A Phase III Randomized, Open-Label, Multi-Center, Global Study of MEDI4736 in Combination With Tremelimumab Therapy Versus Standard of Care Platinum-Based Chemotherapy in First-Line Treatment of Patients With Advanced or Metastatic Non Small-Cell Lung Cancer (NSCLC).
Phase: PHASE3
Conditions: Non Small Cell Lung Carcinoma NSCLC
Sponsor: AstraZeneca

1 (174)
Clinical Study Protocol 
Drug Substance
Durvalumab (MEDI4736) 
and tremelimumab
Study Code
D419AC00003
Version
9.0
Date
20 Jan 2020
A Phase III Randomized, Open-Label, Multi-Center, Global Study of 
MEDI4736 in Combination with Tremelimumab Therapy Versus Standard 
of Care Platinum-Based Chemotherapy in First Line Treatment of Patients 
with Advanced or Metastatic Non Small-Cell Lung Cancer (NSCLC) 
(NEPTUNE)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
EudraCT Number: 2015-002197-21

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Version 9.0
Date 20 Jan 2020
2 (174)
VERSION HISTORY
Version 9, 12 Dec 2019
Changes to the protocol are summarized below.
Section 1.3.2 Overall risks

Updates per Durvalumab IB edition 14 section 1.3.2.1 & 1.3.2.3

Updates per Tremelimumab IB edition 9 section 1.3.2.2
Post Data Cut Off (DCO) section in Protocol Synopsis & section 7.2.2
Post Data cut off options were updated to clarify the treatment options post final analysis
Section 6.5 Adverse Events of Special Interest
Updated the AEs of Special interest as per AESI list from Durvalumab IB edition 14 
Section 6.10: Management of IP-related toxicities
Section 6.10 was newly added to align with the requirement of managing the Toxicity 
management guidelines as an Annexure to the protocol. Section 6.10.1 & 6.10.2 were also 
updated
Appendix E Management of investigational product-related toxicities
Appendix E which included the Toxicity management guidelines was removed as link 
provided in Section 6.10 replaces Appendix E.
Section 7.1.1 and 7.1.2
Addition of density to sections 7.1.1 & 7.1.2
Section 7.8: Post study access to study treatment
Section updated to clarify options related to continuation of study treatment post the Final 
analysis of patients in global cohort and China cohort.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Version 9.0
Date 20 Jan 2020
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Version 8, 03 April 2019
Changes to the protocol are summarized below.
International Coordinating Investigator
Update 
 to 
Protocol Synopsis, Section 1.1.5 Rationale for conducting this study, Section 1.2.4 
Rationale for endpoints, Section 2.1Primary Objectives, Section 2.2 Secondary 
Objectives, 
Based on the evolving understanding of immune checkpoint inhibitor therapy there was a 
need for amendment to the original objectives proposed in this study. The primary objective 
was changed from PD-L1 ≥ 25% to bTMB ≥20mut/Mb. Multiple bTMB cutoffs, PD-
L1<1% and tTMB cutoffs were added as additional secondary endpoints.
List of Abbreviations and definition of terms:
Updated the list to include new terms such as IC, INR, APTT, TMB, bTMB and tTMB.
Protocol Synopsis, Section 1.1.1 Immunotherapies
Updated to include the rationale for changing primary endpoint to bTMB ≥ 20mut/Mb.
Protocol Synopsis, Section 1.4 Study Design
Updated to add definition of bTMB high.
Section 1.1.2 MEDI4736
Updated the total number of patients (6000) dosed with MEDI4736 as a part of ongoing 
studies to reflect the latest data based on the updated CSP template.
Section 2.4 Exploratory objectives
The 3 additional exploratory objectives were added with the intention to explore potential 
biomarkers in residual biological samples (e.g. tumor and blood) including but not limited 
to, somatic mutations and gene expression in tumor and blood samples, which may 
influence the progression of cancer (and associated clinical characteristics) and/or 
prospectively identify patients likely to derive increased benefit to durvalumab + 
tremelimumab combination therapy.
Section 5.5 Biomarker analysis，8.5.12 Biomarker data
Updated to include details of bTMB and tTMB testing and analysis.
Section 6.5 Adverse Events of Special Interest
Updated to include AE’s (vasculitis, non-infectious meningitis and non-infectious 
encephalitis) as per the revised AE SI list
Section 6.1.9, Post Data Cut Off (DCO) sections of Protocol Synopsis and Section 7.2.2
PPD
PPD

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Version 9.0
Date 20 Jan 2020
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Updated text to clarify the data collection options for long term overall survival after Final 
analysis
Section 6.9 Medication Error, Appendix A(A1)
Updated to include Medication error reporting process as per new CSP template 
requirement.
Section 8.1 Statistical considerations, Section 8.6 China Cohort
Updated to include the China specific considerations in China specific SAP.
Section 8.2 Sample size estimate
This has been re-estimated in alignment to the revised objectives.
Section 8.3 Definitions of analysis sets
Updated the analysis sets according to revised objectives.
Section 8.5 Methods for statistical analysis
Updated the statistical and sensitivity analysis including update to multiple testing 
procedures for controlling the type I error rate.
Section 9.3 Study timetable and end of study
Updated the study end date as per the latest predictions
Section 11 List of REFERENCES
Updated to include 13 new references. 
Version 7, 02 February 2018
Changes to the protocol are summarized below.
Synopsis, Section 6.1.9 Safety Data to be Collected Following the Final DCO of the 
Protocol Study, Section 7.2.2 Duration of treatment and criteria for treatment through 
progression and for retreatment
Updated to include further clarification on post final Data Cut Off (DCO) procedures.
Protocol Synopsis, Section 8.2 Sample size estimate, Section 8.5 Methods for statistical 
analysis, Section 8.5.13 Interim analysis, Section 8.6 China cohort
In order to ensure sufficient follow-up for both efficacy and safety prior to conducting the 
analysis, the protocol has been updated to outline that only a final analysis of OS will be 
conducted. The interim analysis, planned to occur after approximately 80% of the target 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Version 9.0
Date 20 Jan 2020
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events has been removed. In addition, the maturity of the final analysis has been increased. 
The statistical analysis sections have been updated accordingly.
Section 1.3.2 Potential Risks
Since the NEPTUNE study commenced, the MEDI4736 programme has developed and the 
emerging safety profile has become more established.  As such, the “Potential Risks” section of this 
clinical study protocol has been updated to align and be consistent with the broader MEDI4736 
programme, including the Investigator Brochure
Section 4, Study plan and timing of procedures, Table 2 and Table 3, Section 5.4.3, 
Storage and destruction of pharmacokinetic/ADA samples, Section 5.5.1 Collection of 
patient samples for stratification by PD-L1, Section 5.5.3 Tumour samples collected in 
China for PD-L1 testing will be destroyed or repatriated maximally 5 years after study 
drug is approved for marketing in China, Section 5.5.5 Chain of custody of biological 
samples, Section 5.5.6 Withdrawal of informed consent for donated biological samples
These sections are updated based on China regulatory requirement on handling biological 
samples
Section 6.3.1, Time Period for Collection of Adverse Events
Updated to clarify collection timeline for an event that starts post the defined safety follow up 
period.
6.3.2, Follow-up of unresolved adverse events
Updated to clarify time period for collection of adverse events, and to clarify the follow-up 
of adverse events unresolved at the patient’s last visit in the study or at study completion.
6.4 Reporting of serious adverse events 
Clarity provided on handling safety events post final DCO
6.5 Adverse events of Special interest
Updated based on latest IB
Section 8 Statistical Analysis
Clarified text regarding SAP finalisation/amendment. Updated wording regarding analysis 
populations to be consistent with Table 9. Added further clarity on analysis by stratification factors 
and the handling of re-treatment data.
Section 11 List of References
Updated to include 6 references.
Appendix E Management of investigational product-related toxicities
Updated to align with the most current Investigator Brochure.
Updated to include the web link to the most current Toxicity Management Guidelines.
Updated to include the most current version of the Dosing Modification and Toxicity Management 
Guidelines.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Version 9.0
Date 20 Jan 2020
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Terminology update
Updated terminology from immune-related Adverse Event (irAE) to immune-mediated Adverse 
Event (imAE). Duruvulamub wording has been updated to MEDI4736 keep it consistency 
across the CSP
Version 6, 18 September 2017
Changes to the protocol are summarized below.
Protocol Synopsis, Section 8.2 Sample size estimate, Section 8.5 Methods for statistical 
analysis, Section 8.5.13 Interim analysis, Section 8.6 China cohort
In order to ensure there is sufficient follow-up for both efficacy and safety prior to 
conducting an interim analysis (IA), the protocol will retain only one IA after 
approximately 80% of the target death events have been observed. The first IA, currently 
planned after approximately 60% of the target events will be removed. The statistical 
analysis sections have been updated accordingly. 
Section 1.3.2.1 MEDI4736 
Updated with identified risks to include amylase and lipase increases and myocarditis. 
Additionally the percentage of patients that experienced an SAE that was considered to be 
related to monotherapy MEDI4736 by investigator was updated from 3.5% to 5%.
Section 2.4 Exploratory Objectives, Section 5.5.1 Collection of patient samples for 
stratification by PD-L1, 5.5.2 Exploratory Biomarkers, Section 8.5.12 Biomarker data
These sections were updated to clarify that OS, PFS, ORR, DoR and related outcome 
measures, e.g. OS12 will be assessed in subgroups defined by additional biomarkers e.g. 
tumor mutation burden and/or interferon-gamma signature assessed in tumor biopsies or 
gene expression in blood or circulating tumor DNA. These sections have been updated 
accordingly.
Section 3.2 Inclusion criteria 12
An estimated life expectancy of ≥12 weeks has been added. This is to ensure that patients 
enrolled into the study have a sufficiently long life expectancy such that they have the 
opportunity to gain benefit from study treatment and applicable to recruiting countries
Section 3.2 Exclusion criteria 15 
Changed abbreviation of TB to full word for clarity.
Section 5.3.1 WHO/ECOG performance status

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Version 9.0
Date 20 Jan 2020
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Version 5, 02 February 2017
Changes to the protocol are summarized below. 
Synopsis, Section 1.4 Study design, Section 2.0 Study objectives, Section 5.1.1 Central 
reading of scans and 8.2 Sample size estimate
These sections are updated with addition of options to continue recruitment in mainland 
China, following achievement of the global recruitment target of 800 randomized patients
and a. further objective to evaluate consistency in efficacy and safety among Chinese 
subjects as required by China health authority.
Synopsis, Section 1.4 Study design, Section 2.0 Study objectives and 8.2 Sample size 
estimate
Updated to reflect the design change to incorporate China cohort and co-primary endpoints 
on PD-L1-positive25% population and inclusion of additional analysis population PD-L1-
positive1% and the relevant additional analysis required Synopsis, 
Synopsis, Glossary and Section 1.4
The definitions for the PD-L1 tumour membrane-expression sub-groups are provided.
Synopsis, Section 7.2.2 Duration of treatment and criteria for treatment through 
progression and for retreatment
Title and wordings in these sections were updated based on Durva project level CSP 
standard template to be consistent across program.
Section 1.1 Background and rationale for conducting this study & 1.3 Benefit/risk and 
ethical assessment (subsections)
These sections and subsections were updated based on updated information available.
Section 3.2: Exclusion 9, 14, 15, 18 and 19
This was updated to include numbering and the insertion of criteria 5. Dead for both 
accuracy and clarity on performance status.
Section 6.5 Adverse Events of Special Interest 
Insertion of additional bullet with identified risk for Myocarditis.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Version 9.0
Date 20 Jan 2020
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Due to deletion of exclusion criteria 14, subsequent exclusion criteria numbers changed. 
The exclusion criterion 14 deleted as from current ongoing studies study drugs shown no 
impact on QTcF interval.
Exclusion criteria 9, 15 (previously 16), 18 (previously 19) and 19 (previously 20) have 
been clarified.
Section 3.3 Patient enrollment and randomization, Section 4.0 Study plan and timing 
of procedures, Section 5.6 Pharmacogenetics and Appendices
In previous CSP version 4.0, genetic research option has been removed, as these are no 
more applicable. However, text related to genetic research in above mentioned sections 
along with Appendix C were inadvertently not removed. Hence, these sections have been 
updated by removing relevant texts in this version of the CSP. 
Since, Appendix C is no longer applicable, subsequent appendices numbering have been 
updated.
Section 3.3 Patient enrollment and randomization and Section 4.1 
Enrollment/screening period
This section has been updated to clarify the relationship between informed consent and 
study specific procedure requirements.
Section 3.8 Restrictions, Table 1 Highly effective methods of contraception
Hormonal contraception methods were clarified further. 
Section 3.9.1 Procedures for discontinuation of a patient from investigational product
This section updated to clarify the requirement of RECIST assessment post discontinuation 
of study drugs.
Section 3.10.2Withdrawal of the informed consent
This section has been updated to clarify that necessary questions are to be raised to the 
patient while patient decides to withdraw the consent.
Section 3.10.2.1 Survival status for withdrawn consent and lost to follow up patients
This section has been updated to clarify the difference between lost to follow-up cases and 
withdrawal case.
Section 3.11 Discontinuation of the study
Further clarified with reason for study discontinuation. 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Version 9.0
Date 20 Jan 2020
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Section 4.0 Study plan and timing of procedures, Table 2 Schedule of assessments for 
MEDI4736 + tremelimumab combination therapy treatment and retreatment periods 
and Table 3 Schedule of assessments for Standard of Care therapy treatment period
This Section updated to further clarity on RECIST assessment requirement. 
In previous CSP version 4.0, section 5.2.1 Laboratory safety assessment, table 7 were 
updated stating that ‘Urinalysis should be done at baseline (screening) and then as clinically 
indicated’. However, Table 2 schedule of assessment for urinalysis was not updated 
accordingly. Hence, this has been corrected in this CSP version.
Footnote of table 2 and table 3 updated on pregnancy test requirements.
Section 4.1 Enrollment/screening period
In this section timing of consent in relation to screening assessment are clarified. 
Section 4.3 Follow-up period
This section has been updated to clarify the criteria for patient entering follow-up period. 
Section 5.1 Efficacy assessments
This section was updated to provide clarity on efficacy assessments
Section 5.2.1 Laboratory safety assessments
Table 5 of this section was updated with an additional footnote giving abbreviations.
Table 6 was updated with additional Hematology tests (i.e., Basophils, Eosinophils) which 
should be routinely collected as part of the full blood count and are necessary to monitor 
safety based on the toxicity profile of the IP or SoC arms.
Section 5.2.3 Electrocardiograms
This section was updated by removing the requirement of calculating QTcF interval at 
screening (this is no longer applicable).
Section 5.2.4 Vital signs
Following paragraph has been removed as this procedure is no longer required.
‘Supine or semi-supine BP will be measured using a semi-automatic BP recording device 
with an appropriate cuff size, after the patient has rested for at least 5 minutes.
6.5 Adverse Events of Special Interest 

Clinical Study Protocol
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Study Code D419AC00003
Version 9.0
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This section was added in order to be in line with program level standard requirement. 
Wordings are similar to Appendix E
Section 6.7 Pregnancy
This section was updated by adding exception to pregnancy reporting.
Section 6.8 Management of investigational product-related toxicities
This section was updated to be in line with program level standard requirement. Wordings 
are similar to Appendix E.
Section 7.1.1 MEDI4736 & 7.1.2 Tremelimumab
These sections have been updated to provide further clarity on drug administration. 
Removed drug preparation information as it has been now referred to single document i.e., 
Drug Handling Instructions
Section 7.2.1 Treatment regimens
This updated by providing clarity on MEDI and TREME infusion timings
Section 7.2.2 Duration of treatment and criteria for retreatment
In this section, the statement below was inadvertently added and this has been removed (as 
fixed dosing is not applicable for this protocol.
‘During the retreatment period, patients in the durvalumab (MEDI4736) + tremelimumab 
combination therapy group will resume durvalumab (MEDI4736) dosing at 1500mg Q4W 
with 75 mg of tremelimumab Q4W for 4 doses/cycles each. Patients will then continue with 
durvalumab (MEDI4736) monotherapy at 1500mg Q4W, beginning at Week 16, 4 weeks 
after the last dose of combination therapy, until disease progression’.
Section 7.4 Storage
Detailed clarity has been provided on storage requirement of study drugs.
Section 7.7 Concomitant and other treatments
List of prohibited medications and its use have been updated based on treatment arm.
Section 7.7.2 MEDI4736 drug-drug interactions
New section on drug-drug interaction information was added.
Section 8 Statistical Analysis by AstraZeneca

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Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Version 9.0
Date 20 Jan 2020
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Include a revise multiple testing strategy (as in figure 4)
Update relevant sections to reflect required changes to analysis based on inclusion of co-
primary endpoint, the additional patient population of PD-L1-positive1% and the change to 
the multiple testing strategy
Includes a summary of the handling of the China cohort data (Section 8.6)
Section 10.5 Changes to the protocol and informed consent form
Japan specific wordings updated.
Appendix A Additional Safety Information
Drug-drug interaction wording removed as these are now added in CSP main section 7.7.2
Appendix B International Airline Transportation Association (IATA) 6.2 Guidance 
Document  
This appendix with typo corrections added.
Appendix C Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law
This Appendix has been updated to clarify PHL reporting as per the new AZ CSP template.
Appendix D
Guidelines for Evaluation of Objective Tumor Response Using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumors)   
Updated RECIST 1.1 guidelines have been incorporated which providing more clarity to 
Investigators during tumor evaluation. Additionally, typo corrections were completed. 
Appendix E Management of investigational product-related toxicities
This appendix was updated with the addition of new AEs of special interests.
Version 4, 04 October 2016
Changes to the protocol are summarized below.
Title pages
MEDI4736 is identified as MEDI4736 in Drug substance in the header box, and referred to 
as MEDI4736 thereafter.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Version 9.0
Date 20 Jan 2020
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Synopsis
Patient follow-up post discontinuation of study drug was separately added to emphasize on 
the patient follow-up along with Survival.
Synopsis and Section 1.4 Study design
The timing for patients to provide a tumor tissue sample was clarified as being the 
enrollment visit.
Also clarified that crossover of SoC patient to MEDI4736 or MEDI4736 + tremelimumab 
combination therapy will not be permitted.
Synopsis, Section 1.3.1.3 MEDI4736 + tremelimumab combination therapy, Section 
1.4 Study Design, Section 3.1 Inclusion criteria 6 and Section 8.3.2 PD-L1-negative 
population analysis set
Updated 
.
Synopsis, Section 1.4 Study design and Section 8.2 Sample size
Total number of enrolled patients has been increased from 960 to 1330 by taking into 
consideration of the current screen failure rate.
Synopsis and Section 7.2.2 Duration of treatment and criteria for retreatment
There remains a need to further investigate outcomes of patients on immunotherapy 
treatments who continue treatment until disease progression. Duration of treatment was 
therefore modified so that patients in the immunotherapy group can continue therapy until 
disease progression rather than stopping therapy at 12 months. This will allow patients who 
are benefitting from the immunotherapy treatment to continue on treatment and potentially 
reduce the risk of patients loosing clinical benefit after treatment is discontinued at 12 
months.
In immunotherapy group, patients with PD (unconfirmed and confirmed) who, in the 
Investigator’s opinion, would continue to receive benefit from their assigned treatment, and 
who meet the criteria for treatment in the setting of PD, may continue to receive treatment. 
It was also clarified that patients on MEDI4736 alone will not be permitted to continue 
immunotherapy, if the progression occurs after confirmed response to immunotherapy 
treatment within the target lesion (regardless of the appearance of new lesions), and if 
progression events occurred in the target lesions while the patient was receiving 
immunotherapy during the same treatment period. 
Synopsis and Section 2.2 Secondary Objectives
CCI

Clinical Study Protocol
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Study Code D419AC00003
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Order of secondary objective changed to ensure PFS, ORR, DoR, and APF12 using 
Investigator assessments according to RECIST 1.1 comes before PFS, and ORR in patients 
with PD-L1–negative NSCLC.
Section 1.1.1 Immunotherapies, 1.1.2 MEDI4736, 1.1.3 Tremelimumab, 1.1.4 
MEDI4736 in combination with tremelimumab
These sections are updated based on updated information available from ongoing studies.
Section 1.2.1 MEDI4736 and tremelimumab dose and treatment regimen justification 
and subsections
These sections are updated based on the updated information available from ongoing 
studies.
Section 1.2.5 Rationale of retreatment option
The rational for the retreatment option is amended to enable patients in the MEDI4736 + 
tremelimumab combination group who complete 4 dosing cycles (providing clinical benefit 
per Investigator judgement), and subsequently have PD during treatment with MEDI4736 
alone, to restart combination treatment, if they also meet eligibility criteria. 
Section 1.3 Benefit/risk and ethical assessment & subsections
This section updated based on new safety information available in accordance with current 
Investigator Brochure.
Section 3.1 Inclusion criteria 4 and 10 
Have been clarified.
Section 3.2 Exclusion criteria
Following Criteria were updated to provide clarity.

Sarcomatoid variant of NSCLC is added as an exclusion criteria

The part of the exclusion criteria of brain metastases or spinal cord compression and off 
steroids and anticonvulsants for at least 1 month prior to study treatment is amended to 
and off steroids for at least 14 days prior to study treatment. In addition, following 
radiotherapy and/or surgery, patients with brain metastases must wait 4 weeks after the 
intervention and must confirm stability with imaging before randomization

Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 

Clinical Study Protocol
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Study Code D419AC00003
Version 9.0
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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 (e.g., 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

Supplementary information on the diagnoses are given: 
HIV diagnosis requires positive HIV 1 or 2 antibodies
Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen 
(HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of 
hepatitis B core antibody and absence of HBsAg) are eligible
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain 
reaction is negative for HCV ribonucleic acid (RNA)

Any condition that, in the opinion of the Investigator, would interfere with the 
evaluation of IP or interpretation of patient safety or study results, including, but not 
limited to, ongoing or active infection, symptomatic congestive heart failure, 
uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, ILD, or 
psychiatric illness/social situations that would limit compliance with study requirement, 
substantially increase risk of incurring AEs from MEDI4736 or tremelimumab, or SoC 
or compromise the ability of the patient to give written informed consent
Following criteria newly added.

Prior randomization or treatment in a previous MEDI4736 and/or tremelimumab 
clinical study regardless of treatment arm assignment
Section 3.8 Restrictions

The restrictions for female patients of childbearing potential are strengthened from 
2 methods of effective contraception to at least 1 highly effective method (i.e., low 
failure rate of <1% per year). Additionally the male partners of a female patient of child 
bearing potential must use a male condom plus spermicide (except in countries where 
not approved)

Clinical Study Protocol
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Study Code D419AC00003
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
Male patients with a female partner of childbearing potential must use a male condom 
plus spermicide (except in countries where not approved), and it is highly 
recommended for the female partner of a male patient to also use a highly effective 
method of contraception

Restriction of blood donation timelines post study treatment updated
Section 3.9 Discontinuation of IP
The stipulation for discontinuation of IP of any AE that meets the criteria for 
discontinuation was removed. 
Following discontinuation criteria added to be in line with Toxicity Management 
guidelines.
Any AE that meets criteria for discontinuation as defined in the Dosing Modification and 
Toxicity Management Guidelines (see Appendix F) or as defined in the local prescribing 
information for the SoC agent.
Section 4 Study plan and timing of procedures 
Descriptions of assessment timing for all treatment arms and for immunotherapy and SoC 
treatment arms were added before all the tables of Schedules of Assessments to clarify 
dosing delays and subsequent assessments.
In Table 2 (Schedule of Assessments) the following amendments were: 

The window for Cycle 1 was amended from +1 to +3 days

Activated partial thromboplastin time (APTT) and international normalized ratio (INR) 
assessments, which will be performed as clinically indicated and at Screening, were 
added to the table

sPD-L1 (serum), Circulating soluble factors, SNP genotyping, PaxGene-RNA and PGx 
research testing has been removed as these are no longer applicable

For the pharmacokinetic samples, it is now specified that they will take place on the 
same day as the infusion and within 1 hour of end of infusion, as opposed to up to 
1 hour predose and with 10 minutes of the end of the infusion

Clinical chemistry, hematology, TSH, free T3, and free T4 and Urinalysis can 
performed within 3 days prior to randomization there is no need to repeat the same on 
the day of randomization. Hence, footnote ‘d’ has added to these tests

Foot notes are also updated

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Section 5.1 Efficacy Assessments
The timing for performing the baseline assessment was modified to no more than 28 days 
before randomization rather than no more than 28 days before the start of IP treatment.
Also it was clarified that confirmatory scan should occur preferably at the next regularly 
scheduled imaging visit (based on randomization date).
Section 5.2.1 Laboratory safety assessments

In Table 5, provision is made that if the amylase and lipase analysis could not be 
performed in a local laboratory, then 1 or the other would be performed in line with 
local practice

Table 5 is also updated with additional test in line with study plan and procedures. 
Also, footnotes are updated to clarify timing and requirement of the tests

Table 6 was revised to remove the following hematology tests: Basophils, Eosinophils, 
Hematocrit, Mean Corpuscular Hemoglobin, Mean Corpuscular Hemoglobin 
concentration Mean Corpuscular Volume and Red Blood Cells count because these are 
unnecessary for safety and to reduce the amount of blood drawn from the patients. 
Laboratory assessments that are not necessary to monitor safety based on the toxicity 
profile of the IP or SoC arms were removed to reduce patient burden

In Table 6, APPT and INR are added to the table, and it is stipulated that they will be 
assessed at Screening rather than Baseline as indicated in the table footnote

Chemistry panel timing post study drug discontinuation clarified
Section 5.2.4 Vital signs

Blood pressure may now be measured in a supine or semi-supine position rather than 
just a supine position. Monitoring of patient at first infusion and subsequent infusions 
are clarified

Also, it was clarified vital collection based on first infusion and subsequent infusion
Section 5.3.2 Other safety assessments
This new section has been added to closely monitor new or worsening pulmonary 
symptoms (e.g. dyspnoea) or radiological abnormality suggestive of 
pneumonitis/interstitial lung disease. 
Section 5.4 Pharmacokinetics and Section 5.5 Biomarker Analysis

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Storage of samples updated to add that sample will also be stored in AstraZeneca 
designated Biobank.
Section 5.4.3 Storage and destruction of pharmacokinetic/ADA samples and  5.5.5 
Chain of custody of biological samples
It has been clarified that Sample will be retained at AstraZeneca designated biobanks as 
well.
Also, storage duration for MEDI4736 & TREME PK and ADA samples should be changed 
to “a maximum of 15 years after the study ends” in order to harmonize the storage duration 
for all the samples.
Section 5.5.1 Collection of patient samples for stratification by PD-L1
Tumor storage location has been clarified that tumor will be retained at 
 
.
Also clarified that patients with a single target lesion, if screening biopsy is collected prior 
to screening imaging for baseline tumor assessment, allow approximately 2 weeks before 
imaging scans are acquired.
Section 5.5.2 Exploratory Biomarkers
Relevant section related to SNP Genotyping, PGx research, PaxGene-RNA & circulating 
soluble factors removed as these are no longer applicable.
Section 6 Safety reporting and medical management
In accordance with the new protocol template, the following first 3 sub-sections of Section 
6 were reordered from:
6.1 Definition of serious adverse events
6.2 Recording of adverse events
6.3 Definition of adverse events
to
6.1 Definition of adverse events
6.2 Definition of serious adverse events
6.3 Recording of adverse events
Time period of recording adverse events after last dose of both arms updated.
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Section 6.1 Definition of adverse events
Definition of adverse events of adverse event updated to clarify that progression of the 
malignancy under evaluation should not considered as adverse event. 
Section 6.1.2 Relationship to protocol procedures
This section was revised to add “prior to administration of IP or SoC” into the parenthetical 
about SAEs that occur prior to the administration of IP to provide clarity on the non-
treatment emergent SAEs.
Section 6.1.8 Deaths
In accordance with MEDI4736 and Tremelimumab protocol template deaths are to be 
reported to monitor or physician instead only to physician. 
New requirement of death related SAE collection timelines are updated. This is added to 
monitor the late onset of drug related SAEs. 
Section 6.6.2 Paternal Exposure
Timelines of follow-up and documentation of pregnancy outcome are updated.
Section 7.1 Identity of investigational product(s) 
The section for MEDI4736 and tremelimumab is updated with the current 
recommendations for preparation and dose calculations. 
Section 7.3 Labeling, Section 10.3 Ethics and regulatory review and Section 10.5 
Changes to the protocol and informed consent form
Japan specific wordings added.
Section 7.7 Concomitant and other treatments
This section revised for clarity and to include collection of data timelines for safety 
purposes including the table of prohibited medication/class of drug was revised based on 
the updated information available on prohibited and concomitant medications. 
Section 7.8 Post study access to study treatment
Wording related to 12 months treatment removed as patient can continue more than 12 
months treatment based on investigator discretion.
Section 8.4.1 Calculation or derivation of efficacy variables 
Secondary analysis of OS in PD-L1 negative is included.

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Section 8.4.1.2 Progression-free survival
To clarify that in the SoC group treatment can be continued, at investigator’s discretion, 
until disease progression in confirmed. Patients in the SoC are not allowed to continue 
treatment once disease progression in confirmed.
Section 8.4.2.1 Adverse events
This section updated with AE recording timelines.
Appendix C Pharmacogenetics Research
Storage location of link between the patient enrollment/randomization code and the DNA 
number has been updated.
Appendix E Guidelines for Evaluation of Objective Tumor Response Using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumors)
Has been updated to clarify on the target lesions, use of scans with IV contrast, and use of 
FDG-PET/CT scans against dedicated diagnostic contrast-enhanced CT scans. Also, 
criteria for progression as per RECIST has been further clarified. 
Central review section of this appendix is also updated to clarify that contract research 
organization appointed by AstraZeneca is responsible for providing necessary document 
for image collection and transfer. However, management of patients will be based solely 
upon the local assessments conducted by the investigator.
Appendix F Management of investigational product-related toxicities, and 
Appendices
Appendix F was updated with the new version of the Dosing Modification and Toxicity 
Management Guidelines for Immune-mediated, Infusion-related, and Nonimmune-
mediated Reactions (MEDI4736 Monotherapy, Tremelimumab Monotherapy, or 
MEDI4736 + Tremelimumab Combination Therapy.
Also a sentence added to clarify that guidelines are prepared by the Sponsor to assist the 
Investigator in the exercise of his/her clinical judgment in treating these types of toxicities.
Also, MEDI4736 + tremelimumab and MEDI4736 monotherapy adverse events of special 
interest (AESI) of Appendix F was updated to reduce the emphasis on MEDI4736 and 
tremelimumab’s biochemical properties in relation to AESIs, and also to remove the 
explanation of MEDI4736’s main AESIs and refer the reader to the current IB where these 
are explained in full, together with specific guidelines for their evaluation and treatment.

