partner of Childbearing Potential
Non-sterilized male patients (including males sterilized by a method other than bilateral 
orchidectomy, eg, vasectomy) who intend to be sexually active with a female partner of 


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childbearing potential must be using an acceptable method of contraception such as male 
condom plus spermicide (condom alone in countries where spermicides are not approved) 
from the time of screening throughout the total duration of the study and the drug washout 
period (90 days after the last dose of durvalumab/placebo or 180 days after the last dose of 
chemotherapy, whichever is longer) to prevent pregnancy in a partner. 
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception. Male patients should refrain from sperm donation or banking 
throughout this period.
Vasectomised (ie, sterile) males are considered fertile and should still use a male condom plus 
spermicide as indicated above during the clinical study.
Even if the female partner is pregnant, male patients should still use a condom plus spermicide 
(where approved), as indicated above during the clinical study, if there is a concern about 
damaging the developing fetus from drug in ejaculate.
Female partners (of childbearing potential) of male patients must also use a highly effective 
method of contraception throughout this period (Table 18).
H 3
Highly Effective Methods of Contraception
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly, are described in Table 18. 
Note that some contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills).


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Table 18
Highly Effective Methods of Contraception (<1% Failure Rate)
Non-Hormonal Methods
Hormonal Methods
•
Total sexual abstinence (evaluate in relation to 
the duration of the clinical study and the 
preferred and usual lifestyle choice of the 
participant)
•
Vasectomised sexual partner (with participant 
assurance that partner received post-vasectomy 
confirmation of azoospermia)
•
Tubal occlusion
•
Intrauterine device (provided coils are 
copper-banded)
•
Injection: Medroxyprogesterone injection 
(eg, Depo-Provera®)a
•
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®)a
•
Implants: Etonogestrel-releasing implants 
(eg, Implanon® or Norplant®)
•
Intravaginal devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®) 
•
Combined pill: Normal and low dose combined 
oral contraceptive pill
•
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Ortho Evra®)
•
Mini pill: Progesterone-based oral contraceptive 
pill using desogestrel: Cerazette® is currently the 
only highly effective progesterone-based pill
a
Hormonal methods not prone to drug-drug interactions.


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Patient-Reported Outcomes
This appendix includes example copies of the following patient-reported outcome (PRO) 
questionnaires:
!
European Organisation for Research and Treatment of Cancer (EORTC) 30-item Core 
Quality of Life Questionnaire
!
EORTC 13-item Lung Cancer Quality of Life Questionnaire
!
!
 
!
!
CCI
CCI
CCI
CCI


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Study Number: D0000C00000
Site Number:
Subject Number: 
Visit Number:
Assessment Date:
 
CCI
CCI


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Study Number: D0000C00000
Site Number:
Subject Number: 
Visit Number:
Assessment Date:
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Study Participant Feedback Questionnaire Template 
Patient Experience Initiative
Study Participant Feedback 
Questionnaire (SPFQ)
Version 1.0
Prepared by:
TransCelerate Patient Experience Initiative Team 
This deliverable prepared by TransCelerate BioPharma can be adopted by member companies 
and others, but all adoption is purely voluntary and based solely on the particular company’s 
unilateral decision. TransCelerate has provided this Study Participant Feedback Questionnaire 
(“SPFQ”) and the corresponding User Guide (collectively the “Work Product”) for 
informational purposes only.  By using the Work Product, you manifest your assent to the 
terms of use set out in this paragraph.  The Work Product are not tailored to any particular 
factual situation and are provided ‘AS IS’ WITHOUT WARRANTY OF ANY KIND, 
EITHER EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, THE 
IMPLIED WARRANTIES OF FITNESS FOR A PARTICULAR PURPOSE, NON-








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Abbreviations 
Abbreviation or special term
Explanation
ABCP
atezolizumab, bevacizumab, carboplatin, and paclitaxel
ADA
antidrug antibody(ies)
AE
adverse event
AESI
adverse event of special interest
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the serum drug concentration-time curve
BCP
bevacizumab, carboplatin, and paclitaxel 
BICR
blinded independent central review
BP
blood pressure
CCTG
Canadian Cancer Trials Group
CD
cluster of differentiation
CI
confidence interval
CL
clearance
COA
clinical outcome assessment
CSP
clinical study protocol
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
circulating tumor DNA
CTLA-4
cytotoxic T-lymphocyte-associated antigen-4
DBL
Database lock
DCO
data cut-off
DFS
disease-free survival
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EGFR
epidermal growth factor receptor
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire – Core 30 items
EORTC QLQ-LC13
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire – Lung Cancer 13 items


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Abbreviation or special term
Explanation
ePRO
electronic patient-reported outcomes
FAS
full analysis set
FDA
Food and Drug Administration
FDG-PET
18F-Fluoro-deoxyglucose positron emission tomography
GCP
Good Clinical Practice
GHS
global health status
HBV
hepatitis B virus
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HL
Hy’s law
HR
hazard ratio
HRCT
high-resolution computed tomography
HRQoL
health-related quality of life
IASLC
International Association for the Study of Lung Cancer
IB
Investigator’s Brochure
IC
immune cells
ICF
informed consent form
ICF1
informed consent form 1
ICF2
informed consent form 2
ICH
International Council for Harmonisation
iCRO
imaging Contract Research Organization
IDMC
independent data monitoring committee
IEC
independent ethics committee, synonymous with institutional review board 
(IRB)
IHC
immunohistochemistry
ILD
interstitial lung disease
imAE
immune-mediated adverse event
IMRT
intensity-modulated radiation therapy 
IP
investigational product
International Coordinating 
Investigator
If a study is conducted in several countries, the International Coordinating 
Investigator is the Investigator coordinating the Investigators and/or activities 
internationally. 
IO
immuno-oncologic
IRB
institutional review board
CCI


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Abbreviation or special term
Explanation
ITT
intent-to-treat
IV
intravenous
IWRS
interactive web response system
LIMS
Laboratory Information Management System
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities 
MRD
minimal residual disease
MRD+
MRD-positive
MRD-
MRD-negative
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
NTL
non-target lesion
ORR
objective response rate
OS
overall survival
PD
progression of disease
PD-1
programmed cell death 1
PD-L1
programmed cell death-ligand 1
PD-L2
programmed cell death-ligand 2
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic(s)
PORT
postoperative radiation therapy
PR
partial response
PRO
patient-reported outcome
 
q2w
every 2 weeks
q3w
every 3 weeks
q4w
every 4 weeks
q12w
every 12 weeks
CCI
CCI
CCI
CCI


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Abbreviation or special term
Explanation
 
QoL
quality of life
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
SAE
serious adverse event 
SAP
statistical analysis plan
SAS
safety analysis set
SD
stable disease
SoA
Schedule of Activities
SoC
standard of care
sPD-L1
soluble programmed cell death-ligand 1
TC
tumor cell
TL
target lesion
TMB
tumor mutational burden
TMG
toxicity management guidelines
TPS
tumor proportion score
UICC
Union for International Cancer Control
ULN
upper limit of normal
VATS
video-assisted thoracoscopic surgery
WBDC
Web Based Data Capture
WES
whole exome sequencing
WHO
World Health Organization
w/v
weight per volume
CCI
CCI
CCI


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d910lc00001-csp-v4
Document Title:
D910LC00001 Clinical Study Protocol version 4
Document ID:
Doc ID-004122806
Version Label:
4.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
03-Aug-2022 20:44 UTC
Content Approval
03-Aug-2022 16:53 UTC
Content Approval
03-Aug-2022 16:58 UTC
Management Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan 
Study Code
D910LC00001
Version Number 
2.0
Date
15 December 2022
A Phase III, Randomized, Multicenter, Double-blind, Placebo-controlled 
Study to Determine the Efficacy of Adjuvant Durvalumab in Combination 
with Platinum-based Chemotherapy in Completely Resected Stage II-III 
NSCLC (MERMAID-1)
ed 
III, Random
III, Random
ermine
ermin
b
Redacted
ed for 
he E
he E
sed Chem
ed Ch
NSCL
N
or Public Disclosure


Statistical Analysis Plan, v2.0
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Study Code D910LC00001
Date 15 December 2022
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A Phase III, Randomized, Multicenter, Double-blind, Placebo-controlled 
Study to Determine the Efficacy of Adjuvant Durvalumab in Combination 
with Platinum-based Chemotherapy in Completely Resected Stage II-III 
NSCLC (MERMAID-1)
SIGNATURE OF STUDY STATISTICIAN
Study Statistician
Date
PPD


Statistical Analysis Plan, v2.0
AstraZeneca 
Study Code D910LC00001
Date 15 December 2022
CONFIDENTIAL AND PROPRIETARY
3 of 56
A Phase III, Randomized, Multicenter, Double-blind, Placebo-controlled 
Study to Determine the Efficacy of Adjuvant Durvalumab in Combination 
with Platinum-based Chemotherapy in Completely Resected Stage II-III 
NSCLC (MERMAID-1)
SIGNATURE OF STUDY STATISTICIAN
Global Product Statistician
Date
PPD


Statistical Analysis Plan, v2.0
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Study Code D910LC00001
Date 15 December 2022
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TABLE OF CONTENTS
TABLE OF CONTENTS...................................................................................................... 4
LIST OF ABBREVIATONS................................................................................................. 7
AMENDMENT HISTORY................................................................................................. 10
1
STUDY DETAILS ........................................................................................... 13
1.1
Study Objectives............................................................................................... 13
1.1.1
Primary Objective............................................................................................. 13
1.1.2
Secondary Objectives........................................................................................ 14
1.1.3
Safety Objective ............................................................................................... 14
1.1.4
a.................................................................................... 14
1.2
Study Design .................................................................................................... 16
1.3
Number of Patients ........................................................................................... 17
2
ANALYSIS SETS ............................................................................................ 18
2.1
Definition of Analysis Sets ............................................................................... 18
2.1.1
Full Analysis Set (Intention to Treat) ................................................................ 19
2.1.2
MRD+ Analysis Set.......................................................................................... 19
2.1.3
Safety Analysis Set........................................................................................... 19
2.2
Protocol Deviations........................................................................................... 19
3
PRIMARY AND SECONDARY VARIABLES ............................................... 21
3.1
Derivation of RECIST Visit Responses............................................................. 21
3.1.1
New Lesions – Site Investigator Data................................................................ 21
3.1.2
Overall Visit Response – Site Investigator Data................................................ 22
3.2
Efficacy Variables ............................................................................................ 22
3.2.1
Disease-free Survival (DFS) ............................................................................. 22
3.2.2
Overall Survival (OS) ....................................................................................... 24
3.3
Safety Variables................................................................................................ 24
3.3.1
Study Treatments.............................................................................................. 25
3.3.1.1
Exposure and Dose Interruptions ...................................................................... 25
3.3.2
Dose Intensity................................................................................................... 26
3.3.3
Adverse Events................................................................................................. 27
3.3.4
Laboratory Data................................................................................................ 28
3.3.5
Electrocardiograms........................................................................................... 29
3.3.6
Vital Signs........................................................................................................ 30
3.4
....................................................................................... 30
3.4.1
......................................................................... 30
3.4.1.1
....................................................................... 30
3.4.1.2
.................................... 30
3.4.2
................................. 31
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3.4.2.1
 