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Version 3, 21 August 2015
Changes to the protocol are summarized below.
Appendix G has been updated based on new guidelines to 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) July 2nd, 2015. Details of changes to the 
protocol are summarized in Amendment 2.
Version 2, 06 August 2015
Changes to the protocol are summarized below.
CSP amended to clarify the inclusion and exclusion criteria. Also, study assessments were 
clarified. Details of changes to the protocol are summarized in Amendment 1.
Version 1, 11 June 2015
Initial Version

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PROTOCOL SYNOPSIS
A Phase III Randomized, Open-Label, Multi-Center, Global Study of 
MEDI4736 in Combination with Tremelimumab Therapy Versus Standard 
of Care Platinum-Based Chemotherapy in First Line Treatment of Patients 
with Advanced or Metastatic Non Small-Cell Lung Cancer (NSCLC) 
(NEPTUNE)
International Coordinating Investigator
01246-000 – São Paulo – SP, Brazil
Tel.:  
Study site(s) and number of patients planned
The study will enroll approximately 1330 patients to identify approximately 800 patients who 
will be randomized to receive MEDI4736 + tremelimumab combination therapy or platinum-
based Standard of Care (SoC) therapy (400 patients in each group, including approximately 
336 patients with programmed cell death ligand 1 [PD-L1]–positive non-small-cell lung 
cancer [NSCLC], defined as PD-L1 tumoral expression ≥25%). Global recruitment will be 
complete once approximately 800 patients have been randomized of which 30 patients are 
from mainland China. Once global enrollment is completed, the recruitment will continue in 
mainland China only. A total of approximately 160 patients from mainland China will be 
randomized (refer to section 8.6 for more details).
Study period
Phase of development
Estimated date of first patient enrolled
Q3 2015
III
Estimated date of last patient last visit for final 
analysis of the study
Q3 2020
III
Study design
This is a randomized, open-label, multi-center, global, Phase III study to determine the 
efficacy and safety of MEDI4736 + tremelimumab combination therapy versus platinum-
based SoC chemotherapy in the first-line treatment of patients with epidermal growth factor 
receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type advanced or metastatic 
NSCLC. 
PPD
PPD

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Patients will provide a tumor tissue sample at enrolment to determine PD-L1 expression status 
(defined by the 
). Mutation assessments 
for blood tumor mutational burden (bTMB) will be performed on 
 
!
≥20 mut/Mb tumor mutational burden in blood is considered as bTMB high
!
<20 mut/Mb tumor mutational burden in blood is considered as bTMB low
!
≥25% PD-L1 and ≥1% PD-L1 membrane expression in tumoral tissue are considered as 
relevant positive sub-groups
!
<25% PD-L1 is considered low/negative
!
<1% PD-L1 is considered negative 
For clarity, these subgroups are referred to hereafter as patients with PD-L1-positive25%, PD-
L1-positive1%, PD-L1-low/negative or PD-L1-negative tumors, respectively). 
Patients will be randomized in a 1:1 ratio in a stratified manner according to PD-L1 tumor 
expression status (PD-L1-positive25% versus PD-L1-low/negative), histology (squamous 
versus non-squamous), and smoking status (never smoker versus ever smoker) to receive 
treatment with MEDI4736 + tremelimumab combination therapy or SoC therapy. 
Tumor assessments will be performed every 6 weeks for the first 48 weeks and then every 
8 weeks until confirmed disease progression, with categorization of objective tumor response 
by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). 
Global recruitment will be complete once approximately 800 patients have been randomized 
of which 30 patients are from mainland China. Once global enrollment is completed the 
recruitment will continue in mainland China only. A total of approximately 160 patients from 
mainland China will be randomized (refer to Section 8.6 for more details). This is to ensure 
adequate Chinese patient participation to satisfy China health authority requirements to 
evaluate consistency in safety and efficacy of MEDI4736 + tremelimumab in Chinese patients 
with advanced or metastatic EGFR and ALK wild-type NSCLC. 
Objectives
All objectives will be evaluated for all patients, unless otherwise indicated. The primary 
objective is assessment of overall survival (OS) in patients with bTMB ≥ 20mut/Mb. 
Primary objectives:
Outcome measures:
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy compared 
to SoC in terms of Overall survival (OS) in 
patients with bTMB ≥ 20mut/Mb.
OS 
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Secondary objectives:
Outcome measures:
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy compared 
to SoC in terms of OS 
OS in patients with

bTMB ≥ 16mut/Mb NSCLC

bTMB ≥12 mut/Mb NSCLC

PD-L1-negative NSCLC

All patients with NSCLC

bTMB < 20 mut/Mb NSCLC

bTMB non-evaluable population
To further assess the efficacy of MEDI4736 + 
tremelimumab combination therapy compared 
to SoC in terms of PFS, ORR, DoR, OS12, 
OS18, OS24, APF12, and PFS2
PFS, ORR, DoR and APF12 using Investigator 
assessments according to RECIST 1.1 in patients 
with 

bTMB ≥ 20mut/Mb NSCLC

bTMB ≥ 16mut/Mb NSCLC

bTMB ≥ 12mut/Mb NSCLC

PD-L1 negative NSCLC 

All patients with NSCLC
PFS2 using local standard clinical practicea, OS12, 
OS18 and OS24 in patients with 

bTMB ≥ 20mut/Mb NSCLC

bTMB ≥ 16mut/Mb NSCLC

bTMB ≥ 12mut/Mb NSCLC

PD-L1 negative NSCLC

All patients with NSCLC
To assess efficacy of MEDI4736 + 
tremelimumab combination therapy compared 
to SoC in terms of ORR, PFS and OS in 
further PD-L1 defined populations
OS in patients with PD-L1 TC ≥ 25% and PD-L1 TC 
≥ 50%
PFS and ORR using Investigator assessments 
according to RECIST 1.1 in patients with PD-L1 TC 
≥ 25% and PD-L1 TC ≥ 50%.
To further assess efficacy of MEDI4736 + 
tremelimumab combination therapy compared 
to SoC in terms of ORR, PFS and OS 
(including OS12, OS18 and OS24)
OS in patients in analysis sets defined by tTMB 
cutoffs. 
PFS and ORR using Investigator assessments 
according to RECIST 1.1 in patients in analysis sets 
defined by tTMB cutoffs b. 

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Secondary objectives:
Outcome measures:
To assess the pharmacokinetics (PK) of 
MEDI4736 + tremelimumab combination 
therapy
Concentration of MEDI4736 and tremelimumab in 
blood and non-compartmental PK parameters, such as 
peak concentration and trough (as data allow; sparse 
sampling)
To investigate the immunogenicity of 
MEDI4736 and tremelimumab
Presence of anti-drug antibodies (ADAs) for 
MEDI4736 and tremelimumab (confirmatory results: 
positive and negative; titers)
a
PFS2 will be defined as the time from the date of randomization to the earliest of the progression event 
subsequent to that used for the PFS endpoint, or death
b
tTMB cutoffs will be defined in the SAP ahead of the DBL from a dataset independent of data collected 
in this study.
Safety objective:
Outcome measures:
To assess the safety and tolerability profile of 
MEDI4736 + tremelimumab combination 
therapy compared to SoC in the first-line 
setting for treatment of advanced or metastatic 
NSCLC patients
Adverse events (AEs), physical examinations, 
laboratory findings, and vital signs
An objective to meet China Health Authority requirement is to evaluate consistency in 
efficacy and safety among Chinese patients for benefit-risk assessment of MEDI4736 + 
tremelimumab combination therapy compared to SoC. Further details regarding the Chinese 
specific analysis, please refer the China specific SAP.
Target patient population
Adult patients (age ≥18 years) with advanced or metastatic (Stage IV) histologically or 
cytologically documented EGFR and ALK wild-type NSCLC who are treatment naive.
Duration of treatment
Unless specific treatment discontinuation criteria are met patients in all groups will continue 
therapy until disease progression.
Progression during treatment
Patients in all groups may continue receiving therapy in the setting of unconfirmed 
progressive disease (PD) at the Investigator’s discretion until PD is confirmed. According to 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) modified for
confirmation of progression, a confirmatory scan will be required following an overall 
radiologic time point assessment of progression, preferably at the next scheduled visit and no 
earlier than 4 weeks after the previous assessment of PD.
Patients in the immunotherapy arm with PD according to RECIST 1.1(unconfirmed and 
confirmed) who, in the Investigator’s opinion, continue to receive benefit from their assigned 
treatment and who meet the criteria for treatment in the setting of PD may continue to receive 

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their assigned treatment for as long as they are gaining clinical benefit. However, patients in 
the immunotherapy group will not be permitted to continue immunotherapy if progression 
occurs after confirmed response [CR defined as CR or PR as defined by RECIST 1.1] to 
immunotherapy treatment in the target lesions (regardless of the appearance of new lesions) 
i.e., the response and then the progression events both occurred in the target lesions while the 
patient was receiving immunotherapy during the same treatment period.
Patients in the MEDI4736 + tremelimumab group may restart treatment with the combination 
therapy if they complete the 4 dosing cycles with MEDI4736 + tremelimumab (with clinical 
benefit per Investigator judgement) but subsequently have PD during treatment with 
MEDI4736 alone and if they meet eligibility criteria for retreatment.
Follow up of patients post discontinuation of study drug
Patients who have discontinued treatment due to toxicity or symptomatic deterioration, 
clinical progression, or who have commenced subsequent anticancer therapy, will be followed 
up until confirmed disease progression and for survival.
Survival
All patients randomized in the study should be followed up for survival.
Post Data Cut Off (DCO)
For patients continuing to receive MEDI4736 or MEDI4736 + tremelimumab treatment 
following the scheduled DCO for final analysis of the global cohort, it is recommended that 
the patients continue the scheduled site visits. For those patients from China who are in the 
Global cohort, final DCO and DBL will be when the China cohort conducts its final DCO and 
final DBL.
Based on the analysis results of the global cohort, a decision was made to move the following 
patients of global cohort to a roll over study

Patients who are still receiving study treatment (MEDI4736/tremelimumab treatment)

Patients who were receiving study treatment (MEDI4736/tremelimumab treatment) 
and are now being followed up for survival
No further data collection in to the Neptune study database is required until the patients in 
global cohort (with the exception of patients from China) are transitioned to a roll over study. 
Survival data of patients who are ongoing on MEDI4736/tremelimumab treatment or in follow 
up after discontinuation of the MEDI4736/tremelimumab treatment, should be documented in 
patient records. Upon enrolment into the roll over study these data may be retrieved.
All SAEs that occur in patients still receiving MEDI4736/tremelimumab treatment (or within 
the 90 days following the last dose of MEDI4736/tremelimumab treatment) post the final 
DCO and database closure must be reported as detailed in Section 6.4

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Patients moving to the roll over study will require a new Informed Consent. The OS data 
collected in the roll over study may be combined with the OS data from NEPTUNE and 
evaluated as a combined dataset.
Investigational product, dosage, and mode of administration
MEDI4736 + tremelimumab combination therapy

MEDI4736 20 mg/kg via intravenous (IV) infusion every 4 weeks (q4w), starting on 
Week 0, for up to a total of 4 doses/cycles, and then continue MEDI4736 20 mg/kg via IV 
infusion q4w, starting on Week 16

Tremelimumab 1 mg/kg via IV infusion q4w, starting on Week 0, for up to 4 doses/cycles
Standard of Care therapy
Patients randomized to SoC therapy will receive 1 of the following:

Paclitaxel + carboplatin: Paclitaxel 200 mg/m2 and carboplatin area under the curve 
(AUC) 5 or 6 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles or until 
documented PD

Gemcitabine + cisplatin (squamous patients only): Gemcitabine 1000 or 1250 mg/m2 via 
IV infusion on Days 1 and 8 of each 21-day cycle + cisplatin 75 or 80 mg/m2 via IV 
infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles or until documented PD

Gemcitabine + carboplatin (squamous patients only): Gemcitabine 1000 or 1250 mg/m2 
via IV infusion on Days 1 and 8 of each 21-day cycle + carboplatin AUC 5 or 6 via IV 
infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles or until documented PD

Pemetrexed + cisplatin (non-squamous patients only): Pemetrexed 500 mg/m2 and 
cisplatin 75 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles or 
until documented PD. Non-squamous patients who have not progressed after 4 cycles will 
be eligible for pemetrexed maintenance therapy

Pemetrexed + carboplatin (non-squamous patients only): Pemetrexed 500 mg/m2 and 
carboplatin AUC 5 or 6 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles or 
until documented PD. Non-squamous patients who have not progressed after 4 cycles will 
be eligible for pemetrexed maintenance therapy
Statistical methods
The primary objectives of this study are to assess the efficacy of MEDI4736 + tremelimumab 
combination therapy compared with SoC in terms of overall survival (OS) in patients with 
EGFR and ALK wild type advanced or metastatic NSCLC and bTMB ≥ 20 mut/Mb. OS will 

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be defined as the time from the date of randomization until death due to any cause. Secondary 
efficacy variables include OS in patients with bTMB ≥16 mut/Mb, bTMB  ≥12 mut/Mb, PD-
L1-negative tumours, all-comers FAS population, bTMB < 20 mut/Mb, and bTMB non-
evaluable population, as well as progression-free survival (PFS), objective response rate 
(ORR),  duration of response (DoR), proportion of patients alive and progression free at 12 
months from randomization (APF12), proportion of patients alive at 12 months from 
randomization (OS12), proportion of patients alive at 18 months from randomization (OS18), 
proportion of patients alive at 24 months from randomization (OS24), and time from 
randomization to second progression (PFS2) in patients with bTMB ≥20 mut/Mb, bTMB ≥16 
mut/Mb, bTMB  ≥12 mut/Mb, PD-L1-negative tumours and the all-comers FAS population. 
All tumor-assessment-related endpoints are as per Investigator assessments. OS, PFS and 
ORR will also be evaluated in patients with PD-L1 TC ≥ 25% and TC ≥ 50%, and in analysis 
sets defined by tTMB cutoffs.
Efficacy data will be summarized and analyzed on an intent-to-treat (ITT) basis and the 
treatment groups will be compared on the basis of randomized treatment, regardless of the 
treatment actually received. Patients who were randomized but did not subsequently go on to 
receive IP are included in the ITT population.
Approximately 800 patients will be randomized globally 1:1 to MEDI4736 + tremelimumab 
combination therapy or SoC (including approximately 336 patients with PD-L1-positive25%
NSCLC, and approximately 520 patients with PD-L1-positive1% NSCLC). The randomization 
will be stratified based on PD-L1 tumor expression status (≥25% versus <25%), histology 
(squamous versus non-squamous), and smoking status (never smoker versus ever smoker).
A hypothesis of improved OS will be tested in the bTMB ≥ 20 mut/Mb population when there 
is (approximately) 87% maturity in the bTMB ≥ 20 mut/Mb population.
With a 12-month recruitment period and a minimum follow up period of 43 months assumed, 
it is anticipated that this analysis will be performed 55 months after the first patient has been 
recruited.
MEDI4736 + tremelimumab versus SoC (OS in bTMB≥20 mut/Mb population)
Assuming the true OS average hazard ratio (HR) is 0.49 and the median OS in SoC 
chemotherapy alone arm is 10 months following an exponential distribution for both 
MEDI4736 + tremelimumab and SoC arm in the bTMB≥20 mut/Mb population, with 
approximately 140 patients, 122 OS events from the global cohort (approximately 87% 
maturity) will provide greater than 90% power to demonstrate statistical significance at the 2-
sided alpha overall level of 5%. The smallest treatment difference that is statistically 
significant will be an HR of 0.70.
A HR of 0.49 is based on observation from D419AC00001 study, as well as based on what 
would be considered a clinically meaningful improvement in the biomarker selected 
population.

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No interim analysis is planned.
OS and PFS will be analyzed using a log-rank test. The effect of treatment will be estimated 
by the HR together with appropriately sized confidence interval and p-value.
Safety data will be summarized descriptively and will not be formally analyzed.
China data
Global recruitment will be complete once approximately 800 patients have been randomized 
of which 30 patients are from mainland China. Once global enrollment is completed, the 
recruitment will continue in mainland China only. A total of approximately 160 patients from 
mainland China will be randomized (refer to Section 8.6 for more details).  Details of the 
anlaysis for China will be detailed in the China specific SAP. The data cut-off for the China 
cohort analysis may be different from the global data cut-off to ensure an appropriate 
evaluation. Safety and tolerability will be summarized for the China Safety Analysis Set.

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Edition Number 9.0
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TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
PROTOCOL SYNOPSIS................................................................................... 21
TABLE OF CONTENTS................................................................................... 29
1.
INTRODUCTION ............................................................................................. 39
1.1
Background and rationale for conducting this study ........................................... 39
1.1.1
Immunotherapies ............................................................................................... 39
1.1.2
MEDI4736......................................................................................................... 42
1.1.3
Tremelimumab................................................................................................... 43
1.1.4
MEDI4736 in combination with tremelimumab.................................................. 43
1.1.5
Rationale for conducting this study .................................................................... 43
1.2
Rationale for study design, doses, and control groups......................................... 44
1.2.1
MEDI4736 + tremelimumab dose and treatment regimen justification ............... 44
1.2.1.1
MEDI4736+ tremelimumab combination therapy dose rationale ........................ 44
1.2.1.2
Rationale for 4 cycles of combination therapy followed by MEDI4736 
monotherapy...................................................................................................... 46
1.2.2
Rationale for Standard of Care as a comparator.................................................. 47
1.2.3
Rationale for retreatment option......................................................................... 47
1.2.4
Rationale for endpoints ...................................................................................... 47
1.3
Benefit/risk and ethical assessment .................................................................... 48
1.3.1
Potential benefits................................................................................................ 48
1.3.1.1
MEDI4736......................................................................................................... 48
1.3.1.2
MEDI4736 + tremelimumab combination therapy.............................................. 48
1.3.2
Overall risks....................................................................................................... 49
1.3.2.1
MEDI4736......................................................................................................... 50
1.3.2.2
Tremelimumab................................................................................................... 50
1.3.2.3
MEDI4736 + tremelimumab combination therapy.............................................. 51
1.3.3
Overall benefit: risk and ethical assessment........................................................ 51
1.4
Study design ...................................................................................................... 52
2.
STUDY OBJECTIVES...................................................................................... 55
2.1
Primary objective............................................................................................... 55
2.2
Secondary objectives.......................................................................................... 55
2.3
Safety objective.................................................................................................. 56
2.4
Exploratory objectives ....................................................................................... 57

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3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL.................... 58
3.1
Inclusion criteria ................................................................................................ 58
3.2
Exclusion criteria ............................................................................................... 60
3.3
Patient enrollment and randomization ................................................................ 63
3.4
Procedures for handling incorrectly enrolled patients ......................................... 64
3.5
Methods for assigning treatment groups............................................................. 64
3.6
Methods for ensuring blinding ........................................................................... 65
3.7
Methods for unblinding...................................................................................... 65
3.8
Restrictions........................................................................................................ 65
3.9
Discontinuation of investigational product ......................................................... 67
3.9.1
Procedures for discontinuation of a patient from investigational product ............ 68
3.10
Criteria for withdrawal of the patient from the study .......................................... 68
3.10.1
Screen failures ................................................................................................... 68
3.10.2
Withdrawal of the informed consent................................................................... 69
3.10.2.1
Survival status for withdrawn consent and lost to follow up patients .................. 69
3.11
Discontinuation of the study............................................................................... 70
4.
STUDY PLAN AND TIMING OF PROCEDURES........................................... 70
4.1
Enrollment/screening period .............................................................................. 80
4.2
Treatment period................................................................................................ 80
4.3
Follow-up period................................................................................................ 80
5.
STUDY ASSESSMENTS.................................................................................. 81
5.1
Efficacy assessments.......................................................................................... 81
5.1.1
Central reading of scans ..................................................................................... 83
5.1.2
Survival assessments.......................................................................................... 84
5.2
Safety assessments............................................................................................. 84
5.2.1
Laboratory safety assessments............................................................................ 84
5.2.2
Physical examination ......................................................................................... 86
5.2.3
Electrocardiograms ............................................................................................ 86
5.2.4
Vital signs.......................................................................................................... 87
5.3
Other assessments.............................................................................................. 88
5.3.1
WHO/ECOG performance status........................................................................ 88
5.3.2
Other safety assessments.................................................................................... 88
5.4
Pharmacokinetics ............................................................................................... 88
5.4.1
Collection of samples and determination of drug concentration.......................... 88
5.4.2
Collection of samples to measure for the presence of ADAs............................... 89
5.4.3
Storage and destruction of pharmacokinetic/ADA samples................................. 89

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5.5
Biomarker analysis............................................................................................. 89
5.5.1
Collection of patient samples for stratification by PD-L1 and for 
expression of PD-L1 and Tumor Mutation Burden (TMB) ................................. 90
5.5.2
Exploratory biomarkers...................................................................................... 92
5.5.3
Storage, re-use, and destruction of biological samples........................................ 93
5.5.4
Labeling and shipment of biological samples ..................................................... 93
5.5.5
Chain of custody of biological samples .............................................................. 93
5.5.6
Withdrawal of informed consent for donated biological samples........................ 94
5.6
Pharmacogenetics (Not applicable) .................................................................... 94
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 94
6.1
Definition of adverse events............................................................................... 95
6.1.1
Causality collection............................................................................................ 95
6.1.2
Relationship to protocol procedures ................................................................... 95
6.1.3
Adverse events based on signs and symptoms.................................................... 95
6.1.4
Adverse events based on examinations and tests ................................................ 96
6.1.5
Hy’s law ............................................................................................................ 96
6.1.6
Disease progression............................................................................................ 96
6.1.7
New cancers....................................................................................................... 96
6.1.8
Deaths................................................................................................................ 97
6.1.9
Safety Data to be Collected Following the Final DCO of the Study.................... 97
6.2
Definitions of serious adverse event ................................................................... 97
6.3
Recording of adverse events............................................................................... 98
6.3.1
Time period for collection of adverse events ...................................................... 98
6.3.2
Follow-up of unresolved adverse events............................................................. 98
6.3.3
Variables............................................................................................................ 98
6.4
Reporting of serious adverse events ................................................................. 100
6.5
Adverse Events of Special Interest ................................................................... 101
6.6
Overdose.......................................................................................................... 102
6.7
Pregnancy ........................................................................................................ 102
6.7.1
Maternal exposure............................................................................................ 102
6.7.2
Paternal exposure............................................................................................. 103
6.8
Study governance and oversight....................................................................... 103
6.9
Medication Error.............................................................................................. 104
6.10
Management of IP-related toxicities................................................................. 104
6.10.1
Specific toxicity management and dose modification information –
Durvalumab and durvalumab + tremelimumab................................................. 104
6.10.2
Specific toxicity management and dose modification information –
Standard of Care .............................................................................................. 105
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................. 106

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7.1
Identity of investigational product(s)................................................................ 106
7.1.1
MEDI4736....................................................................................................... 106
7.1.2
Tremelimumab................................................................................................. 106
7.1.3
Standard of Care treatment............................................................................... 107
7.2
Dose and treatment regimens ........................................................................... 107
7.2.1
Treatment regimens.......................................................................................... 107
7.2.2
Duration of treatment and criteria for treatment through progression and 
for retreatment ................................................................................................. 109
7.3
Labeling........................................................................................................... 111
7.4
Storage............................................................................................................. 111
7.5
Compliance...................................................................................................... 111
7.6
Accountability.................................................................................................. 112
7.7
Concomitant and other treatments .................................................................... 112
7.7.1
Other concomitant treatment ............................................................................ 114
7.7.2
MEDI4736 drug-drug interactions.................................................................... 114
7.8
Post study access to study treatment................................................................. 114
7.8.1
Special roll over study...................................................................................... 114
8.
STATISTICAL ANALYSIS BY ASTRAZENECA......................................... 115
8.1
Statistical considerations .................................................................................. 115
8.2
Sample size estimate ........................................................................................ 115
8.3
Definitions of analysis sets............................................................................... 116
8.3.1
Full analysis set................................................................................................ 118
8.3.2
bTMB ≥20 mut/Mb analysis set ....................................................................... 118
8.3.3
bTMB≥ 16 mut/Mb analysis set ....................................................................... 118
8.3.4
bTMB ≥ 12 mut/Mb analysis set ...................................................................... 118
8.3.5
bTMB non-evaluable analysis set..................................................................... 118
8.3.6
PD-L1-negative analysis set............................................................................. 118
8.3.7
tTMB - based analysis sets............................................................................... 119
8.3.8
Safety analysis set............................................................................................ 119
8.3.9
Pharmacokinetic analysis set............................................................................ 119
8.4
Outcome measures for analysis ........................................................................ 119
8.4.1
Calculation or derivation of efficacy variables.................................................. 119
8.4.1.1
Investigator RECIST 1.1-based endpoints........................................................ 120
8.4.1.2
Secondary endpoints ........................................................................................ 120
8.4.2
Calculation or derivation of safety variables..................................................... 122
8.4.2.1
Adverse events................................................................................................. 122
8.4.2.2
Other significant adverse events....................................................................... 123
8.4.2.3
Safety assessments........................................................................................... 123
8.4.3
Calculation or derivation of pharmacokinetic variables .................................... 123
8.4.3.1
Population pharmacokinetics and exposure-response/safety analysis................ 123

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8.4.3.2
Pharmacokinetic non-compartmental analysis .................................................. 124
8.4.3.3
Immunogenicity analysis.................................................................................. 124
8.4.4
Calculation or derivation of biomarker variables .............................................. 124
8.5
Methods for statistical analysis......................................................................... 124
8.5.1
Analysis of primary endpoint - overall survival................................................ 128
8.5.2
Progression-free survival.................................................................................. 130
8.5.3
Objective response rate .................................................................................... 131
8.5.4
Duration of response ........................................................................................ 131
8.5.5
Survival rate at 12 months, 18, and 24 months ................................................. 132
8.5.6
Proportion of patients alive and progression free at 12 months from 
randomization .................................................................................................. 132
8.5.7
Time from randomization to second progression .............................................. 132
8.5.8
Safety data ....................................................................................................... 133
8.5.9
Pharmacokinetic data ....................................................................................... 133
8.5.10
Immunogenicity analysis.................................................................................. 133
8.5.11
Pharmacokinetic/Pharmacodynamic relationships ............................................ 134
8.5.12
Biomarker data................................................................................................. 134
8.5.13
Exploratory analysis......................................................................................... 134
8.6
China Cohort.................................................................................................... 134
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA....................... 135
9.1
Training of study site personnel ....................................................................... 135
9.2
Monitoring of the study.................................................................................... 136
9.2.1
Source data ...................................................................................................... 136
9.2.2
Direct access to source data in Japan................................................................ 136
9.2.3
Study agreements............................................................................................. 136
9.2.4
Archiving of study documents.......................................................................... 137
9.3
Study timetable and end of study...................................................................... 137
9.4
Data management by AstraZeneca or delegate ................................................. 137
10.
ETHICAL AND REGULATORY REQUIREMENTS..................................... 138
10.1
Ethical conduct of the study ............................................................................. 138
10.2
Patient data protection...................................................................................... 138
10.3
Ethics and regulatory review ............................................................................ 138
10.4
Informed consent ............................................................................................. 139
10.5
Changes to the protocol and informed consent form......................................... 140
10.6
Audits and inspections ..................................................................................... 141
11.
LIST OF REFERENCES ................................................................................. 142

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LIST OF TABLES
Table 1
Highly effective methods of contraception (<1% failure rate)................67
Table 2
Schedule of assessments for MEDI4736 + tremelimumab 
combination therapy treatment and retreatment periods.........................72
Table 3
Schedule of assessments for Standard of Care therapy treatment 
period....................................................................................................75
Table 4
Schedule of assessments for patients who have 
completed/discontinued treatment with MEDI4736 + 
tremelimumab combination therapy or Standard of Care therapy...........78
Table 5
Clinical chemistry (serum or plasma) ....................................................85
Table 6
Hematology ..........................................................................................85
Table 7
Urinalysis..............................................................................................85
Table 8
List of investigational products for this study ...................................... 106
Table 9
Summary of outcome variables and analysis populations..................... 117
Table 10
Pre-planned statistical and sensitivity analysis to be conducted ........... 125
LIST OF FIGURES
Figure 1
Overall study design a............................................................................53
Figure 2
Study flow chart....................................................................................54
Figure 3
MEDI4736 + tremelimumab combination therapy dosing scheme....... 108
Figure 4
Multiple testing procedures for controlling the type I error rate ........... 128
LIST OF APPENDICES
Appendix A
Additional Safety Information............................................................. 151
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document............................................................................ 154
Appendix C
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ...................................................................... 155
Appendix D
Guidelines for Evaluation of Objective Tumor Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid 
Tumors) .............................................................................................. 160

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List of abbreviations and definition of terms
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
ADA
Anti-drug antibody
AE
Adverse event
ALK
Anaplastic lymphoma kinase
ALT
Alanine aminotransferase
APF12
Proportion of patients alive and progression free at 12 months from 
randomization
APTT
Activated Partial Thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the plasma drug concentration-time curve
AUCss
Area under the plasma drug concentration-time curve at steady state
BoR
Best objective response
BP
Blood pressure
C
Cycle
CD
Cluster of differentiation
CI
Confidence interval
CL
Clearance
Cmax
Maximum plasma concentration
Cmax,ss
Maximum plasma concentration at steady state
CR
Complete response
CSA
Clinical study agreement
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
CTLA-4
Cytotoxic T–lymphocyte-associated antigen 4
Ctrough,ss
Trough concentration at steady state
CXCL
Chemokine (C-X-C motif) ligand
D5W
5% dextrose in water
DoR
Duration of response
DNA
Deoxyribonucleic acid

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Abbreviation or 
special term
Explanation
EC
Ethics Committee, synonymous to Institutional Review Board and 
Independent Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDoR
Expected duration of response
EGFR
Epidermal growth factor receptor
EU
European Union
FAS
Full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
Gastrointestinal
GMP
Good Manufacturing Practice
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HIV
Human immunodeficiency virus
HR
Hazard ratio
IB
Investigator’s Brochure
IC
Immune Cells
ICF
Informed consent form
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IFN
Interferon
IgG
Immunoglobulin G
IHC
Immunohistochemistry
IL
Interleukin
ILD
Interstitial lung disease
IM
Intramuscular
imAE
Immune- mediated adverse event
IMT
Immunomodulatory therapy
INR
International normalized ratio

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Abbreviation or 
special term
Explanation
IP
Investigational product 
IRB
Institutional Review Board
ITT
Intent-to-Treat
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LFT
Liver function test
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MHLW
Minister of Health, Labor, and Welfare
miRNA
Micro-ribonucleic acid
MRI
Magnetic resonance imaging
MTP
Multiple testing procedure
NCI
National Cancer Institute
NE
Not evaluable
NOS
Not otherwise specified
NSCLC
Non–small-cell lung cancer
NTL
Non-target lesion
OAE
Other significant adverse event
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PD-L1 positive25%
≥25% of tumor cells with membrane staining for PD-L1 at any intensity
PD-L1-positive1%
≥1% of tumor cells with membrane staining for PD-L1 at any intensity
PD-L1-low/negative
<25% of tumor cells with membrane staining for PD-L1 at any intensity
PD-L1-negative
<1% of tumor cells with membrane staining for PD-L1 at any intensity
PD-L2
Programmed cell death ligand 2
PFS
Progression-free survival
PFS2
Time from randomization to second progression
PK
Pharmacokinetic(s)

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Abbreviation or 
special term
Explanation
PR
Partial response
q2w
Every 2 weeks
q3w
Every 3 weeks
q4w
Every 4 weeks
q6w
Every 6 weeks
q8w
Every 8 weeks
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, Version 1.1
RNA
Ribonucleic acid
RR
Response rate
RT-QPCR
Reverse transcription quantitative polymerase chain reaction
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SAS
Safety analysis set
SD
Stable disease
SNP
Single nucleotide polymorphism
SoC
Standard of Care
sPD-L1
Soluble programmed cell death ligand 1
T3
Triiodothyronine
T4
Thyroxine
TL
Target lesion
TMB
Tumor mutational burden
tTMB
Tissue tumor mutational burden
bTMB
Blood tumor mutational burden
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States
WBDC
Web-Based Data Capture
WHO
World Health Organization

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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Lung cancer has been the most common cancer in the world for several decades, with an 
estimated 1.8 million new cases in 2012 (12.9% of all new cancers), and was also the most 
common cause of death from cancer in 2012, with 1.59 million deaths (19.4% of the total 
cancer deaths; GLOBOCAN 2012). Non-small-cell lung cancer (NSCLC) represents 
approximately 80% to 85% of all lung cancers. Unfortunately, at the time of diagnosis, 
approximately 70% of patients with NSCLC already have advanced or metastatic disease not 
amenable to surgical resection. Furthermore, a significant percentage of patients with early 
stage NSCLC who have undergone surgery subsequently develop distant recurrence and die as 
a result of their lung cancer (Pisters and LeChevalier 2005). 
Despite advances in the diagnosis, imaging, staging, and treatment of NSCLC, the estimated 
overall 5-year survival for patients in Europe and the United States (US) continues to be low 
(11% and 17%, respectively; D’Addario et al 2010, Howlander et al 2014). Patients presenting 
with advanced NSCLC have a median overall survival (OS) of 10 to 12 months (Ayers et al 
2017, Balar et al Dec 2017, Bonomi 2010). Patients without a targetable mutation 
(i.e., epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] 
mutation) demonstrate responses to systemic treatment of approximately 20% to 30% and 
progression-free survival (PFS) of 4 to 5 months (Scagliotti et al 2008, Schiller et al 2002). 
The duration of responses (DoRs) is also limited, and toxicities can be a major limiting factor. 
The 1-year survival rate is 30% to 40% for patients with a good performance status. 
Maintenance therapy, with either continuation or switch, has also been recommended for 
certain histologic subtypes of NSCLC; for example, maintenance with pemetrexed has been 
shown to improve OS and PFS, particularly in non-squamous histologies (Carbone et al 2017, 
Ciuleanu et al 2009, Paz-Ares et al 2013).
Common first-line treatment regimens for advanced NSCLC in major global markets are 
typically platinum-based doublets and include carboplatin and paclitaxel, carboplatin and 
gemcitabine (squamous only), carboplatin and pemetrexed (non-squamous only), cisplatin and 
gemcitabine (squamous only), and cisplatin and pemetrexed (non-squamous only). 
Platinum-based doublet chemotherapy regimens vary to some extent with regard to 
convenience, associated toxicities, and cost, with the selection of a specific regimen often 
dictated by local practice and individualized on a case-by-case basis.
1.1.1
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 a member of the B7 family of ligands that inhibit T-cell activity through binding to 
the PD-1 receptor (Johnson et al 2016, Keir et al 2008) and to CD80 (Butte et al, 2007). PD-
L1 expression is an adaptive response that helps tumors evade detection and elimination by 