...................................................................................... 31
3.4.2.2
................................................................... 31
3.4.2.3
32
3.4.2.4
....................................................................... 32
4
ANALYSIS METHODS................................................................................... 33
4.1
General Principles............................................................................................. 33
4.1.1
Baseline............................................................................................................ 34
4.1.2
General Considerations for Safety and PRO Assessments ................................. 34
4.2
Analysis Methods ............................................................................................. 36
4.2.1
Multiplicity....................................................................................................... 36
4.2.2
Disease-free Survival (DFS) ............................................................................. 37
4.2.2.1
Primary Analysis of DFS .................................................................................. 37
4.2.2.2
Subgroup Analyses ........................................................................................... 39
4.2.2.3
Secondary Analysis of DFS .............................................................................. 40
4.2.3
Overall Survival (OS) ....................................................................................... 40
4.2.4
....................................................................... 40
4.2.5
.................................... 40
4.2.6
.................................................................................................... 41
4.2.7
.................................................................. 41
4.2.8
Safety ............................................................................................................... 42
4.2.8.1
Adverse Events (AEs)....................................................................................... 42
4.2.8.2
AEs of Special Interest and Possible Interest..................................................... 45
4.2.8.3
Laboratory Assessments ................................................................................... 46
4.2.8.4
Electrocardiograms........................................................................................... 48
4.2.8.5
Vital Signs........................................................................................................ 48
4.2.8.6
Other safety ...................................................................................................... 48
4.2.9
Demographics and Baseline Characteristics ...................................................... 48
4.2.10
Concomitant and Other Treatments................................................................... 49
4.2.11
Exposure........................................................................................................... 50
4.2.12
Coronavirus Disease 2019 (COVID-19)............................................................ 50
5
INTERIM ANALYSES.................................................................................... 51
5.1
Interim Efficacy Analysis ................................................................................. 51
5.2
Independent Data Monitoring Committee ......................................................... 51
6
CHANGES OF ANALYSIS FROM PROTOCOL............................................ 51
7
REFERENCES................................................................................................. 53
8
APPENDICES.................................................................................................. 54
LIST OF TABLES
Table 1
Summary of Outcome Variables and Analysis Populations ............................... 18
Table 2
RECIST 1.1 Overall Visit Responses................................................................ 22
Table 3
Study Treatments.............................................................................................. 25
Table 4
Statistical Analyses to be Conducted................................................................. 36
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LIST OF FIGURES
Figure 1
Overall Study Design According to CSP v4.0 ................................................... 17
LIST OF APPENDICES
APPENDIX A Visit Windows ............................................................................................ 54
APPENDIX B Missing/Partial Dates Imputation................................................................. 55


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LIST OF ABBREVIATONS
Abbreviation or 
special term
Explanation
AE
Adverse event
AEPI
Adverse event of possible interest
AESI
Adverse event of special interest
ALK
Anaplastic lymphoma kinase
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area under the serum drug concentration-time curve
BICR
Blinded independent central review
BMI
Body mass index
CI
Confidence interval
COVID-19
Coronavirus disease 2019
CRO
Contract research organization
CSP
Clinical study protocol
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
ctDNA
Circulating tumor DNA
CV
Coefficient of variation
DBL
Database lock
DBP
Diastolic blood pressure
DCO
Data cut-off
DFS
Disease-free survival
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EGFR
Epidermal growth factor receptor
 
 
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Abbreviation or 
special term
Explanation
FAS
Full analysis set
GHS
Global health status
HLT
Higher level term
HR
Hazard ratio
HRQoL
Health related quality of life
ICF1
Informed consent form 1
ICF2
Informed consent form 2
IDMC
Independent data monitoring committee
IHC
Immunohistochemistry
IP
Investigational product (in this study, durvalumab/placebo)
IPD
Important protocol deviations
ITT
Intent-to-treat
IV
Intravenous
LLN
Lower limit of normal
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Minimal residual disease
MRD+
MRD-positive
MRD-
MRD-negative
NA
Not applicable
NE
Not evaluable
NED
No evidence of disease
NL
New lesion
NSCLC
Non-small cell lung cancer
OS
Overall survival
PD
Progression of disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death-ligand 1
PFS
Progression-free survival
PORT
Post-operative radiotherapy
PRO
Patient reported outcome
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Abbreviation or 
special term
Explanation
 
PT
Preferred term
q3w
Every 3 weeks
q4w
Every 4 weeks
QoL
Quality of Life
RDI
Relative dose intensity
RECIST
Response Evaluation Criteria in Solid Tumours
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS!
A commercially available integrated system of software products, commonly 
used for reporting and analysis of Clinical Studies
SBP
Systolic blood pressure
SoC
Standard of care
SOC
System organ class
SI
International system of units
TC
Tumor cell
TEAE
Treatment-emergent adverse event
TMB
Tumor mutational burden
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
VAF
Variant allele frequencies
VAS
Visual analogue scale
WES
Whole exome sequencing
WHODD
World Health Organization drug dictionary
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AMENDMENT HISTORY
Date
Brief description of change
V1.0 (29Jan2021)
NA – first version
V2.0 (15Dec2022)
Updated to reflect CSP v4, including changes to primary, secondary and 
exploratory objectives.
Updated the planned analyses throughout the document (there will be 
one analysis (ie, primary analysis) which will occur after DCO)
Removed any references to PK and ADA analysis sets, endpoints and 
analyses throughout the document to reflect CSP v4.
Removed any references to MRD- analysis set as it is no longer needed 
to support the primary endpoint due to CSP v4.
Removed any references to health care resource use endpoints, variables 
and analyses to reflect CSP v4.
Removed any references to BICR endpoints and analyses throughout the 
document.
 
Throughout the document, when both the MRD+ analysis set and the 
FAS are mentioned, changed the order so that FAS is mentioned first and 
thereafter the MRD+ analysis set, to align with revised primary endpoint 
as per CSP v4.
Section 2.1.3 – updated the treatment assignment for summaries for 
patients who only received SoC and did not receive any doses of either 
durvalumab or placebo (from “as randomized” to “in the placebo plus 
SoC chemotherapy treatment group”). 
Section 2.2 – removed exclusion criteria 10 as per latest Protocol 
Deviations Plan.
Section 3.2.1 and 4.2.2.1 – removed 3- and 9-month DFS rates to align 
with CSP v4.
Section 3.3.4 – added Hemoglobin, Lymphocytes and Leukocytes to the 
list of parameters that have CTCAE grades defined for both high and low 
values to align with CTCAE v5.0. 
Section 3.3.5 – removed reference to calculation of means for triplicates 
and summaries of ECG data and derivation of QTcF.
Section 3.3.6 – removed any references relating to summaries, on-
treatment and change from baseline.
 
 
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Date
Brief description of change
Section 3.4.2.4 – removed weighted health state utility derivation and 
evaluable population definition.
 
Section 4 and section 4.2.1 – in alignment with CSP v4 clarified that no 
formal statistical analyses will be performed, and all analyses will be 
exploratory.
Section 4.1.1 – Updated baseline definition for efficacy and PROs to last 
observed measurement prior to randomization (not on or prior to 
randomization).
Section 4.1.2 – Imputation rules, added clarification that imputation of 
partial dates will only be applied for patients exposed to treatment.
Section 4.2 and Table 4 – revised in line with changes to objectives.
Sections 4.2.2 – 4.2.6 – revised in line with changes to objectives, 
endpoints, and analyses as per CSP v4.
 
 
Section 4.2.8.1 – Removed summaries for time to first onset of AE, 
duration of AE, and event rate, and longer-term toxicity profile (will 
only be flagged in listings).
Section 4.2.8.1 – Added imAEs (per Investigator) and infusion reaction 
AEs (per Investigator) to bulleted list.
Section 4.2.8.2 – Removed AESI/AEPI summaries leading to steroid 
use, discontinuation of study treatment, and dose delay of study 
treatment.
Section 4.2.8.2 – Removed summaries for time to onset and resolution of 
imAEs.
Section 4.2.8.3 – Removed all graphical presentations of laboratory data 
(including liver enzymes), as well as summaries of absolute value and 
change from baseline in hematology and chemistry, and urinalysis shift 
table.
Section 4.2.8.3 – Thyroid functions tests: removed summaries for 
subjects for on-treatment elevated TSH. Added shift tables to maximum 
and minimum on-treatment.
Section 4.2.8.3– Renal function tests: removed summaries of CrCl 
reversibility, and added clarification that worst CrCl rate on-treatment 
will be presented in summaries.
Section 4.2.8.5 – Removed all graphical presentations and summaries of 
vital signs data.
Section 5.1 – Aligned with CSP v4: no interim analysis planned.
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Date
Brief description of change
Section 7 – Removed references no longer used in this document due to 
updates as listed above.
Minor formatting changes throughout
Section 4.1.2 – Removed cut-off rule for summaries.
Table 1 and related paragraphs in Section 4.2 – updated based on 
requirements due to small number of patients expected in MRD+ 
analysis set.
Table 4 – removed analyses for MRD+ analysis set (only simple 
summaries will be provided, as further noted in Section 4.2)


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1
STUDY DETAILS
This SAP contains a more detailed description of the analyses in the CSP and is based on 
version 4 of the CSP, dated 02 August 2022, and on version 3 of the Protocol Deviations Plan, 
dated 25 May 2021. Any changes to any specifications in the CSP will be described in Section 
6 of this document.
Prior to CSP V4.0, the primary objective of this study was to compare the efficacy of 
durvalumab plus SoC chemotherapy to placebo plus SoC chemotherapy in terms of DFS in 
the MRD+ analysis set. A secondary objective was to compare the efficacy of durvalumab 
plus SoC chemotherapy to placebo plus SoC chemotherapy in terms of DFS in the FAS. The 
study was sized for the primary endpoint of DFS in the MRD+ analysis set and for the 
secondary endpoint of DFS in the FAS. 
Following approvals of neoadjuvant and adjuvant immunotherapy options for patients with 
resectable NSCLC, AstraZeneca has decided to close enrolment to MERMAID-1. These 
approvals were based on the two Phase III clinical studies (IMpower010 and 
PEARLS/KEYNOTE-091) that reported positive results for PD-(L)1 inhibitors (used as 
monotherapy) in the adjuvant setting. One Phase III clinical study (Checkmate816) has 
reported positive results for nivolumab (anti-PD-1 immunotherapy) in the neoadjuvant setting.
Under CSP V4.0 as a result of the decision to close study enrollment, the intended patient 
numbers will not be reached. The primary objective of this study is now to compare the 
efficacy of durvalumab plus SoC chemotherapy to placebo plus SoC chemotherapy in terms of 
DFS in the FAS rather than in the MRD+ analysis set. A secondary objective is now to 
compare the efficacy of durvalumab plus SoC chemotherapy to placebo plus SoC 
chemotherapy in terms of DFS in the MRD+ analysis set. No multiple testing procedure for 
controlling the type I error rate will be implemented (see Section 4.2.1).
1.1
Study Objectives
1.1.1
Primary Objective
Primary objective:
Endpoint/variables:
To assess the efficacy of durvalumab + SoC 
chemotherapy compared to placebo + SoC 
chemotherapy as measured by DFS in all 
patients
DFS in FAS (using Investigator assessments 
according to RECIST 1.1)
DFS Disease-free survival; RECIST Response Evaluation Criteria in Solid Tumours; SoC Standard of care.