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the immune system. In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is 
constitutively expressed by regulatory T cells and upregulated on activated T cells. Binding of 
CTLA-4 to CD80 or CD86 on IC leads to inhibition of T-cell activation (Fife and Bluestone, 
2008). Expression of PD-L1 protein on both tumor cells (TC) and tumor infiltrating IC is 
induced by inflammatory signals that are typically associated with an adaptive immune 
response (e.g., IFNγ). The binding of PD L1 to PD-1 on activated T cells delivers an 
inhibitory signal to the T cells, protecting the tumor from immune elimination (Zou and Chen 
2008). PD-L1 may also inhibit T cells through binding to CD80, although the exact 
mechanism is still not elucidated (Butte et al, 2007; Paterson et al, 2011).
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. This activity overcomes PD-L1-mediated inhibition of antitumor 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.
In vivo studies have shown that MEDI4736 inhibits tumor growth in xenograft models via a T 
cell-dependent mechanism (Stewart et al 2015).
PD-L1 is expressed in a broad range of cancers with a high frequency, up to 88% in some 
types 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 
non-clinical 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 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.
Pre-clinical data has now been added to with a wealth of clinical data showing that blockade 
of negative regulatory signals to T-cells such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) 
and programmed death ligand 1 (PD-L1) has promising clinical activity.  Ipilimumab was 
granted United States (US) Food and Drug Administration (FDA) approval for the treatment 
of metastatic melanoma and is currently under investigation for several other malignancies 

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whilst nivolumab and pembrolizumab, two anti-PD-1 agents and atezolizumab, an anti PD-L1 
agent have been granted approvals by agencies such as the United States of America Food and 
Drug Administration and the European Medicines Agency approval for the treatment of a 
number of malignancies including metastatic melanoma, squamous and non-squamous cell 
non-small-cell lung cancer, squamous cell carcinoma of the head and neck, and urothelial 
carcinoma. In addition, there is data from agents in the anti-PD-1/PD-L1class showing clinical 
activity in a wide range of tumor types.
However, PD-L1 expression alone does not appear to fully explain the OS benefit seen in 
patients treated with these drugs (Reck et al 2014, Carbone et al 2017,Hui et al 2017).  
Increasing evidence suggests the overall number of mutations of NSCLC tumors shape their 
immunogenicity and can also influence the response to immunotherapies.  Tumor mutational 
burden (TMB), defined as the number of nonsynonymous somatic mutations within a tumor's 
genome and characterised from tumor tissue (tTMB) or from circulating tumor DNA in blood 
(bTMB) is an encouraging and important predictive biomarker for immune checkpoint 
inhibitor treatment. Multiple studies have shown that TMB may be a surrogate for overall 
neoantigen frequency (Rizvi et al 2015, Rooney et al 2015).  High neoantigen frequency has 
been associated with upregulation of effector T cells in the tumor microenvironment.  Immune 
checkpoint inhibitors by their ability to block negative regulatory signals to T cells, likely 
enhance this neoantigen specific T cell reactivity.  This theory has been supported by multiple 
publications across tumor types, immune checkpoint inhibitor treatments and lines of 
treatment.  The first published study of TMB as a biomarker of clinical outcomes 
demonstrated efficacy in metastatic melanoma with anti-CTLA-4 therapy (Snyder, A. et al 
2014).  A subsequent study in NSCLC reported improved survival with PD-1 and CTLA-4 
inhibitors in tumors enriched for clonal neoantigens (Rizvi et al 2015). Recently, a 
retrospective analysis of two large datasets with anti-PD-L1 therapy in metastatic NSCLC 
explored a range of bTMB cut-points that correlated to clinically meaningful improvements in 
overall survival (Gandara et al 2018).  Interim data with the same PD-L1 inhibitor suggested 
patients with high bTMB (defined as ≥14.5mut/Mb), trended to a PFS benefit (Vamsidhar 
Velcheti et al 2018, E S Kim et al 2018).  Two additional clinical trials with a PD-1 inhibitor 
in combination with a CTLA-4 inhibitor demonstrated better clinical outcomes in patients 
with high tTMB (defined as ≥10mut/Mb) with both squamous and non-squamous NSCLC 
(Hellmann et al 2018).  The observed association of TMB with improved survival with ICI 
treatment has also been examined more broadly in an analysis involving a range of advanced 
tumor histologies.  This analysis found that overall survival was better for patients with higher 
levels of TMB (highest 20% in each histology). (Samstein et al 2019).
Published data with MEDI4736 in combination with tremelimumab also support the 
hypothesis that high TMB can be predictive of clinical outcomes.  Tumor tissue from Study 
, a phase 1b study of patients with NSCLC, analysed tTMB in patients with 
non-squamous histology and reported median PFS of 7.1m (1.7m-9.1m) in patients with 
tTMB high (defined as 11.41mut/Mb) vs 1.7m (1.6m-3.6m) in patients with tTMB low (Higgs 
BW et al 2018).
In Study D419AC00001 a study of MEDI4736 with or without tremelimumab vs standard of 
CCI

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Edition Number 9.0
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care platinum doublet chemotherapy, in patients with Stage IV NSCLC, bTMB was evaluated 
as a prespecified exploratory analysis. bTMB was evaluated with the 
 
 and the analysis comprised the largest dataset to date with over 800 patients in the 
bTMB evaluable set.  Both the MEDI4736 monotherapy and MEDI4736 in combination with 
tremelimumab arms demonstrated clinically meaningful efficacy compared to SoC in TMB 
high patients defined by a range of TMB cut-points, however the effect observed in the 
combination therapy arm was consistently greater compared to the monotherapy arm.  In 
patients with high bTMB (defined as ≥16mut/Mb), combination immunotherapy when 
compared with SoC demonstrated a median OS of 16.5m vs 10.5m, HR 0.62 (95% CI 0.451-
0.855) and survival rate at 24months was 39% vs 18%, respectively (Rizvi et al 2018).  In the 
subgroup, TMB ≥ 12mut/Mb, the HR of D+T vs SoC was 0.65 (95% CI 0.50-0.84) (Peters et 
al 2019). D+T vs SoC in the exploratory PD-L1 negative population also demonstrated 
improved outcomes with D+T (HR 0.73, 95% CI 0.512-1.041) (Rizvi et al 2018). 
In patients with bTMB ≥20mut/Mb, the survival benefit was even more pronounced: HR 0.49 
(95% CI 0.32,0.74) with combination therapy vs SoC and the 24month survival rate was 
48.1% (95% CI 35.5, 59.7) in the combination therapy arm.  The 24 month survival rate for 
SoC was 19.4%, for MEDI4736 monotherapy was 33.8% (95% CI 23.4, 44.5) and MEDI4736 
vs SoC demonstrated HR0.72 (95% CI 0.50, 1.05) (Peters et al 2019)
These data not only supports the hypothesis that bTMB can be considered as a predictive 
marker for clinical outcomes including OS and PFS, it also provides evidence of the additive 
effect of CTLA-4 inhibition by tremelimumab in the subset of patients with increased 
mutational burden.  The totality of the data suggests that TMB is a biomarker of clinical 
efficacy for immunotherapy and perhaps more useful as a biomarker than PD-L1 when 
considering anti-PD-L1/PD-1 in combination with anti-CTLA-4 therapy.   
1.1.2
MEDI4736
MEDI4736 is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with 
PD-1 on T cells and CD80 (B7.1) on immune cells (IC). It is being developed by 
AstraZeneca/MedImmune for use in the treatment of cancer (MedImmune is a wholly owned 
subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to as AstraZeneca 
throughout this document.)  MEDI4736 has been engineered to reduce antibody-dependent 
cellular cytotoxicity and complement-dependent cytotoxicity.  In vitro studies demonstrate 
that MEDI4736 antagonizes the inhibitory effect of PD-L1 on primary human T cells, 
resulting in their restored proliferation and release of interferon gamma (IFN) (Stewart et al 
2015). To date MEDI4736 has been given to more than 6000 patients as part of ongoing 
studies either as monotherapy or in combination with other anti-cancer agents. Details on the 
safety profile of MEDI4736 monotherapy are summarized in Section 1.3.2.1 and Toxicity 
Management Guideline (please see section 6.10). Refer to the current MEDI4736 
Investigator’s Brochure (IB) for a complete summary of non-clinical and clinical information 
including safety, efficacy and pharmacokinetics. 
CCI

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1.1.3
Tremelimumab
Tremelimumab is a human immunoglobulin (Ig)G2 mAb that is directed against CTLA-4; 
cluster of differentiation [CD]152), a cell surface receptor that is expressed primarily on 
activated T cells and acts to inhibit their activation. Tremelimumab completely blocks the 
interaction of human CTLA-4 with CD80 and CD86, resulting in increased release of 
cytokines (interleukin [IL]-2 and interferon [IFN]-γ) from human T cells, peripheral blood 
mononuclear cells and whole blood (Tarhini and Kirkwood 2008). Tremelimumab is being 
developed by AstraZeneca for use in the treatment of cancer.  
To date tremelimumab has been given to more than 1000 patients as part of ongoing studies 
either as monotherapy or in combination with other anticancer agents. Details on the safety 
profile of tremelimumab monotherapy are summarized in Section 1.3.2.2.  Refer to the current 
tremelimumab Investigator’s Brochure for a complete summary of non-clinical and clinical 
information including safety, efficacy and pharmacokinetics.  
1.1.4
MEDI4736 in combination with tremelimumab
Because the mechanisms of action of CTLA-4 and PD-1 are non-redundant, targeting both 
PD-1 and CTLA-4 pathways may have additive or synergistic activity (Pardoll 2012); 
therefore, in addition to evaluating both agents in the monotherapy setting in a number of 
cancer indications AstraZeneca is also investigating the use of MEDI4736 + tremelimumab 
combination therapy for the treatment of cancer.
Study D4190C00006 is a Phase Ib dose-escalation study to establish safety, 
PK/pharmacodynamics, and preliminary antitumor activity of MEDI4736 + tremelimumab 
combination therapy in patients with advanced NSCLC. The dosing schedule utilized is 
MEDI4736 every 2 or 4 weeks (Q2W, Q4W) up to 12 months, combined with tremelimumab 
Q4W up to Week 24 for 7 doses then every 12 weeks (Q12W) for 2 additional doses for up to 
12 months. The study is ongoing and continues to accrue. In addition, other clinical studies 
have since started looking at the combination in both NSCLC and other oncology indications.
To date more than 800 patients have received the combination using a number of doses and 
dosing schedules.  Details on the safety profile of MEDI4736 + tremelimumab combination 
therapy are summarized in Sections 1.2.1.1 and 1.3.2.3.  Refer to the current editions of the 
MEDI4736 and tremelimumab IBs for a complete summary of non-clinical and clinical 
information including safety, PK and efficacy. 
1.1.5
Rationale for conducting this study
Current therapies for advanced NSCLC have poor outcomes (low 5-year survival of 17% for 
the US), with responses to systemic chemotherapy in the first-line setting of approximately 
20% to 30%, and a median OS of approximately 10 to 12 months (Ayers et al 2017, Balar et al 
Dec 2017, Bonomi 2010, D’Addario et al 2010, Scagliotti et al 2008, Schiller et al 2002). 
Responses are also limited in duration. Systemic chemotherapy is associated with significant 
side effects, including neutropenia, nausea, vomiting and dehydration, and alopecia 
(Rosenberg et al 2016, Sandler et al 2006, Scagliotti et al 2008). There is still a significant 

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unmet medical need for additional treatment options for use in this patient population as the 1-
year survival rate is 30% to 40%.
As an antibody that blocks the interaction between PD-L1 and its receptors, MEDI4736 may 
relieve PD-L1-dependent immunosuppressive effects and, therefore, enhance the cytotoxic 
activity of antitumor T-cells. This hypothesis is supported by emerging clinical data from 
other mAbs targeting the PD-L1/PD-1 pathway, which provide early evidence of clinical 
activity and a manageable safety profile (Brahmer et al 2012, Garon et al 2015, 
Gettinger et al 2015, Topalian et al 2012). Responses have been observed in patients with PD-
L1-positive tumors and patients with PD-L1-negative tumors. In addition, MEDI4736 
monotherapy has shown durable responses in NSCLC in Study 1108 (see Section 1.3.1.1).
The rationale for combining MEDI4736 and tremelimumab is that the mechanisms of 
CTLA-4 and PD-1 are non-redundant, suggesting that targeting both pathways may have 
additive or synergistic activity (Pardoll 2012). In fact, combining immunotherapy agents has 
been shown to result in improved response rates (RRs) relative to monotherapy. For example, 
the concurrent administration of nivolumab and ipilimumab to patients with advanced 
melanoma induced higher objective response rates (ORRs) than those obtained with 
single-agent therapy. Importantly, responses appeared to be deep and durable (Wolchok 
et al 2013). Similar results have been observed in an ongoing study of MEDI4736 + 
tremelimumab combination therapy in NSCLC (Antonia et al 2014a), with further updated 
details presented in this Clinical Study Protocol.
Based on the preliminary clinical efficacy and safety data observed in patients with NSCLC in 
Study D4190C00006 (with MEDI4736 + tremelimumab combination therapy), AstraZeneca 
plans to determine the activity of MEDI4736 in combination with tremelimumab as first-line 
treatment in patients with NSCLC. The preliminary efficacy, safety, and tolerability data of 
the MEDI4736 + tremelimumab combination in Study D4190C00006 support the 
development of these treatments in NSCLC. The primary endpoints of this Phase III study are 
to determine the OS benefit of MEDI4736 + tremelimumab combination therapy compared to 
Standard of Care (SoC) in patients with EGFR and ALK wild-type NSCLC when used as 
first-line treatment in patients with bTMB ≥ 20mut/Mb. 
1.2
Rationale for study design, doses, and control groups
This study will utilize an open-label design due to the different treatment administration 
schedules and treatment durations.
1.2.1
MEDI4736 + tremelimumab dose and treatment regimen justification
1.2.1.1
MEDI4736+ tremelimumab combination therapy dose rationale
The MEDI4736 + tremelimumab combination therapy doses and regimen selected for this 
study are based on the goal of selecting an optimal combination dose of MEDI4736 and 
tremelimumab that would yield sustained target suppression (sPD-L1), demonstrate promising 
efficacy, and have an acceptable safety profile. 

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Pharmacokinetics/Pharmacodynamics data
Study D4190C00006 included dose cohorts with both a Q4W and a Q2W schedule of 
MEDI4736 in combination with a Q4W schedule of tremelimumab. The Q4W schedule was 
included to align with the Q4W dosing of tremelimumab. PK simulations from MEDI4736 
monotherapy data indicated that a similar area under the plasma drug concentration-time 
curve at steady state (AUCss; 4 weeks) was expected following both 10 mg/kg Q2W and 
20 mg/kg Q4W dosing with MEDI4736. The observed MEDI4736 PK data from the 
D4190C00006 study were in line with the predicted monotherapy PK data developed pre-
clinically and in line with that seen in the first-time-in-human (FTIH), single agent study (CD-
ON-MEDI4736-1108) in patients with advanced solid tumors. This demonstrates similar 
exposure of MEDI4736 20 mg/kg Q4W and 10 mg/kg Q2W, with no alterations in PK when 
MEDI4736 and tremelimumab (doses ranging from 1 to 3 mg/kg) are dosed together. While 
the median maximum plasma concentration at steady state (Cmax,ss) is expected to be higher 
with 20 mg/kg Q4W (approximately 1.5 fold) and median trough concentration at steady state 
(Ctrough,ss) is expected to be higher with 10 mg/kg Q2W (approximately 1.25 fold), this is not 
expected to impact the overall safety and efficacy profile, based on existing preclinical and 
clinical data.
Monotonic increases in pharmacodynamic activity were observed with increasing doses of 
tremelimumab relative to the activity observed in patients treated with MEDI4736 
monotherapy. There was evidence of augmented pharmacodynamic activity relative to 
MEDI4736 monotherapy with combination doses containing 1 mg/kg tremelimumab, 
including both the 15 and 20 mg/kg MEDI4736 plus 1 mg/kg tremelimumab combinations. 
Clinical data
In Study D4190C00006 various dose combinations have been explored, with doses of 
tremelimumab ranging from 1 to 10 mg/kg and doses of MEDI4736 ranging from 3 to 20 
mg/kg. Tremelimumab was given on a Q4W schedule whilst MEDI4736 was explored in both 
a Q4W and Q2W schedule, with the goal of identifying the dose combination that best 
optimizes the risk:benefit profile in an acceptable range of PK and pharmacodynamic values.
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse 
events (AEs), including discontinuations due to AEs, serious AEs (SAEs), and severe AEs. 
Between the 10 mg/kg MEDI4736 + 1 mg/kg tremelimumab and 10 mg/kg MEDI4736 + 
3 mg/kg tremelimumab cohorts treated at the Q2W schedule, the number of patients reporting 
any AE, ≥Grade 3 AEs, SAEs, and treatment-related AEs was higher in the 10 mg/kg 
MEDI4736 + 3 mg/kg tremelimumab cohort than the 10 mg/kg MEDI4736 + 1 mg/kg 
tremelimumab cohort. A similar pattern was noted in the Q4W regimens, suggesting that, as 
the dose of tremelimumab increased above 1 mg/kg, a higher rate of treatment-related events 
may be anticipated. Further, the SAEs frequently attributed to immunotherapy, pneumonitis, 
colitis and other immune mediated events, were more commonly seen in cohorts using either 3 
mg/kg or 10 mg/kg of tremelimumab compared to the 1-mg/kg dose cohorts. Together, these 
data suggest that a combination using a tremelimumab dose of 1 mg/kg appeared to minimize 
the rate of toxicity when combined with MEDI4736. As a result, all combination doses 

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utilizing either the 3 or 10-mg/kg doses of tremelimumab were eliminated in the final dose 
selection.
In contrast, cohorts assessing higher doses of MEDI4736 with a constant dose of 
tremelimumab did not show an increase in the rate of AEs. The data suggested that increasing 
doses of MEDI4736 may not impact the safety of the combination as much as the 
tremelimumab dose. Further, safety data between the 10-mg/kg and 20-mg/kg cohorts were 
similar, with no change in safety events with increasing dose of MEDI4736.
In Study D4190C00006, of all treatment cohorts, the cohort of patients treated in the 20 mg/kg 
MEDI4736 + 1 mg/kg tremelimumab group had a tolerable safety profile, but still showed 
strong evidence of clinical activity. No dose-limiting toxicities (DLTs) were reported in this 
cohort. 
Preliminary clinical activity of the MEDI4736 and tremelimumab combination did not appear 
to change with increasing doses of tremelimumab. The 15- and 20-mg/kg MEDI4736 Q4W 
cohorts demonstrated objective responses at all doses of tremelimumab and increasing doses 
of tremelimumab did not provide deeper or more rapid responses.
Efficacy data suggested that the 20 mg/kg MEDI4736 + 1 mg/kg tremelimumab dose cohort 
may demonstrate equivalent clinical activity to other dose combinations.
All together, the data suggested that a 20 mg/kg MEDI4736 + 1 mg/kg tremelimumab dose 
combination should be selected for further development. 
Refer to the current MEDI4736 Investigator’s Brochure for a complete summary of non-
clinical and clinical information on the MEDI4736 + tremelimumab combination, including 
safety, efficacy and pharmacokinetics. 
1.2.1.2
Rationale for 4 cycles of combination therapy followed by MEDI4736 
monotherapy
Long-term follow up on melanoma patients treated with ipilimumab, an anti-CTLA-4 
targeting antibody (dosed every 3 weeks [q3w] for 4 doses and then discontinued), shows that 
patients responding to ipilimumab derive long-term benefit, with a 3-year OS rate of 
approximately 22%. Furthermore, the survival curve in this population reached a plateau at 
3 years and was maintained through 10 years of follow up (Schadendorf et al 2013). 
Similar data have been presented for other anti-PD-1/PD-L1 targeting antibodies: 

Nivolumab (anti-PD-1) was dosed Q2W for up to 96 weeks in a large Phase I dose 
escalation and expansion study, and showed responses were maintained for a median 
of 22.94 months for melanoma (doses 0.1 mg/kg to 10 mg/kg), 17 months for NSCLC 
(doses 1, 3, and 10 mg/kg), and 12.9 months for renal cell carcinoma patients (doses 1 
and 10 mg/kg) at the time of data analysis (Brahmer et al 2014, Drake et al 2013, Hodi 
et al 2014)

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Similar long term results may be expected with use of other immune-mediated cancer 
therapeutics such as tremelimumab, MEDI4736, or the combination of the two agents. 
The MEDI4736 + tremelimumab combination therapy will be administered for 4 doses 
followed by monotherapy MEDI4736 20 mg/kg q4w until disease progression or unless other 
specific discontinuation criteria are met.
1.2.2
Rationale for Standard of Care as a comparator
The choice of SoC options provided in this study includes carboplatin and paclitaxel, 
carboplatin (or cisplatin) and gemcitabine (squamous only), carboplatin (or cisplatin) and 
pemetrexed (non-squamous only), and for eligible patients, pemetrexed maintenance 
(non-squamous only). Patients in the SoC group will receive treatment determined by the 
Investigator, from the SoC agents approved for use in NSCLC in their local market, until 
progression per standard practice. The SoC options provided in this study include agents that 
are commonly used in advanced or metastatic NSCLC and allow sufficient flexibility for 
Investigators and patients to select the agents that reflect their normal clinical practice and 
national guidelines (NCCN 2014 and Reck et al 2014).
1.2.3
Rationale for retreatment option
In contrast to patients treated with chemotherapy, who are unlikely to respond to rechallenge 
with the same agent upon progression, responses have been observed upon retreatment with 
IMTs. Several potential mechanisms of resistance to IMT exist, including loss of T-cell 
“memory” or recurrence of immune escape, which suggest retreatment for patients who 
initially respond or demonstrate SD is reasonable. Preliminary data in patients previously 
treated with IMTs suggest that responses are similar to those observed following initial 
treatment (Forde et al 2014, Higgs et al 2017, Hodi et al 2010). 
Patients in the MEDI4736 + tremelimumab group who complete 4 dosing cycles (with clinical 
benefit per Investigator judgement), and subsequently have PD during treatment with 
MEDI4736 alone may restart treatment if they meet eligibility criteria for retreatment.
1.2.4
Rationale for endpoints
The primary aim of this study is to determine the efficacy of MEDI4736 + tremelimumab 
combination therapy versus SoC in terms of OS in patients with high bTMB, defined as 
bTMB ≥20mut/Mb.
The secondary efficacy endpoints of OS in bTMB ≥ 16mut/Mb, OS in bTMB ≥ 12mut/Mb, 
OS in PD-L1 negative, OS in all patients, OS in bTMB < 20 mut/Mb and bTMB non-
evaluable, PD-L1 TC ≥ 25%, OS in PD-L1 TC ≥ 50%, OS in tTMB-based analysis sets, PFS, 
ORR, DoR and, proportion of patients alive at 12 months from randomization (OS12), 
proportion of patients alive at 18 months from randomization (OS18), proportion of patients 
alive at 24 months from randomization (OS24), proportion of patients alive and progression 
free at 12 months from randomization (APF12) and time from randomization to second 

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progression (PFS2) will be examined to further evaluate the antitumor effect and survival 
benefit of MEDI4736 + tremelimumab combination therapy versus SoC. PFS, ORR, DoR, and 
APF12 will be assessed using Investigator assessments according to RECIST 1.1. 
The PK and immunogenicity of MEDI4736 and tremelimumab are being examined to assess 
the PK of both agents when administered in combination, and to assess their potential impact 
on PK, pharmacodynamics, and safety and efficacy parameters. Biological samples will be 
used to explore potential biomarkers in tumor, whole blood, plasma, and/or serum that may 
influence pathogenesis, response, and clinical characteristics.
1.3
Benefit/risk and ethical assessment
The following sections include summaries of the potential benefits and risks associated with 
MEDI4736 monotherapy, tremelimumab monotherapy, and MEDI4736 + tremelimumab 
combination therapy, respectively, prior to the overall benefit: risk assessment.
1.3.1
Potential benefits
1.3.1.1
MEDI4736
The majority of the safety and efficacy data currently available for MEDI4736 are based on 
the first time in-human, single-agent study (Study 1108) in patients with advanced solid 
tumors. Data from Study 1108 were presented at the European Society for Medical Oncology 
2014 Congress. As of 21 August 2014, 162 patients with NSCLC were evaluable for response 
analysis. The disease control rate (DCR) at 12 weeks in patients receiving 10-mg/kg 
MEDI4736 q2w was 39%, and the ORR was 15% (26% [12 out of 47 patients] with known 
PD-L1-positive25% NSCLC [i.e., ≥25% PD-L1 expression] and 10% [7 out of 74 patients] with 
known PD-L1-low/negative NSCLC [i.e., <25% PD-L1 expression]). A total of 24% of 
patients receiving 10-mg/kg MEDI4736 q2w had SD for ≥12 weeks (including 21% [10 out of 
47 patients] with known PD-L1-positive25% NSCLC and 32% [24 out of 74 patients] with 
known PD-L1-low/negative NSCLC). Responses were ongoing in 96% of responding patients 
with NSCLC receiving MEDI4736 10 mg/kg q2w, with an objective response duration 
ranging from 0.1 to 32.4 weeks (Antonia et al 2014b).
1.3.1.2
MEDI4736 + tremelimumab combination therapy
The preclinical and clinical justification for this combination as noted in Section 1.2.1 also 
supports the synergy of this combination. Available data, such as those presented by 
Wolchok et al, suggest that the combination of agents targeting PD-1/PD-L1 and CTLA-4 
may have profound and durable benefits in patients with melanoma (Wolchok et al 2013). 
Further, preliminary efficacy data from Study D4190C00006 has demonstrated that this 
combination is clinically active and well tolerated. As of 27 January 2015, 53 patients were 
evaluable for response across various MEDI4736 + tremelimumab combination therapy dose 
regiments. Of these, 12 patients (23%) had a best response of PR and 14 patients (26%) had a 
best response of SD. In the 20-mg/kg MEDI4736 plus 1-mg/kg tremelimumab q4w cohort, a 
total of 5 of 11 patients were evaluable for efficacy with at least 8 weeks of follow-up. Of 
these, there were 2 patients (40%) with PR, 1 patient (20%) with SD, and 1 patient (20%) with 

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PD. (The fifth patient had only a single scan, which was conducted outside the window for 
these evaluations.)
Current experience with single-agent IMT studies suggests that clinical responses may be 
restricted to a subset of any given patient population and that it might be beneficial to enrich 
the patient population by selecting patients likely to respond to therapy. To date, no assay has 
been established or validated, and no single approach has proven accurate, for patient 
enrichment for IMTs. However, independent data from multiple sources using different assays 
and scoring methods suggests that PD-L1 expression on tumor cells and/or tumor infiltrating 
cells may be associated with greater clinical benefit.
Data from ongoing studies with MEDI4736 and other agents targeting the PD-1/PD-L1 
pathway suggest, as shown in a number of tumor types (e.g., NSCLC, renal cell carcinoma, 
and melanoma), that monotherapy may be more efficacious (in terms of ORR) in patients who 
have PD-L1-positive tumors. 
Given these findings, a number of ongoing studies are assessing the activity of agents in 
patients with PD-L1–positive tumors. Though biomarker development is ongoing and the final 
boundaries of these populations are yet to be established, there is also a potential unmet 
medical need in patients with PD-L1–low/negative tumors that needs to be addressed. Data, as 
of 27 January 2015 from Study 006 show that with the addition of tremelimumab to 
MEDI4736, the ORR can be increased to 25% (6 of 24 patients) in patients with PD-L1-
low/negative NSCLC (as defined by the 
 
). As patients with PD-L1-positive25% tumors can also have an increase in ORR, from 
25% (12 of 48 patients) with MEDI4736 monotherapy, to 36% with the combination of 
MEDI4736 and tremelimumab, the study will enroll all patients with NSCLC, with efficacy 
analysis performed in the overall study population, and pre-defined PD-L1 subgroups.
1.3.2
Overall risks
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed cell 
death ligand 1 (PD-L1) as well as those directed against programmed cell death-1 (PD-1) or 
cytotoxic T-lymphocyte antigen-4 (CTLA-4), aim to boost endogenous immune responses 
directed against tumor cells. By stimulating the immune system however, there is the potential 
for adverse effects on other 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 which 
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 hepatitis and 
liver enzyme elevations, skin events such as rash and dermatitis and endocrinopathies 
including hypo- and hyper-thyroidism.
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1.3.2.1
MEDI4736
Risks with MEDI4736 include, but are not limited to, diarrhea/colitis, pneumonitis/ILD, 
endocrinopathies (i.e. 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 (e.g. Guillain Barre syndrome, myasthenia gravis).
For information on all identified and potential risks with MEDI4736 please always refer to the 
current version of the MEDI4736 IB.
In monotherapy clinical studies AEs reported at an incidence of > 20% include events such as 
fatigue, cough, decreased appetite, dyspnea and nausea. Approximately 10% of patients 
discontinued drug due to an AE.  Please see the current version of the IB for a detailed 
summary of the monotherapy data including AEs, SAEs, and CTC Grade 3 to 5 events 
reported across the MEDI4736 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.  (Please refer to guidance in Section 6.10).
A detailed summary of MEDI4736 monotherapy AE data can be found in the current version 
of the MEDI4736 IB.
1.3.2.2
Tremelimumab
Risks with tremelimumab monotherapy include, but are not limited to, GI effects (colitis, 
diarrhea, enterocolitis, and intestinal perforation); endocrine disorders (hypo- and 
hyperthyroidism, hypophysitis, and adrenal insufficiency); skin effects (rash and pruritus); 
elevations in lipase and amylase and clinical manifestations of pancreatitis; hepatic events 
(including immune mediated hepatitis and liver enzyme elevations); pneumonitis and ILD; 
neurotoxicity (including encephalitis, peripheral motor and sensory neuropathies, and 
Guillain-Barré syndrome); thrombocytopenia, anemia, and neutropenia; infusion-related 
reactions and  hypersensitivity/anaphylactic reactions; renal events (including 
nephritis/autoimmune nephritis and acute kidney injury, autoimmune arthritis, Sjogren’s 
syndrome, giant cell temporal arteritis and ulcerative colitis); hyperglycemia and diabetes 
mellitus. 
For information on all identified and potential risks with tremelimumab, please always refer to 
the current version of the tremelimumab IB.
In monotherapy clinical studies, AEs reported at an incidence of > 20% include events such as 
diarrhea, nausea, fatigue, pruritus, decreased appetite, rash, vomiting and dyspnea. 

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Approximately 16% of patients experienced an AE that resulted in permanent discontinuation 
of tremelimumab, and approximately 45% of patients experienced an SAE. Please see the 
current version of the IB for a detailed summary of monotherapy data, including AEs, SAEs, 
and CTC Grade 3 to 5 events reported across the tremelimumab program.
A detailed summary of tremelimumab monotherapy AE data can be found in the current 
version of the tremelimumab IB.
1.3.2.3
MEDI4736 + tremelimumab combination therapy
The safety of durvalumab + tremelimumab combination therapy was initially evaluated in the 
ongoing dose escalation and dose expansion Study D4190C00006 in patients with NSCLC, is 
being studied in a number of other ongoing clinical studies in a number of different 
indications and has to date shown a manageable safety and tolerability profile. 
The types of risks with the combination of durvalumab + tremelimumab (based on an 
equivalent durvalumab dose of 20 mg/kg and a tremelimumab dose of 1 mg/kg) are similar to 
those for durvalumab and tremelimumab monotherapy. Emerging data from Study 
D4190C00006, from other studies evaluating the combination, and from combinations of 
other agents in the same class indicate an increased frequency and/or severity of some of these 
immune-mediated toxicities. 
For information on all identified and potential risks with the durvalumab + tremelimumab 
combination, please always refer to the current version of the durvalumab IB.
In durvalumab + tremelimumab combination studies at the dose of durvalumab 20 mg/kg and 
tremelimumab 1 mg/kg, AEs reported at an incidence of > 20% included events such as 
fatigue, diarrhea, nausea, decreased appetite, pruritus, dyspnea, constipation and anemia. 
Please see the current version of the durvalumab IB for a detailed summary of combination 
therapy data, including AEs, SAEs, and CTC Grade 3 to 5 events reported across the 
durvalumab program, including durvalumab in combination with tremelimumab.
Approximately 15% of patients experienced an AE that resulted in permanent discontinuation 
of study drug, and approximately 16% of patients experienced an SAE that was related to 
durvalumab and tremelimumab by the study Investigator.
A detailed summary of durvalumab + tremelimumab combination AE data can be found in the 
current version of the durvalumab IB.
1.3.3
Overall benefit: risk and ethical assessment
There remains a significant unmet medical need for additional treatment options for patients 
with EGFR and ALK wild-type, advanced or metastatic NSCLC who have not received prior 
chemotherapy or any systemic therapy for advanced or metastatic NSCLC. 