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1.1.2
Secondary Objectives
Secondary objectives:
Endpoint/variables:
To assess the efficacy of durvalumab + SoC 
chemotherapy compared to placebo + SoC 
chemotherapy as measured by DFS in MRD+  
patients
DFS in MRD+ analysis set (using Investigator 
assessments according to RECIST 1.1)
To assess the efficacy of durvalumab + SoC 
chemotherapy compared to placebo + SoC 
chemotherapy as measured by OS in MRD+ 
patients and in all patients
OS in MRD+ analysis set and in FAS
DFS Disease-free survival; FAS Full analysis set; MRD+ Minimal residual disease-positive; OS Overall 
survival; RECIST Response Evaluation Criteria in Solid Tumours; SoC Standard of care.
1.1.3
Safety Objective
Safety objective:
Endpoint/variables:
To assess the safety and tolerability profile of 
durvalumab + SoC chemotherapy compared to 
placebo + SoC chemotherapy in MRD+ patients 
and in all patients
AEs, physical examinations, vital signs, and 
laboratory findings
AE Adverse event; MRD+ Minimal residual disease-positive; SoC Standard of care.
1.1.4
a
 
 
 
 
 
 
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1.2
Study Design
This is a Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-arm 
study to evaluate the efficacy and safety of durvalumab plus SoC chemotherapy compared to 
placebo plus SoC chemotherapy in patients with completely resected stage II-III NSCLC who 
are MRD+ post-surgery.
Prior to CSP V4.0, the study was designed to screen approximately 
 patients and 
randomize approximately 
 patients with stage II-III NSCLC, whose tumors are EGFR and 
ALK wild type, and who have undergone complete resection. Randomized patients were to 
include approximately 
 MRD+ and 
 MRD- patients. The number of MRD- patients 
was to be capped at 100. Within the randomized MRD- population, it was expected to have 
approximately 30%/70% Asian/non-Asian patients. 
Following a decision to close recruitment on 25 May 2022, a total of 691 patients were 
enrolled, and up to approximately 100 patients were expected to be randomized within the 
study. The randomized population is expected to include up to approximately 25 MRD+ and 
75 MRD- patients.
The study has opened in 188 centers globally. Note that enrollment has closed for this study.
Patients will be randomized 1:1 to durvalumab plus SoC chemotherapy or placebo plus SoC 
chemotherapy. Randomization will be stratified by disease stage (stage II vs stage III), MRD 
status (MRD+ vs MRD-), and PD-L1 TC expression (< 1% vs ≥ 1%). Patients will receive one 
of the following SoC regimens, depending on histology and per Investigator’s decision: 
paclitaxel/carboplatin (squamous), pemetrexed/cisplatin (non-squamous), or 
pemetrexed/carboplatin (non-squamous). 
Patients will receive SoC chemotherapy q3w for up to 4 cycles plus durvalumab or placebo 
via IV infusion q3w for up to 4 cycles. Patients will then receive up to 10 additional cycles of 
durvalumab or placebo q4w (for a total of 12 months of treatment), until disease recurrence, or 
until other specific treatment discontinuation criteria are met (whichever occurs first). Prior to 
CSP V4.0, all patients were to be followed for disease recurrence until the primary analysis, 
and were to be followed for survival until the completion of the study. For an overview of the 
original study design, see Figure 1 in the CSP.
On 25 May 2022, AstraZeneca closed study recruitment. This was based on changes in the 
treatment landscape as outlined in Section 2.1 of the CSP. All randomized patients will be 
followed until the primary DCO (defined as the date of the last visit of the last patient in the 
study, which is approximately 12 months after last patient was randomized) when no further 
visits will occur. For an overview of the revised study design, see Figure 1.
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Figure 1
Overall Study Design According to CSP v4.0
a While it is preferred that patients are identified and sign ICF1 prior to surgery, patients will be permitted to sign 
ICF1 after surgery. In this case, whole blood and resected tumor tissue must be collected as soon as possible for 
creation of the personalized panel. A plasma sample must still be collected at Week 3-5 (Day 21-35) post-
surgery, even if creation of the personalized panel is delayed. Note that enrollment has closed for this study.
b EGFR/ALK status should be assessed on pre-surgical biopsy. If pre-surgical biopsy is not available or 
evaluable, testing will be conducted on resected tumor tissue while the personalized MRD panel is in 
development. Patients will still be allowed to continue with first screening procedures while testing is ongoing 
but will not be eligible for randomization if their tumor tissue tests positive for EGFR mutations or ALK 
translocations.
c PD-L1 status is required for randomization.
d The plasma sample used to determine MRD status must be collected at Week 3-5 (Day 21-35) post-surgery. 
Investigators will not be notified of the patient’s MRD status and eligibility to continue into second screening 
will be managed through the IWRS.
e A CT scan performed once a patient signs ICF2 can be used as the baseline scan provided this scan was 
performed 28 days + 7 days prior to randomization.
ALK Anaplastic lymphoma kinase; CT Computed tomography; d Day; DFS Disease-free survival; EGFR 
Epidermal growth factor receptor; FAS Full analysis set; ICF1 Informed consent form 1; ICF2 Informed consent 
form 2; MRD Minimal residual disease; MRD+ MRD-positive; MRD- MRD-negative; NSCLC Non-small cell 
lung cancer; OS Overall survival; PD-L1 Programmed cell death-ligand 1; PD-L1 TC<1%/≥1% Expression of 
PD-L1 on tumor membrane, at any intensity, in<1% or ≥1% of tumor cells; PRO Patient-reported outcomes; q3w 
Every 3 weeks; q4w Every 4 weeks; R Randomization; SoC Standard of care; w Week; WES Whole exome 
sequencing.
1.3
Number of Patients
Prior to CSP V4.0, approximately 
 eligible patients were planned to be randomized 1:1 to 
durvalumab plus SoC chemotherapy or placebo plus SoC chemotherapy. Of the patients 
randomized into the study, approximately 
 patients were required to be MRD+, as 
determined by the result from their post-surgical plasma sample. The study was sized for the 
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primary endpoint of DFS in the MRD+ analysis set and for the secondary endpoint of DFS in 
the FAS. 
Under CSP V4.0, the originally planned number of randomized patients will not be met. There 
will be one analysis (ie, primary DFS analysis) which will occur after DCO (see Section 4.2.6) 
and OS will be analyzed at this time. 
2
ANALYSIS SETS
2.1
Definition of Analysis Sets
The populations for analyses are summarized in Table 1 per outcome variable.
Table 1
Summary of Outcome Variables and Analysis Populations
Outcome variable
Population
Primary efficacy data
  DFS (using Investigator assessments)
FAS
Secondary efficacy data
  DFS (using Investigator assessments)
MRD+
  OS
FAS, MRD+
  
  
  
  
  
Study population/Demography data
  Demography
FAS, MRD+
  Baseline and disease characteristics
FAS, MRD+
  Important deviations
FAS, MRD+
  Medical/surgical history
FAS
  Previous anti-cancer therapy
FAS
  Concomitant medications/procedures
FAS
  Subsequent anti-cancer therapy (including radiotherapy)
FAS, MRD+
Safety data
  Exposure
Safety
  AEs
Safety
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Outcome variable
Population
  Laboratory measurements
Safety
  Vital signs
Safety
  ECGs
Safety
AE Adverse event; DFS Disease-free survival; 
, 
 
; FAS Full analysis set; MRD+ Minimal residual disease-positive; OS Overall survival; PFS 
Progression-free survival; 
 
; 
; 
 
2.1.1
Full Analysis Set (Intention to Treat)
The FAS will include all randomized patients. The FAS will be used for all efficacy analyses, 
including 
 Treatment groups will be assigned based on the randomized study treatment, 
regardless of the treatment actually received. Patients who were randomized but did not 
subsequently receive study treatment are included in the analysis in the treatment group to 
which they were randomized. The analysis of data using the FAS therefore follows the 
principles of ITT.
2.1.2
MRD+ Analysis Set 
The MRD+ analysis set will include all patients in the FAS who are MRD+, as determined by 
results from the post-surgical plasma sample based on the assay that was used at the time of 
randomization. Treatment groups will be assigned based on the randomized study treatment, 
regardless of the treatment actually received. Patients who were randomized but did not 
subsequently receive study treatment are included in the analysis in the treatment group to 
which they were randomized.
2.1.3
Safety Analysis Set
The safety analysis set will consist of all randomized patients who received at least 1 dose 
(any amount) of study treatment (durvalumab/placebo and/or SoC). Safety data will not be 
formally analyzed but summarized using the safety analysis set according to the treatment 
received. If a patient receives any amount of durvalumab, with or without SoC, they will be 
summarized in the durvalumab plus SoC chemotherapy treatment group. If a patient only 
receives placebo, with or without SoC, they will be summarized in the placebo plus SoC 
chemotherapy treatment group. Patients who only received SoC and did not receive any doses 
of either durvalumab or placebo will be summarized in the placebo plus SoC chemotherapy 
treatment group.
2.2
Protocol Deviations
The following general categories will be considered IPDs and will be listed and discussed in 
the CSR as appropriate:
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∀
Inclusion criteria deviations: Patients who deviate from inclusion criteria 1, 4, 5, 6, and/or 
12 per Section 5.1 of the CSP. 
∀
Exclusion criteria deviations: Patients who deviate from exclusion criteria 1 and/or 2 per 
Section 5.2 of the CSP. 
∀
Discontinuation criteria for study product met but patient not withdrawn from study 
treatment.
∀
IP deviation:
(a) Patient received incorrect IP to that to which they were randomized.
(b) Patients who were randomized but did not receive IP or chemotherapy.
∀
Excluded medications taken: Received prohibited concomitant systemic anti-cancer 
therapy.
∀
Deviations related to study procedure: Baseline RECIST scan > 49 days before 
randomization. 
Patients who receive the wrong treatment at any time will be included in the safety analysis 
set as described in Section 2.1. During the study, decisions on how to handle errors in 
treatment dispensing (with regard to continuation/discontinuation of study treatment or, if 
applicable, analytically) will be made on an individual basis with written instruction from the 
study team leader and/or statistician.
The IPDs will be listed and summarized by randomized treatment group. IP deviation of 
patients who were randomized but did not receive IP or chemotherapy will lead to exclusion 
from the safety analysis set. None of the other deviations will lead to patients being excluded 
from the analysis sets described in Section 2.1. A per-protocol analysis excluding patients 
with specific IPDs is not planned.
The programmatic determination of the IPDs above will be a separate process outlined in the 
study Protocol Deviations Plan, which will also include full details regarding IPDs as well as 
the activities and responsibilities related to the IPD process.
In addition, other study deviations captured from the eCRF module for inclusion/exclusion 
criteria will be tabulated and listed. Any other deviations from monitoring notes or reports will 
be reported in an appendix to the CSR.
A ‘deviation bias’ sensitivity analysis may be performed, excluding patients with deviations 
that may affect the efficacy of the trial therapy if > 10% of patients in either treatment group:
∀
Did not have the intended disease or indication or
∀
Did not receive any randomized therapy.


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The need for such a sensitivity analysis will be determined following review of the protocol 
deviations ahead of DBL and will be documented prior to the primary analysis being 
conducted.
3
PRIMARY AND SECONDARY VARIABLES
3.1
Derivation of RECIST Visit Responses
For this adjuvant study, where patients with no evidence of disease at baseline (as assessed by 
CT/MRI) will be entered in the study, the definition of NLs in RECIST 1.1 is used to for the 
assessment of disease recurrence.
For all patients, the RECIST tumor response data will be used to determine each patient’s visit 
response according to RECIST version 1.1. It will also be used to determine if and when a 
patient has disease recurrence in accordance with RECIST. 
Baseline radiological tumor assessments are to be performed no more than 28 days + 7 days 
before randomization and ideally as close as possible to the date of randomization. Tumor 
assessments are then performed every 12 weeks ± 1 week following randomization until 
unequivocal disease recurrence or primary DFS analysis. Upon detection of disease 
recurrence, an additional follow-up scan should be performed 4 to 8 weeks later and evaluated 
using post progression radiological criteria.
If an unscheduled assessment is performed, and the patient has not had disease recurrence, 
every attempt should be made to perform the subsequent assessments according to the original 
imaging visit schedule (relative to the date of randomization). If a dose delay of study 
treatment (ie, durvalumab/placebo and/or SoC) occurs, RECIST scans should continue 
according to the original imaging visit schedule. This schedule is to be followed in order to 
minimize any unintentional bias caused by some patients being assessed at a different 
frequency than other patients.
3.1.1
New Lesions – Site Investigator Data
At each post-baseline visit the Investigator should record an overall assessment based on the 
presence or absence of unequivocal NLs. This section provides the definitions of the criteria 
used to determine and record overall response at the investigational site at each visit.
Details of any NLs will be recorded with the date of assessment. The presence of one or more 
unequivocal NLs is assessed as progression and will indicate disease recurrence.


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A lesion identified at a follow-up assessment as local/regional, distant, or second primary 
NSCLC is considered a NL and will indicate disease recurrence. The development of a new 
cancer other than NSCLC should be regarded as an SAE. 
The finding of a NL should be unequivocal: ie, not attributable to differences in scanning 
technique, change in imaging modality or findings thought to represent something other than 
tumor. If a NL is equivocal, for example, because of its small size, the treatment and tumor 
assessments should be continued until the previously (pre-existing) NL has been assessed as 
unequivocal at a follow-up visit. If repeat scans (at least 4 weeks later, but preferably at the 
next scheduled visit) definitively confirm there is a NL, then recurrence should be declared 
using the date of the initial post-baseline scan where the equivocal NL was first identified, 
without an intervening period of lesion absence.
Both equivocal and unequivocal NLs will be recorded in the eCRF. Unequivocal NLs will be 
identified via a Yes/No tick box on the unequivocal new lesions eCRF form. If the question 
‘Any unequivocal new lesions since baseline’ has not been answered with Yes or No and the 
NL details are blank this is not evidence that no unequivocal NLs are present, but should not 
overtly affect the derivation. This scenario (ie, whereby NL response is NE), should only 
occur in exceptional cases, as missing data for the NL field should always be queried.
3.1.2
Overall Visit Response – Site Investigator Data
Table 2 defines how NL information will be used to determine an overall visit response.
Table 2
RECIST 1.1 Overall Visit Responses
Target lesions
Non-target lesions
New lesions
Overall visit response
NA
NA
NE
NE
NA
NA
No
NED
NA
NA
Equivocal
NED*
NA
NA
Yes
PD
* Disease recurrence (ie, PD) may be backdated to a timepoint where an equivocal new lesion was identified, 
under specific conditions outlined in Section 3.1.
NA Not applicable, NE Not evaluable; NED No Evidence of Diseases; PD Progressive disease.
3.2
Efficacy Variables
3.2.1
Disease-free Survival (DFS) 
Disease-free survival as assessed by the Investigator is the primary endpoint in this study and 
is defined as the time from the date of randomization until any one of the following events 
below, whichever occurs first, regardless of whether the patient withdraws from randomized 
therapy or receives another anti-cancer therapy prior to disease recurrence (ie, date of DFS 
event or censoring – date of randomization + 1 day):


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∀
Date of disease recurrence using Investigator RECIST 1.1 assessments
#
Local, regional, or distant disease recurrence
#
Diagnosis of a second primary NSCLC
∀
Date of death from any cause
Disease-free survival rate at 6 and 12 months is defined as the proportion of patients alive and 
disease free at 6 and 12 months respectively, estimated from Kaplan-Meier plots of the 
primary endpoint of DFS.
Disease recurrence should be based on the finding of an unequivocal NL. However, if a NL is 
initially equivocal (ie, where an equivocal lesion converts to unequivocal), then the 
progression date should be backdated to the post-baseline follow-up scan when the NL first 
appeared without an intervening period of lesion absence. If equivocal lesions are present at 
baseline, they will not be documented on the baseline eCRF.
Patients who have not experienced disease recurrence and are alive at the time of analysis, 
will be censored at the latest date of assessment from their last evaluable RECIST 1.1 
assessment.
However, if the patient experiences disease recurrence or dies after 2 or more missed visits, 
the patient will be censored at the latest evaluable RECIST 1.1 assessment prior to the 
2 missed visits (note: an NE visit is not considered a missed visit). Given the scheduled visit 
assessment scheme (ie, every 12 weeks ± 1 week after randomization until appearance of
disease recurrence or until primary DFS analysis) the definition of 2 missed visits will be 26 
weeks (2 × 12 weeks + 1 week for an early assessment and + 1 week for a late assessment). 
If the patient has no evaluable assessments or does not have baseline data, they will be 
censored at day 1 unless they die within 2 visits of baseline (ie, 25 weeks [2 × 12 weeks + 
1 week for a late assessment]), then they will be treated as an event with the date of death as 
the event date. Additionally, patients with unequivocal evidence of disease at baseline (as 
assessed by the Investigator) will be censored at randomization (day 1).
The primary endpoint analysis of DFS will be based on Investigator RECIST 1.1 assessments. 
The DFS time will always be derived based on scan/assessment dates and not visit dates.
RECIST 1.1 assessments/scans contributing toward a particular visit may be performed on 
different dates. The following rules will be applied:
∀
For Investigator assessments, the date of disease recurrence will be determined based on 
the earliest of the RECIST assessment/scan dates of the component that indicates disease 
recurrence.


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∀
When censoring a patient for DFS, the patient will be censored at the latest of the scan 
dates contributing to a particular overall visit assessment.
3.2.2
Overall Survival (OS)
Overall survival is defined as the time from the date of randomization until death due to any 
cause regardless of whether the patient discontinues from randomized therapy or receives 
another anti-cancer therapy (ie, date of death or censoring – date of randomization + 1 day). 
Any patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the patient was known to be alive (SUR_DAT, recorded within the 
SURVIVE module of the eCRF). 
Survival calls will be made in the week following the date of DCO for the primary analysis, 
and if patients are confirmed to be alive or if the death date is after the DCO date these 
patients will be censored at the date of DCO. The status of ongoing, withdrawn (from the 
study) and ‘lost to follow-up’ patients at the time of the final OS analysis should be obtained 
by the site personnel by checking the patient’s notes, hospital records, contacting the patient’s 
general practitioner, and checking publicly-available death registries. In the event that the 
patient has actively withdrawn consent to the processing of their personal data, the vital status 
of the patient can be obtained by site personnel from publicly available resources where it is 
possible to do so under applicable local laws. In instances where the SURVIVE module is not 
completed then all relevant eCRF fields will be used to determine the last recorded date on 
which the patients were known to be alive.
If a patient is known to have died where only a partial death date is available, then the date of 
death will be imputed as the latest of the last date known to be alive + 1 day from the database 
and the death date using the available information provided. Refer to Appendix B for 
imputation rules for missing or partial death dates.
3.3
Safety Variables
Safety and tolerability will be assessed in terms of AEs (including SAEs), deaths, laboratory 
data, vital signs, ECGs, and exposure. These will be collected for all patients. For physical 
examination, only information on whether the assessment was performed or not is recorded, 
and any abnormal findings are reported as either medical history or AEs.
Safety data will be summarized from the ‘On-treatment’ period, unless otherwise specified.
‘On-treatment’ is defined as assessments between the date/time of start of study treatment (ie, 
durvalumab/placebo and/or SoC) and 90 days following discontinuation of study treatment 
(ie, the last dose of durvalumab/placebo and/or SoC), or up to and including the date of 
initiation of the first subsequent anti-cancer therapy (including radiotherapy, except for 
palliative radiotherapy), whichever occurs first.


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3.3.1
Study Treatments
Study treatment in this study refers to durvalumab plus SoC chemotherapy or placebo plus 
SoC chemotherapy. Study treatments are described in Table 3. Exposure will be defined for 
durvalumab, placebo and SoC chemotherapy regimens.
Table 3
Study Treatments
Study treatment name
Route of 
administration
Dosing instructions
Durvalumab
IV
1500 mg infusion over 60 min q3w × 4 cycles 
followed by 1500 mg over 60 min q4w × 10 cycles 
up to a total of 12 months of treatment
Placebo
IV
Infusion over 60 min q3w × 4 cycles followed by 
infusion over 60 min q4w × 10 cycles up to a total of 
12 months of treatment
Standard of 
carea
Carboplatin/ 
Paclitaxel
IV
Paclitaxel (200 mg/m2) and carboplatin (AUC 6) 
Day 1 of each 3-week cycle for 4 cycles
Cisplatinb/ 
Pemetrexed
IV
Pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) 
Day 1 of each 3-week cycle for 4 cycles
Carboplatin/ 
Pemetrexed
IV
Pemetrexed (500 mg/m2) with carboplatin (AUC 5) 
Day 1 of each 3-week cycle for 4 cycles
a Patients will receive one of the specified SoC regimens, depending on histology and per Investigator’s decision.
b In the event of unfavorable tolerability, patients can switch from cisplatin to carboplatin therapy at any point during the 
study. However, it is preferred that all patients receive at least 1 cycle of cisplatin.
AUC Area under the serum drug concentration-time curve; IV Intravenous; min Minutes; q3w Every 3 weeks; q4w Every 4 
weeks; SoC Standard of care.
3.3.1.1
Exposure and Dose Interruptions
Exposure (ie, duration of treatment) will be defined as follows:
∀
Total (or intended) exposure of durvalumab/placebo
#
Total (or intended) exposure = min (last dose date where dose > 0 mg + xx days, date 
of death, date of DCO) – first dose date + 1 day
where xx = 20 if the last dose occurs during the durvalumab/placebo plus SoC portion 
of the study (cycles 1 to 4), and 27 if the last dose occurs during the 
durvalumab/placebo monotherapy portion of the study (cycles 5 to 14)
∀
Actual exposure of study treatment (defined for durvalumab and placebo only)
#
Actual exposure = intended exposure – total duration of dose interruptions and cycle 
delays


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∀
Calculation of duration of dose delays/interruptions (for actual exposure, defined for 
durvalumab and placebo only)
#
Duration of dose delays/interruptions = sum of positive values of [date of the dose –
date of previous dose – (xx + 3) days] 
where xx is 21 for the durvalumab/placebo plus SoC portion of the study (cycles 1 to 
4), and 28 for the durvalumab/placebo monotherapy portion of the study (cycles 5 to 
14)
Dose reductions of durvalumab/placebo are not permitted, and the actual exposure calculation 
makes no adjustment for any dose reductions that may have occurred.
The total (or intended) exposure for each SoC regimen (ie, combination of SoC agents) will 
also be summarized by combining the SoC agents together (ie, the maximum total exposure 
among all SoC agents will be considered).
∀
The total (or intended) exposure for each SoC agent is defined as follows: 
#
Total (or intended) exposure = min (last dose date where dose > 0 mg + 20 days, date 
of death, date of DCO) – first dose date + 1 day
Number of Treatment Cycles Received
Exposure will also be measured by the number of cycles received. For SoC, a cycle 
corresponds to a period of 21 days, and for durvalumab/placebo a cycle corresponds to one 
dose of treatment. If a cycle is delayed or prolonged due to toxicity, this should still be 
counted as one cycle. A cycle will be counted if treatment is started even if the full dose is not 
delivered.
Patients who Permanently Discontinue During a Dose Delay
If a decision is made to permanently discontinue study treatment (ie, durvalumab/placebo 
and/or SoC) in-between cycles or during a dose delay then the date of last administration of 
study medication recorded will be used in the calculation of exposure. 
3.3.2
Dose Intensity 
Relative dose intensity (RDI) is the percentage of the actual dose delivered relative to the 
intended dose through to treatment discontinuation. Relative dose intensity will be derived for 
durvalumab or placebo and is defined as follows:
∀
RDI = 100% × d/D, where d is the actual cumulative dose delivered up to the actual last 
day of dosing and D is the intended cumulative dose up to the actual last day of dosing. 
D is the total dose that would be delivered, if there were no modification to dose or 


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schedule. When accounting for the calculation of intended cumulative dose 3 days should 
be added to the date of last dose to reflect the protocol allowed window for dosing.
When deriving actual dose administered the volume before and after infusion will also be 
considered.
3.3.3
Adverse Events
Adverse events and SAEs will be collected throughout the study, from date of informed 
consent (SAEs will be collected following signature of the first informed consent [ICF1]; all 
SAEs and AEs will be collected following signature of the second informed consent [ICF2]) 
until 90 days after the last dose of study treatment (durvalumab/placebo and/or SoC). A TEAE 
is defined as an AE with an onset date, or a pre-existing AE worsening (by Investigator report 
of a change in intensity), during the ‘on-treatment’ period as defined in Section 3.3. The 
Medical Dictionary for Regulatory Activities (using the latest or current MedDRA version) 
will be used to code the AEs. Adverse events will be graded according to the NCI CTCAE 
version 5.0.
In the unlikely event that durvalumab/placebo and SoC chemotherapy are delivered on 
separate dates, AEs with date of onset on or after the earliest first dose of any of the 
components of the combination should be considered to be treatment emergent. 
Adverse Events of Special Interest and Possible Interest
Some clinical concepts (including some selected individual PTs and HLTs) have been 
considered ‘AEs of special interest’ (AESI) and ‘AEs of possible interest’ (AEPI) to the 
durvalumab program.
The AESIs reported in the AstraZeneca-sponsored durvalumab studies are defined as AEs 
with a likely inflammatory or immune-mediated pathophysiological basis resulting from the 
mechanism of action of durvalumab and requiring more frequent monitoring and/or
interventions such as corticosteroids, immunosuppressants, and/or endocrine therapy. 
Endocrine therapies include standard endocrine supplementation, as well as treatment of 
symptoms resulting from endocrine disorders (eg, therapies for hyperthyroidism include beta 
blockers [eg, propranolol], calcium channel blockers [eg, verapamil, diltiazem], methimazole, 
propylthiouracil, and sodium perchlorate).
The AEPIs reported in the AstraZeneca-sponsored durvalumab studies are defined as AEs that 
could have a potential inflammatory or immune-mediated pathophysiological basis resulting 
from the mechanism of action of durvalumab but are more likely to have occurred due to other 
pathophysiological mechanisms, thus, the likelihood of the event being inflammatory or 
immune-mediated in nature is not high and/or is most often or usually explained by the other 
causes.