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The study design aims to minimize potential risks; intensive monitoring, including early safety 
assessment, is in place for those risks deemed to be most likely based on prior experience with 
the IPs (i.e. MEDI4736 + tremelimumab combination therapy and SoC).
Based upon the available non-clinical and clinical safety data, the limited survival benefit 
provided by the currently available treatment options to patients, the limited life expectancy 
due to malignant disease, the activity seen with MEDI4736 and the MEDI4736 + 
tremelimumab combination therapy in this tumor type, and the strength of the scientific 
hypotheses under evaluation, the MEDI4736 + tremelimumab combination therapy proposed 
for evaluation in this study may have the potential to provide meaningful clinical benefit with 
a manageable safety and tolerability profile by generating durable clinical responses, thereby 
potentially extending survival. 
Therefore, the investigation of the potential therapeutic efficacy of the combination of 
MEDI4736 with tremelimumab in patients with PD-L1-positive and -negative tumors is 
acceptable, and the overall benefit/risk assessment supports the proposed study design.
1.4
Study design
This is a randomized, open-label, multi-center, global Phase III study to determine the 
efficacy and safety of MEDI4736 + tremelimumab combination therapy versus 
platinum-based SoC chemotherapy in the first-line treatment of patients with EGFR and ALK 
wild-type advanced or metastatic NSCLC. Crossover from SoC to MEDI4736 monotherapy or 
MEDI4736 + tremelimumab combination therapy will not be permitted. A schematic diagram 
of the overall study design is shown in Figure 1, and a detailed study flow chart is shown in 
Figure 2.
This study will enroll approximately 1330 patients at sites in North America, Latin America, 
Asia, Europe, and Gulf countries to randomize approximately 800 patients (including 
approximately 336 patients with PD-L1-positive25% NSCLC) to treatment. Global recruitment 
will be complete once approximately 800 patients have been randomized of which 30 patients 
are from mainland China. Once global enrollment is completed, the recruitment will continue 
in mainland China only. A total of approximately 160 patients from mainland China will be 
randomized (refer to Section 8.6 for more details). 
Patients will provide a tumor tissue sample at enrollment (newly acquired or archived sample 
<3 months old) to determine PD-L1 expression status (defined by the 
 
). Mutation assessments for blood tumor mutational burden 
(bTMB) will be performed on the 
.
!
≥20 mut/Mb tumor mutational burden in blood is considered as bTMB high
!
<20 mut/Mb tumor mutational burden in blood is considered as bTMB low
!
≥25% PD-L1 and ≥1% PD-L1 membrane expression in tumoral tissue are considered 
as relevant positive sub-groups
CCI
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
<25% PD-L1 is considered low/negative

<1% PD-L1 is considered negative 
Patients will be randomized in a 1:1 ratio in a stratified manner according to PD-L1 tumor 
expression status (≥25% versus <25%), histology (squamous versus non-squamous), and 
smoking status (never smoker versus ever smoker) to receive treatment with MEDI4736 + 
tremelimumab combination therapy or SoC therapy. Doses and treatment regimens are 
described in Section 7.2. Assessments will be conducted as indicated in Table 2, Table 3, and 
Table 4.
Figure 1
Overall study design a
Randomization stratification factors:
1. PD-L1 tumour expression status (≥25% versus <25%)
2. Histology (squamous versus nonsquamous)
3. Smoking status (never smoker versus ever smoker)
Patient with EGFR and 
ALK wild-type 
advance/metastatic 
NSCLC
N= 1330 patients
Randomization
N = 800 patients
MEDI4736 +tremelimumab
N = 400
Standard of Carec
N = 400
Objective 
Disease 
Progression
Follow 
up for 
OS
Subsequent 
treatmentsb
a       The same study design will be applied to the China cohort. The number of patients in Figure 1 reflects 
those for the global cohort. Enrollment in China will continue after the global cohort enrollment is 
completed
b
Offer of standard chemotherapy per Investigator’s discretion
c
SoC is an Investigator choice from the following: paclitaxel + carboplatin, gemcitabine + cisplatin (or 
carboplatin) (squamous only), pemetrexed + cisplatin (or carboplatin) (non-squamous only), and for eligible 
patients, pemetrexed maintenance (non-squamous only following pemetrexed/platinum induction)

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Figure 2
Study flow chart 
Screening Visita – completion of eligibility assessments (Day -28 to -1)
Day 1: First treatment day for enrolled patients
MEDI4736+tremelimumab Assessment per 
Table 2 Tumor assessmentsb at Screening, 
then every 6 weeks for the first 48 weeks, 
followed by every 8 weeks until confirmed 
progressionc
Standard of Care Assessment per Table 3 
Tumor assessmentsb at Screening, then 
every 6 weeks for the first 48 weeks, 
followed by every 8 weeks until 
confirmed progressionc
Discontinuation 
of treatment due 
to confirmed PD 
or any other 
reason
Disease control after initial 4-
months of combination therapy 
followed by PDc during the 
MEDI4736 monotherapy 
(MEDI4736+tremelimumab)
Discontinuation of treatment 
(for any reason)
Retreatment with MEDI4736+tremelimumab 
Assessments as per Table 2 Tumor assessmentsb at 
Screening, then every 6 weeks for the first 48 
weeks, followed by every 8 weeks until confirmed 
progressionc
Discontinuation of treatment (for any reason)
Follow-up assessments as per Table 4
a
Informed consent of study procedures and tumor biopsy sample may be obtained prior to the 28-day 
screening window, if necessary, in order to permit tumor biopsy sample acquisition and analysis prior to 
randomization
b
Tumor assessments were performed using RECIST 1.1
c
A confirmatory scan is always required following the initial demonstration of PD (See Section 5.1 for more 
information) 

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2.
STUDY OBJECTIVES
All objectives will be evaluated for all patients, unless otherwise indicated.  The primary 
objective is assessment of overall survival (OS) in patients with bTMB ≥ 20mut/Mb.
2.1
Primary objective
Primary objectives:
Outcome measures:
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy compared 
to SoC in terms of OS in patients with bTMB ≥ 
20mut/Mb.
OS 
2.2
Secondary objectives
Secondary objectives:
Outcome measures:
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy compared 
to SoC in terms of OS 
OS in patients with

bTMB ≥ 16mut/Mb NSCLC

bTMB ≥ 12 mut/Mb NSCLC

PD-L1-negative NSCLC

All patients with NSCLC

bTMB < 20 mut/Mb NSCLC

bTMB non-evaluable population
To further assess the efficacy of MEDI4736 + 
tremelimumab combination therapy compared 
to SoC in terms of PFS, ORR, DoR, OS12, 
OS18, OS24, APF12, and PFS2
PFS, ORR, DoR and APF12 using Investigator 
assessments according to RECIST 1.1 in patients 
with 

bTMB ≥ 20mut/Mb NSCLC,

bTMB ≥ 16mut/Mb NSCLC

bTMB ≥ 12mut/Mb NSCLC

PD-L1 negative NSCLC 

All patients with NSCLC
PFS2 using local standard clinical practicea, OS12, 
OS18 and OS24 in patients with 

bTMB ≥ 20mut/Mb NSCLC

bTMB ≥ 16mut/Mb NSCLC

bTMB ≥ 12mut/Mb NSCLC

PD-L1 negative NSCLC

All patients with NSCLC

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Secondary objectives:
Outcome measures:
To assess efficacy of MEDI4736 + 
tremelimumab combination therapy compared 
to SoC in terms of ORR, PFS and OS in 
further PD-L1 defined populations
OS in patients with PD-L1 TC ≥ 25% and PD-L1 TC 
≥ 50%
PFS and ORR using Investigator assessments 
according to RECIST 1.1 in patients with PD-L1 TC 
≥ 25% and PD-L1 TC ≥ 50%.
To further assess efficacy of MEDI4736 + 
tremelimumab combination therapy compared 
to SoC in terms of ORR, PFS and OS 
(including OS12, OS18 and OS24)
OS in patients in analysis sets defined by tTMB 
cutoffs. 
PFS and ORR using Investigator assessments 
according to RECIST 1.1 in patients in analysis sets 
defined by tTMB cutoffs b.
To assess the pharmacokinetics (PK) of 
MEDI4736 + tremelimumab combination 
therapy
Concentration of MEDI4736 and tremelimumab in 
blood and non-compartmental PK parameters, such as 
peak concentration and trough (as data allow; sparse 
sampling)
To investigate the immunogenicity of 
MEDI4736 and tremelimumab
Presence of anti-drug antibodies (ADAs) for 
MEDI4736 and tremelimumab (confirmatory results: 
positive and negative; titers)
a
PFS2 will be defined as the time from the date of randomization to the earliest of the progression event subsequent to 
that used for the PFS endpoint, or death
b
tTMB cutoffs will be defined in the SAP ahead of the DBL from a dataset independent of data collected in this study.
2.3
Safety objective
Safety objective:
Outcome measures:
To assess the safety and tolerability profile of 
MEDI4736 + tremelimumab combination 
therapy compared to SoC in the first-line 
setting for treatment of advanced or metastatic 
NSCLC patients
AEs, physical examinations, laboratory findings, and 
vital signs

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2.4
Exploratory objectives
Exploratory objectives:
Outcome measures:
To investigate the relationship between PK 
exposure and clinical outcomes, efficacy, AEs, 
exploratory biomarkers, and/or safety 
parameters, if deemed appropriate
A graphical and/or a data modeling approach will be 
used to analyze PK exposure and the relationship 
with clinical outcomes, efficacy, AEs, exploratory 
biomarkers, and/or safety parameters, as deemed 
appropriate
To explore potential biomarkers in residual 
biological samples (eg, tumor and blood)
including but not limited to, somatic mutations 
and gene expression in tumor and blood 
samples, which may influence the progression 
of cancer (and associated clinical 
characteristics) and/or prospectively identify 
patients likely to derive increased benefit to 
durvalumab + tremelimumab combination 
therapy 
Correlation of candidate biomarkers with 
response/efficacy to durvalumab + tremelimumab 
combination therapy 
To investigate the relationship between a 
patient’s PD-L1 expression levels in the tumor 
micro-environment and efficacy outcomes with 
durvalumab + tremelimumab, and SoC
Tumoral and/or infiltrating IC expression of PD-L1 
relative to efficacy outcomes (APF12, PFS, and OS)
To investigate the relationship between a 
patient’s tumor mutational burden (TMB) 
measured in tumor and/or blood and efficacy 
outcomes with durvalumab + tremelimumab, 
and SoC
Correlation of bTMB and tTMB
To investigate the relationship between 
biomarkers and clinical outcomes, efficacy, 
AEs, and/or safety parameters. 
OS, PFS, ORR, DoR and related outcome measures, 
e.g. OS12 will be assessed in subgroups defined by 
additional biomarkers e.g. tumor mutation burden 
and/or interferon-gamma signature assessed in tumor 
biopsies or gene expression in blood or circulating 
tumor DNA
A graphical and/or a data modeling approach will be 
used to analyze additional biomarkers and the 
relationship with clinical outcomes, efficacy, AEs, 
and/or safety parameters, as deemed appropriate.
To explore the impact of subsequent anticancer 
therapies on OS
An unbiased estimate of the comparison of OS 
between MEDI4736 + tremelimumab combination 
therapy and SoC in context of patients’ subsequent 
therapies (e.g., patients from the SoC group who 
receive subsequent immuno-oncology treatments)
Note: Exploratory objective analysis may be reported separately from the main Clinical Study Report

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China patients will not undergo bTMB testing and analysis. Details of the China analysis will 
be outlined in detail in the China specific SAP. A further objective to meet China health 
authority requirement is to evaluate consistency in efficacy and safety among Chinese patients 
for benefit-risk assessment of MEDI4736 + tremelimumab combination therapy compared to 
SoC.
3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL 
Each patient must meet all of the inclusion criteria (Section 3.1) and none of the exclusion 
criteria (Section 3.2) for this study. Under no circumstances, will there be exceptions to this 
rule.
3.1
Inclusion criteria
For inclusion in the study, patients should fulfill the following criteria:
1.
Age ≥18 years at the time of screening.
2.
Written informed consent and any locally required authorization (e.g., Health 
Insurance Portability and Accountability Act in the US, European Union [EU] Data 
Privacy Directive in the EU) obtained from the patient/legal representative prior to 
performing any protocol-related procedures, including screening evaluations. (For 
patients aged <20 years and enrolling in Japan, a written informed consent should 
be obtained from the patient and his or her legally acceptable representative).
3.
Histologically or cytologically documented Stage IV NSCLC not amendable to 
curative surgery or radiation (according to Version 7 of the International 
Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology; 
IASLC Staging Manual in Thoracic Oncology).
4.
Patients must have tumors that lack sensitizing EGFR mutation 
(e.g., exon 19 deletion or exon 21 L858R, exon 21 L861Q, exon 18 G719X, or 
exon 20 S768I mutation) and ALK rearrangement. (If a patient has squamous 
histology or is known to have a tumor with a KRAS mutation, then EGFR and ALK 
testing is not required).
5.
No prior chemotherapy or any other systemic therapy for advanced or metastatic 
NSCLC. Patients who have received prior platinum-containing adjuvant, 
neoadjuvant, or definitive chemoradiation for advanced disease are eligible, 
provided that progression has occurred >6 months from last therapy.   
6.
Tumor PD-L1 status, confirmed by a reference laboratory using the 
 
, must be known prior to randomization. As such, all patients must 
be able to undergo a fresh tumor biopsy during screening or to provide an available 
CCI

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tumor sample taken <3 months prior to enrollment. Tumor lesions used for fresh 
biopsies should not be target lesions, unless there are no other lesions suitable for 
biopsy. Fine needle aspirate specimens are not acceptable. Specimens from 
metastatic bone lesions are typically unacceptable unless there is a significant soft 
tissue component. The tumor specimen submitted to establish eligibility should be 
of sufficient quantity to allow for PD-L1 IHC and other exploratory biomarker 
analysis and is preferred in formalin-fixed paraffin embedded blocks.
7.
WHO/ ECOG performance status of 0 or 1 at enrollment.
8.
At least 1 lesion, not previously irradiated, that can be accurately measured at 
baseline as ≥10 mm in the longest diameter (except lymph nodes which must have a 
short axis ≥15 mm) with computed tomography (CT) or magnetic resonance 
imaging (MRI) and that is suitable for accurate repeated measurements as per 
RECIST 1.1 guidelines.
9.
No prior exposure to immune-mediated therapy including, but not limited to, other 
anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 
(anti-PD-L2) antibodies, excluding therapeutic anticancer vaccines.
10.
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

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 × ULN

Calculated creatinine clearance (CL) ≥50 mL/min as determined by Cockcroft-
Gault (using actual body weight) or 24 hour urine collection
Males:
Creatinine clearance = 
Weight (kg) × (140 - Age)
(mL/min)
72 × serum creatinine (mg/dL)
Females:
Creatinine clearance = 
Weight (kg) × (140 - Age) 
× 0.85
(mL/min)
72 × serum creatinine (mg/dL)

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11.
Evidence of post-menopausal status or negative urinary or serum pregnancy test for 
female pre-menopausal patients. Women will be considered post-menopausal if 
they have been amenorrheic 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 amenorrheic for 12 months or more following cessation of exogenous 
hormonal treatments and if they have luteinizing hormone and follicle-
stimulating hormone levels in the post-menopausal range for the institution or 
underwent surgical sterilization (bilateral oophorectomy or hysterectomy) 

Women ≥50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced oophorectomy with last menses 
>1 year ago, had chemotherapy-induced menopause with >1 year interval since 
last menses, or underwent surgical sterilization (bilateral oophorectomy or 
hysterectomy)
12.
An estimated life expectancy of ≥12 weeks.
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site).
2.
Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional 
study.
3.
Mixed small-cell lung cancer and NSCLC histology, sarcomatoid variant.
4.
Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer 
treatment. Concurrent use of hormonal therapy for non-cancer-related conditions 
(e.g., hormone replacement therapy) is acceptable.
5.
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. Note: Local treatment of isolated 
lesions, excluding target lesions, for palliative intent is acceptable.
6.
Major surgical procedure (as defined by the Investigator) within 28 days prior to the 
first dose of IP. Note: Local surgery of isolated lesions for palliative intent is 
acceptable.
7.
History of allogenic organ transplantation.

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8.
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [e.g., 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 (e.g., following Hashimoto syndrome) stable on 
hormone replacement or psoriasis not requiring systemic treatment

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, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina 
pectoris, cardiac arrhythmia, interstitial lung disease (ILD), serious chronic 
gastrointestinal conditions associated with diarrhea or psychiatric illness/social 
situations that would limit compliance with study requirement, substantially 
increase risk of incurring AEs or compromise the ability of the patient to give 
written informed consent.
10.
Medical contraindication to platinum (cisplatin or carboplatin)-based doublet 
chemotherapy.
11.
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 (e.g., cervical 
cancer in situ)
12.
History of leptomeningeal carcinomatosis.
13.
Brain metastases or spinal cord compression unless the patient is stable 
(asymptomatic; no evidence of new or emerging brain metastases) and off steroids 
for at least 14 days prior to start of study treatment. Following radiotherapy and / or 

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surgery, patients with brain metastases must wait 4 weeks following the 
intervention and must confirm stability with imaging before randomization. Patients 
with suspected brain metastases at screening should have a CT/MRI of the brain 
prior to study entry.
14.
History of active primary immunodeficiency 
15.
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 (known positive HBV surface antigen (HBsAg) 
result), hepatitis C, or human immunodeficiency virus (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 hepatitis C (HCV) antibody are eligible only if polymerase 
chain reaction is negative for HCV RNA.
16.
Current or prior use of immunosuppressive medication within 14 days before the 
first dose of MEDI4736 or tremelimumab. The following are exceptions to this 
criterion:

Intranasal, inhaled, topical steroids, or local steroid injections 
(e.g., 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 (e.g., CT scan 
premedication)
17.
Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP. 
Note: Patients, if enrolled, should not receive live vaccine during the study and up 
to 30 days after the last dose of IP.
18.
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 MEDI4736 monotherapy or180 days after 
the last dose of MEDI4736 + tremelimumab combination therapy.
19.
Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients.
20.
Prior randomization or treatment in a previous MEDI4736 and/or tremelimumab 
clinical study regardless of treatment arm assignment.
Procedures for withdrawal of incorrectly enrolled patients are presented in Section 3.4.

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3.3
Patient enrollment and randomization
Investigators should keep a record (i.e., the patient screening log) of patients who entered 
screening. 
At screening (Days -28 to -1), the Investigators or suitably trained delegate will:
1.
Obtain signed informed consent before any study specific procedures 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 screening laboratory and imaging results must 
have been obtained within 28 days of randomization. For patients with a single 
target lesion, if screening biopsy is collected prior to screening imaging for baseline 
tumor assessment, allow approx. 2 weeks before imaging scans are acquired.  
(Informed consent of study procedures may be obtained prior to the 28 day 
screening window in order to permit tumor biopsy sample acquisition which must 
be analyzed prior to randomization).
2.
Obtain a unique 7-digit enrollment number (E-code), through the Interactive Voice 
Response System (IVRS)/Interactive Web Response System (IWRS) in the 
following format (ECCNNXXX: 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 electronic 
case report forms (eCRFs).
3.
Obtain tumor sample and send for centralized PD-L1 testing. (Obtaining the tumor 
biopsy sample should be given the highest priority and, as such, the sample may be 
obtained and sent for PD-L1 expression status evaluation prior to the 28-day 
screening window (after obtaining signed informed consent) in order to permit 
analysis prior to randomization). The sample should be sent only for the patient 
with known EGFR and ALK status (if a patient has squamous histology or is known 
to have a tumor with a KRAS mutation, then EGFR and ALK testing is not 
required).
If EGFR and ALK status is unknown, then the tumor sample (archive or fresh, 
primary or metastatic) should also be used to test for (local or central) EGFR 
mutation and ALK rearrangement in accordance with inclusion criteria 4.
4.
Determine patient eligibility (see Sections 3.1 and 3.2).
At randomization, once the patient is confirmed to be eligible, the Investigator or suitably 
trained delegate will:
1.
Define the SoC treatment (based on the most appropriate option for the patient) that 
the patient would receive if randomized to the SoC group prior to randomization of 

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the patient. This must be completed for all patients. The information will be 
recorded in the IVRS/IWRS system.
Note, for all patients with non-squamous tumor histology would be scheduled to 
receive pemetrexed if randomized to the SoC group, folic acid and vitamin B12 
should commence prior to randomization for up to 7 days, in line with local 
practice. This is to ensure SoC treatment can begin on Day 1.
2.
Obtain a unique randomization number via the IVRS/IWRS. Numbers will start at 
001 and will be assigned strictly sequentially by IVRS/IWRS as patients are eligible 
for entry into the study. The system will randomize the eligible patient to 1 of the 
2 treatment groups. (PD-L1 expression status results must be received from the 
central laboratory by the IVRS/IWRS prior to randomization).
If the patient is ineligible and not randomized, the IVRS/IWRS should be contacted to 
terminate the patient in the system.
Patients will begin treatment on Day 1. Patients must not be randomized and treated unless all 
eligibility criteria have been met.
If a patient withdraws from participation in the study, then his or her 
enrollment/randomization code cannot be reused. Withdrawn patients will not be replaced.
3.4
Procedures for handling incorrectly enrolled patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive IP. There can be no exceptions to this rule. Patients who are enrolled 
but found to not meet all the eligibility criteria must not be randomized, and must not be 
initiated on treatment and must be withdrawn from the study as a screen failure.
When 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 the Study Physician and the Investigator should discuss whether to continue 
or discontinue the patient from treatment. The Study Physician must ensure that all decisions 
are appropriately documented.
3.5
Methods for assigning treatment groups
The actual treatment given to patients will be determined by the randomization scheme in the 
IVRS/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 IVRS/IWRS per country regulations. Randomization codes 
will be assigned strictly sequentially, within each stratum, as patients become eligible for 

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randomization. The IVRS/IWRS will provide the kit identification number to be allocated to 
the patient at the randomization visit. 
3.6
Methods for ensuring blinding
Not applicable; this study is not blinded.
3.7
Methods for unblinding 
Not applicable; this study is not blinded.
3.8
Restrictions
The following restrictions apply while the patient is receiving IP and for the specified times 
before and after:
1.
Female patients of child-bearing potential

Females of childbearing potential who are sexually active with a non-sterilized 
male partner must use at least 1 highly effective method of contraception 
(Table 1) from the time of screening and must agree to continue using such 
precautions for 180 days after the last dose of MEDI4736 + tremelimumab 
combination therapy or 90 days after the last dose of MEDI4736 monotherapy. 
Male partners of a female patient must use a male condom plus spermicide 
throughout this period. Cessation of birth control after this point should be 
discussed with a responsible physician. Not engaging in sexual activity for the 
total duration of the drug treatment and the drug washout period is an acceptable 
practice; however, periodic abstinence, the rhythm method, and the withdrawal 
method are not acceptable methods of birth control. Female patients should also 
refrain from breastfeeding throughout this period
2.
Male patients with a female partner of childbearing potential

Non-sterilized males who are sexually active with a female partner of 
childbearing potential must use a male condom plus spermicide (see Table 1) 
from screening through 180 days after receipt of the final dose of MEDI4736 + 
tremelimumab combination therapy or 90 days after receipt of the final dose of 
MEDI4736 monotherapy. Not engaging in sexual activity is an acceptable 
practice; however, occasional abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of contraception. Male patients 
should refrain from sperm donation throughout this period

It is strongly recommended for the female partner of a male patient to also use 
a highly effective method of contraception throughout this period  

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Note - Females of childbearing potential are defined as those who are not surgically sterile 
(i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-
menopausal. 
Women will be considered post-menopausal if they have been amenorrheic 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 amenorrheic for 12 months or more following cessation of exogenous 
hormonal treatments and if they have luteinizing hormone and follicle-
stimulating hormone levels in the post-menopausal range for the institution or 
underwent surgical sterilization (bilateral oophorectomy or hysterectomy) 

Women ≥50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses >1 
year ago, had chemotherapy-induced menopause with last menses >1 year ago, 
or underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy)
Highly effective methods of contraception, defined as one that results in a low failure rate 
(i.e., less than 1% per year) when used consistently and correctly are described in Table 1. 
Note that some contraception methods are not considered highly effective (e.g., 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).
Patients in the SoC group: Follow the local prescribing information relating to contraception, 
the time limits for such precautions, and any additional restrictions for agents in the SoC 
group.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Edition Number 9.0
Date 20 Jan 2020
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Table 1
Highly effective methods of contraception (<1% failure rate)
Barrier/Intrauterine methods
Hormonal methods

Copper T intrauterine device

Levonorgesterel-releasing intrauterine 
system (e.g., Mirena®)a

Implants: Etonogestrel-releasing 
implants: e.g. Implanon® or Norplan®

Intravaginal Devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices: e.g. NuvaRing® 

Injection: Medroxyprogesterone 
injection: e.g. Depo-Provera® 

Combined Pill: Normal and low dose 
combined oral contraceptive pill

Patch: Norelgestromin/ethinylestradiol-
releasing transdermal system: e.g. Ortho 
Evra®   

Minipill: Progesterone based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only highly 
effective progesterone based pill
a
This is also considered a hormonal method
3.
All patients: Patients should not donate blood or blood components while 
participating in this study and through 180 days after receipt of the final dose of 
MEDI4736 + tremelimumab combination therapy or 90 days after receipt of the 
final dose of MEDI4736 or until alternate anti-cancer therapy is started. 
4.
Restrictions relating to concomitant medications are described in Section 7.7.
3.9
Discontinuation of investigational product
An individual patient will not receive any further IP (MEDI4736 + tremelimumab 
combination therapy or 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 
unless they specifically withdraw their consent to further participation in any study 
procedures and assessments (see Section 3.10.2) 

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 (please see Section 6.10) or as 
defined in the local prescribing information for the SoC agent

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Drug Substance Durvalumab (MEDI4736) and tremelimumab
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Edition Number 9.0
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
Pregnancy or intent to become pregnant

Non-compliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from treatment with IP (e.g., refusal to adhere to 
scheduled visits)

Initiation of alternative anticancer therapy including another investigational agent

Confirmed PD and Investigator determination that the patient is no longer 
benefiting from treatment with IP
3.9.1
Procedures for discontinuation of a patient from investigational product 
At any time, patients are free to discontinue IP without prejudice to further treatment. A 
patient who decides to discontinue IP will always be asked about the reason(s) for 
discontinuation and the presence of any AE. If possible, they will be seen and assessed by an 
Investigator. AEs will be followed up (see Section 6). The Study Physician should be notified 
of any ongoing AE that may delay treatment or necessitate permanent discontinuation of 
treatment.
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment. Patients who are permanently 
discontinued will enter follow-up (see Table 4). 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 an alternative. 
Patients who permanently discontinue study drug for reasons other than objective RECIST 
disease progression should continue to have RECIST scans performed q6w ± 1w for the first 
48 weeks (relative to the date of randomization), and then q8w ± 1w thereafter until confirmed 
objective disease progression/death (whichever comes first) as defined in Table 2 and Table 4.
For patients who permanently completed/discontinued treatment AND have had confirmed 
radiologic progression, additional scans are to be completed per standard practice post-
progression (PFS2 follow-up).
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IVRS/IWRS.
3.10
Criteria for withdrawal of the patient from the study
3.10.1
Screen failures 
Screen failures are patients who do not fulfill the eligibility criteria for the study, and therefore 
must not be randomized. These patients should have the reason for study withdrawal recorded 
as “eligibility criteria not fulfilled” (i.e., patient does not meet the required inclusion/exclusion 
criteria). This reason for study withdrawal is only valid for screen failures (i.e., not 
randomized patients). Patients can be rescreened a single time, but they cannot be 
re-randomized. 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
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3.10.2
Withdrawal of the informed consent
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.
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 (e.g., survival 
contact telephone calls)

Withdrawal to the use of any samples (see Section 5.5.6)
3.10.2.1
Survival status for withdrawn consent and lost to follow up patients
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (see Section 9.3), 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 all the attempts to re-establish 
contact with missing patients throughout the study period. If contact with a missing patient is 
reestablished, the patient should not be considered lost to follow-up and evaluations should 
resume according to the protocol.
At the time of PFS and OS analysis, the survival status of all patients in the full analysis and 
the safety analysis sets should be re-checked, this includes those patients who withdrew 
consent or are classified as “lost to follow up.”    