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These AESIs and AEPIs are identified as a list of categories provided by the clinical team. 
Other categories may be added as necessary or existing terms may be merged. An 
AstraZeneca medically qualified expert, after consultation with the Global Patient Safety 
Physician, has reviewed the AEs of interest and identified which PTs contribute to each 
AESI/AEPI. A further review will take place prior to DBL to ensure any further terms not 
already included are captured within the categories.
Immune-mediated Adverse Events (imAE)
Durvalumab belongs to a class of drugs called immune checkpoint inhibitors. Because the 
mechanism of action of this class of drugs is to block the inhibitory signals that prevent T-cell 
activation, this drug may potentially cause imAEs.
Immune-mediated adverse drug reactions will be identified from both AESIs and AEPIs based 
on programmatic rules that consider interventions involving systemic steroid therapy, 
immunosuppressant use, and/or endocrine therapy (which, in the case of AEPIs, occurs after 
first considering an Investigator’s causality assessment and/or an Investigator’s designation of 
an event as immune-mediated). Infusion-related reactions and hypersensitivity/anaphylactic 
reactions are not considered imAE because they are common to monoclonal antibody drugs in 
general and occur due to a mechanism of action different than that for imAEs as defined in the 
imAE charter. Further details are provided in the imAE charter. 
In addition, medical review of those AESI/AEPI may be performed to classify them as imAEs 
or not imAEs via an independent manual adjudication process. This process is in addition to 
the Investigator assessment of imAEs as recorded in the eCRF.
3.3.4
Laboratory Data
Laboratory data will be collected throughout the study, from second screening to the second 
follow-up visit (12 weeks ± 1 week after completion or discontinuation of study treatment ie, 
durvalumab/placebo and/or SoC). Blood and urine samples for determination of hematology, 
clinical chemistry, and urinalysis will be collected as described in Section 8.2.1 of the CSP. 
For the definition of baseline and the derivation of post-baseline visit values considering visit 
window and how to handle multiple records, derivation rules as described in Section 4.1.2 will 
be used.
Change from baseline in hematology and clinical chemistry variables will be calculated for 
each postdose visit on-treatment. Common Terminology Criteria for Adverse Event (CTCAE) 
grades will be defined at each visit according to the CTCAE grade criteria using local or 
project ranges as required, after conversion of lab result to corresponding SI units. The 
following parameters have CTCAE grades defined for both high and low values: Hemoglobin, 
Leukocytes, Lymphocytes, Potassium, Sodium, Magnesium, and Corrected calcium.


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Corrected calcium will be derived during creation of the reporting database using the 
following formula:
Corrected calcium (mmol/L) = Total Calcium (mmol/L) + ([40 – Albumin (g/L)] × 0.02)
Creatinine clearance (CL) will be derived according to the Cockroft-Gault formula (Cockcroft 
and Gault 1976).
Males:
Creatinine CL (mL/min) = 
Weight (kg) × (140-Age at randomization)
72 × serum creatinine (mg/dL)
Females:
Creatinine CL (mL/min) = 
Weight (kg) × (140-Age at randomization)
72 × serum creatinine (mg/dL)
× 0.85
Absolute values will be compared to the project reference range and classified as low (below 
range), normal (within range or on limits of range) and high (above range).
The maximum or minimum on-treatment value (depending on the direction of an adverse 
effect) will be defined for each laboratory parameter as the maximum (or minimum) 
post-baseline value at any time.
Local reference ranges will be used for the primary interpretation of laboratory data at the 
local laboratory. Project reference ranges will be used throughout for reporting purposes. The 
denominator used in laboratory summaries of CTCAE grades will only include evaluable 
patients, in other words those who had sufficient data to have the possibility of an 
abnormality.
For example:
∀
If a CTCAE criterion involves a change from baseline, evaluable patients would have 
both a baseline and at least 1 post-baseline (scheduled or unscheduled) value recorded.
∀
If a CTCAE criterion does not consider changes from baseline, to be evaluable the patient 
need only have at least 1 post-baseline (scheduled or unscheduled) value recorded.
3.3.5
Electrocardiograms
Resting 12-lead ECGs will be recorded at second screening and as clinically indicated 
throughout the study. Overall evaluation of ECG is collected in terms of normal or abnormal, 


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and the relevance of the abnormality is termed as ‘clinically significant’ or ‘not clinically 
significant’. Triplicate ECGs will be obtained in case of clinically significant ECG 
abnormalities. 
At each time point the Investigator’s assessment of the ECG will be collected locally. Heart 
rate, duration of QRS complex, RR, PR and QT intervals will be collected. 
3.3.6
Vital Signs
Vital signs data will be collected throughout the study, from second screening to the first 
follow-up visit (4 weeks ± 3 days after completion or discontinuation of study treatment, ie, 
durvalumab/placebo and/or SoC). 
3.4
Exploratory Variables
No analyses will be performed on exploratory variables as part of this SAP. All data will be 
either summarized or listed only.
3.4.1
3.4.1.1
 
 
 
 
 
 
 
 
 
3.4.1.2
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI


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3.4.2
 
 
 
3.4.2.1
 
 
 
 
 
 
3.4.2.2
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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3.4.2.3
 
 
3.4.2.4
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI


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4
ANALYSIS METHODS
Prior to CSP V4.0, a formal statistical analysis was to be performed to test the main 
hypotheses:
∀
H0: No difference between durvalumab plus SoC chemotherapy and placebo plus SoC 
chemotherapy
∀
H1: Difference between durvalumab plus SoC chemotherapy and placebo plus SoC 
chemotherapy
Under CSP V4.0 no formal statistical analyses will be performed, and all analyses will be 
exploratory.
4.1
General Principles
The below mentioned general principles will be followed throughout the study:
∀
Descriptive statistics will be used for all variables, as appropriate, and will be presented 
by treatment group. Continuous variables will be summarized by the number of 
observations, mean, standard deviation, median, upper and lower quartiles, minimum, and 
maximum. For log transformed data it is more appropriate to present geometric mean, 
CV, median, minimum and maximum. Categorical variables will be summarized by 
frequency counts and percentages for each category. 
∀
Unless otherwise stated, percentages will be calculated out of the population total for the 
corresponding treatment group. Overall totals will be calculated for baseline summaries 
only. 
∀
For continuous data, the mean, median and quartiles will be rounded to 1 additional 
decimal place compared to the original data. The standard deviation will be rounded to 2 
additional decimal places compared to the original data. Minimum and maximum will be 
displayed with the same accuracy as the original data.
∀
For categorical data, percentages will be rounded to 1 decimal place.
∀
For efficacy analysis summaries, hazard ratios will be rounded to 2 decimal places. CIs 
will be rounded to 3 decimal places. P-values will be rounded to 3 decimal places, except 
p-values less than 0.0005 (eg, 0.0002) which will be displayed as <0.001. P-values output 
as <0.0001 by statistical software will not be rounded and displayed in the same way 
(‘<0.0001’).
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∀
SAS® version 9.4 or later will be used for all analyses.
4.1.1
Baseline
In general, for efficacy and PRO endpoints the last observed measurement prior to 
randomization will be considered the baseline measurement. However, for PRO endpoints, if 
an evaluable assessment is only available after randomization but before the first dose of study 
treatment (ie, durvalumab/placebo and/or SoC) then this assessment will be used as baseline. 
For safety endpoints the last observation before the first dose of study treatment will be 
considered the baseline measurement unless otherwise specified. For assessments on the day 
of first dose where time is not captured, a nominal predose indicator, if available, will serve as 
sufficient evidence that the assessment occurred prior to first dose.
Assessments on the day of the first dose, where neither time nor a nominal predose indicator 
are captured, will be considered prior to the first dose if such procedures are required by the 
protocol to be conducted before the first dose.
If two visits are equally eligible to assess patient status at baseline (eg, screening and baseline 
assessments both on the same date prior to first dose with no washout or other intervention in 
the screening period), the average can be taken as a baseline value. For non-numeric 
laboratory tests (ie, some of the urinalysis parameters) where taking an average is not possible 
the best value would be taken as baseline as this is the most conservative. In the scenario 
where there are two assessments on day 1, one with time recorded and the other without time 
recorded, the one with time recorded would be selected as baseline. Where safety data are 
summarized over time, study day will be calculated in relation to date of first study treatment.
In all summaries change from baseline variables will be calculated as the post-treatment value 
minus the value at baseline. The percentage change from baseline will be calculated as 
(post-baseline value – baseline value) / baseline value × 100. 
4.1.2
General Considerations for Safety and PRO Assessments
Time windows will be defined for any safety and PRO presentations that summarize values by 
visit. The following conventions will apply: 
∀
The time windows will be exhaustive so that data recorded at any time point has the 
potential to be summarized. Inclusion within the time window will be based on the actual 
date and not the intended date of the visit.
∀
All unscheduled visit data have the potential to be included in the summaries.
∀
The window for the visits following baseline will be constructed in such a way that the 
upper limit of the interval falls half way between the 2 visits (the lower limit of the first 
post-baseline visit will be day 2). If an even number of days exists between 2 consecutive 


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visits then the upper limit will be taken as the midpoint value minus 1 day. An example is 
provided in Appendix A. 
∀
For summaries showing the maximum or minimum values, the maximum/minimum value 
recorded on-treatment will be used (regardless of where it falls in an interval).
∀
Listings should display all values contributing to a time point for a patient.
∀
For visit-based summaries
#
If there is more than one value per patient within a time window then the closest 
value to the scheduled visit date will be summarized, or the earlier, in the event the 
values are equidistant from the nominal visit date. If there are two values recorded on 
the same day and CTCAE grades are available then the record with the highest 
toxicity grade should be used. Alternatively, if there are two records recorded on the 
same day and the toxicity grade is the same (or is not calculated for the parameter) 
then the average of the two records should be used. The listings will highlight the 
value for the patient that contributed to the summary table, wherever feasible. Note: 
in summaries of extreme values all post-baseline values collected are used including 
those collected at unscheduled visits regardless of whether or not the value is closest 
to the scheduled visit date. 
∀
For summaries at a patient level, all values will be included, regardless of whether they 
appear in a corresponding visit-based summary, when deriving a patient level statistic 
such as a maximum. 
Imputation Rules
Missing safety data will generally not be imputed. However, safety assessment values of the 
form of ‘< x’ (ie, below the lower limit of quantification) or ‘> x’ (ie, above the upper limit of 
quantification) will be imputed as ‘x’ in the calculation of summary statistics but displayed as 
‘< x’ or ‘> x’ in the listings. Additionally, AEs that have missing causality (after data 
querying) will be assumed to be related to durvalumab/placebo, or SoC (whichever is 
missing).
Partial dates will be imputed for prior cancer therapy, previous radiotherapy, and prior and 
concomitant medications and AEs, as well as for other modules, where required, and only for 
patients exposed to treatment.
The original incomplete or missing dates will be presented in the listings.
All AEs will be considered as treatment-emergent unless the opposite can be clearly stated. 
Imputation will be done only in the context of identifying TEAEs.


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All medications/therapies will be considered as concomitant unless the opposite can be clearly 
stated.
For the handling of partial date of birth and missing/partial start and/or stop dates of AEs, 
medications/therapies, deaths and subsequent anti-cancer therapies (including radiotherapy), 
refer to Appendix B.
4.2
Analysis Methods
The following table (Table 4) details the statistical analysis planned for each endpoint, making 
it clear which analysis is regarded as primary for that endpoint, where applicable. All 
endpoints compare durvalumab plus SoC chemotherapy vs placebo plus SoC chemotherapy in 
all randomized patients (FAS), unless stated otherwise.  
Table 4
Statistical Analyses to be Conducted
Endpoints Analyzed
Notes
Disease-free survival (DFS)
Primary analysis using stratified log-rank test using Investigator 
assessments (RECIST 1.1) for the FAS
Subgroup analysis using Cox proportional hazards model using 
Investigator assessments (RECIST 1.1) for the FAS
Kaplan-Meier estimates of DFS rates at 6 and 12 months using 
Investigator assessments (RECIST 1.1) for the FAS and MRD+ 
analysis set
Overall survival (OS)
Secondary analysis using stratified log-rank test for the FAS
Subgroup analysis using Cox proportional hazards model for the 
FAS
Kaplan-Meier estimates of OS rates at 6 and 12 months for the 
FAS and MRD+ analysis set
DFS Disease-free survival; FAS Full analysis set; RECIST Response Evaluation Criteria in Solid Tumors
4.2.1
Multiplicity 
Prior to CSP V4.0, in order to provide strong control of the type I error rate, α=5% (2-sided), a 
multiple testing procedure with gatekeeping strategy was to be used across the primary 
endpoint of DFS in the MRD+ analysis set, the secondary endpoint of DFS in the FAS, the 
secondary endpoint of OS in the MRD+ analysis set and the secondary endpoint of OS in the 
FAS.  
Under CSP V4.0, no methods for multiplicity control will be performed and the analyses of all 
endpoints will be considered exploratory.


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4.2.2
Disease-free Survival (DFS)
4.2.2.1
Primary Analysis of DFS
Disease-free survival, using Investigator assessment according to RECIST 1.1, will be 
analyzed using the log-rank test stratified by disease stage (stage II vs III), PD-L1 TC 
expression (< 1% vs ≥ 1%) and MRD status (MRD+ vs MRD-) on the FAS. 
The treatment effect will be estimated in terms of the HR and its associated 95% CI from a 
Cox proportional hazards model (Cox 1972) (with ties = Efron) stratified by disease stage, 
PD-L1 TC expression and MRD status and the CI calculated using a profile likelihood 
approach. 
The stratification factor covariates in the statistical modelling will be based on the values 
entered into IWRS at randomization, even if it is subsequently discovered that these values 
were incorrect. A sensitivity analysis may be performed based on the values entered in the 
eCRF if more than 10% of randomized patients have discrepancies in stratification factors 
between IWRS and eCRF data. 
For the purpose of statistical analysis of the primary and relevant secondary endpoints, a plan 
for collapsing levels of stratum will be agreed upon, in case there are insufficient events in one 
level of any strata.
Supportive Summaries/Graphs
Kaplan-Meier plots of DFS will be presented by treatment group. Summaries of the number 
and percentage of patients experiencing a DFS event will be provided along with median time 
to DFS with 95% CI for each treatment group estimated based on the Kaplan-Meier curves. 
The CIs for median DFS will be derived based on Brookmeyer-Crowley method with a 
log-log transformation.
The assumption of proportionality will be assessed. Proportional hazards will be tested firstly 
by examining plots of complementary log-log (event times) vs log (time) and, if these raise 
concerns, by fitting a time-dependent covariate to assess the extent to which this represents 
random variation. If a lack of proportionality is evident, the variation in treatment effect can 
be described by presenting piecewise HR calculated over distinct time periods. In such 
circumstances, the HR can still be meaningfully interpreted as an average HR over time unless 
there is extensive crossing of the survival curves. If lack of proportionality is found, this may 
be a result of treatment-by-covariate interactions, which will be investigated. In addition, the 
Kaplan-Meier curve along with landmark analyses (eg, 1-year DFS rate) will also help in 
understanding the treatment benefit. In the presence of non-proportional hazards, a rank-based 
Max-Combo test will be performed. The Max-Combo test is robust to different scenarios of 
non-proportional hazards.


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The location of the disease recurrence (local/regional, distant or second primary NSCLC) will 
be summarized by treatment group.
The DFS rates at month 6 (DFS-6) and month 12 (DFS-12) will be estimated based on the 
Kaplan-Meier curves along with their 95% CIs and presented by treatment group. 
The treatment status of patients at disease recurrence will be summarized. This will include 
the number (%) of patients who were on treatment at the time of disease recurrence, the 
number (%) of patients who have completed study treatment prior to disease recurrence, the 
number (%) of patients who discontinued study treatment prior to disease recurrence, the 
number (%) of patients who have not had disease recurrence and were on treatment, have 
completed treatment, or discontinued treatment. A distribution of the number of days prior to 
disease recurrence will also be provided for the patients who have discontinued treatment.
The number of patients prematurely censored will be summarized by treatment group. A 
patient would be defined as prematurely censored if they have not had disease recurrence or 
died and the latest scan prior to DCO was more than one scheduled tumor assessment interval 
plus 2 weeks (14 weeks) prior to the DCO date.
Additionally, summary statistics will be presented for the number of days from censoring to 
DCO for all censored patients. A summary of the duration of follow-up will be summarized 
using median time from randomization to date of censoring (date last known to have not had 
disease recurrence or died) in censored patients only (patients who have not had disease 
recurrence or died), presented by treatment group.
Additionally, summary statistics for the number of weeks between the time of disease 
recurrence and the last RECIST assessment prior to disease recurrence will be presented for 
each treatment group.
Summaries of the number and percentage of patients who miss two or more consecutive 
RECIST assessments will be presented for each treatment group.
All the collected RECIST 1.1 data will be listed for all randomized patients. In addition, a 
summary of disease recurrence (ie, sites of recurrence) will be produced.
A summary table of first subsequent cancer therapies relative to recurrence by treatment group 
will be provided.


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4.2.2.2
Subgroup Analyses
4.2.2.2.1 Graphical Approaches
Subgroup analyses may be conducted on the FAS comparing DFS, using Investigator 
assessments according to RECIST 1.1, between durvalumab plus SoC chemotherapy vs 
placebo plus SoC chemotherapy in the following subgroups (but not limited to): 
∀
PD-L1 status (TC < 1% vs ≥ 1%)
∀
PD-L1 status (TC < 25% vs ≥ 25%)
∀
TMB (high vs low)
∀
Histology (squamous vs non-squamous)
∀
Sex (male vs female)
∀
Age at randomization (< 65 vs ≥ 65)
∀
Smoking status (smoker [current or former smoker] vs non-smoker [never smoked])
∀
Race (Asian vs non-Asian)
The subgroup analyses for the stratification factors will be based on the values recorded in the 
eCRF. Should the value not have been captured in the eCRF the value entered into the IWRS 
will be used.
Other baseline variables may also be assessed if there is clinical justification or an imbalance 
is observed between the treatment groups. The purpose of the subgroup analyses is to assess 
the consistency of treatment effect across expected prognostic and/or predictive factors. If a 
baseline imbalance is observed between treatment groups, an ad-hoc subgroup analysis may 
be used to investigate any potential for impact on the main results.
No adjustment to the significance level for subgroup and sensitivity analyses will be made 
since all these analyses will be considered supportive of the analysis of DFS.
Additionally, for each subgroup level of a factor, the HR (durvalumab plus SoC 
chemotherapy : placebo plus SoC chemotherapy) and 95% CI will be calculated from a Cox 
proportional hazards model that only contains a term for treatment. The Cox models will be 
fitted using SAS® PROC PHREG with the Efron method to control for ties, and using a BY 
statement for the subgroup factor. These HRs and associated two-sided 95% profile likelihood 
CIs will be summarized and presented on a forest plot, along with the results of the overall 
primary analysis. 
If there are too few events available for a meaningful analysis of a particular subgroup (it is 
not considered appropriate to present analyses where there are less than 20 events in a 
subgroup), the relationship between that subgroup and DFS will not be formally analyzed. In 
this case, only descriptive summaries will be provided.


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4.2.2.3
Secondary Analysis of DFS
Disease-free survival, using Investigator assessment according to RECIST 1.1, will be 
presented for the MRD+ analysis set as described below.
Kaplan-Meier plots of DFS will be presented by treatment group. Summaries of the number 
and percentage of patients experiencing a DFS event will be provided along with median time 
to DFS with 95% CI for each treatment group estimated based on the Kaplan-Meier curves.
Additionally, the DFS rates at month 6 (DFS-6) and month 12 (DFS-12) will be estimated 
based on the Kaplan Meier curves along with their 95% CIs and presented by treatment group.
4.2.3
Overall Survival (OS)
Overall survival will be analyzed for the FAS using a stratified log-rank test, using the same 
methodology as described for the primary DFS endpoint. The effect of treatment will be 
estimated by the HR together with its corresponding 95% CI from a Cox proportional hazards 
model. 
For both the FAS and MRD+ analysis set, Kaplan-Meier plots of OS will be presented by 
treatment group. The OS rates at month 6 (OS-6) and month 12 (OS-12) will be estimated 
based on the Kaplan-Meier curves along with their 95% CIs and presented by treatment group. 
Summaries of the number and percentage of patients who have died, those still in survival 
follow-up, those lost to follow-up, and those who have withdrawn consent will be provided 
along with the median time to OS and corresponding 95% CI for each treatment. 
4.2.4
 
 
4.2.5
 
 
 
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4.2.6
Data Cut-offs
All randomized patients will be followed until the primary DCO when no further visits will 
occur. This will be followed by DBL and then the primary DFS analysis. The study will then 
be concluded.
Details regarding the approach used for removing post-DCO data from SAS datasets can be 
found in the AstraZeneca Oncology Guidance on Data Cut-off Processing and Clean file/ 
DBL Considerations document as well as the DCO Specifications for this study.
4.2.7
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI