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Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Edition Number 9.0
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
Lost to Follow up – site personnel should check hospital records, the patients’ current 
physician, and a publicly available death registry (if available) to obtain a current 
survival status in the 7 days following data cut-off. (The applicable CRF 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  in the 7 days following data 
cutoff. (The applicable CRF modules will be updated). 
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, study patients are placed at 
undue risk because of clinically significant findings that meet any of the following criteria:

Meet individual stopping criteria or are otherwise considered significant 

Are assessed as causally related to IP

Are not considered to be consistent with continuation of the study
The study may be stopped if, in the judgment of AstraZeneca, study patients are placed at 
undue risk because of clinically significant findings.
In addition, the study may be stopped based on the findings of the interim safety analysis 
conducted by the Independent Data Monitoring Committee (IDMC) (see Section 6.8).
Regardless of the reason for termination, all data available for the patients at the time of 
discontinuation of follow-up must be recorded in the eCRFs. All reasons for discontinuation 
of treatment must be documented.
In terminating the study, AstraZeneca will ensure that adequate consideration is given to the 
protection of the patients’ interests. If this study is discontinued, all other studies involving 
MEDI4736 or tremelimumab will remain open to enrollment and screening, if deemed 
appropriate by AstraZeneca.
4.
STUDY PLAN AND TIMING OF PROCEDURES 
The procedures for the screening and treatment periods in this study are presented in Table 2
and Table 3, and the procedures for the follow-up period are presented in Table 4.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Edition Number 9.0
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For all treatment arms

Tumor efficacy (RECIST) assessment dates are not affected by dose delays and 
remain as originally scheduled, as they are based on the date of randomization (not 
the date of therapy)

All other scheduled assessments must be performed relative to the start of the 
dosing cycle such that all laboratory procedures, etc. required for dosing should be 
performed within 3 days prior to dosing
For MEDI4736 + tremelimumab combination arms

Patients may delay dosing under certain circumstances

Dosing may be delayed per Toxicity Management Guidelines, due to either an 
immune or a non-immune-mediated AE

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 tumor efficacy 
(RECIST) assessments. Subsequent time between 2 consecutive doses cannot 
be less than 22 days, based on the half-lives of MEDI4736 and tremelimumab 
(see current Investigator Brochures for MEDI4736 and tremelimumab)
Standard of Care Arm:

Patients may delay and subsequently resume dosing per local standard clinical 
practice

If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will occur as soon as feasible

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Edition Number 9.0
Date 20 Jan 2020
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Table 2
Schedule of assessments for MEDI4736 + tremelimumab combination therapy treatment and retreatment 
periods 
Screening
C1
C2
C3
C4
C5
C6
C7
C8 to C12
C13a 
etc
For 
details 
see 
Section
Week
-4 to -1
0
4
8
12
16
20
24
28, 32, 36, 40, 44
48 etc
Day
-28 to -1
1
29
57
85
113
141
169
197, 225, 253, 281, 309
337 etc
Window (days)
NA
+3b
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
Informed consent: study procedures
X c
4.1, 10.4
Study procedures
Physical exam (full)
X
5.2.2
Targeted physical exam (based on symptoms)
X
X
X
X
X
X
X
X
X
5.2.2
Vital signsd
X
X
X
X
X
X
X
X
X
X
5.2.4
ECGe
X
As clinically indicated
5.2.3
Concomitant medications
<----------------------------------------------------------------------------------------------------------------------------->
7.7
Demography, including baseline characteristics 
and tobacco use
X
4.1
Eligibility criteria
X
3.1, 3.2
Laboratory assessments
Clinical chemistry
X
Xf
X
X
X
X
X
X
X
X
Table 5
Hematology
X
Xf
X
X
X
X
X
X
X
X
Table 6
APTT and INR
<----------------------------------------------------------------------------------------------------------------------------->
TSH, free T3, and free T4g
X
Xf
X
X
X
X
X
X
X
X
5.2.1
Urinalysis
X
As clinically indicated
Table 7
Hepatitis B and C and HIV
X
5.2.1
Pregnancy testh
X
X
X
X
X
X
X
X
X
X
5.2.1

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Edition Number 9.0
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Screening
C1
C2
C3
C4
C5
C6
C7
C8 to C12
C13a 
etc
For 
details 
see 
Section
Week
-4 to -1
0
4
8
12
16
20
24
28, 32, 36, 40, 44
48 etc
Day
-28 to -1
1
29
57
85
113
141
169
197, 225, 253, 281, 309
337 etc
Window (days)
NA
+3b
±3
±3
±3
±3
±3
±3
±3
±3
Pharmacokinetics
MEDI4736 PK sample (serum)
Xi
Xi
Xj
5.4.1
Tremelimumab PK sample (serum; combination 
therapy group only)
Xi
Xi
5.4.1
Monitoring
WHO/ECOG performance status
X
X
X
X
X
X
X
X
X
X
5.3.1
AE/SAE assessment
<----------------------------------------------------------------------------------------------------------------------------->
6.3.1
Drug accountability
X
X
X
X
X
X
X
X
X
7.6
Pre-randomization medication
Folic acidk
X
Discontinue as randomized to combination therapy
3.3
IM Vitamin B12k
X
Discontinue as randomized to combination therapy
3.3
IP administration
MEDI4736 (combination therapy)l,m
X
X
X
X
X
X
X
X
X
7.2.1
Tremelimumabl,m
X
X
X
X
7.2.1
Other laboratory assessments and assays
Immunogenicity assessment (ADA sampling to 
identify ADA responses in patient circulation)
X
X
Xr
5.4.2
Tumor biopsy (newly acquired or archived 
<3 months old)
Xc
5.5.1
Archival tumor sample ≥3 months old, if available
n
X
5.5.1
EGFR and ALK test
Xo
3.3
Tumor evaluation (CT or MRI) (RECIST 1.1)p,q
X
q6w±1w for the first 48 weeks relative to the date of randomization, and then q8w±1w 
thereafter
5.1

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Edition Number 9.0
Date 20 Jan 2020
74 (174)
a
Patients who continue on treatment will be assessed in the same manner 
b
Every effort should be made to minimize the time between randomization and starting treatment. (i.e. on the same day after randomization)
c
Informed consent of study procedures and tumor biopsy sample may be obtained prior to the 28-day screening window, if necessary, in order to permit tumor biopsy 
sample acquisition and analysis prior to randomization. The collection of tumor biopsies at the time of progression prior to retreatment is mandated; the Investigator must 
consult with the Study Physician if such sampling is not feasible. The collection of additional biopsies upon progression is strongly encouraged
d
Body weight is recorded along with vital signs
e
Any clinically significant abnormalities detected require a confirmatory ECG
f
If screening laboratory assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need to be repeated at Day 1
g
Except screening visit, free T3 and 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
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 study drug and then every 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
i
Pre-dose same day as infusion and within 1 hour of end of infusion  
j
Pre-dose only
k
To be administered in line with local practice for patients with non-squamous tumors who will receive pemetrexed if randomized to SoC group
l
During the combination portion of treatment, tremelimumab will be administered first; the MEDI4736 infusion will start approximately 1 hour  after the end of the 
tremelimumab infusion. If there are no clinically significant infusion reactions with the first cycle, then for all other cycles, the MEDI4736 can be given immediately after 
the tremelimumab infusion has finished 
m
Results for urea and electrolytes, full blood count, and LFTs must be available before commencing an infusion (within 3 days)
n
Not collected in China
o
For patients with unknown status of ALK and/or EGFR NSCLC (if patients have squamous histology or are known to have a tumor with a KRAS mutation, then EGFR 
and ALK testing is not required)
p
RECIST 1.1 assessments will be performed on CT/MRI images of the chest and abdomen (including liver and adrenal glands). Additional anatomy should be imaged 
based on signs and symptoms of individual patients at baseline and follow-up. Baseline assessments should be performed no more than 28 days before the date of 
randomization and, ideally, should be performed as close as possible and prior to the start of IP. The radiological progression confirmatory scans should be performed no 
less than 4 weeks after the prior assessment of PD and preferably at the next scheduled visit (in the absence of clinically significant deterioration). If an unscheduled 
assessment was performed and the patient has not progressed, every attempt should be made to perform the subsequent assessments at their next scheduled visit 
q
Patients with confirmed PD can continue to receive MEDI4736 + tremelimumab combination therapy at the discretion of the Investigator 
r
MEDI4736 sample only at this time point
Note: For “retreatment”, the same assessments should be done as in the first treatment period, with the exception of the PK, ADA,  which do not need to be collected a second 
time 
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated
Note: “Retreatment” is not permitted after the completion of final analysis for the respective patient.
ADA Anti-drug antibody; AE Adverse event; ALK Anaplastic lymphoma kinase; APTT activated partial thromboplastin time; C Cycle; CT Computed tomography; 
ECG Electrocardiogram; ECOG Eastern Cooperative Oncology Group;  EGFR Epidermal growth factor receptor; HIV Human immunodeficiency virus; IM Intramuscular; 
IP Investigational product; INR international normalized ratio; MRI Magnetic resonance imaging; NSCLC Non-small-cell lung cancer; PD Progressive disease;; ; 
PK Pharmacokinetic(s); RNA Ribonucleic acid; SAE Serious adverse event; q6w Every 6 weeks; q8w Every 8 weeks; SNP Single nucleotide polymorphism; 
T3 Triiodothyronine; T4 Thyroxine; TSH Thyroid-stimulating hormone; w Week; WHO World Health Organization

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
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Date 20 Jan 2020
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Table 3
Schedule of assessments for Standard of Care therapy treatment period 
Screening
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 to C17
C18, C19, 
etc
For 
details 
see 
Section
Week
-4 to -1
0
3
6
9
12
15
18
21
24
27, 30, 33, 36, 39, 42, 45, 48
51, 54, etc
Day
-28 to -1
1
22
43
64
85
106
127
148
169
190, 211, 232, 253, 274, 295, 
316, 337
358, 379, 
etc
Window (days)
NA
+3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
Informed consent: study 
procedures
Xb
4.1, 
10.4
Study procedures
Physical exam (full)
X
5.2.2
Targeted physical exam (based 
on symptoms)
X
X
X
X
X
X
X
X
X
X
X
5.2.2
Vital signsc
X
X
X
X
X
X
X
X
X
X
X
X
5.2.4
ECGd
X
As clinically indicated
5.2.3
Concomitant medications
<-------------------------------------------------------------------------------------------------------------------------------------------------------->
7.7
Demography, including 
baseline characteristics and 
tobacco use
X
4.1
Eligibility criteria
X
3.1, 3.2
Laboratory assessments
Clinical chemistry e,f
X
X
X
X
X
X
X
X
X
X
X
X
Table 5
Hematology e,f
X
X
X
X
X
X
X
X
X
X
X
X
Table 6
APTT and INR
<-------------------------------------------------------------------------------------------------------------------------------------------------------->
TSH, free T3, and free T4g
X
X
X
5.2.1
Urinalysis
X
Table 7
Hepatitis B and C and HIV
X
5.2.1
Pregnancy testh
X
As clinically indicated
5.2.1

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Edition Number 9.0
Date 20 Jan 2020
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Screening
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 to C17
C18, C19, 
etc
For 
details 
see 
Section
Week
-4 to -1
0
3
6
9
12
15
18
21
24
27, 30, 33, 36, 39, 42, 45, 48
51, 54, etc
Day
-28 to -1
1
22
43
64
85
106
127
148
169
190, 211, 232, 253, 274, 295, 
316, 337
358, 379, 
etc
Window (days)
NA
+3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Monitoring
WHO/ECOG performance 
status
X
X
X
X
X
X
X
X
X
X
X
X
5.3.1
AE/SAE assessment 
<-------------------------------------------------------------------------------------------------------------------------------------------------------->
6.3.1
Pre-randomization medication
Folic acidi
X
Continue in line with local practice
3.3
IM Vitamin B12i
X
Continue in line with local practice
3.3
SoC administration
Platinum-based chemotherapy
X
Cycle q3w
7.2.1
Other laboratory assessments and assays
Tumor biopsy (newly acquired 
or archived <3 months old)
Xb
5.5.1
Archival tumor sample ≥ 
3 months old, if availablek
X
5.5.1
EGFR and ALK test
Xj
3.3
Tumor evaluation (CT or MRI) 
(RECIST 1.1)l
X
q6w ± 1w for the first 48 weeks relative to the date of randomization, and then q8w±1w thereafter
5.1
a
Every effort should be made to minimize the time between randomization and starting treatment. (ie. on the same day after randomization)
b
Informed consent of study procedures and tumor biopsy sample may be obtained prior to the 28-day screening window, if necessary, in order to permit tumor biopsy 
sample acquisition and analysis prior to randomization
c
Before every infusion or administration and as clinically indicated. Body weight is included in vital signs
d
Any clinically significant abnormalities detected require a confirmatory ECG  
e
To be collected q3w prior to the start of infusion and as clinically indicated
f
If screening laboratory assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need to be repeated at Day 1
g
Free T3 and 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
For women of childbearing potential only. A urine or serum pregnancy test is acceptable.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Edition Number 9.0
Date 20 Jan 2020
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i
To be administered in line with local practice for patients with non-squamous tumors who will receive pemetrexed if randomized to SoC group
j
For patients with unknown status of ALK and/or EGFR NSCLC (if patients have squamous histology or are known to have a tumor with a KRAS mutation, then EGFR 
and ALK testing is not required)
k
Not collected in China
l
RECIST 1.1 assessments will be performed on CT/MRI images of the chest and abdomen (including liver and adrenal glands). Additional anatomy should be imaged 
based on signs and symptoms of individual patients at baseline and follow-up. Baseline assessments should be performed no more than 28 days before the date of 
randomization and, ideally, should be performed as close as possible and prior to the start of IP. The radiological progression confirmatory scans should be performed no 
less than 4 weeks after the prior assessment of PD and preferably at the next scheduled visit (in the absence of clinically significant deterioration). If an unscheduled 
assessment was performed and the patient has not progressed, every attempt should be made to perform the subsequent assessments at their next scheduled visit
Note: All assessments on treatment days are to be performed prior to infusion or administration, unless otherwise indicated
ADA Anti-drug antibody; AE Adverse event; ALK  Anaplastic lymphoma kinase; APTT activated partial thromboplastin time; C Cycle; CT Computed tomography; 
ECG Electrocardiogram; ECOG Eastern Cooperative Oncology Group; EGFR  Epidermal growth factor receptor; HIV Human immunodeficiency virus; IM Intramuscular; 
INR international normalized ratio; IP Investigational product; MRI Magnetic resonance imaging; NSCLC  Non-small-cell lung cancer; q6w Every 6 weeks; q8w Every 
8 weeks; PD Progressive disease;; PK Pharmacokinetic(s); RNA Ribonucleic acid; SAE Serious adverse event; SNP Single nucleotide polymorphism; T3 Triiodothyronine; 
T4 Thyroxine; TSH Thyroid-stimulating hormone; w Week; WHO World Health Organization

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Edition Number 9.0
Date 20 Jan 2020
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Table 4
Schedule of assessments for patients who have completed/discontinued treatment with MEDI4736 + 
tremelimumab combination therapy or Standard of Care therapy
Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
12 months and 
every 2 months 
(±2 weeks)
For details 
see Section
30
2
3
4
6
8
10
Physical examination (full)a
X
5.2.2
Vital signs (temperature, respiratory 
rate, blood pressure, and pulse)
X
5.2.4
Weight
X
X
X
X
5.2.4
Pregnancy testb
X
As clinically indicated
5.2.1
AE/SAE assessmentc
X
X
X
6.3.1
Concomitant medications
X
X
X
7.7
WHO/ECOG performance status
At timepoints consistent with tumor assessments; at 30, 60, and 90 days; and then at initiation of subsequent 
anticancer therapyd
5.3.1
Subsequent anticancer therapye; and 
second progression assessmentf,g
<------------------------------------------------------------------------------------------------------------------------------------>
NA
Survival statush
X
X
X
X
X
X
X 
5.1
Hematology
X
X
X
Table 6
Clinical chemistry
X
X
X
Table 5
TSH, free T3, and free T4i
X
5.2.1
PK assessmentj
X
5.4.1
Immunogenicity assessment (ADA 
sampling) to identify ADA responses 
in patient circulationj
X
X
5.4.2
Tumor assessment (CT or MRI)k
q6w ± 1w for the first 48 weeks (relative to the date of randomization), and then q8w ± 1w thereafter until 
confirmed objective disease progression/death (whichever comes first). Additional scans to be completed per 
standard practice post-progression.
5.1
a
Physical exams are described in Section 5.2.2
b
For women of childbearing potential only. A urine or serum pregnancy test is acceptable
c
The AE/SAE follow-up for SoC is only 30 days

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d
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
e
Details of any treatment for NSCLC (including surgery) post the last dose of IP must be recorded in the eCRF. At minimum, collect the start date and description of the 
subsequent anticancer therapy 
f
PFS2 assessment will be performed by the Investigator and defined according to local standard clinical practice and may involve any of the following: objective 
radiological imaging, symptomatic progression, or death 
g
For patients who discontinue their assigned IP following confirmed progression, available readings of CT/MRI from local practice will be collected from patients’ 
medical charts while information on subsequent anticancer treatment and/or PFS2 is collected
h
Patients may be contacted in the week following data cut-offs to confirm survival status. Details of any treatment for NSCLC (including surgery) post the last dose of IP 
must be recorded in the eCRF
i
Free T3 and free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system
j
For patients in the MEDI4736 + tremelimumab combination therapy group only. The follow-up samples (3 and 6 months) for each molecule is relative to the respective 
last dose
k
Only for patients yet to progress, RECIST 1.1 assessments will be performed using CT/MRI assessments of the chest and abdomen (including liver and adrenal glands). 
Additional anatomy should be imaged based on signs and symptoms of individual patients. The confirmatory scans should preferably be performed no less than 4 weeks 
after the initial assessment of PD and preferably at the next scheduled visit (in the absence of clinically significant deterioration). If an unscheduled assessment was 
performed and the patient has not progressed, every attempt should be made to perform the subsequent assessments at their scheduled visits (relative to the date of 
randomization). All confirmatory scans should be recorded on the database 
ADA Anti-drug antibody; AE Adverse event; CT Computed tomography; ECOG Eastern Cooperative Oncology Group; eCRF electronic case repot form; IP Investigational 
product; MRI Magnetic resonance imaging; NA Not applicable; NSCLC Non-small-cell lung cancer; PD Progressive disease; q6w Every 6 weeks; q8w Every 8 weeks; 
RECIST Response Evaluation Criteria In Solid Tumors; SAE Serious adverse event; T3 Triiodothyronine; T4 Thyroxine; TSH Thyroid-stimulating hormone; w Week; 
WHO World Health Organization

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4.1
Enrollment/screening period
All screening and enrollment procedures will be performed according to the assessment 
schedule in Table 2 and Table 3. Demographic data and other characteristics will be recorded 
including date of birth or age, gender, smoking history, and race/ethnicity, according to local 
regulations. A standard medical and surgical history will be obtained.
Written informed consent and any locally required privacy act document authorization must 
be obtained prior to performing any protocol-specific procedures, including screening/baseline 
evaluations. 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 screening laboratory and imaging results must be obtained within 28 days of 
randomization. All patients will be required to provide consent to supply a sample of their 
tumor (archived or newly acquired biopsy) for entry into this study. This consent is included 
in the main patient informed consent form (ICF). 
Screening evaluations may be performed over more than 1 visit.
The timing of vital sign assessments should be such that it allows the blood draw (e.g., PK 
blood sample) to occur at the timepoints indicated in Table 2 and Table 3.
4.2
Treatment period
All procedures to be conducted during the treatment period will be performed according to the 
assessment schedule (see Table 2 and 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 (e.g., PK blood 
sample) to occur at the timepoints indicated in Table 2 and Table 3.
4.3
Follow-up period
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 
Table 4).
Whenever vital signs, electrocardiograms (ECGs), 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 (e.g., PK blood sample) to occur at the timepoints indicated in Table 4.

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5.
STUDY ASSESSMENTS
A Web-Based Data Capture (WBDC) system will be used for data collection and query 
handling. The Investigator will ensure that data are recorded on the eCRFs as specified in this 
study protocol and in accordance with the instructions provided.
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
the provision of answers to data queries according to the Clinical Study Agreement (CSA). 
The Investigator will sign the completed eCRFs. A copy of the completed eCRFs will be 
archived at the study site.
5.1
Efficacy assessments
This study will evaluate the primary endpoint of OS. In addition, RECIST 1.1 criteria will be 
used to assess patient response to treatment by determining PFS, ORR, DoR, and APF12 
using Investigator assessments. The RECIST 1.1 guidelines for measurable, non-measurable, 
target, and non-target lesions and the objective tumor response criteria (CR, PR, SD, or PD) 
are presented in Appendix D. PFS2 defined by local standard clinical practice will also be 
evaluated.
Tumor assessments utilize images from CT (preferred) or MRI, each preferably with IV 
contrast, of the chest and abdomen including the entire liver and both adrenals, collected 
during screening/baseline and at regular (follow-up) intervals during study treatment. Any 
other areas of disease involvement should be additionally imaged based on the signs and 
symptoms of individual patients. 
The RECIST 1.1 guidelines (Appendix D) provide a method of assessment of change in tumor 
burden in response to treatment. Screening/Baseline imaging should be performed no more 
than 28 days before start of study treatment, and ideally should be performed as close as 
possible to and prior to the start of study treatment. The RECIST 1.1 assessments of baseline
images identify target (defined measurable) and non-target lesions, and each lesion (and any 
new lesion) is evaluated in subsequent, on-treatment follow-up images. This allows 
determination of follow-up target lesion response, non-target lesion response, and overall 
time-point tumor responses (CR, PR, SD, PD or NE).
Efficacy for all patients (all cohorts) will be assessed on images collected q6w ±1w for the 
first 48 weeks relative to the date of randomization, and q8w ± 1w thereafter until confirmed 
objective disease progression or off-study. It is important to follow the assessment schedule as 
closely as possible [refer to the study plans in Table 2, and Table 3 (screening and treatment 
period), and Table 4 (follow up)]. If an unscheduled imaging assessment is performed and the 
patient has not progressed, every attempt should be made to perform the subsequent 
assessments at his or her next regularly scheduled imaging visit.
According to RECIST 1.1 modified for confirmation of progression, a confirmatory scan is 
required following an overall time point assessment of progression, preferably at the next 
scheduled imaging visit and no earlier than 4 weeks after the previous assessment of PD in the 

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absence of clinically significant deterioration. Treatment will continue between the initial 
assessment of progression and confirmation for progression.
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) after the 
initial assessment of progression, then the patient should continue to be followed with 
scheduled imaging until confirmed objective disease progression.
Confirmation of progression guidelines are set for the following reasons: 

For patient management and treatment decisions

In the absence of significant clinical deterioration, to promote the collection of 
additional scans after the first radiologic RECIST 1.1 assessment of progressive 
disease (PD) in order to distinguish pseudo-progression from true radiologic 
progression, also known as RECIST 1.1 modified for confirmation of progression

When scans are evaluated by Investigator and by BICR, to reduce informative 
censoring by Investigator assessments (Investigator assesses PD at a time-point 
earlier than does BICR)
Confirmed objective disease progression refers to either of the following scenarios: 1. clinical 
progression/deterioration confirmed by a radiological scan if clinically feasible; or 2. in the 
absence of significant clinical deterioration, radiologic PD by RECIST 1.1 followed by a 
second radiologic confirmation scan with PD assessed according to the specific confirmation 
of progression criteria listed below. RECIST 1.1 modified for confirmation of progression 
refers to the second scenario above. The confirmatory scan should occur preferably at the next 
scheduled imaging visit and no earlier than 4 weeks following the date of the immediate prior 
assessment of RECIST 1.1 PD.
Immediate prior radiologic progression would be considered confirmed if any the following 
criteria are met in the confirmatory scan:

≥20% increase in the sum diameters of target lesions (TLs) compared with the nadir 
at 2 consecutive visits, with an absolute increase of at least 5 mm in sum of 
diameters compared to nadir

and/or significant progression (worsening) of non-target lesions (NTLs) and/or of 
pre-existing new lesions at the confirmatory scan time-point compared with the 
immediate prior time-point (Note: Pre-existing new lesions are evaluated as NTLs 
at the confirmatory scan time-point)

and/or additional new unequivocal lesions at the confirmatory scan time-point
NOTE: In order to have confirmed objective disease progression, there should be two
consecutive PD’s, the first PD by RECIST 1.1 and the second PD using the confirmation of 
progression criteria (above). If the first PD by RECIST 1.1 is not confirmed, continue with 

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assessments until the next PD by RECIST 1.1, which in turn will need its own immediate 
subsequent confirmation scan.
In the absence of significant clinical deterioration, treatment with study drug may continue 
between the initial assessment of progression and the scan to confirm progression.
If the confirmation scan confirms progression, then the date of the prior scan with PD should 
be declared as the date of progression.
If progression is not confirmed, in the absence of significant clinical deterioration, then the 
patient should continue study drug and on-treatment assessments until the next PD which will 
also require a follow-up confirmation scan. If the first PD is not confirmed by the 
immediate next scan, then the Investigator should not change the PD assessment of the 
first scan.
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) prior to 
radiologic progression, then the patient should still continue to be followed until confirmed 
objective disease progression.
Following confirmed progression, patients should continue to be followed-up for survival 
every 2 months (8 weeks) as outlined in the follow-up schedules of assessments (Table 4). In 
addition, all patients will be contacted in the week following data cutoff to confirm survival 
status.
Patients in the MEDI4736 + tremelimumab combination arm who complete 4 doses/dosing 
cycles (with clinical benefit per Investigator judgment) and subsequently have PD during 
treatment with MEDI4736 alone may restart combination treatment if they meet eligibility 
criteria for retreatment (see Section 7.2.2).  Patients who restart treatment after PD must have 
a baseline tumor assessment within 28 days of restarting treatment with MEDI4736 + 
tremelimumab combination therapy; all further scans should occur q6w (±7 days) relative to 
the date of randomization until confirmed disease progression.
5.1.1
Central reading of scans
Blinded Independent Central Review assessments are not planned for this study. However, all 
images will be collected centrally so that the scans will be available if such verification 
becomes necessary. Guidelines for imaging collection and storage will be provided in a 
separate document. The management of patients will be based solely upon the results of the 
RECIST assessment conducted by the Investigator.
After data cut-off for the primary analysis of OS in the patients randomized prior to the end of 
global recruitment has been completed, no further central collection of scans is required 
except for sites in China. Any patients in China (either recruited prior to the end of the global 
recruitment or as part of the additional China cohort) should continue with central collection 
of until the cut-off date of China OS analysis.

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5.1.2
Survival assessments
Assessments for survival must be made every 2 months following treatment discontinuation. 
Survival information may be obtained via telephone contact with the patient, 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 data 
cut-off for the primary analysis and all subsequent survival analysis to provide complete 
survival data. These contacts should generally occur within 7 days of the data cut off.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood samples for determination of clinical chemistry and hematology will be taken at the 
times indicated in the assessment schedules and as clinically indicated (see Table 2, Table 3, 
and Table 4). Urine samples for analysis will be taken at screening.
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. Urine 
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).
Pregnancy tests on either urine (human chorionic gonadotropin [hCG]) or blood (serum 
β-hCG) samples will be performed for pre-menopausal women of childbearing potential at 
screening and subsequent visits as specified in the assessment schedule (see Table 2, Table 3, 
and Table 4). Tests will be performed by the hospital’s local laboratory. If results are positive, 
the patient must not start or continue treatment. In the event of a suspected pregnancy during 
the study, the test should be repeated.
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.
The laboratory variables to be measured are presented in Table 5 (clinical chemistry), Table 6
(hematology), and Table 7 (urinalysis).
Other safety tests to be performed at screening include assessment for HBV surface antigen, 
HCV antibodies, HIV antibodies, thyroid-stimulating hormone, free triiodothyronine (T3), and 
free thyroxine (T4).

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Table 5
Clinical chemistry (serum or plasma)
Albumin
Lactate dehydrogenase
Alkaline phosphatase
Lipaseb
ALTa
Magnesiumc
Amylaseb
Potassium
ASTa
Sodium
Bicarbonatec
Total bilirubinb
Calcium 
Total protein
Chloridec
TSH
Creatinine clearancec
T3 freed (reflex)
Creatinine
T4 freed (reflex)
Gamma glutamyltransferasec
Urea or blood urea nitrogen, depending on local practice
Glucose
a
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently. 
If total bilirubin is ≥2x 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 then either lipase or amylase is acceptable
c
Bicarbonate (where available), Chloride, Creatinine clearance, gamma glutamyltransferase, magnesium, 
testing are to be performed at screening, on Day 0 (unless screening laboratory assessments are performed 
within 3 days prior to Day 0), and if clinically indicated
d
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
ALT Alanine aminotransferase; AST Aspartate aminotransferase, TSH Thyroid Stimulating Hormone
Table 6
Hematology
Basophils
Mean corpuscular volume
Eosinophils
Monocytes
Hematocrit
Neutrophils
Hemoglobin
Platelet count
Lymphocytes
Red blood cell count
Mean corpuscular hemoglobin
Total white cell count
Mean corpuscular hemoglobin concentration
Activated partial thromboplastin time and 
international normalized ratioa
a
For coagulation parameters, activated partial thromboplastin time and international normalized ratio are to 
be assessed at baseline and as clinically indicated
Table 7
Urinalysis
Urinalysis should be done at baseline (screening) and then as clinically indicated.

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Bilirubin
Ketones
Blood
pH
Color and appearance
Protein
Glucose
Specific gravity
Note: Microscopy should be used as appropriate to investigate white blood cells and use the high power field for 
red blood cells
If a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, refer to 
Appendix C for further instructions. 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.
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 6.1.4.
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.
5.2.2
Physical examination
Physical examinations will be performed according to the assessment schedules (see Table 2, 
Table 3, and Table 4). Full physical examinations will include assessments of the head, eyes, 
ears, nose, and throat and the respiratory, cardiovascular, GI, urogenital, musculoskeletal, 
neurological, dermatological, hematologic/lymphatic, and endocrine systems. Height will be 
measured at screening only. 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 6.1.4. 
5.2.3
Electrocardiograms
Resting 12-lead electrocardiograms (ECGs) will be recorded at screening and as clinically 
indicated throughout the study (see 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 QTcF value >470 ms, 
2 additional 12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm 
the finding. 
Situations in which ECG results should be reported as AEs are described in Section 6.1.4.

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5.2.4
Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the assessment schedules (see Table 2, Table 3, and Table 4). Body weight is also 
recorded along with vital signs.
First Infusion
For the first infusion day, patients in the MEDI4736 + tremelimumab treatment group will be 
monitored and vital signs collected/recorded in eCRF prior to, during and after infusion of IP 
as presented in the bulleted list below.
BP and pulse will be collected from patients in the MEDI4736 + tremelimumab combination 
therapy group 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 [i.e., the beginning of the infusion])

Approximately 30 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 MEDI4736 and tremelimumab.
Subsequent Infusion
BP, pulse and other vital signs should be measured, collected/recorded in eCRF 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 and as clinically 
indicated. Any clinically significant changes in vital signs should be entered onto an 
unscheduled vital signs CRF page.
Patients in the SoC group will be monitored before every infusion or administration and as 
clinically indicated.
The date and time of collection and measurement will be recorded on the appropriate eCRF. 
Additional monitoring with assessment of vital signs is at the discretion of the Investigator per 
standard clinical practice or as clinically indicated. 
Situations in which vital signs results should be reported as AEs are described in 
Section 6.1.4. For any adverse events of infusion reactions please enter the vital signs values 
into the CRF.

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5.3
Other assessments
5.3.1
WHO/ECOG performance status
WHO/ECOG performance status will be assessed at the times specified in the assessment 
schedules (see Table 2, Table 3, and Table 4) 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 (e.g., 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.
5. Dead
Any significant change from baseline or screening must be reported as an AE.
5.3.2
Other safety assessments
If new or worsening pulmonary symptoms (e.g. dyspnoea) or radiological abnormality 
suggestive of pneumonitis/interstitial lung disease is observed, toxicity management as 
described in detail in the Dosing Modification and Toxicity Management Guidelines (please 
see Section 6.10) will be applied. The results of the full diagnostic workup including high-
resolution computed tomography (HRCT), blood and sputum culture, haematological 
parameters etc will be captured in a separate questionnaire. 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.
5.4
Pharmacokinetics
5.4.1
Collection of samples and determination of drug concentration
Blood samples for determination of MEDI4736 and tremelimumab concentration in serum 
will be obtained according to the assessment schedules (see Table 2 and Table 4). 
Samples for determination of MEDI4736 and tremelimumab concentration in serum will be 
analyzed by a designated third party on behalf of AstraZeneca. Samples will be collected, 
labeled, stored, and shipped as detailed in the Laboratory Manual. Full details of the analytical 
method used will be described in a separate Bioanalytical Validation Report.

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5.4.2
Collection of samples to measure for the presence of ADAs
The presence of ADA will be assessed in serum samples taken according to the assessment 
schedules (see Table 2 and Table 4). 
Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for 
both IPs (MEDI4736 and tremelimumab) using validated assays. Tiered analysis will be 
performed to include screening, confirmatory, and titer assay components, and 
positive-negative cut points previously statistically determined from drug-naïve validation 
samples will be employed.
5.4.3
Storage and destruction of pharmacokinetic/ADA samples
PK and ADA samples will be disposed of a maximum of 15 years after the study ends.
PK and ADA samples may be disposed of or destroyed and anonymized by pooling. 
Additional analysis may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method. Results from such analysis may be reported 
separately from the Clinical Study Report (CSR).
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Validation Report.
Any residual back-up PK samples may be used for future exploratory biomarker research (in 
this case, residual back-up PK samples will be shipped to AstraZeneca or it’s designated 
Biobank; see details in the Laboratory Manual).
PK and ADA amples collected in China will be destroyed after finalization of the 
bioanalytical reports. 
5.5
Biomarker analysis
The patient’s consent to the use of donated biological samples is mandatory. Tissue samples 
will be obtained from all screened patients.
Pre-treatment bTMB and tTMB will be evaluated in all patients with available samples. Data 
will be compared between groups to determine if baseline TMB is prognostic and/or 
predictive of outcomes associated with MEDI4736 + tremelimumab combination therapy vs 
SoC. 
The 
, a next generation sequencing platform, will be used to 
assess the tumor mutational burden in circulating tumor DNA from blood samples at baseline. 
For tissue based tumor mutational burden (tTMB), the assessment will be performed by 
.
Pre-treatment tumor PD-L1 expression will also be evaluated in all randomized patients. Data 
will be compared between groups to determine if baseline PD-L1 expression is prognostic 
CCI
CCI

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and/or predictive of outcomes associated with MEDI4736 + tremelimumab combination 
therapy versus SoC. Baseline tumor requirements are briefly described in Section 5.5.1. 
Based on availability of tissue, additional exploratory biomarkers may be evaluated as 
described in Section 5.5.2. Also, descriptions of exploratory, peripheral measures are 
described in this section. Samples will be obtained according to the assessment schedules 
provided in Table 2, Table 3, and Table 4.
Details for collection, volumes, storage, and shipment of biologic samples are presented in a 
separate Laboratory Manual.
All samples collected for biomarker analysis 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 immunotherapy.
The results may be pooled with biomarker data from other MEDI4736/tremelimumab studies 
to evaluate biological responses across indications and to compare results in monotherapy 
versus combination settings.
5.5.1
Collection of patient samples for stratification by PD-L1 and for expression of 
PD-L1 and Tumor Mutation Burden (TMB)
At screening, there are 2 mandatory options for provisions of tissue to be used for 
determination of eligibility. There is 1 subsequent mandatory provision of tissue at 
progression:

MANDATORY: Provision of a recent tumor biopsy formalin fixed and embedded 
in paraffin. A freshly collected tumor biopsy is strongly preferred; however, if not 
clinically feasible, an archival sample taken less than 3 months prior to screening 
may be submitted
Samples should be collected via a core needle (18 gauge or larger) or be collected 
as an excisional or incisional tumor biopsy sample. 
When tissue is newly obtained for the purpose of entry into this study, 2 cores 
should be placed in formalin and processed to a single paraffin embedded block, as 
described in the Laboratory Manual.
The tumor specimen submitted to establish eligibility should be of sufficient 
quantity to allow for PD-L1 IHC analysis (see the Laboratory Manual). Newly 
acquired or archived specimens with limited tumor content and fine needle aspirates 
are inadequate for defining tumor PD-L1 status.
Tumor lesions used for fresh biopsies should not be the same lesions used as 
RECIST 1.1 target lesions, unless there are no other lesions suitable for biopsy For 
patients with a single target lesion, if screening biopsy is collected prior to 

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screening imaging for baseline tumor assessment, allow approximately 2 weeks 
before imaging scans are acquired
!
MANDATORY: The collection of additional archived tumor tissue block greater 
than 3 months old (formalin-fixed paraffin-embedded) is mandated, where such 
samples exist in a quantity sufficient to allow for analysis. Tumor tissue block is 
preferred. If a tissue block is unavailable, unstained sections from the tissue block 
may be submitted. Please consult the laboratory manual for specific instructions and 
guidelines regarding sections. Sample not collected in China.  
!
MANDATORY: The collection of tumor biopsies at the time of progression prior to 
retreatment is mandated. The Investigator can consult with the Study Physician if 
such sampling is not feasible, but retreatment is indicated. Sample not collected in 
China.
!
OPTIONAL: The collection of additional biopsies upon progression of patients in 
the MEDI4736 + tremelimumab combination therapy group is strongly encouraged. 
Also, the collection of biopsies upon progression for patients in the SoC group is 
optional. Not applicable in China.
!
Additional tumor biopsies collected as part of clinical care (e.g., for mixed 
responses or upon PD) can be submitted for further analysis. Not applicable in 
China.
See the Laboratory Manual for further details of requirements including sample quality 
control and shipping.
A brief description of exploratory tumor markers likely to be explored by IHC, DNA or 
ribonucleic acid (RNA) analysis is provided in Section 5.5.2. 
Plasma sample collected at baseline for biomarker analysis will be used for assessment of 
blood TMB, on which the primary and secondary objectives are based.
The 
 will be used to determine PD-L1 status in this study for 
the purposes of stratification and for the analysis of the original diagnostic sample.
To meet the requirement of Food and Drug Administration (FDA) approval of a companion 
diagnostic, sections of the tumor will be retained at 
 for 
potential additional studies, as requested by the FDA, to support potential test approval.
Tumor Mutational Burden
Tissue TMB will be assessed in tumor tissue using the 
 
, where sufficient tumor sample is available. Blood TMB will be assessed in ctDNA 
from plasma, using the 
 
CCI
CCI
CCI
CCI

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Based on blood TMB or tissue TMB levels, OS, PFS ORR and other outcome variables will 
be evaluated for durvalumab + tremelimumab combination therapy versus SoC therapy in 
patients with high TMB levels and also with low TMB levels according to pre-specified and 
exploratory cut-off points. 
Note: In China ctDNA samples will not be collected, nor will TMB be assayed in tumor 
samples.
5.5.2
Exploratory biomarkers
Tumor samples for exploratory biomarker analysis will be obtained according to the schedules 
presented in Table 2, Table 3, and Table 4 and section 5.5and Laboratory manual. Details for 
collection, storage, and shipment of biologic samples are presented in a separate Laboratory 
Manual. 
OS, PFS, ORR, DoR and related outcome measures, e.g. OS12 will be assessed in subgroups 
defined by additional biomarkers e.g.  interferon-gamma signature assessed in tumor biopsies 
or gene expression in blood or circulating tumor DNA.
Note that samples will be obtained from patients randomized to each treatment group. 
Comparisons will be made between baseline measures to determine if biomarkers (or 
combination of markers) are prognostic or predictive of outcomes associated with MEDI4736 
+ tremelimumab combination therapy versus SoC therapies, subgrouped by histology.
Additional sample collections and analysis may be completed at select study sites by site-
specific amendment. All samples collected for such exploratory analysis 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.
Tumor markers
Tissue obtained as part of screening procedures and for establishing PD-L1 expression status 
will be analyzed for additional markers by IHC. A primary goal is to measure cluster of 
differentiation (CD)8 and CD4/FoxP3 protein expression in an effort to enumerate cytotoxic 
versus regulatory T cells. Based on availability of tissue, a panel of additional, immune-
relevant markers expressed on tumor-infiltrating lymphocytes or on tumour cells may be 
assessed. Markers of special interest include, but are not limited to, Ox40, GITR, PD-L2, Tim-
3, CD137, and Lag 3.
Other tissue-based approaches may be pursued including RT-QPCR and in situ hybridization 
(e.g., for detection of IFN gamma signaling genes such as CXCL9, CXCL10, and IFN gamma 
itself), and/or somatic mutation detection methodologies.
IFN gamma is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer 
and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to 
anti–PD-1/PD-L1 therapies in NSCLC (Higgs et al 2017) and other settings (Ayers et al 

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2017).  Therefore, baseline expression of IFN gamma signaling genes such as CXCL9, 
CXCL10, and IFN gamma itself are of interest as a biomarker of response to MEDI4736 + 
tremelimumab.
Management of biomarker data
The biomarker data will have unknown clinical significance. AstraZeneca will not provide 
biomarker research results 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 study protocol.
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.
5.5.3
Storage, re-use, and destruction of biological samples
Samples will be stored for a maximum of 15 years from the end of study, after which they will 
be destroyed. Summaries and analysis 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 
MEDI4736 or tremelimumab to generate hypotheses to be tested in future research.
Tumour samples collected in China for PD-L1 testing will be destroyed or repatriated 
maximally 5 years after study drug is approved for marketing in China.
5.5.4
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 B “IATA 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.
5.5.5
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 sample shipments.