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4.2.8
Safety
Safety and tolerability data from all cycles of treatment will be combined. The safety analysis 
set will be used for reporting of safety according to actual treatment group as defined in 
Section 2.1.3. Safety summaries will be descriptive only. No formal statistical analyses will be 
performed on the safety variables.
4.2.8.1
Adverse Events (AEs)
All AEs, both in terms of current MedDRA PT and CTCAE grade, will be summarized 
descriptively by count (n) and percentage (%) for each treatment group. Any AE occurring 
before study treatment (ie, before the administration of the first dose of durvalumab/placebo 
and/or SoC) will be included in the AE listings, but will not be included in the summary tables 
(unless otherwise stated). These will be referred to as ‘pre-treatment’. However, any AE 
occurring before the administration of the first dose of study treatment on study day 1 that 
increases in severity after the first dose will be regarded as treatment emergent and thus will 
be included in the majority of summary tables.
Adverse events observed up until 90 days following discontinuation of study treatment (ie, the 
last dose of durvalumab/placebo and/or SoC) or until the initiation of the first subsequent anti-
cancer therapy (including radiotherapy, except for palliative radiotherapy) following 
discontinuation of study treatment (whichever occurs first) will be used for the reporting of 
the AE summary tables. This will more accurately depict AEs attributable to study treatment 
only, as a number of AEs up to 90 days following discontinuation of study treatment are likely 
to be attributable to subsequent therapy.
Any AEs that occur between the start of subsequent anti-cancer therapy and up until 90 days 
following discontinuation of study treatment will be flagged in the data listings.
All reported AEs will be listed along with the date of onset, date of resolution (if AE is 
resolved) and Investigator’s assessment of severity and relationship to durvalumab/placebo or 
SoC. Frequencies and percentages of patients reporting each PT will be presented (ie, multiple 
events per patient will not be accounted for apart from on the episode level summaries).
Summary information (the number and percentage of patients by SOC and PT separated by 
treatment group) will be tabulated for:
∀
All AEs
∀
All AEs possibly related to durvalumab/placebo only (as determined by the reporting 
Investigator)
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∀
All AEs possibly related to SoC only (as determined by the reporting Investigator)
∀
All AEs possibly related to durvalumab/placebo or SoC (as determined by the reporting 
Investigator)
∀
AEs with maximum CTCAE grade 3 or 4
∀
AEs with maximum CTCAE grade 3 or 4, possibly related to durvalumab/placebo only 
(as determined by the reporting Investigator)
∀
AEs with maximum CTCAE grade 3 or 4, possibly related to SoC only (as determined by 
the reporting Investigator)
∀
AEs with maximum CTCAE grade 3 or 4, possibly related to durvalumab/placebo or SoC 
(as determined by the reporting Investigator)
∀
AEs with outcome of death
∀
AEs with outcome of death possibly related to durvalumab/placebo only (as determined 
by the reporting Investigator)
∀
AEs with outcome of death possibly related to SoC only (as determined by the reporting 
Investigator)
∀
AEs with outcome of death possibly related to durvalumab/placebo or SoC (as 
determined by the reporting Investigator)
∀
All SAEs
∀
All SAEs possibly related to durvalumab/placebo only (as determined by the reporting 
Investigator)
∀
All SAEs possibly related to SoC only (as determined by the reporting Investigator)
∀
All SAEs possibly related to durvalumab/placebo or SoC (as determined by the reporting 
Investigator)
∀
AEs leading to discontinuation of durvalumab/placebo only
∀
AEs leading to discontinuation of SoC only
∀
AEs leading to discontinuation of durvalumab/placebo or SoC 
∀
AEs leading to discontinuation of durvalumab/placebo only, possibly related to 
durvalumab/placebo only (as determined by the reporting Investigator)
∀
AEs leading to discontinuation of SoC only, possibly related to SoC only (as determined 
by the reporting Investigator)
∀
AEs leading to discontinuation of durvalumab/placebo or SoC, possibly related to 
durvalumab/placebo or SoC (as determined by the reporting Investigator)
∀
AEs leading to dose interruption of durvalumab/placebo only
∀
AEs leading to dose interruption of SoC only
∀
AEs leading to dose interruption of durvalumab/placebo or SoC


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∀
Immune mediated AEs (as determined by the reporting Investigator)
∀
Infusion reaction AEs (as determined by the reporting Investigator)
An overall summary of the number and percentage of patients in each category will be 
presented, as well as an overall summary of the number of episodes in each category. 
Summaries of the number and percentage of patients with AEs will be provided by maximum 
reported CTCAE grade, SOC, PT and treatment group. In addition, a truncated AE table of 
most common AEs and another table showing most common AEs with CTCAE grade 3 or 4, 
showing all events that occur in at least 5% (ie, ≥5%) of patients overall will be summarized 
by PT, by decreasing frequency in the total column (the total column will not be displayed in 
the AE tables). This cut-off may be modified after review of the data. When applying a cut-off 
(ie, x%), the raw percentage should be compared to the cut-off, no rounding should be applied 
first (ie, an AE with frequency of 4.9% will not appear if a cut-off is 5%).
Fluctuations observed in CTCAE grades during study will be listed for those AEs which have 
CTCAE grade ≥ 3.
In addition, all AEs will be listed (including listings for AEs that required treatment with 
steroids, immunosuppressants, or endocrine treatment, grade changes for AEs of CTCAE 
grade ≥ 3, and grade changes for AEs of CTCAE grade ≥ 3 that required treatment with 
steroids, immunosuppressants, or endocrine treatment). Listings of key patient information for  
SAEs, and AEs leading to discontinuation of durvalumab/placebo or SoC will also be 
provided.
4.2.8.1.1 Deaths
Two summaries of all deaths will be provided with number and percentage of patients in the 
safety analysis set and FAS by treatment group, categorized as:
∀
Total number of deaths (regardless of date of death)
∀
Death related to disease under investigation only as determined by the Investigator
∀
Death related to disease under investigation and an AE with outcome of death
(a) AE onset prior to subsequent anti-cancer therapy, defined as an AE with onset date 
(or pre-treatment AEs that increase in severity) on or after the date of first dose of 
study treatment and up to and including the earlier of 90 days following the date of 
last dose of study treatment or the date of initiation of the first subsequent anti-cancer 
therapy 
(b) AE onset after start of subsequent anti-cancer therapy, defined as an AE with onset 
date more than 90 days following the date of last dose of study treatment or after the 
date of initiation of the first subsequent anti-cancer therapy (whichever occurs first)


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∀
AE with outcome of death only
(a) AE onset prior to subsequent anti-cancer therapy, defined as an AE with onset date 
(or pre-treatment AEs that increase in severity) on or after the date of first dose of 
study treatment and up to and including the earlier of 90 days following the date of 
last dose of study treatment or the date of initiation of the first subsequent anti-cancer 
therapy 
(b) AE onset after start of subsequent anti-cancer therapy, defined as an AE with onset 
date more than 90 days following the date of last dose of study treatment or after the 
date of initiation of the first subsequent anti-cancer therapy (whichever occurs first)
∀
Death after end of safety follow-up period (last dose of study treatment 
[durvalumab/placebo and/or SoC] + 90 days) and not due to disease under investigation
∀
Unknown reason for death
∀
Other deaths
This summary will be repeated for all deaths on-treatment or within 90 days of last dose of 
study treatment. All deaths will be listed along with time from first and last dose, primary and 
secondary causes, and relationship to disease using the FAS.
4.2.8.2
AEs of Special Interest and Possible Interest
Preferred terms used to identify AESI/AEPI will be listed before DBL and documented in the 
Trial Master File. Grouped summary tables of certain MedDRA PTs will be produced and 
may also show the individual PTs which constitute each AESI grouping. Groupings will be 
based on PTs provided by the medical team prior to DBL, and a listing of the PTs in each 
grouping will be provided.
Summaries of the above-mentioned grouped AE categories will include number (%) of 
patients who have:
∀
Any AESI/AEPI
∀
Any AESI/AEPI by SOC, PT and maximum CTCAE grade
∀
Any AESI/AEPI of maximum CTCAE grade 3 or 4
∀
Any serious AESI/AEPI
∀
Any AESI/AEPI with outcome of death
∀
Any AESI/AEPI possibly related to study treatment (durvalumab/placebo or SoC)
∀
Any AESI/AEPI leading to concomitant medication use (high dose steroids)
∀
Any AESI/AEPI leading to concomitant medication use (endocrine therapy)
∀
Any AESI/AEPI leading to concomitant medication use (other immunosuppressants)


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An overall AESI/AEPI summary will be presented, including number and percentage of 
patients in each of these categories. Any AESI/AEPI presented by outcome will also be 
provided.
In addition, a listing of key patient information for AESI/AEPI will be provided.
Immune-mediated Adverse events (imAEs)
The imAEs (as classified by the Sponsor) will be summarized in the similar manner as for the 
summaries for AESI/AEPI described above. Time to onset and resolution of imAE will also 
be summarized. Further details are covered in the latest version of the imAE charter.
4.2.8.3
Laboratory Assessments
Data obtained up until the 90 days following discontinuation of study treatment (ie, 
durvalumab/placebo and/or SoC) or until the initiation of subsequent anti-cancer therapy 
(including radiotherapy, except for palliative radiotherapy) following discontinuation of study 
treatment (whichever occurs first) will be used for reporting. This will more accurately depict 
laboratory toxicities attributable to study treatment only as some toxicities up to 90 days 
following discontinuation of the study treatment are likely to be attributable to subsequent 
therapy. Any data post 90 days after the last dose of the study treatment will not be 
summarized.
Data summaries will be provided in SI units.
Shift tables for laboratory values by worst CTCAE grade will be produced, and for specific 
parameters separate shift tables indicating hyper- and hypo- directionality of change will be 
produced. The laboratory parameters for which CTCAE grade shift outputs will be produced 
are:
∀
Hematology: Hemoglobin (low and high); Leukocytes (low and high); Lymphocytes (low 
and high - count, absolute); Neutrophils (low - count, absolute); Platelets (low)
∀
Clinical chemistry: ALT (high), AST (high), ALP (high), Total Bilirubin (high), Albumin 
(low), Magnesium (hypo and hyper), Sodium (hypo and hyper), Potassium (hypo and 
hyper), Corrected Calcium (hypo and hyper), Glucose (low), Creatinine (high), GGT 
(high), Amylase (high), Lipase (high).
In addition, all laboratory data will be listed.
4.2.8.3.1 Liver Enzyme Elevations and Hy's Law
The following summaries will include the number (%) of patients who have:


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∀
Elevated ALT, AST, and Total bilirubin on-treatment
#
ALT ≥ 3× – ≤ 5×, > 5× – ≤ 8×, > 8× – ≤ 10×, > 10× – ≤ 20×, and > 20× ULN 
on-treatment
#
AST ≥ 3× – ≤ 5×, > 5× – ≤ 8×, > 8× – ≤ 10×, > 10× – ≤ 20×, and > 20× ULN 
on-treatment
#
Total bilirubin ≥ 2× – ≤ 3×, > 3× – ≤ 5×, > 5× ULN on-treatment
#
ALT or AST ≥ 3× – ≤ 5×, > 5× – ≤ 8×, > 8× – ≤ 10×, > 10× – ≤ 20×, > 20× ULN 
on-treatment
#
ALT or AST ≥ 3× ULN and Total bilirubin ≥ 2× ULN on-treatment (Potential Hy’s 
law): The onset date of ALT or AST elevation should be prior to or on the date of 
Total Bilirubin elevation
Individual patient data where ALT or AST (ie, ≥ 3× ULN) plus Total Bilirubin (ie, ≥ 2× ULN) 
are elevated at any time will be listed also.
4.2.8.3.2 Assessment of Thyroid Function Test Results
The following summaries will include the number and percentage of patients who have 
elevated or low thyroid stimulating hormone (TSH).
∀
TSH > ULN
∀
TSH > ULN with TSH ≤ ULN at baseline
∀
TSH > 3 × ULN
∀
TSH > 3 × ULN with TSH ≤ ULN at baseline
∀
TSH > 10 × ULN
∀
TSH > 10 × ULN with TSH ≤ ULN at baseline 
∀
TSH < LLN
∀
TSH < LLN with TSH ≥ LLN at baseline
In addition, summaries will include shift tables comparing baseline value to maximum 
on-treatment value and baseline value to minimum on-treatment value. Thyroid function test 
data will be listed also.
4.2.8.3.3 Assessment of Renal Function Test Abnormalities
In addition to the analysis for serum creatinine, the number and percentage of patients with 
worst CrCl rate on-treatment (derived per Section 3.3.4) meeting the following categories will 
be presented:


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∀
Normal: CrCl ≥ 90 mL/min
∀
Mild Impairment: CrCl ≥ 60 - < 90 mL/min
∀
Moderate Impairment: CrCl ≥ 30 - < 60 mL/min
∀
Severe Impairment: CrCl ≥ 15 - < 30 mL/min
∀
Kidney Failure: CrCl < 15 mL/min
4.2.8.4
Electrocardiograms
Since ECGs are only collected as clinically indicated, abnormalities in ECG data obtained at 
any time during the study will be listed only. No summaries will be produced.
4.2.8.5
Vital Signs
All vital signs data (SBP, DBP, pulse rate, temperature, respiratory rate and weight) will be 
listed only. No summaries will be produced.
4.2.8.6
Other safety
Listings will be provided for pregnancy reports and medication error reports occurring 
throughout the study. 
4.2.9
Demographics and Baseline Characteristics
The following will be summarized for all patients in the FAS and MRD+ analysis set (unless 
otherwise specified) by treatment group:
∀
Patient disposition (all patients, including screening failures [split by whether or not ICF2 
was signed] and reason for screening failure) 
∀
Important protocol deviations
∀
Inclusion in analysis sets (all patients only)
∀
Demographics (age, age group [< 50, ≥ 50 - < 65, ≥ 65 - < 75 and ≥ 75 years], sex, race 
and ethnicity)
∀
Patient characteristics at baseline (height, weight, weight group [< 70, 70-90, > 90 kg], 
BMI, BMI group [< 18.5, ≥ 18.5 - < 25, ≥ 25 - < 30, ≥ 30 kg/m2])
∀
Patient recruitment by region, country and center
∀
Previous disease-related treatment modalities (chemotherapy and radiation therapy)
∀
Disease characteristics at baseline (ECOG performance status, primary tumor location, 
histology type [squamous, non-squamous, other], tumor grade, extent of resection, pleural 
invasion status, surgical methods, and overall disease classification)
∀
Extent of disease at baseline
∀
Pathological TNM classification post-surgery


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∀
Disease related medical history (past and current) (FAS only)
∀
Relevant surgical history (FAS only)
∀
Nicotine use, categorized (non-smoker [never], smoker [current, former])
∀
Stratification factors as per IWRS and eCRF
The data mentioned above will also be presented in listings. Additionally, a listing of 
EGFR/ALK results will also be provided.
4.2.10 Concomitant and Other Treatments
Information on any medications or therapies from first screening to 90 days after the last dose 
of study treatment (ie, durvalumab/placebo and/or SoC) will be recorded in the eCRF. 
Thereafter, only subsequent regimens of anti-cancer therapy will be recorded in the eCRF.
Other anti-cancer therapies, investigational agents, and radiotherapy should not be given once 
the patient has had their surgical resection and while they are randomized and on study drug. 
The only exception is for PORT. 
Medications received prior to, concomitantly, or post-study treatment will be coded using the 
WHODD ATC classification codes. Concomitant medications/therapies will be summarized 
for the FAS by ATC classification codes.
For the purpose of inclusion in prior and/or concomitant medication or therapy summaries, 
incomplete medication or radiotherapy start and stop dates will be imputed as detailed in 
Section 4.1.2.
Prior, concomitant and post-study treatment medications and therapies are defined based on 
imputed start and stop dates as follows:
∀
Prior medications/therapies are those taken prior to study treatment with a stop date prior 
to the first dose of study treatment.
∀
Concomitant medications/therapies are those that started prior to study treatment and are 
ongoing at the first dose date of study treatment, or that started on or after the first dose 
date of study treatment but on or before the last dose date of study treatment.
∀
Post-study treatment medications/therapies are those with a start date after the last dose 
date of study treatment.
In addition, all post-treatment anti-cancer medications and surgical procedures will be 
summarized for the FAS and MRD+ analysis set.
The following summaries will be produced for the FAS (unless otherwise specified):


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∀
Summary of allowed concomitant medications 
∀
Summary of disallowed concomitant medications 
∀
Summary of post-study treatment anti-cancer therapies (including radiotherapy) (FAS and 
MRD+ analysis set)
∀
Summary of PORT
All concomitant and other treatment data will be listed.
Missing coding terms should be listed and summarized as ‘Not coded’.
4.2.11 Exposure
Exposure will be summarized for the safety analysis set. The following summaries will be 
produced by treatment group:
∀
Total exposure
∀
Actual exposure (durvalumab/placebo only)
∀
Number of, and reasons for, interruptions and delays of durvalumab/placebo
∀
Number of, and reasons for, delays and dose reductions/increases of chemotherapy
∀
Cumulative exposure over time for durvalumab/placebo 
∀
Number of treatment cycles received
∀
RDI (durvalumab/placebo only)
Exposure of durvalumab/placebo over time will be plotted in a line graph. The plot will show 
percentage of patients still on treatment against time since first dose.
Details of study drug administration and dose intensity will also be provided in listings.
4.2.12 Coronavirus Disease 2019 (COVID-19)
Summaries of data relating to patients diagnosed with COVID-19 and the impact of 
COVID-19 on study conduct (eg, missed visits, delayed or discontinued study treatment [ie, 
durvalumab/placebo and/or SoC], and other protocol deviations) may be generated. In 
addition, DFS and OS sensitivity analyses may be performed by repeating the summaries and 
analyses except that any patient who had a death with primary/secondary cause as being 
COVID-19 related (including infection) will be censored at their COVID related death date. 
For AE and Deaths summaries of COVID-19 related events including infections and deaths 
maybe produced.


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5
INTERIM ANALYSES
5.1
Interim Efficacy Analysis
Prior to CSP v4.0, one interim and one final analysis of OS was to be performed. Under CSP 
V4.0, there will be one analysis of OS at the time of the DFS (ie, primary DFS analysis) which 
will be the final analysis.
5.2
Independent Data Monitoring Committee
This study will use an external IDMC to assess ongoing safety analyses in an unblinded 
manner. The committee will first meet to review the safety data from the study from a DCO 
approximately 12 months after the first patient has been dosed with IP or after the first 50 
patients have received at least 1 dose of IP (whichever occurs first). The frequency of 
subsequent reviews will be determined by the IDMC, but will be no more frequent than every 
6 months.
This committee will be composed of therapeutic area experts and biostatisticians, who are not 
employed by AstraZeneca and are free from conflict of interest.
Following the reviews, the IDMC will recommend whether the study should continue 
unchanged, be stopped, or be modified in any way based on the safety data that has been 
reviewed. Once the IDMC has reached a recommendation, a report will be provided to 
AstraZeneca. The report will include the recommendation and any potential protocol 
amendments, and will not contain any unblinding information.
The final decision to modify or stop the study will sit with the sponsor. The sponsor or IDMC 
may call additional meetings if at any time there is concern about the safety of the study.
Full details of the IDMC procedures and processes can be found in the IDMC Charter. The 
safety of all AstraZeneca/MedImmune clinical studies is closely monitored on an ongoing 
basis by AstraZeneca/MedImmune representatives in consultation with the Patient Safety 
Department. Issues identified will be addressed; this could involve, for instance, amendments 
to the CSP and letters to Investigators.
6
CHANGES OF ANALYSIS FROM PROTOCOL
The following are changes, additions or clarifications from the planned analyses described in 
version 4 of the CSP.
The secondary efficacy endpoints of DFS in MRD+ analysis set (using Investigator 
assessments according to RECIST 1.1) and OS in MRD+ analysis set will not be analyzed, 
only descriptive summaries will be provided.


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7
REFERENCES
 
 
Cockcroft and Gault 1976
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976; 16(1):31-41.
Cox 1972
Cox DR. Regression models and life-tables. J R Stat Soc Series B Stat Methodol 
1972;34(2):187-220.
 user guide: basic information on how to use the 
 
 version 3.0, September 2019. Available from: 
 
 
Litwin et al 1998
Litwin MS, Lubeck DP, Henning JM, Carroll PR. Differences in urologist and patient 
assessments of health related quality of life in men with prostate cancer: results of the 
CaPSURE database. J Urol 1998;159:1988-92.
Sprangers and Aaronson 1992
Sprangers MA, Aaronson NK. The role of health care providers and significant others in 
evaluating the quality of life of patients with chronic disease: a review. J Clin Epidemiol 
1992;45:743-60.
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8
APPENDICES
APPENDIX A Visit Windows
For example, the visit windows for vital signs data (with 3 weeks between scheduled 
assessments during the first 4 cycles and 4 weeks between scheduled assessments during 
subsequent cycles) are:
#
Day 22, visit window 2 – 32
#
Day 43, visit window 33 – 53
#
Day 64, visit window 54 – 74
#
Day 85, visit window 75 – 98
#
Day 113, visit window 99 – 126
#
Day 141, visit window 127 – 154
#
Day 169, visit window 155 – 182
#
Day 197, visit window 183 – 210
#
Day 225, visit window 211 – 238
#
Day 253, visit window 239 – 266
#
Day 281, visit window 267 – 294
#
Day 309, visit window 295 – 322
#
Day 337, visit window 323 – 350
Note: The same rules should be followed if a patient has more than 14 cycles due to delayed 
durvalumab/placebo. Also, due to the differing assessment schedules the visit windows will be 
different for the different endpoints.


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APPENDIX B Missing/Partial Dates Imputation
Imputation of partial date of birth
Patients with a partial date of birth will have an assumed date of birth of 1st January [given 
year]) for calculation of age at randomization.
Imputation of partial start/end dates for AEs and medications/therapies
In practice, for AEs and medications/therapies, original incomplete or missing start dates will 
be imputed as below:
∀
Missing day: impute the 1st of the month unless month is same as month of first dose of 
study treatment (ie, durvalumab/placebo and/or SoC) then impute first dose date;
∀
Missing day and month: impute 1st January unless year is the same as year of first dose of 
study treatment (ie, durvalumab/placebo and/or SoC) then impute first dose date;
∀
Completely missing: impute first dose date unless the end date suggests it could have 
started prior to this in which case impute the 1st January of the same year as the end date.
When imputing a start date, ensure that the new imputed date is sensible ie, is prior to the end 
date of the AE or medication.
Original incomplete or missing stop dates for AEs and medications/therapies will be imputed 
as below:
∀
Missing day: impute the last day of the month unless month is same as month of last dose 
of study treatment (ie, durvalumab/placebo and/or SoC) then impute last dose date;
∀
Missing day and month: impute 31st December unless year is the same as year of last dose 
of study treatment (ie, durvalumab/placebo and/or SoC) then impute last dose date;
∀
Completely missing: 
#
AE: since there is no ongoing flag recorded in eCRF, then assume that AE is still 
present (ie, do not impute a date);
#
Medication/therapy: if the ongoing flag is missing then assume that medication is still 
being taken (ie, do not impute a date). If the medication has stopped and start date of 
medication is prior to first dose of study treatment (ie, durvalumab/placebo and/or 
SoC) then impute the first dose date, if the medication started on or after first dose of 
study treatment (ie, durvalumab/placebo and/or SoC) then impute a date that is after 
the last dose date.
When imputing a stop date, ensure that the new imputed date is sensible ie, is after the start 
date of the AE or medication/therapy.


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Duration of AEs or medications/therapies will not be derived using imputed dates.
Imputation of partial death dates
If a patient is known to have died where only a partial death date is available then the date of 
death will be imputed as the latest of the last date known to be alive + 1 day from the database 
and the death date using the available information provided:
∀
For missing day only – using the 1st of the month
∀
For missing day and month – using the 1st of January
∀
If there is evidence of death but the date is entirely missing, it will be treated as missing 
ie, censored at the last known alive date.
Imputation of partial start dates of subsequent anti-cancer therapy (including radiotherapy)
∀
For missing day only – using the 1st of the month
∀
For missing day and month – using the 1st of January
If the imputed start date for a subsequent anti-cancer therapy (including radiotherapy) results 
in a start date that is not after the date of last dose of study treatment (ie, durvalumab/placebo 
and/or SoC), this will be flagged and discussed with the clinical team.
Other parameters
∀
No other imputation will be made.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d910lc00001-sap-ed-2
Document Title:
Statistical Analysis Plan Edition 2
Document ID:
Doc ID-004476203
Version Label:
2.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
19-Dec-2022 18:34 UTC
Author Approval
20-Dec-2022 13:23 UTC
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
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