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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 sample 
shipments.
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 biobank and will 
be registered with the AstraZeneca Biobank Team during the entire life cycle.
This does not apply to samples collected in China.
5.5.6
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 patients’ 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 laboratory(ies) holding the samples is/are immediately informed 
about the withdrawn consent and that samples are disposed of or destroyed, the 
action is documented.

Ensure that the patient and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the action is 
documented and the study site is informed.
5.6
Pharmacogenetics (Not applicable)
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.

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6.1
Definition of adverse events
An AE is the development of an undesirable medical condition (other than progression of the 
malignancy under evaluation) or the deterioration of a pre-existing medical condition during 
or following exposure to a pharmaceutical product, whether or not the condition is considered 
to be causally related to the product. An undesirable medical condition can be a symptom 
(e.g., nausea or chest pain), sign (e.g., tachycardia or enlarged liver), or the abnormal result of 
an investigation (e.g., laboratory findings or ECG). In clinical studies, an AE can include an 
undesirable medical condition occurring at any time, including run-in or washout periods, 
even if no IP has been administered.
The term “AE” is used to include both serious and non-serious AEs.
6.1.1
Causality collection
The Investigator will assess the causal relationship between the IPs 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 investigational product?”
For SAEs, causal relationship will also be assessed for other medications 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 is found in Appendix A.
6.1.2
Relationship to protocol procedures
The Investigator is also required to provide an assessment of the relationship of SAEs to 
protocol procedures on the SAE report form. This includes both non-treatment–emergent 
(i.e., SAEs that occur prior to the administration of IP or SoC) and treatment-emergent SAEs. 
A protocol-related SAE may occur as a result of a procedure or intervention required during 
the study (e.g., blood collection). The following guidelines should be used by Investigators to 
assess the relationship of SAEs to the protocol:

Protocol related: The event occurred due to a procedure or intervention that was 
described in the protocol for which there is no alternative etiology present in the 
patient’s medical record

Not protocol related: The event is related to an etiology other than the procedure or 
intervention that was described in the protocol. The alternative etiology must be 
documented in the study patient’s medical record
6.1.3
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 personnel: “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 eCRF. 
When collecting AEs, the recording of diagnoses is preferred, when possible, to recording a 

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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.
6.1.4
Adverse events based on examinations and tests
The results from protocol-mandated laboratory tests and vital signs measurements will be 
summarized in the 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 IPs.
If deterioration in a laboratory value or vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory result 
or vital sign will be considered as additional information. Whenever possible, the reporting 
Investigator should use the clinical rather than the laboratory term (e.g., anemia versus low 
hemoglobin value). In the absence of clinical signs or symptoms, clinically relevant 
deteriorations in non-mandated parameters should be reported as AEs.
Deterioration of a laboratory value that is unequivocally due to disease progression 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.
6.1.5
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 C for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s law.
6.1.6
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP is being studied. It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease. The development of new 
or progression of existing metastasis to the primary cancer under study should be considered 
as disease progression and not an AE. Events that are unequivocally due to disease 
progression should not be reported as an AE during the study.
6.1.7
New cancers
The development of a new cancer 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.

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6.1.8
Deaths
All deaths that occur during the study, 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 progression should be reported to the Study 
Monitor/Physician at the next monitoring visit and should be documented in the 
eCRF. It should not be reported as an SAE

Where death is not due (or not clearly due) to 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. 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. 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 
Drug 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 study drug should be documented in the Statement of Death page. If the death 
occurred as a result of an event that started post the defined safety follow up period and the 
event is considered to be due to a late onset toxicity to study drug then it should also be 
reported as an SAE.
6.1.9
Safety Data to be Collected Following the Final DCO of the Study
For patients continuing to receive MEDI4736/tremelimumab treatment after scheduled DCO 
for final analysis of the global cohort and database lock, it is recommended that the patients 
continue the scheduled site visits and investigators monitor the patient’s safety laboratory 
results prior to and periodically during treatment with MEDI4736/tremelimumab to manage 
AEs in accordance with the MEDI4736/tremelimumab toxicity management guidelines 
(please see Section 6.10). All data post the scheduled DCO for final analysis for global cohort 
and database lock will be managed as per one of the options listed in “Post Data Cut off” part 
of Section 7.2.2. For those patients from China who are in Global cohort, final DCO and DBL 
will be when the China tail conducts it’s final DCO and DBL.
All SAEs that occur in patients still receiving MEDI4736/tremelimumab treatment (or within 
the 90 days following the last dose of MEDI4736/tremelimumab treatment) post the final 
DCO and database closure must be reported as detailed in Section 6.4
6.2
Definitions of serious adverse event
An SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout, or 
follow-up) that fulfills one or more of the following criteria:

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
Results in death

Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability or incapacity or substantial disruption 
of the ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above
For further guidance on the definition of an SAE, see Appendix A.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
AEs and SAEs will be collected from the time of the patient signing the informed consent 
form until the follow-up period is completed (90 days after the last dose of MEDI4736 +/-
tremelimumab and 30 days after last dose of SoC). AEs and SAEs collected prior to 
randomization will be reported as pre-randomization AEs and SAEs. 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 study drug then it should be reported as an AE or SAE as applicable.
6.3.2
Follow-up of unresolved adverse events
During the course of the study, all AEs and SAEs should be proactively followed up for each 
patient for as long as the event is ongoing. Every effort should be made to obtain a resolution 
for all events, even if the events continue after the patient has discontinued study drug or the 
study has completed.
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, but without further recording in the eCRF. 
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.
6.3.3
Variables 
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

The maximum CTCAE grade reported

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
Changes in CTCAE grade

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

Whether the AE caused the patient’s withdrawal from the study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date the AE met criteria for SAE

Date the Investigator became aware of the SAE

Seriousness criteria fulfilled

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 in relation to other medication, as explained in Section 6.1.1

Description of the AE
The grading scales found in the revised NCI CTCAE Version 4.03 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 4.03 can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity, whereas seriousness is defined by the criteria in Section 6.2. 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 it is not an SAE unless it meets the criteria 

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shown in Section 6.2 On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke, but it would be an SAE if it satisfies the criteria 
shown in Section 6.2
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not they are considered causally related to the IPs or 
to any study procedure. All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then the Investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1 day, i.e., immediately, but 
no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work 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 in which important or relevant information is missing, active 
follow-up is undertaken immediately. The Investigator or other site personnel will inform
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day, i.e. immediately, but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigator or other site personnel indicates that an AE is serious in the WBDC 
system, an automated e-mail alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel will 
report an SAE to the appropriate AstraZeneca representative by telephone.
After the final DCO for the study, any SAEs occurring whilst the patient is either still 
receiving MEDI4736 or MEDI4736 + tremelimumab or in the 90 day safety follow up period 
after receiving the last dose of MEDI4736 or MEDI4736+tremelimumab are to be recorded in 
a paper form and reported directly 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.
The AstraZeneca representative will advise the Investigator or study site personnel how to 
proceed.
The reference documents for the definition of expectedness or listedness are the IBs for 
MEDI4736 and tremelimumab.
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. A medical emergency usually 
constitutes an SAE and is to be reported as such.

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6.5
Adverse Events of Special Interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. 
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 investigational product.
AESIs for MEDI4736 ± tremelimumab 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 
MEDI4736 monotherapy and combination therapy. An immune-mediated adverse event 
(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 alternate aetiology.
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 in regards to an event being an imAE, the Investigator 
should promptly contact the Study Physician.
AESI/imAEs observed with anti PD-L/PD-1 agents such as MEDI4736 and MEDI4736 in 
combination with tremelimumab include pneumonitis, hepatitis, diarrhea/colitis, intestinal 
perforation, endocrinopathies (hypo- and hyper-thyroidism, adrenal insufficiency, 
hypophysitis/hypopituitarism and Type 1 diabetes mellitus), nephritis, rash/dermatitis, 
myocarditis, myositis/polymyositis, pancreatitis and rare/less frequent imAEs including 
neuromuscular toxicities such as myasthenia gravis and Guillain-Barre syndrome.
Other inflammatory responses that are rare / less frequent with a potential immune-mediated 
aetiology include, but are not limited to pericarditis, sarcoidosis, uveitis and other events 
involving the eye, skin, haematological, 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 aetiology are also considered AESIs.
Further information on these risks (e.g. presenting symptoms) can be found in the current 
version of the MEDI4736 and tremelimumab Investigator’s Brochures. More specific 
guidelines for their evaluation and treatment are described in detail in the Dosing Modification 
and Toxicity Management Guidelines (see Section 6.10). 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 
study drug/study regimen by the reporting investigator.

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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 6.4
6.6
Overdose
Use of IP 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 IP, and possible symptoms 
of overdose are not established. 

An overdose with associated AEs will be recorded as the AE diagnosis or 
symptoms in the relevant AE modules of the eCRF and in the Overdose eCRF 
module.

An overdose without associated symptoms will only be reported in the Overdose 
eCRF module.
If an overdose of an AstraZeneca IP occurs in the course of the study, then the Investigator or 
other site personnel will inform appropriate AstraZeneca representatives immediately, or no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work 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; see Section 6.4. 
For other overdoses, reporting must occur within 30 days.
For patients randomized to the SoC arm, please refer to the local prescribing information for 
the treatment of cases of overdose. If any overdose is attributed to an AE or SAE please 
record the AE/SAE diagnosis or symptoms in addition to action taken in the relevant AE 
modules only of the eCRF.
6.7
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

Pregnancy discovered before the study subject has received any study drugs.

Pregnancy of a female partner of male subject, providing there is no restriction of 
male subject fathering a child.
6.7.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the IPs should be discontinued 
immediately.
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 

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abnormalities or 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 
should inform the appropriate AstraZeneca representatives within 1 day, i.e., immediately, but 
no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 to 
5 calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
6.7.2
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
180 days after the last dose of MEDI4736 + tremelimumab combination therapy or 90 days 
after the last dose of MEDI4736 monotherapy, whichever is the longer time period. 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 180 days after the 
last dose of MEDI4736 + tremelimumab combination therapy or 90 days after the last dose of 
MEDI4736 alone, whichever is the longer time period 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 Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use.
6.8
Study governance and oversight
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 study protocol and letters to 
Investigators.
An IDMC comprised of independent experts will be convened and will meet approximately 
6 months after the study has started or after the first 30 patients have been randomized, 
whichever occurs first, to review safety assessments and make recommendations to continue, 

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amend, or stop the study based on safety findings. The committee will meet approximately at 
every 6 months thereafter. 
Full details of the IDMC procedures and processes, can be found in the IDMC Charter.
6.9
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 and within 30 days for all other medication errors.
The definition of a Medication Error can be found Appendix A (A 1)
6.10
Management of IP-related toxicities
The following general guidance should be followed for management of toxicities.

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 4.03. 
6.10.1
Specific toxicity management and dose modification information –
Durvalumab and durvalumab + tremelimumab
Comprehensive toxicity management guidelines (TMGs) have been developed to assist 
investigators with the recognition and management of toxicities associated with use of the 
immune-checkpoint inhibitors, durvalumab [MEDI4736] (PD-L1 inhibitor) and 
tremelimumab (CTLA-4 inhibitor). Given the similar underlying mechanism of toxicities 
observed with these two compounds, these TMGs are applicable to the management of 
patients receiving either drug as monotherapy or both drugs in combination. Additionally, 
these guidelines are applicable when either drug is used alone or both drugs are used in 
combination and, also other anti-cancer drugs (i.e., antineoplastic chemotherapy, targeted 
agents) are administered concurrently or sequentially as part of a protocol-specific treatment 
regimen. The TMGs provide information for the management of immune mediated reactions, 

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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 checkpoint inhibitor-specific dose modifications (including discontinuation) 
and treatment interventions. Investigators are advised however to use local practice guidelines 
and consult local references for the management of toxicities observed with other anti-cancer 
treatment.
The most current version of the TMGs is provided to the investigative site as an Annex to 
Protocol document 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),” and is maintained within the Site Master File. In addition, a current version of 
TMGs is available through the following link: 
. Please contact the 
clinical study associate for information on how to gain access to this website.
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 
and tremelimumab should be permanently discontinued (see Section 3.9 of this protocol and 
the TMGs). Following the first dose of IP, subsequent administration of durvalumab and 
tremelimumab 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 
durvalumab monotherapy and the durvalumab + tremelimumab regimen by the reporting 
Investigator.
6.10.2
Specific toxicity management and dose modification information – Standard of 
Care
Investigators should follow local standard clinical practice regarding dose modifications for 
agents used in the SoC arm. For specific information regarding the individual agent used in 
this study, please refer to the local prescribing information for the relevant agent.
CCI

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7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
AstraZeneca will supply MEDI4736 and tremelimumab, while the SoC treatments (paclitaxel 
+ carboplatin, gemcitabine + cisplatin, gemcitabine + carboplatin, pemetrexed + cisplatin, 
pemetrexed + carboplatin, and pemetrexed maintenance) will be supplied locally (Table 8). 
Table 8
List of investigational products for this study
Investigational product
Dosage form and strength
Manufacturer
MEDI4736
50 mg/mL, solution, IV
MedImmune
Tremelimumab
20 mg/mL, solution, IV
MedImmune
SoC
Paclitaxela
IV (as sourced locally)
Sourced locally
Carboplatina
IV (as sourced locally)
Sourced locally
Gemcitabinea
IV (as sourced locally)
Sourced locally
Cisplatina
IV (as sourced locally)
Sourced locally
Pemetrexeda
IV (as sourced locally)
Sourced locally
a
Under certain circumstances when local sourcing is not feasible, a SoC treatment may be supplied centrally 
through AstraZeneca
7.1.1
MEDI4736
MEDI4736 will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution. The solution contains 50 mg/mL MEDI4736, 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume 
(w/v) polysorbate 80; it has a pH of 6.0 and density of 1.054 g/mL. The nominal fill volume is 
10 mL. Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be 
frozen. Drug product should be kept in original packaging until use to prevent prolonged light 
exposure.
Preparation of MEDI4736 doses for administration with an intravenous bag
Preparations are to be in accordance with the study-specific drug handling instructions.
7.1.2
Tremelimumab
Tremelimumab will be supplied by AstraZeneca as a 400 mg vial solution for infusion after 
dilution. The solution contains 20 mg/mL tremelimumab, 20 mM histidine/histidine-
hydrochloride, 222 mM trehalose dihydrate, 0.27 mM disodium edetate dihydrate and 0.02% 
(w/v) polysorbate 80; it has a pH of 5.5 and density of 1.034 g/mL. The nominal fill volume is 
20 mL. Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be 

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frozen. Drug product should be kept in original container until use to prevent prolonged light 
exposure.
Product preparation and reconstitution of tremelimumab
Preparations are to be in accordance with the study-specific drug handling instructions.
7.1.3
Standard of Care treatment
Each SoC agent will be sourced as commercially available material/locally sourced, 
prescribed according to local regulations, 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, and SoC will be supplied centrally by 
AstraZeneca. This will be labeled with local language translated text in accordance with 
regulatory guidelines.
7.2
Dose and treatment regimens
Patients will be randomized in a 1:1 ratio to receive treatment with MEDI4736 + 
tremelimumab combination therapy or SoC.
7.2.1
Treatment regimens
MEDI4736 + tremelimumab combination therapy
Patients in the MEDI4736 + tremelimumab combination therapy group will receive 20-mg/kg 
MEDI4736 via IV infusion q4w for up to 4 doses/cycles and 1-mg/kg tremelimumab via IV 
infusion q4w for up to 4 doses/cycles, and then continue 20-mg/kg MEDI4736 q4w starting 
on Week 16 (see Figure 3). Dosing outside the window should be discussed with the Study 
Physician. Tremelimumab will be administered first. MEDI4736 infusion will start 
approximately 1 hour after the end of tremelimumab infusion. Standard infusion time for each 
drug is 60 minutes (± 5 minutes).  Less than 55 minutes is considered a deviation.  In the event 
that there are interruptions during infusion, the total allowed time should not exceed 8 hours at 
room temperature. The duration will be approximately 1 hour for an infusion. A 1-hour 
observation period is recommended after the first infusion of MEDI4736 and tremelimumab. 
If no clinically significant infusion reactions are observed during or after the first cycle, 
subsequent infusion observation periods can be at the Investigator’s discretion (suggested 30 
minutes after each MEDI4736 and tremelimumab infusion). 

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Figure 3
MEDI4736 + tremelimumab combination therapy dosing scheme
Q4W: every 4 weeks.
Standard of Care treatment
Patients in the SoC group will receive 1 of the following treatments until documented PD 
(Unconfirmed and confirmed), initiation of alternative anticancer therapy, unacceptable 
toxicity, withdrawal of consent to continued treatment, or other reasons to discontinue 
treatment criterion occur:

Paclitaxel + carboplatin: Paclitaxel 200 mg/m2 and carboplatin area under the curve 
(AUC) 5 or 6 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles or 
until documented PD

Gemcitabine + cisplatin (squamous patients only): Gemcitabine 1000 or 
1250 mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + cisplatin 75 or 
80 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles or until 
documented PD 

Gemcitabine + carboplatin (squamous patients only): Gemcitabine 1000 or 
1250 mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + carboplatin 
AUC 5 or 6 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles or until 
documented PD 

Pemetrexed + cisplatin (non-squamous patients only): Pemetrexed 500 mg/m2 and 
cisplatin 75 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles 
or until documented PD. Non-squamous patients who have not progressed after 
4 cycles will be eligible for pemetrexed maintenance therapy

Pemetrexed + carboplatin (non-squamous patients only): Pemetrexed 500 mg/m2
and carboplatin AUC 5 or 6 via IV infusion on Day 1 of each 21-day cycle, for 4 to 
6 cycles or until documented PD. Non-squamous patients who have not progressed 
after 4 cycles will be eligible for pemetrexed maintenance therapy
For all SoC therapies, a particular treatment (paclitaxel, gemcitabine, cisplatin, carboplatin, or 
pemetrexed) will not be used in patients who have experienced recurrence or progression of 
disease within 6 months of prior multimodal therapy using that particular treatment. 

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In addition to CR and PR, a confirmatory scan is always required following the initial 
demonstration of PD for all patients in the SoC group, even if a subsequent treatment is 
started.
7.2.2
Duration of treatment and criteria for treatment through progression and for 
retreatment
All treatment will be administered beginning on Day 1 and all patients in all groups will 
continue therapy until disease progression unless there is unacceptable toxicity, withdrawal of 
consent, or another discontinuation criterion is met. 
Patients with rapid tumor progression or with symptomatic progression that requires urgent 
medical intervention (e.g., central nervous system metastasis, respiratory failure due to tumor 
compression, spinal cord compression) will not be eligible for continuing MEDI4736 
(MEDI4736) ± tremelimumab.
At the Investigator’s discretion, patients in all groups may continue receiving therapy in the 
setting of unconfirmed PD, until confirmed PD unless there is unacceptable toxicity, 
withdrawal of consent, or another discontinuation criterion is met. In patients who are 
clinically stable, a confirmatory scan is required following an overall radiologic time point 
assessment of progression (PD), preferably at the next scheduled visit and no earlier than 4 
weeks after the previous assessment of PD. 
Patients in the immunotherapy arm with PD according to RECIST 1.1(unconfirmed and 
confirmed) who, in the Investigator’s opinion, continue to receive benefit from their assigned 
treatment and who meet the criteria for treatment in the setting of PD may continue to receive 
their assigned treatment for as long as they are gaining clinical benefit. 
Patients in the MEDI4736 (MEDI4736) + tremelimumab combination therapy arm meeting 
the retreatment criteria below, will follow the same treatment guidelines followed during the 
initial treatment period, including the same dose and frequency of treatments and the same 
schedule of assessments.
Retreatment is not permitted for patients in the SoC arm.
Patients who meet the criteria for retreatment may only receive retreatment once. 
Crossover within the study will not be permitted.
Patients randomized to the durvalumab (MEDI4736) + tremelimumab combination therapy 
arm may undergo retreatment as described below:

Patients who complete the 4 dosing cycles of the combination of MEDI4736 
(MEDI4736) and tremelimumab portion of the regimen (with clinical benefit per 
Investigator judgment), but subsequently have evidence of PD during the 
durvalumab (MEDI4736) monotherapy portion of the combination regimen, with or 

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without confirmation according to RECIST 1.1, may restart treatment with the 
combination
For all patients who are treated through progression and for patients who are restarting 
durvalumab (MEDI4736) + tremelimumab, the Investigator should ensure that:

The patient does not have any significant, unacceptable, or irreversible toxicities 
that indicate continuing treatment will not further benefit the patient

There is absence of clinical symptoms or signs indicating clinically significant 
disease progression accompanied by a decline in WHO/ECOG performance status 
to >1

There is absence of rapid disease progression or threat to vital organs or critical 
anatomical sites (e.g., central nervous system metastasis, respiratory failure due to 
tumor compression, or spinal cord compression) requiring urgent alternative 
medical intervention

The patient still fulfills the eligibility criteria for this study (see Section 3.1 and 
3.2). Patients must also agree to re-consenting to restart durvalumab (MEDI4736) + 
tremelimumab combination therapy
Patients in the immunotherapy arm(s) will not be permitted to continue immunotherapy if
progression occurs after confirmed response (CR or PR as defined by RECIST 1.1) to 
immunotherapy treatment in the target lesions (regardless of the appearance of new lesions) 
i.e. the response and progression events both occurred in the target lesions while receiving 
immunotherapy during the same treatment period. 
Patients who AstraZeneca and the Investigator determine may not continue treatment after PD 
will be followed up for survival. Patients who have discontinued treatment due to toxicity or 
symptomatic deterioration, or who have commenced subsequent anticancer therapy, will be 
followed up until confirmed disease progression and for survival. 
Post Data Cut Off (DCO)
For patients continuing to receive MEDI4736 or MEDI4736 + tremelimumab treatment 
following the scheduled DCO for final analysis of the global cohort, it is recommended that 
the patients continue the scheduled site visits. For those patients from China who are in the 
Global cohort, final DCO and DBL will be when the China cohort conducts its final DCO and 
final DBL.
Based on the analysis results of the global cohort, a decision was made to move the following 
patients of global cohort to a roll over study

Patients who are still receiving study treatment (MEDI4736/tremelimumab treatment)

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
Patients who were receiving study treatment (MEDI4736/tremelimumab treatment) 
and are now being followed up for survival
No further data collection in to the Neptune study database is required until the patients in 
global cohort (with the exception of patients from China) are transitioned to a roll over study. 
Survival data of patients who are ongoing on MEDI4736/tremelimumab treatment or in follow 
up after discontinuation of the MEDI4736/tremelimumab treatment, should be documented in 
patient records. Upon enrolment into the roll over study these data may be retrieved.
All SAEs that occur in patients still receiving MEDI4736/tremelimumab treatment (or within 
the 90 days following the last dose of MEDI4736/tremelimumab treatment) post the final 
DCO and database closure must be reported as detailed in Section 6.4
Patients moving to the roll over study will require a new Informed Consent. The OS data 
collected in the roll over study may be combined with the OS data from NEPTUNE and 
evaluated as a combined dataset.
7.3
Labeling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfill GMP Annex 13 requirements for labelling. Label 
text will be translated into the local language.
Labels will be provided as either a single panel label or as multi-language booklet labels.
Japan and other countries where this is applicable: Labels will be prepared in accordance 
with Good Clinical Practice (GCP) Ordinance. Details are specified in the document 
explaining the reconstitution procedures and other handling procedures for the investigational 
products.
7.4
Storage
The Investigator, or an approved representative (e.g., 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 
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.
7.5
Compliance
The administration of all IPs should be recorded in the appropriate sections of the eCRF.
Treatment compliance will be assured by reconciliation of site drug accountability logs.

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7.6
Accountability
The IP provided for this study will be used only as directed in the study protocol. The study 
personnel will account for all IPs. 
Drug accountability should be performed until the patient stops IP completely. Study site 
personnel will account for all IPs received at the site, for all unused IPs, and for appropriate 
destruction of IPs. Certificates of delivery, destruction, and return should be signed.
7.7
Concomitant and other treatments 
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical treatment phase of the study including the 90 day 
follow up period following the last dose of study drug. Any concomitant medication(s), 
including herbal preparations, taken during the study will be recorded in the eCRF.
Restricted, prohibited, and permitted concomitant medications are described in the following 
tables. Refer to section 6.10 for guidance on management of IP-related toxicities.
Prohibited medication/class of drug:
Usage:
For all treatment arms
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 therapy, 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 [e.g., insulin for 
diabetes and hormone replacement therapy] is 
acceptable. Local treatment of isolated lesions, 
excluding target lesions, for palliative intent is 
acceptable [e.g., by local surgery or radiotherapy])
Live attenuated vaccines 
Should not be given through 30 days after the last 
dose of IP
For the MEDI4736 ± tremelimumab treatment arms only

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Prohibited medication/class of drug:
Usage:
Immunosuppressive medications, including, 
but not limited to, systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or 
its equivalent, methotrexate, azathioprine, and 
tumor necrosis factor α blockers  
Should not be given concomitantly or used for 
premedication prior to the I-O infusions. The 
following are allowed exceptions:

Use of immunosuppressive medications for 
the management of IP-related AEs

Short-term premedication for patients 
expected to receive SoC where the 
prescribing information for the agent requires 
the use of steroids for documented 
hypersensitivity reactions 

Use in patients with contrast allergies

In addition, 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 (e.g., 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 90 days after 
the last dose of tremelimumab during the study
Sunitinib
Should not be given concomitantly or through 90 
days after the last dose of tremelimumab (acute renal 
failure has been reported with tremelimumab + 
sunitinib combination therapy)
EGFR TKIs
Should not be given concomitantly whilst the patient 
is on study treatment.
In addition, they should be used with caution in the 
90 days after the last dose of MEDI4736. (Increased 
incidences of pneumonitis (with third generation 
EGFR TKIs) and increased incidence of transaminase 
increases (with 1st generation EGFR TKIs) has been 
reported when MEDI4736 has been given 
concomitantly).
Herbal and natural remedies which may have 
immune-modulating effects
Should not be given concomitantly unless agreed by 
the sponsor

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Rescue/supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(e.g., acetaminophen or diphenhydramine) 
deemed necessary by the Investigator 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, growth factor support, 
correction of metabolic disorders, optimal 
symptom control, and pain management 
[including palliative radiotherapy, etc.])
Should be used when necessary for all patients
Inactivated viruses, such as those in the 
influenza vaccine
Permitted
7.7.1
Other concomitant treatment
Medications other than those described in Section 7.7 that are considered necessary for the 
patient’s safety and well-being may be given at the discretion of the Investigator and should 
be recorded in the appropriate sections of the eCRF.
7.7.2
MEDI4736 drug-drug interactions
There is no information to date on drug-drug interactions with MEDI4736 either pre-clinically 
or in patients. As MEDI4736 is a monoclonal antibody and therefore a protein, it will be 
degraded to small peptides and amino acids and will be eliminated by renal and 
reticuloendothelial clearance. It is therefore not expected that MEDI4736 will induce or 
inhibit the major drug metabolizing cytochrome P450 pathways. As a result, there are no 
expected pharmacokinetic drug-drug interactions. The mechanism of action of MEDI4736 
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.
7.8
Post study access to study treatment
After the final analysis, AstraZeneca will continue to supply open-label drug to patients 
receiving MEDI4736 + tremelimumab combination therapy (see Section 7.2.2). Patients will 
continue to receive study treatment until they are transitioned to the roll over study.
7.8.1
Special roll over study 

These are available for patients remaining in this study after analysis finalized, they 
can be transferred to such umbrella protocol.

Roll over study must be fully approved by Regulatory and Ethics bodies applicable for 
patient’s site.

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
Such a study would ensure proper treatment continuation with visits assessment per its 
protocol.

Visit assessments will cover the minimum information required for safety oversight 
and may cover assessments required for long term use analysis.

Any patient that would be proposed to move to such study, would be required to sign a 
new Informed Consent Form.
8.
STATISTICAL ANALYSIS BY ASTRAZENECA
8.1
Statistical considerations
All statistical analysis will be performed by AstraZeneca or its representatives. 
A comprehensive Statistical Analysis Plan (SAP) will be prepared and finalized and any 
subsequent amendments will be documented, with final amendments completed prior to 
reporting of the data. The primary aim of the study is to compare the efficacy and safety of 
MEDI4736 in combination with tremelimumab to SoC. 
Section 8.2 to 8.5 describes the statistical analysis that applies to the global cohort data. For 
the China cohort, the same definitions of outcome measures (Section 8.4 on Outcome 
measures) and methods of statistical analysis (Section 8.5) will be applied unless specified in 
Section 8.6or the China specific SAP.
8.2
Sample size estimate
The study will plan to enroll approximately 1330 patients in order to randomize 800 eligible 
patients 1:1 to MEDI4736 + tremelimumab combination therapy or SoC globally. The 
800 patients will comprise approximately 336 patients who have PD-L1-positive25% tumors 
and approximately 520 patients who have PD-L1-positive1% tumours. Global recruitment will 
be complete once approximately 800 patients have been randomized of which 30 patients are 
from mainland China. Once global enrollment is completed, the recruitment will continue in 
mainland China only. A total of approximately 160 patients from mainland China will be 
randomized (refer to Section 8.6 for more details).
The primary analysis will be performed when approximately 87% maturity in the population 
with bTMB ≥20 mut/Mb is achieved.
The sample size calculation assumes a 3-month delay in separation of the OS curves between 
each group and with a 12-month recruitment period and a minimum follow up period of 43 
months assumed, it is anticipated that this analysis will be performed 55 months after the first 
patient has been recruited.   The true OS average hazard ratios (HR) in bTMB≥20, ≥16, ≥12, 
and PD-L1 negative population are based on observation from D419AC00001 study, as well 
as based on what would be considered a clinically meaningful improvement in the biomarker 

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selected population.  The expected number of patients and prevalence in this study are based 
on observation from D419AC00001 study.
MEDI4736 + tremelimumab versus SoC (OS in bTMB≥20 mut/Mb population)
Assuming the true OS average hazard ratio (HR) is 0.49 and the median OS in SoC 
chemotherapy alone arm is 10 months following an exponential distribution for both 
MEDI4736 + tremelimumab and SoC arm in the bTMB≥20 mut/Mb population, with 
approximately 140 patients, 122 OS events from the global cohort (approximately 87% 
maturity) will provide greater than 90% power to demonstrate statistical significance at the 2-
sided alpha overall level of 5%. The smallest treatment difference that is statistically 
significant will be an HR of 0.70.
MEDI4736 + tremelimumab versus SoC (OS in bTMB≥16 mut/Mb population)
Assuming the true OS average HR is 0.62 and the median OS in SoC chemotherapy alone arm 
is 10 months following an exponential distribution for both MEDI4736 + tremelimumab and 
SoC arm in the bTMB≥16 mut/Mb population, with approximately 212 patients, 193 OS 
events from the global cohort (approximately 91% maturity) will provide greater than 90% 
power to demonstrate statistical significance at the 2-sided alpha overall level of 5%. The 
smallest treatment difference that is statistically significant will be an HR of 0.75.
MEDI4736 + tremelimumab versus SoC (OS in bTMB≥12 mut/Mb population)
Assuming the true OS average HR is 0.65 and the median OS in SoC chemotherapy alone arm 
is 10 months following an exponential distribution for both MEDI4736 + tremelimumab and 
SoC arm in the bTMB≥12 mut/Mb population, with approximately 304 patients, 280 OS 
events from the global cohort (approximately 92% maturity) will provide greater than 90% 
power to demonstrate statistical significance at the 2-sided alpha overall level of 5%. The 
smallest treatment difference that is statistically significant will be an HR of 0.79.
MEDI4736 + tremelimumab versus SoC (OS in PD-L1 negative population)
Assuming the true OS average HR is 0.73 and the median OS in SoC chemotherapy alone arm 
is 10 months following an exponential distribution for both MEDI4736 + tremelimumab and 
SoC arm in the PD-L1 negative population, with approximately 194 patients, 182 OS events 
from the global cohort (approximately 94% maturity) will provide 57% power to demonstrate 
statistical significance at the 2-sided alpha overall level of 5%. The smallest treatment 
difference that is statistically significant will be an HR of 0.75.
8.3
Definitions of analysis sets
Definitions of the analysis sets for each outcome variable are provided in Table 9.

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Table 9
Summary of outcome variables and analysis populations
Outcome variable
Population
Efficacy data
OS
bTMB ≥ 20 mut/Mb analysis set
OS
bTMB ≥16 mut/Mb analysis set
OS
bTMB ≥12 mut/Mb analysis set
OS
PD-L1-negative analysis set
OS
FAS (ITT population)
OS
bTMB < 20 mut/Mb analysis set
OS
bTMB non-evaluable analysis set
OS
PD-L1≥ 25%
OS
PD-L1≥ 50%
OS
tTMB cutoff-based analysis sets
PFS, ORR 
bTMB ≥20 mut/Mb analysis set
PFS, ORR 
bTMB ≥16 mut/Mb analysis set
PFS, ORR 
bTMB ≥12 mut/Mb analysis set
PFS, ORR
PD-L1-negative analysis set
PFS, ORR
FAS (ITT population)
PFS, ORR 
PD-L1≥ 25%
PFS, ORR
PD-L1≥ 50%
PFS, ORR
tTMB cutoff-based analysis sets
APF12, OS12, OS18, OS24 and PFS2, DoR
bTMB ≥20 mut/Mb analysis set
APF12, OS12, OS18, OS24 and PFS2, DoR
bTMB ≥16, mut/Mb analysis sets
APF12, OS12, OS18, OS24 and PFS2, DoR
bTMB ≥12 mut/Mb analysis set
APF12, OS12, OS18, OS24 and PFS2, DoR
PDL1-negative analysis set
APF12, OS12, OS18, OS24 and PFS2, DoR
FAS (ITT population)
Demography
FAS (ITT population)
PK data
PK analysis set
Safety Data
Exposure
Safety Analysis Set
AEs
Safety Analysis Set
Laboratory measurements
Safety Analysis Set
Vital signs
Safety Analysis Set

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Outcome variable
Population
ECGs
Safety Analysis Set
FAS: Full analysis set
8.3.1
Full analysis set
The full analysis set (FAS) will include all randomized patients prior to the end of global 
recruitment. Any patients recruited in China, after global recruitment has ended, will not be 
included in the FAS (see Section 8.6). China patients will not undergo bTMB analysis and 
testing and details of the analysis of this population will be described in the China specific 
SAP. Treatment groups will be compared on the basis of randomized IP, regardless of the 
treatment actually received. Patients who were randomized but did not subsequently go on to 
receive IP are included in the analysis in the treatment group to which they were randomized.
8.3.2
bTMB ≥20 mut/Mb analysis set
The bTMB ≥20 mut/Mb analysis set will include the subset of patients in the FAS whose 
blood TMB status is ≥20 mut/Mb as defined by the 
 
8.3.3
bTMB≥ 16 mut/Mb analysis set
The bTMB ≥16 mut/Mb analysis set will include the subset of patients in the FAS whose 
blood TMB status is ≥16 mut/Mb as defined by the 
.
8.3.4
bTMB ≥ 12 mut/Mb analysis set
The bTMB ≥ 12 mut/Mb analysis set will include the subset of patients in the FAS whose 
blood TMB status is ≥ 12 mut/Mb as defined by the 
.
8.3.5
bTMB non-evaluable analysis set
The bTMB non-evaluable analysis set will include the subset of patients in the FAS 
!
Whose blood TMB status cannot be determined by the 
 
!
Whose sample for evaluation of bTMB is not available
8.3.6
PD-L1-negative analysis set
The PD-L1-negative population analysis set will include the subset of patients in the FAS 
whose PD-L1 status is PD-L1-negative as defined by the 
(i.e., <1% PD-L1–membrane expression in tumoral tissue).
CCI
CCI
CCI
CCI
CCI

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8.3.7
tTMB - based analysis sets
Methods for determining analysis sets based on tissue TMB will be defined in the SAP. 
Cutoffs for tTMB-based analysis sets will be based on data collected outside of this study, 
independent of the data collected for Neptune.
8.3.8
Safety analysis set
The safety analysis set (SAS) will consist of all patients including those patients recruited 
prior to the end of global recruitment who received at least 1 dose of IP. Any patients 
recruited in China, after global recruitment has ended, will not be included in the safety 
analysis set (see Section 8.6). Safety data will not be formally analyzed but summarized using 
the SAS, according to the treatment received, that is, erroneously treated patients (e.g., those 
randomized to treatment A but actually given treatment B) will be summarized according to 
the treatment they actually received.
8.3.9
Pharmacokinetic analysis set 
All patients who received at least 1 dose of IP per the protocol for whom any post-dose data 
are available and who do not violate or deviate from the protocol in ways that would 
significantly affect the PK analysis will be included in the PK analysis set. The population 
will be defined by the Study Physician, Pharmacokineticist, and Statistician prior to any 
analysis being performed.
8.4
Outcome measures for analysis
8.4.1
Calculation or derivation of efficacy variables
This study will analyze the primary endpoint of OS. In addition, the analysis of the secondary 
endpoints of PFS, ORR, DoR, and APF12 will be based on Investigator tumor assessments 
according to RECIST 1.1. PFS2 will be defined by local clinical practice, and survival rate 
(OS12, OS18 and OS24) will also be analyzed. 
Primary 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 will be made following the date of data cut-off for the analysis (these 
contacts should generally occur within 7 days of the data cut off). If patients are confirmed to 
be alive or if the death date is post the data cut-off date, these patients will be censored at the 
date of data cut-off. Death dates may be found by checking publicly available death registries.
The Kaplan-Meier estimates of OS12 ,OS18, OS24 (survival rate, that is, proportion of 
patients alive at 12 , 18 and 24 months) will also be derived as secondary endpoints.

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8.4.1.1
Investigator RECIST 1.1-based endpoints
All RECIST assessments, whether scheduled or unscheduled, will be included in the 
calculations. This is also regardless of whether a patient discontinues IP or receives another 
anticancer therapy. 
At each visit, patients will be programmatically assigned a RECIST 1.1 visit response of CR, 
PR, SD, or PD depending on the status of their disease compared with baseline and previous 
assessments. Baseline will be assessed within the 28 days prior to randomization. If a patient 
has had a tumor assessment that cannot be evaluated, then the patient will be assigned a visit 
response of not evaluable (NE; unless there is evidence of progression in which case the 
response will be assigned as PD).
The definitions of CR, PR, SD, and PD are given in Appendix D.
8.4.1.2
Secondary endpoints
Progression-free survival
PFS (per RECIST 1.1 using Investigator assessments) will be defined as the time from the 
date of randomization until the date of objective disease progression or death (by any cause in 
the absence of progression) regardless of whether the patient withdraws from randomized 
therapy or receives another anticancer therapy prior to progression. Patients who have not 
progressed or died at the time of analysis will be censored at the time of the latest date of 
assessment from their last evaluable RECIST 1.1 assessment. However, if the patient 
progresses or dies after 2 or more missed visits, the patient will be censored at the time of the 
latest evaluable RECIST 1.1 assessment prior to the 2 or more missed visits. If the patient has 
no evaluable visits or does not have baseline data, they will be censored at 0 days unless they 
die within 2 visits of baseline. 
The PFS time will always be derived based on scan/assessment dates not visit dates.
RECIST 1.1 assessments/scans contributing towards a particular visit may be performed on 
different dates. The following rules will be applied:

For investigational assessments, the date of progression will be determined based on 
the earliest of the RECIST assessment/scan dates of the component that indicates 
progression

When censoring a patient for PFS, the patient will be censored at the latest of the 
dates contributing to a particular overall visit assessment
Note: For target lesions, only the latest scan date is recorded out of all scans performed at that 
assessment for the target lesions, and similarly for non-target lesions, only the latest scan date 
is recorded out of all scans performed at that assessment for the non-target lesions.
PFS based on RECIST 1.1 modified for confirmation of progression will be performed for 
exploratory purposes using the algorithm described above for the RECIST 1.1 Investigator 

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assessments, but following a modification whereby any objective disease progression must be 
confirmed by the next scheduled scan. The confirmatory scan must be no sooner than 4 weeks 
after the initial suspected progression and preferably at the next scheduled visit. If disease 
progression is confirmed (or disease progression occurs and no further scans are recorded) 
then the date of progression will be when it was originally observed. Patients with a single 
disease progression and no further tumor assessment scans will be treated as PD in the 
analysis. In the absence of significant clinical deterioration, the investigational site is advised 
to continue the patient on their randomized MEDI4736 + tremelimumab combination therapy 
until progression has been confirmed. If progression is not confirmed, the patient should 
continue their randomized MEDI4736 + tremelimumab combination therapy and on-treatment 
assessments. In the SoC arm, treatment through PD, until PD is confirmed is at the 
Investigator’s discretion; however, a confirmatory scan is required for all patients in the SoC 
group, even if a subsequent treatment is started.
Objective response rate
ORR (per RECIST 1.1 using Investigator assessments) is defined as the number (%) of 
patients with at least 1 visit response of CR or PR. Data obtained up until progression, or the 
last evaluable assessment in the absence of progression, will be included in the assessment of 
ORR. Patients who go off treatment without progression, receive a subsequent therapy, and 
then respond will not be included as responders in the ORR. 
Duration of response
DoR (per RECIST 1.1 using Investigator assessments) will be defined as the time from the 
date of first documented response until the first date of documented progression or death in 
the absence of disease progression. The end of response should coincide with the date of 
progression or death from any cause used for the RECIST 1.1 PFS endpoint. 
The time of the initial response will be defined as the latest of the dates contributing towards 
the first visit response of CR or PR. If a patient does not progress following a response, then 
their DoR will be censored at the PFS censoring time. DoR will not be defined for those 
patients who do not have documented response.
Proportion of patients alive and progression free at 12 months from randomization
The APF12 will be defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed 
using Investigator assessments) at 12 months.
Time from randomization to second progression
PFS2 will be defined as the time from the date of randomization to the earliest of the 
progression event subsequent to that used for the PFS endpoint or death. The date of 
second progression will be recorded by the Investigator in the eCRF and defined according to 
local standard clinical practice and may involve any of the following: objective radiological 
imaging, symptomatic progression, or death. Second progression status will be reviewed (q6w 
for the first 48 weeks relative to the date of randomization and then q8w thereafter) following 
the progression event used for the primary variable PFS (the first progression) and status 

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recorded. Patients alive and for whom a second disease progression has not been observed 
should be censored at the last time known to be alive and without a second disease 
progression, that is, censored at the latest of the PFS or PFS2 assessment date if the patient has 
not had a second progression or death.
Best objective response
Best objective response (BoR) is calculated based on the overall visit responses from each 
RECIST assessment, described in Appendix D. It is the best response a patient has had during 
their time in the study up until RECIST progression or the last evaluable assessment in the 
absence of RECIST progression.
Categorization of BoR will be based on RECIST (Appendix D) using the following response 
categories: CR, PR, SD, PD, and NE.
BoR will be determined programmatically based on RECIST using all Investigator 
assessments up until the first progression event. For patients whose progression event is death, 
BoR will be calculated based upon all evaluable RECIST assessments prior to death.
For patients who die with no evaluable RECIST assessments, if the death occurs ≤90 days 
(i.e., 2*(6 weeks ±3 days)) after randomization, then BoR will be assigned to the progression 
(PD) category. For patients who die with no evaluable RECIST assessments, if the death 
occurs >90 days (ie, 2*(6 weeks ±3 days)) after the date of randomization then BoR will be 
assigned to the NE category. 
Progression events that have been censored due to them being >90 days after the last 
evaluable assessment will not contribute to the BoR derivation. 
8.4.2
Calculation or derivation of safety variables
8.4.2.1
Adverse events
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. 
Any AE occurring before treatment with IP will be included in the data listings but will not be 
included in the summary tables of AEs. Any AE occurring within 90 days of discontinuation 
of the last dose of MEDI4736 + tremelimumab combination therapy or within 30 days of the 
last dose of SoC may be included in the AE summaries, but the majority of those summaries 
will omit those AEs observed after a patient has received further therapy for cancer. Further 
details will be provided in the SAP. Any events in this period that occur after a patient has 
received further therapy for cancer (following discontinuation of IP) will be flagged in the 
data listings.
A separate data listing of AEs occurring more than 90 days after discontinuation of 
MEDI4736 + tremelimumab combination therapy or more than 30 days after discontinuation 
of SoC will be produced. These events will not be included in AE summaries. 

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8.4.2.2
Other significant adverse events
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and AEs leading to discontinuation. Based on 
the expert’s judgment, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered other significant AEs 
(OAEs) and reported as such in the CSR. A similar review of laboratory/vital signs/ECG data 
will be performed for identification of OAEs. Examples of these are marked hematological 
and other laboratory abnormalities, and certain events that lead to intervention (other than 
those already classified as serious) or significant additional treatment. 
8.4.2.3
Safety assessments
For the change from baseline summaries for vital signs, laboratory data, ECGs, and physical 
examination, the baseline value will be the latest result obtained prior to the start of IP. 
The QTcF will be derived during creation of the reporting database using the reported ECG 
values (RR and QT).
QTcF = QT/RR^(1/3) where RR is in seconds
Corrected calcium will be derived during creation of the reporting database using the 
following formulas:
Corrected calcium (mmol/L) = Total calcium (mmol/L) + ([40 – albumin (g/L)] × 0.02)
The denominator used in laboratory summaries 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 pre-dose and at least 1 post-dose value recorded

If a CTCAE criterion does not consider changes from baseline, to be evaluable the 
patient need only have 1 post dose-value recorded
The denominator in vital signs data should include only those patients with recorded data.
8.4.3
Calculation or derivation of pharmacokinetic variables
8.4.3.1
Population pharmacokinetics and exposure-response/safety analysis
A population PK model will be developed using a non-linear mixed-effects modeling 
approach. The impact of physiologically-relevant patient characteristics (covariates) and 
disease on PK will be evaluated. The relationship between the PK exposure and the effect on 
safety and efficacy endpoints will be evaluated. The results of such an analysis will be 
reported in a separate report. The PK, pharmacodynamics, demographic, safety, and efficacy 

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data collected in this study may also be combined with similar data from other studies and 
explored using population PK and/or PK-pharmacodynamic methods.
8.4.3.2
Pharmacokinetic non-compartmental analysis
The PK analysis will be performed at AstraZeneca. The actual sampling times will be used in 
the PK calculations. PK concentration data and summary statistics will be tabulated. 
Individual and mean blood concentration-time profiles will be generated. PK parameters will 
be determined using standard non-compartmental methods. The following PK parameters will 
be determined after the first and steady-state doses: peak and trough concentration (as data 
allow). Samples below the lower limit of quantification will be treated as missing in the 
analysis.
8.4.3.3
Immunogenicity analysis
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADAs against MEDI4736 and tremelimumab. 
The immunogenicity titer and presence of neutralizing ADAs will be reported for samples 
confirmed positive for the presence of ADAs. The effect of immunogenicity on PK, 
pharmacodynamics, efficacy, and safety will be evaluated, if the data allow.
8.4.4
Calculation or derivation of biomarker variables
Biomarker status, as defined in the secondary objectives, will be assessed according to 
pre-specified criteria that will be detailed in the SAP.
8.5
Methods for statistical analysis
The formal statistical analysis will be performed to test the main hypotheses: 

H0: No difference between MEDI4736 + tremelimumab combination therapy and 
SoC

H1: Difference between MEDI4736 + tremelimumab combination therapy and SoC
The primary endpoint is OS in patients with bTMB ≥ 20 mut/Mb tumors. The study has been 
sized to characterize the OS benefit of MEDI4736 + tremelimumab combination therapy 
versus SoC. The analysis will be performed when: 

approximately 87% maturity in the bTMB ≥ 20 mut/Mb analysis set is achieved
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. 

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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 data will be summarized and analyzed based on the 
bTMB ≥ 20 mut/Mb analysis set, bTMB ≥ 16 mut/Mb analysis set, bTMB ≥ 12 mut/Mb 
analysis set and the PDL1-negative analysis set, FAS, PDL1 ≥ 25%, PDL1 ≥ 50% and tTMB-
based analysis sets. PK data will be summarized and analyzed based on the PK analysis set. 
Safety data will be summarized based on the Safety Analysis Set. 
Results of all statistical analysis will be presented using appropriately sized confidence 
intervals (CIs) and 2-sided p-values, unless otherwise stated.
The following table (Table 10) details which endpoints are to be subjected to formal statistical 
analysis, together with pre-planned sensitivity analysis, making it clear which analysis is 
regarded as primary for that endpoint.
Table 10
Pre-planned statistical and sensitivity analysis to be conducted
Endpoints analyzed
Notes
OS
log-rank test for:
Primary analysis in:

bTMB ≥ 20 mut/Mb analysis set 
Secondary analysis in: 

bTMB ≥ 16 mut/Mb analysis set

bTMB ≥ 12 mut/Mb analysis set

PDL1-negative analysis set

FAS (ITT population)

bTMB < 20 mut/Mb analysis set

bTMB non-evaluable analysis set

PD-L1≥ 25%

PD-L1≥ 50% 

tTMB cutoff-based analysis set
Weighted log-rank test for primary analysis in:

bTMB ≥ 20 mut/Mb analysis set 

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Endpoints analyzed
Notes
OS12, OS18 and OS24
HR using the Kaplan-Meier estimates of survival rate at 12 months, 
18 months and 24 months (following method described by 
Klein et al 2007) in:

bTMB ≥ 20 mut/Mb analysis set 

bTMB ≥ 16 mut/Mb analysis set 

bTMB ≥ 12 mut/Mb analysis set

PDL1-negative analysis set

FAS (ITT population)

tTMB cutoff based analysis set
PFS
Log-rank tests for:

Investigator RECIST 1.1 assessments in:

bTMB ≥ 20 mut/Mb analysis set 

bTMB ≥ 16 mut/Mb analysis set 

bTMB ≥ 12 mut/Mb analysis set

PDL1-negative analysis set

FAS (ITT population)

PD-L1≥ 25%

PD-L1≥ 50%

tTMB cutoff-based analysis sets
Sensitivity analysis based on RECIST 1.1 modified for confirmation 
of progression using Investigator assessments 
ORR 
Logistic regression for:

Secondary analysis using Investigator RECIST 1.1 
assessments in:

bTMB ≥ 20 mut/Mb analysis set 

bTMB ≥ 16 mut/Mb analysis set 

bTMB ≥ 12 mut/Mb analysis set

PDL1-negative analysis set

FAS (ITT population)

PD-L1≥ 25%

PD-L1≥ 50%

tTMB cutoff-based analysis sets 

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Endpoints analyzed
Notes
DoR
Analysis methods as described by Ellis et al 2008 for:

Secondary analysis using Investigator assessments 
(RECIST 1.1) in:

bTMB ≥ 20 mut/Mb analysis set 

bTMB ≥ 16 mut/Mb analysis set 

bTMB ≥ 12 mut/Mb analysis set

PDL1-negative analysis set

FAS (ITT population)
APF12 
HR using the Kaplan-Meier estimates of PFS at 12 months 
(following method described by Klein et al 2007) in:

≥ bTMB ≥ 20 mut/Mb analysis set 

bTMB ≥ 16 mut/Mb analysis set 

bTMB ≥ 12 mut/Mb analysis set

PDL1-negative analysis set

FAS (ITT population)
PFS2 
Log-rank test in:

bTMB ≥ 20 mut/Mb analysis set 

bTMB ≥ 16 mut/Mb analysis set 

bTMB ≥ 12 mut/Mb analysis set

PDL1-negative analysis set

FAS (ITT population)
Multiple testing strategy
In order to strongly control the type I error at 5% 2-sided, a multiple testing procedure (MTP) 
with gatekeeping strategy will also be used across the primary endpoints (OS) in the bTMB ≥ 
20 mut/Mb populations and key secondary endpoint bTMB ≥ 16 mut/Mb, bTMB ≥ 12 
mut/Mb, OS in PD-L1-negative analysis population. If the higher level hypothesis in the MTP 
is rejected for superiority, the following hypothesis will then be tested in the MTP as shown 
in Figure 4. 

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Figure 4
Multiple testing procedures for controlling the type I error rate
The above testing procedure will ensure strong control of the family-wise error rate (Glimm et 
al 2010). Additional details of the multiple testing procedure will be provided in the statistical 
analysis plan.
8.5.1
Analysis of primary endpoint - overall survival
The primary OS analysis will be performed in the bTMB ≥ 20 mut/Mb populations using a  
log-rank test The effect of MEDI4736 + tremelimumab combination therapy versus SoC 
treatment will be estimated by the HR together with its appropriately sized CI and p-value.
The HR and its CI can be estimated from the Cox proportional hazards model (Cox 1972).
Kaplan-Meier plots of OS will be presented by treatment group, and by treatment group and 
PD-L1 tumor status subgroup, where appropriate. Summaries of the number and percentage of 
Combo vs SoC - OS 
bTMB ≥20 mut/Mb
5% α
Combo vs SoC - OS 
bTMB ≥16 mut/Mb
5% α
Combo vs SoC - OS 
bTMB ≥12 mut/Mb
5% α
Combo vs SoC - OS 
PD-L1 negative 
5% α

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patients who have died, who are still in survival follow-up, who are lost to follow-up, and who 
have withdrawn consent will be provided along with the median OS for each treatment.
Secondary analysis of OS will be performed to compare MEDI4736 + tremelimumab 
combination therapy versus SoC in the bTMB ≥ 16 mut/Mb, bTMB ≥ 12 mut/Mb and PD-L1
negative analysis sets, and analysis sets mentioned in Table 10 using a log-rank test. The 
analysis in PD-L1-negative population will be performed using a stratified log-rank test 
adjusting only for histology (squamous versus non-squamous) and smoking status. The effect 
of treatment will be estimated by the HR together with its appropriately sized CI and p-value. 
The HR and CI will be estimated using the Cox proportional hazards model.
Subgroup analysis will be conducted comparing OS between MEDI4736 + tremelimumab 
combination therapy versus SoC in the following subgroups of primary population (TMB≥ 20 
mut/Mb) and FAS analysis sets as deemed appropriate (but not limited to):  

Sex (male versus female)

Age at randomization (<65 versus ≥ 65 years of age)

Histology (squamous versus non-squamous)

Smoking status (never smoker versus ever smoker)

Race (Asian versus non-Asian)

bTMB (≥ 12 versus < 12 mut/Mb, ≥ 16 versus < 16 mut/Mb, (≥ 20 versus < 20 
mut/Mb) , bTMB evaluable vs non-evaluable population.  (FAS only) 

PD-L1 using cutpoints of 1%, 10%, 25% and 50% tumour expression (≥1% versus 
<1%, <10% versus ≥10%, ≥ 25% versus <25% and <50% versus ≥50%) and 
immune cell expression (IC ≥ 25% versus < 25%)

ECOG (0 versus 1)

Baseline Liver Metastases (Yes versus No)
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 analysis is to assess 
the consistency of treatment effect across expected prognostic and/or predictive factors.
No adjustment to the significance level for testing of the subgroup and sensitivity analysis will 
be made since all these analysis will be considered supportive of the analysis of OS.
Cox proportional hazards modeling will be employed to assess the effect of covariates on the 
HR estimate. For the bTMB -based analysis sets, a model will be constructed, containing 
treatment alone, to ensure that any output from the Cox modeling is likely to be consistent 

Clinical Study Protocol
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with the results of the log-rank test. For PDL1-based analysis set and the FAS, the model will 
contain treatment and stratification factors, to be consistent with the results of the stratified 
log-rank test.
Interactions between treatment and stratification factor will also be tested to rule out any 
qualitative interaction using the approach of Gail and Simon 1985.
Additionally, for each subgroup, the HR (MEDI4736 + tremelimumab combination therapy: 
SoC) and appropriately sized CI will be calculated from a single model that contains treatment 
and subgroup factor. These will be presented on a forest plot including 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 analysis where there are less than 20 events in a 
subgroup), the relationship between that subgroup and OS will not be formally analyzed. In 
this case, only descriptive summaries will be provided.
8.5.2
Progression-free survival
The main PFS analysis will be based on the programmatically derived RECIST 1.1 using the 
Investigator tumor assessments in the bTMB ≥ 20, bTMB ≥ 16, bTMB ≥ 12, and PDL1-
negative analysis sets, and analysis sets mentioned in Table 10 for the PFS endpoint. PFS will 
be analyzed using a log-rank test, using the same methodology described for the OS endpoint. 
The effect of MEDI4736 + tremelimumab combination therapy versus SoC will be estimated 
by the HR together with its corresponding CI and p-value.
Kaplan-Meier plots will be presented by treatment group. Summaries of the number and 
percentage of patients experiencing a PFS event and the type of event (RECIST 1.1 or death) 
will be provided along with median PFS for each treatment.
Sensitivity analysis will be performed to assess possible evaluation-time bias that may be 
introduced if scans are not performed at the protocol-scheduled timepoints. The midpoint 
between the time of progression and the previous evaluable RECIST assessment will be 
analyzed using a log-rank test. For patients whose death was treated as PFS event, the date of 
death will be used to derive the PFS time used in the analysis. This approach has been shown 
to be robust even in highly asymmetric assessment schedules (Sun and Chen 2010).
Attrition bias will be assessed by repeating the PFS analysis except that the actual PFS event 
times, rather than the censored times, of patients who progressed or died in the absence of 
progression immediately following 2 or more non-evaluable tumor assessments will be 
included. In addition, patients who take subsequent therapy prior to progression or death will 
be censored at their last evaluable assessment prior to taking the subsequent therapy. This 
analysis will be supported by a Kaplan-Meier plot of the time to censoring where the 
censoring indicator of the PFS analysis is reversed.
Secondary analysis of PFS based on the programmatically derived RECIST 1.1 using the 
Investigator tumor assessments will be performed to compare MEDI4736 + tremelimumab 
combination therapy versus SoC in thebTMB based analysis sets and in the  PD-L1-negative 

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population, and analysis sets mentioned in Table 10. This analysis will be performed using a 
log-rank test in the bTMB analysis sets, and a stratified log-rank test adjusting only for 
histology (squamous versus non-squamous) and smoking status in the PD-L1-negative 
population. The effect of treatment will be estimated by the HR together with its 
corresponding appropriately sized CI and p-value. The HR and CI will be estimated using the 
same approach as specified above for the primary analysis of OS. Details will be included in 
the SAP.
An exploratory analysis of PFS using Investigator assessment based on RECIST 1.1 modified 
for confirmation of progression will be performed. The log-rank test used for the primary 
analysis of PFS will be repeated. 
Subgroup analysis will be conducted comparing PFS (per RECIST 1.1 using Investigator 
assessments) between MEDI4736 + tremelimumab combination therapy versus SoC using the 
same methodology as described in Section 8.5.1 for the primary endpoint of OS. 
8.5.3
Objective response rate
The ORR will be based on the programmatically derived RECIST using the Investigator 
tumor data. The ORR will be compared between MEDI4736 + tremelimumab combination 
therapy versus SoC using logistic regression models adjusting for the same factors as the 
primary endpoint (PD-L1 tumor expression, histology, and smoking status), as appropriate 
and wherever used. The results of the analysis will be presented in terms of an odds ratio 
together with its associated profile likelihood CI and p-value (based on twice the change in 
log-likelihood resulting from the addition of a treatment factor to the model). This analysis 
will be performed in the analysis sets mentioned in Table 10. The analysis of the patients with 
PD-L1-negative population tumors will be performed using a logistic regression model 
adjusting for only histology and smoking status. 
Summaries will be produced that present the number and percentage of patients with a tumor 
response (CR/PR). Overall visit response data will be listed for all patients. For each treatment 
group, BoR will be summarized by n (%) for each category (CR, PR, SD, PD, and NE). No 
formal statistical analysis are planned for BoR.
8.5.4
Duration of response
In order to analyze the DoR between MEDI4736 + tremelimumab combination therapy and 
SoC, the expected DoR (EDoR) will be derived for each treatment group (Ellis et al 2008) 
using the Investigator tumor data. The EDoR is the product of the proportion of patients 
responding to treatment and the mean DoR in responding patients and provides an estimate 
based on all randomized patients. Treatments will be compared by calculating the ratio of 
EDoRs, using an appropriate probability distribution (to be specified in the SAP) for DoR in 
responding patients. Additionally, descriptive data will be provided for the DoR in responding 
patients, including the associated Kaplan-Meier curves (without any formal comparison of 
treatment groups or p-value attached). These analysis will be performed in theanalysis sets 
mentioned for DoR in Table 10.

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8.5.5
Survival rate at 12 months, 18, and 24 months 
OS12, OS18 and OS 24 will be summarized using the Kaplan-Meier curve and presented by 
treatment group. These landmark survival rates will be compared between MEDI4736 + 
tremelimumab combination therapy and SoC by using the Kaplan-Meier estimator of OS at 
corresponding landmark times for each treatment to obtain the HR. The HR and CI will be 
presented using the following approach (Klein et al 2007): 

The HR(group1:group2) is estimated as 

The variance for ln(HR) is estimated as 
where 




t
t
i
i
i
i
i
i
d
n
n
d
t
)
(
)
(
ˆ
2

is the variance for ln{S(t) derived from greenwood’s formula 
for the variance of S(t) and can be estimated from standard software packages, where di and ni 
refer to the number of events and patients at risk for each risk set. 
The ln(HR) and its variance in each stratum will be estimated and combined by weighting 
inversely proportionately according to each within stratum variance (Whitehead and 
Whitehead 1991). 
This analysis will be performed in the analysis sets mentioned for OS12, OS18 and OS24 in 
Table 10.
8.5.6
Proportion of patients alive and progression free at 12 months from 
randomization
The APF12 will be summarized (using the Kaplan-Meier curve) and presented by treatment 
group. APF12 will be compared between MEDI4736 + tremelimumab combination therapy 
and SoC by using the same methodology as described for the survival rate at 12 months.
This analysis will be performed in the analysis sets mentioned for APF12 in Table 10.
8.5.7
Time from randomization to second progression
Second progression (PFS2 will be analyzed using log-rank tests, using the same methodology 
as described for the primary PFS endpoint. The effect of MEDI4736 + tremelimumab 
combination therapy versus SoC will be estimated by the HR together with its corresponding 
CI and p-value. Kaplan-Meier plots will be presented by treatment group. Summaries of the 
number and percentage of patients who have an event as well as who were censored will be 
provided along with the medians for each treatment.
For supportive purposes, the time to the start of subsequent therapy will be analyzed using the 
same methodology and model. The HR for the treatment effect together with its 95% CI will 
be presented. In addition, a Kaplan-Meier plot of the time to the start of subsequent therapy 
)
(
ˆ
ln
)
(
ˆ
ln
2
1
t
S
t
S
)
(
ln
)
(
ˆ
)
(
ln
)
(
ˆ
2
2
2
2
1
2
2
1
t
S
t
t
S
t




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will be presented by treatment group and the time between progression and starting 
subsequent therapy will be assessed. No multiplicity adjustment will be applied as these are 
viewed as supportive endpoints.
A summary table of first subsequent therapies by treatment group will be provided, as well as 
response to first subsequent therapy by treatment group.
This analysis will be performed in the analysis sets mentioned for PFS2 as mentioned in Table 
10.
8.5.8
Safety data
Safety and tolerability data will be presented by treatment group using the safety population.
Data from all cycles of treatment will be combined in the presentation of safety data. Initial 
treatment and re-treatment will generally be combined into one treatment period. AEs (both in 
terms of 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. Any safety summaries examining specifically the impact of retreatment 
with MEDI4736 + tremelimumab combination therapy may be produced separately, if 
required.
Other safety data will be assessed in terms of physical examination, clinical chemistry, 
hematology, vital signs, and ECGs. Exposure to MEDI4736 + tremelimumab combination 
therapy and SoC will be summarized. Time on study, MEDI4736 + tremelimumab 
combination therapy and SoC, dose delays/interruptions and dose reductions will also be 
summarized. At the end of the study, appropriate summaries of all safety data will be 
produced, as defined in the SAP. 
8.5.9
Pharmacokinetic data
PK concentration data will be listed for each patient and each dosing day, and a summary 
provided for all evaluable patients in the PK analysis population.
8.5.10
Immunogenicity analysis
Immunogenicity results will be listed by patient and a summary will be provided of the 
number and percentage of patients who develop detectable anti-MEDI4736 and 
anti-tremelimumab antibodies. The immunogenicity titer and neutralizing ADA data will be 
listed for samples confirmed positive for the presence of anti-MEDI4736 and anti-
tremelimumab antibodies. 
The effect of immunogenicity on PK, pharmacodynamics, efficacy and safety will be 
evaluated if data allow.

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8.5.11
Pharmacokinetic/Pharmacodynamic relationships
If the data are suitable, the relationship between PK exposure and efficacy/safety parameters 
may be investigated graphically or using an appropriate data modeling approach.
8.5.12
Biomarker data
The relationship of PD-L1 expression and bTMB/tTMB, and if appropriate, other exploratory 
biomarkers (e.g., IFN-γ) with clinical outcomes (including but not restricted to) OS, PFS and 
ORR may be presented. Cutoffs for these biomarkers will be determined based on data outside 
of this clinical study. 
 
Summaries and analysis for 
exploratory biomarkers will be documented in a separate analysis plan and will be reported 
outside the CSR in a separate report.
8.5.13
Exploratory analysis
Exploratory analysis of OS adjusting for impact of subsequent therapy may be performed if a 
sufficient proportion of patients switch. Methods such as Rank Preserving Structural Failure 
Time (Robins and Tsiatis 1991), Inverse Probability of Censoring Weighting (Robbins 1993) 
and other methods in development will be explored. The decision to adjust and final choice of 
methods will be based on a blinded review of the data and the plausibility of the underlying 
assumptions. Baseline and time-dependent characteristics will be explored, and summaries of 
baseline characteristics will be summarized for SoC patients, splitting between those who 
have and have not switched at the time of the analysis. In addition, OS may be analyzed in 
centers where crossover does not occur.
8.6
China Cohort
The global cohort has approximately 1330 patients enrolled from sites in North America, 
Latin America, Asia, Europe, and Gulf countries to randomize approximately 800 patients. 
The China cohort consists of all Chinese patients from sites accredited by China health 
authority and enrolled prior to the last patient last visit (LPLV) of the global cohort. The 
China cohort will have approximately 160 randomized patients. The global cohort consists of 
all patients recruited by the documented date of last patient first visit (LPFV) of the global 
cohort. Global recruitment will be complete once approximately 800 patients have been 
randomized of which 30 patients are from mainland China. Once global enrollment is 
completed, recruitment across all sites except for those in mainland China will be closed, and 
the recruitment of China patients will continue until the total number of randomized China 
patients is reached. Hence, a patient randomized in the China cohort prior to the LPFV of the 
global cohort enrollment will be included in both the (globally recruited) FAS and the China 
FAS. A patient randomized in the China cohort after the LPFV of the global cohort enrollment 
will be included only in the China FAS.
Per China regulatory guidance, in addition to the evaluation of the global cohort data for 
primary, secondary and safety objectives, evaluation of consistency in efficacy and safety in 
CCI

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China and Asia population is required to facilitate the benefit-risk assessment for Chinese 
patients. Hence, the safety and efficacy date in the China cohort will be analyzed separately 
where the same endpoint definitions (as described in Section 8.4) will hold.  The primary 
comparison of OS between the treatment arms in the China cohort will be done on the PD-L1 
defined population. Details of this analysis can be found in the China specific SAP.
The China full analysis set (China FAS) will include all patients randomized in the China 
cohort and will be used for all China only efficacy analysis.
The China safety analysis set will consist of all patients recruited in the China cohort who 
received at least one dose of study treatment.
Efficacy analysis for the China cohort will be performed when the OS data from the China 
patients is of similar maturity where significant clinical efficacy is established in the global 
cohort, i.e. if OS efficacy is established at the final analysis, a similar maturity to this will be 
used for consistency evaluation.
All statistical analysis will be considered exploratory and only performed if sufficient 
numbers of events or patients are available (e.g. ≥20 OS or PFS events) unless specified, 
otherwise, descriptive statistics only will be presented. No adjustment for multiplicity will be 
made and the procedure for hierarchical testing detailed in Section 8.5 will not be followed. 
OS efficacy evaluation for the China cohort will be performed once.
Details of the China cohort and Asia population analysis, including the vendor to perform the 
analysis, will be specified in the China supplementary SAP, which is to be finalized before the 
global cohort data locks for analysis.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first patient is enrolled in the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and train them in any study-specific procedures and IVRS/IWRS and 
WBDC systems to be utilized.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff).

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9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to

Provide information and support to the Investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, data are being 
accurately and timely recorded in the eCRFs, biological samples are handled in 
accordance with the Laboratory Manual, and IP accountability checks are being 
performed

Perform source data verification (a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice and other records relevant to the 
study), including verification of informed consent of participating patients. This will 
require direct access to all original records for each patient (e.g., clinic charts)

Ensure that withdrawal of informed consent for the use of the patient’s biological 
samples is reported, biological samples are identified and disposed of or destroyed 
accordingly, and the action is documented and reported to the patient
The AstraZeneca representative will be available between visits if the Investigators or other 
staff at the centers need information and advice about the study conduct.
9.2.1
Source data
Refer to the CSA for the location of source data.
9.2.2
Direct access to source data in Japan
The Head of the study site and the Principal Investigator/Investigator will cooperate for 
monitoring and audit by AstraZeneca and accept inspection by the IRB or regulatory 
authorities. All study documents such as raw data will be open for direct access to source data 
at the request of the monitor and the auditor of AstraZeneca, the IRB, or regulatory 
authorities.
The monitor will verify data from the eCRFs against source data before the Principal 
Investigator signs the eCRFs to ensure accuracy and completeness of documentation and 
ensure that the Principal Investigator has submitted the eCRFs to AstraZeneca.
9.2.3
Study agreements
The Principal Investigator at each center should comply with all the terms, conditions, and 
obligations of the CSA for this study. In the event of any inconsistency between this Clinical 
Study Protocol and the CSA, the terms of Clinical Study Protocol shall prevail with respect to 

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the conduct of the study and the treatment of patients. In all other respects not relating to study 
conduct or treatment of patients, the terms of the CSA shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place or before any patients are enrolled.
9.2.4
Archiving of study documents
The Investigator will follow the principles outlined in the CSA.
9.3
Study timetable and end of study
The end of the study is defined as the “last visit of the last patient undergoing the study.” The 
Investigator will be notified by AstraZeneca when recruitment is complete.
The study is expected to start in Q3 2015 and end by Q2 2020. 
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP) or if recruitment is slow. AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study involving MEDI4736.
9.4
Data management by AstraZeneca or delegate
Data management will be performed by a chosen vendor according to the Data Management 
Plan. AEs and medical/surgical history will be classified according to the terminology of the 
latest version of MedDRA. Medications will be classified according to the AstraZeneca Drug 
Dictionary. Classification coding will be performed by the chosen vendor.
The data collected through third party sources will be obtained and reconciled against study 
data.
Data queries will be raised for inconsistent, impossible, or missing data. All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan. Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.
When all data have been coded, validated, signed, and locked, a clean file will be declared. 
Any treatment-revealing data may be added thereafter, and the final database will be locked.
Serious adverse event reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 

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Data associated with human biological samples
Data associated with human biological samples will be transferred from laboratories internal 
or external to AstraZeneca.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonization 
(ICH)/GCP, applicable regulatory requirements, and the AstraZeneca policy on Bioethics and 
Human Biological Samples. The applicable regulatory requirements in Japan are “Good 
Clinical Practice for Trials on Drugs” (Ministry of Health, Labor, and Welfare [MHLW] 
Ordinance No. 28, 27 March 1997, partially revised by MHLW Ordinance and their related 
notifications).
10.2
Patient 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.
10.3
Ethics and regulatory review
An EC/IRB should approve the final study protocol, including the final version of the ICF and 
any other written information and/or materials to be provided to the patients. The Investigator 
will ensure the distribution of these documents to the applicable EC/IRB and to the study site 
staff.
The opinion of the EC/IRB should be given in writing. The Investigator should submit the 
written approval to AstraZeneca before enrollment of any patient into the study. 
The EC/IRB should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the EC/IRB annually.
Before enrollment of any patient into the study, the final study protocol, including the final 
version of the ICF, should be approved by the national regulatory authority or a notification to 
the national regulatory authority should be approved, according to local regulations.
AstraZeneca will handle the distribution of these documents to the national regulatory 
authorities.

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AstraZeneca will provide regulatory authorities, ECs/IRBs, and Principal Investigators safety 
updates or reports according to local requirements.
Each Principal Investigator is responsible for providing the EC/IRB with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the IP. 
AstraZeneca will provide this information to the Principal Investigator so that he/she can meet 
these reporting requirements.
Japan and other countries where this is applicable:
An IRB should approve the final study protocol, including the final version of the ICF and any 
other written information and/or materials to be provided to the patients. The head of the study 
site will ensure the distribution of these documents to the applicable IRB, and the Principal 
Investigator to the Investigator and study site staff.
The opinion of the IRB should be given in writing. The head of the study site should submit a 
notification of direction/determination as well as the IRB written approval to AstraZeneca and 
the Principal Investigator before enrollment of any patient should into the study.
The IRB/EC should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the ICF, which are needed to meet local 
requirements.
The head of the study site should seek the opinion of the IRB with respect to the 
appropriateness of continuing the study at the study site at least once a year when the duration 
of the study exceeds 1 year. The Principal Investigator should submit progress reports to the 
IRB via the head of the study site at the time of the protocol re-approval.
Before enrollment of any patient into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.
AstraZeneca will provide regulatory authorities, IRB, the head of the study site, and the PIs 
with safety updates/reports according to local requirements.
The head of the study site should submit a written report to the IRB, providing the details of 
all relative safety information reported by AstraZeneca.
10.4
Informed consent
The Principal Investigator(s) at each center will:

Ensure that each patient is given full and adequate oral and written information 
about the nature, purpose, possible risk, and benefit of the study

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
Ensure that each patient is notified that he or she is free to discontinue from the 
study at any time

Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided

Ensure that each patient provides a signed and dated informed consent before 
conducting any procedure specifically for the study

Ensure that the original, signed ICF(s) is/are stored in the Investigator’s Study File

Ensure that a copy of the signed ICF is given to the patient

Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the ICF that is approved by an EC/IRB
For sites in Japan only
If any new information on the IP becomes available that may influence the decision of the 
patient to continue the study, the Investigator should inform the patient of such information 
immediately, record this in a written form, and confirm with the patient if he or she wishes to 
continue the participation in the study. In addition, if the Investigator deems it necessary to 
revise the ICF, he or she should revise it immediately (refer to Section 10.5). The Investigator 
should re-explain to the patients using the updated ICF even if the patients have already been 
informed of the new information verbally. Written informed consent to continue participation 
in the study should be provided separately.
10.5
Changes to the protocol and informed consent form
For sites outside Japan
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and, where required, in a new version of the study 
protocol.
The new version of the Clinical Study Protocol is to be approved by the relevant EC/IRB and, 
if applicable, the national regulatory authority, before implementation. Local requirements are 
to be followed for new versions of the Clinical Study Protocol.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator. For distribution to EC/IRB, see Section 10.3.

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If a protocol amendment requires a change to a center’s ICF, AstraZeneca and the center’s 
EC/IRB are to approve the revised ICF before the revised form is used.
For Japan sites only:
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.  If it is necessary for the Clinical Study Protocol to be amended, 
the new version of the Clinical Study Protocol should be submitted to the Head of the Study 
Site and be approved by its IRB.  If applicable, AstraZeneca should submit a notification to 
the regulatory authority before it is implemented.  If a Clinical Study Protocol amendment 
requires a change to a particular centre's Informed Consent Form, then AstraZeneca and the 
centre's IRB should be notified by the Principal Investigator.  Approval of the revised 
Informed Consent Form by AstraZeneca and by the IRB is required before the revised form is 
used.
10.6
Audits and inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an EC/IRB may perform 
audits or inspections at the center, including source data verification. The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and to determine if data 
were recorded, analyzed, and accurately reported according to the protocol, GCPs, ICH 
guidelines, and any applicable regulatory requirements. The Investigator will contact 
AstraZeneca immediately if contacted by a regulatory agency about an inspection at the 
center.

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Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Edition Number 9.0
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11.
LIST OF REFERENCES
Alexandrov et al, 2013
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S, Blankin AV, et al. 
Signatures of mutational processes in human cancer. Nature. 2013 Aug 22;500:415-21.
Antonia et al 2014a
Antonia S, Goldberg S, Balmanoukian A, Narwal R, Robbins P, D’Angelo G, et al. A Phase 1 
open-label study to evaluate the safety and tolerability of MEDI4736, an anti-programmed cell 
death-ligand 1 (PD-L1) antibody, in combination with tremelimumab in patients with 
advanced non-small cell lung cancer (NSCLC). Poster presented at European Society of 
Medical Oncology Meeting; 2014 Sep 26-30; Madrid, Spain.
Antonia et al 2014b
Antonia S, Ou SI, Khleif SN, Brahmer J, Blake-Haskins A, Robbins PB, et al. Clinical activity 
and safety of MEDI4736, an anti-programmed cell death ligand-1 (PD-L1) antibody in 
patients with NSCLC. Poster presented at the European Society for Medical Oncology 
Meeting; 2014 Sep 26-30; Madrid, Spain.
Ayers et al 2017
Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, et al. IFN-γ-related 
mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127:2930-
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Appendix A
Additional Safety Information
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS ADVERSE EVENT 
(SAE)
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 (e.g. hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g. bronchospasm, laryngeal edema). 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.
Important medical event or medical intervention
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, hospitalization, disability, or incapacity but may jeopardize the patient or may require 
medical intervention to prevent 1 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 
judgement 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 (e.g. neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse
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.

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
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 etiology 
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.
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.
A 1
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 study drug that either causes harm to the participant 
or has the potential to cause harm to the participant.  

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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 recognize that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error e.g.  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 e.g.  tablet dissolved in water when it should be taken as 
a solid tablet 

Drug not stored as instructed e.g.  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) e.g.  forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

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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Appendix B
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 (DGR) 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, e.g. 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, e.g. Hepatitis A, B, C, D, and E viruses, 
human immunodeficiency virus (HIV) 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 containment standards are encouraged wherever 
possible when road or rail transport is used.

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Appendix C
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law. It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries. Specific guidance on the managing liver abnormalities can be 
found in Sections 5.2.1 and 6.1.5 of the protocol.
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 Hy’s Law (PHL) criteria at any point during the study.
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 Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3 × Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP). 
Hy’s Law (HL)
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, 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, or 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.
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:

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
ALT ≥3 × ULN

AST ≥3 × ULN

TBL ≥2 × ULN
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 two Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory electronic case report form 
(eCRF)
Follow-up
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss, and agree on an 
approach for the study patients’ follow-up 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 

Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician

Complete the three Liver eCRF Modules as information becomes available 

If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures

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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.
No later than 3 weeks 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. The AstraZeneca Medical Science Director 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.
If 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 a SAE

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF

If the alternative explanation is an AE/SAE, record the AE /SAE in the eCRF 
accordingly and follow 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

Report an 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

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 3 weeks, 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:

Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above

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 met. Update the SAE report according to the 
outcome of the review amending the reported term if an alternative explanation for 
the liver biochemistry elevations is determined

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Actions required when potential Hy’s law criteria are met before and after starting 
study treatment 
This section is applicable to patients with liver metastases who meet PHL criteria on study 
treatment having previously met PHL criteria at a study visit prior to starting study treatment.
At the first on study treatment occurrence of PHL criteria being met the Investigator will:

Determine if there has been a significant change in the patients’ condition# 
compared with the last visit where PHL criteria were met#

If there is no significant change no action is required

If there is a significant change notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Potential Hy’s Law Criteria met of this Appendix 
#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.
Actions required for repeat episodes of potential Hy’s law
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:

Was the alternative cause for the previous occurrence of PHL criteria being met 
found to be the disease under study, e.g., chronic or progressing malignant disease, 
severe infection or liver disease, or did the patient meet PHL criteria prior to 
starting study treatment and at their first on study treatment visit as described in 
section “Actions required when potential Hy’s law criteria are met before and after 
starting study treatment” of this appendix
If No: Follow the process described in Section Potential Hy’s Law Criteria met of this 
Appendix.
If Yes: 
Determine if there has been a significant change in the patient’s condition# compared with 
when PHL criteria were previously met

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
If there is no significant change no action is required

If there is a significant change follow the process described in Section Potential 
Hy’s Law Criteria met of this Appendix
#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.
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf

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Appendix D
Guidelines for Evaluation of Objective Tumor Response Using RECIST 1.1 Criteria 
(Response Evaluation Criteria in Solid Tumors) 
Introduction 
This appendix details the implementation of Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines (Eisenhauer et 
al 2009) for this study with regards to Investigator assessment of tumor burden including protocol-specific requirements for this 
study. Additional special guidance is provided for determination of confirmation of radiologic progression.
Definition of measurable, non-measurable, target and non-target lesions
Only patients with measurable disease at baseline should be included in the study. Measurable disease is defined by the presence of 
at least 1 measurable lesion which has not been previously irradiated. 
Tumor lesions selected for screening biopsy must not be used as target lesions, unless there unless imaging occurred at least ~2 
weeks after biopsy, allowing time for healing.
Measurable:
A lesion, not previously irradiated or biopsied per the protocol prior to randomization, that can be accurately measured at baseline 
as ≥10 mm in the longest diameter (except lymph nodes, which must have short axis1 ≥15 mm) with computed tomography (CT) or 
magnetic resonance imaging (MRI) and that is suitable for accurate repeated measurements.
Non-measurable:
(i)
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 mm to <15 
mm short axis at baseline2)
                                               
1 The short axis is defined as the longest axis perpendicular to long axis of the lymph node
2 Nodes with <10 mm short axis are considered non-pathological and should not be recorded or followed as non-target lesions (NTLs).

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(ii)
Truly non-measurable lesions include the following: bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung and abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by CT or MRI
(iii)
Tumor lesions selected for screening biopsy
(iv)
Previously irradiated lesions3
(v)
Skin lesions assessed by clinical examination
(vi)
Brain metastasis
Special cases:

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue components, can be considered measurable 
if the soft tissue component meets the definition of measurability. Blastic lesions are considered non-measurable

Cystic metastases can be considered measurable lesions if they meet the criteria for measurability from a radiological 
point of view, but if non-cystic lesions are present in the same patient, these should be selected as target lesions (TLs)
Target lesions:
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative of all lesions involved suitable for 
accurate repeated measurement, should be identified as TLs at baseline. Lymph nodes, in any location, are collectively considered 
as a single organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ is considered as a single organ.
Non-target lesions:
Additional measurable and non-measurable lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline.
                                               
3 Localised post-radiation changes which affect lesion sizes may occur. Therefore, lesions that have been previously irradiated will not be considered 
measurable and must be selected as NTL at baseline and followed up as part of the NTL assessment

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Methods of assessment
The same method of assessment and the same technique should be used to characterize each identified and recorded lesion 
at baseline and during follow-up visits.
A summary of the methods to be used for RECIST assessment is provided in Table 1 below, and those excluded from tumor 
assessments for this study are highlighted with the rationale provided.
Table 1
Summary of methods of assessment
Target lesions 
Non-target lesions
New lesions
CT (preferred)
MRI
CT (preferred)
MRI
Clinical examination 
X-ray, Chest X-ray
CT (preferred)
MRI
Clinical examination 
X-ray, Chest X-ray
Ultrasound
Bone scan
FDG-PET
CT  Computed tomography; FDG-PET  18-Fluoro-deoxyglucose positron emission tomography; MRI  Magnetic resonance imaging.
CT and MRI 
CT and MRI, each preferably with IV contrast, are generally considered to generate the best currently available and reproducible 
images for measurement of TL assessment of NTL, and identification of any new lesions. 
It is recommended that IV contrast-enhanced CT examinations of the chest and abdomen (including liver and adrenal glands) will 
be used to assess tumor burden at baseline and follow-up visits. Any other areas of disease involvement should be additionally 
imaged based on the signs and symptoms of individual patients. In patients who are sensitive to IV CT contrast, a non-contrast CT 
exam of the chest and an MRI with IV contrast of the abdomen (including liver and adrenal glands) is appropriate. In patients with 
severely compromised renal function a non-contrast CT exam of the chest and abdomen (including liver and adrenal glands) is 
appropriate. For brain lesion assessment, MRI with IV contrast is the preferred method over contrast-enhanced CT. It is strongly 
recommended to maintain use of the same imaging modality (CT or MRI), acquisition protocol, facility, and scanner across all 
imaging time points per patient.

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Clinical examination 
Clinical examination will not be used for assessment of TL. Clinically detected lesions can be selected as TLs if they are assessed 
by CT or MRI scans. Clinical examination can be used to assess NTL and to identify the presence of new lesions.
X-ray
Chest X-ray
Chest X-ray assessment will not be used for assessment of TL as they will be assessed by CT examination or MRI examination. 
Chest X-ray can, however, be used to assess NTL and to identify the presence of new lesions.
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTL and to identify the presence of new bone lesions. 
Ultrasound 
Ultrasound examination will not be used for assessment of TL and NTL as it is not a reproducible method, does not provide an 
accurate assessment of tumor size, and it is subjective and operator dependent. Ultrasound examination can, however, be used to 
identify the presence of new lesions. If new clinical symptoms occur and an ultrasound is performed, then new lesions should be 
confirmed by CT or MRI examination.
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated in the context of tumor assessment.
Tumor markers 
Tumor markers will not be used for tumor response assessments as per RECIST 1.1.
Cytology and histology 
Histology will not be used as part of the tumor response assessment as per RECIST 1.1. 
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment is required when the 
measurable tumor has met criteria for response or stable disease. In such circumstances, the cytology is necessary for the 
Investigator to differentiate between response/stable disease (an effusion may be a side effect of the treatment) and progressive 

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disease (if the neoplastic origin of the fluid is confirmed). Where cytology findings are not available, any effusion that significantly 
worsens (from trace to large) or appearance of clinically significant effusion (requiring change in drug therapy) during the study 
treatment will be considered to be progression of NTL, or disease progression due to new lesions. 
Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or X-ray at baseline should be recorded as 
NTL and followed by the same method as per baseline assessment. 
Isotopic bone scans may be used as a method of assessment to identify the presence of new bone lesions at follow-up visits. New 
lesions will be recorded where a positive hot-spot that was not present on the baseline bone scan assessment is identified on a bone 
scan performed at any time during the study. The Investigator should consider the positive hot-spot to be a significant new site of 
malignant disease and represent true disease progression in order to record the new lesion. Confirmation by CT, MRI, and X-ray is 
recommended where bone scan findings are equivocal.
FDG-PET scan
18F-Fluoro-deoxyglucose positron emission tomography/computed tomography (FDG-PET) scans may be used as a method for 
identifying new lesions, according with the following algorithm: New lesions will be recorded where there is positive 
18F-Fluoro-deoxyglucose uptake4 not present on baseline FDG-PET scan or in a location corresponding to a new lesion on CT/MRI 
at the same follow-up visit. If there is no baseline FDG-PET scan available, and no evidence of new lesions on CT/MRI scans, then 
follow-up CT/MRI assessments should be continued, scheduled as per protocol or clinical indicated, in order to confirm new 
lesions.
At present, low dose or attenuation correction CT portions of a combined FDG-PET/CT scans are 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 tumour 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 
                                               
4 A positive FDG-PET scan lesion should be reported only when an uptake greater than twice that of the surrounding tissue is observed

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of the PET/CT can be used for RECIST measurements. However, 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.
Tumor response evaluation 
Schedule of evaluation
The methods of assessment of tumor burden used at baseline CT/MRI scans of the chest and abdomen (including liver and adrenal
glands) must be used at each subsequent follow-up assessment. Additional imaging may be performed based on the signs and 
symptoms of the patient (e.g., new lesions at follow up).
Baseline assessments should be performed no more than 28 days before start of study treatment, and ideally should be performed as 
close as possible and prior to the start of investigational product. Efficacy for all patients will be assessed by objective tumor 
assessments every 6 weeks ± 1 week for the first 48 weeks (relative to the date of randomization; see Section 5.1 of the clinical 
study protocol), then every 8 weeks ± 1 week thereafter until confirmed objective disease progression as defined by RECIST 1.1 
(irrespective of the reason for stopping treatment/or subsequent therapy). If an unscheduled assessment is performed, and the
patient has not progressed, every attempt should be made to perform the subsequent assessments at the patient’s scheduled visits. 
For patients who discontinue study drug due to toxicity in the absence of confirmed objective progression, objective tumor 
assessments should be continued every 6 weeks ± 1 week for 48 weeks (relative to the date of randomization) then every 8 weeks ± 
1 week until confirmed objective disease progression. 
In addition to partial response and complete response, radiographic progression (PD by RECIST 1.1) requires confirmation; the
confirmatory scan should occur no earlier than 4 weeks after the initial assessment of progression of disease (PD) and preferably at 
the next scheduled visit in the absence of clinically significant deterioration.
If progression is not confirmed then the patient should continue on study treatment and continue with imaging assessments on their 
regular schedule.
If an unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform the 
subsequent assessments at the patient’s scheduled visits. 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.

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Additional assessments will be performed post confirmed objective disease progression for patients remaining on IMT treatment, 
retreatment, or until subsequent cancer therapy according to the clinical study protocol.
Any other anatomical sites at which new disease is suspected should also be adequately imaged at follow-up.
Target lesions
Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including lymph nodes collectively considered as a 
single organ), representative of all lesions involved should be identified as TL at baseline. Target lesions should be selected on the 
basis of their size (longest diameter for non-nodal lesions or short axis for nodal lesions), but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion, which can be measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for non-nodal lesions (or short axis for 
lymph nodes). All measurements should be recorded in millimeters. At baseline the sum of the diameters for all TL will be 
calculated and reported as the baseline sum of diameters. At follow-up visits the sum of diameters for all TL will be calculated and 
reported as the follow-up sum of diameters.
Special cases:

For TL measurable in 2 or 3 dimensions, always report the longest diameter. For pathological lymph nodes measurable in 
2 or 3 dimensions, always report the short axis

If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable disease at baseline should be twice the 
slice thickness of the baseline scan

If a lesion has completely disappeared, the longest diameter should be recorded as 0 mm

If a TL splits into 2 or more parts, then record the sum of the diameters of those parts 

If two or more TLs merge, then the sum of the diameters of the combined lesion should be recorded for one of the lesions 
and 0 mm recorded for the other lesion(s)  

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
If a TL is believed to be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned. 
If an accurate measure can be given, this should be recorded, even if it is below 5 mm

If a TL cannot be measured accurately due to it being too large, provide an estimate of the size of the lesion 

When a TL has had any intervention e.g., definitive radiotherapy, embolization, surgery, etc. during the study, the size of 
the TL should still be provided where possible and the intervention recorded in the RECIST case report form
Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumor visit response for TL (see Table 2 below).
Table 2
Evaluation of target lesions
Complete Response (CR)
Disappearance of all TLs since baseline. Any pathological lymph 
nodes selected as TLs must have a reduction in short axis to 
<10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of the diameters of TL, taking 
as reference the baseline sum of diameters
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD
Progression of disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.
Not Evaluable (NE)
Only relevant if any of the TLs at follow-up were not assessed or 
not evaluable (e.g. missing anatomy) or had a lesion intervention 
at this visit.  Note: if the sum of diameters meets the progressive 
disease criteria, progressive disease overrides not evaluable as a 
TL response
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; SD  Stable disease; TL  Target lesion.

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Non-target lesions
Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline. Measurements are not required for 
these lesions, but their status should be followed at subsequent visits. At each visit an overall assessment of the NTL response 
should be recorded by the Investigator. This section provides the definitions of the criteria used to determine and record overall 
response for NTL at the investigational site at each visit (see Table 3 below).
Table 3
Evaluation of non-target lesions
Complete response (CR)
Disappearance of all NTLs since baseline. All lymph nodes must 
be non-pathological in size (<10 mm short axis).
Non CR/Non PD
Persistence of 1 or more NTL.
Progression (PD)
Unequivocal progression of existing NTLs. Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions. In all cases the progression MUST be 
clinically significant for the physician to consider changing (or 
stopping) therapy.
Not evaluable (NE)
Only relevant when 1 or some of the NTLs were not assessed and, 
in the Investigator’s opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit.
Note: for patients without TLs at baseline, this is relevant if any of 
the NTLs were not assessed at this visit and the progression 
criteria have not been met.
CR  Complete response; PR  Partial response; PD  Progression of disease; NE  Not evaluable; NTL  Non-target lesion; TL  Target lesion
To achieve “unequivocal progression” on the basis of NTLs, there must be an overall level of substantial worsening in non-target 
disease such that, even in presence of stable disease or partial response in TLs, the overall tumor burden has increased sufficiently 
to merit discontinuation of therapy. A modest “increase” in the size of 1 or more NTLs is usually not sufficient to qualify for 
unequivocal progression status.

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New lesions
Details of any new lesions will also be recorded with the date of assessment. The presence of 1 or more new lesions is assessed as 
progression. 
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at baseline is considered a new lesion 
and will indicate disease progression.
The finding of a new lesion should be unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor.
If a new lesion is equivocal, for example because of its small size, the treatment and tumor assessments should be continued until 
the new lesion has been confirmed. If repeat scans confirm there is a new lesion, then the progression date should be declared using 
the date of the initial scan.
Symptomatic deterioration
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for stopping study therapy.
Patients with “symptomatic deterioration” requiring discontinuation of treatment without objective radiological evidence of disease 
progression at that time should continue to undergo tumor assessments where possible until objective disease progression is 
observed.
Evaluation of overall visit response
The overall visit response will be derived using the algorithm shown in Table 4 below.
Table 4
Overall visit response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR

Clinical Study Protocol Appendix D
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Version 9.0Date 20 Jan 2020
170 (174)
Table 4
Overall visit response
Target lesions
Non-target lesions
New lesions
Overall response
CR
Non CR/Non PD 
No
PR
CR
NE
No 
PR
PR
Non PD or NE
No
PR
SD 
Non PD or NE
No
SD
NA
Non-CR/Non-PD
No
SD (Non-CR/non-PD)
NE
Non PD or NE
No
NE
NA
NE
No
NE
NA
NA
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR  Complete response, PR  Partial response, SD  Stable disease, PD  Progression of disease, NE  Not evaluable, NA  Not applicable (only relevant if there 
were no non-target lesions at baseline)
Confirmation of Progression
Confirmation of progression guidelines are set for the following reasons: 

For patient management and treatment decisions

In the absence of significant clinical deterioration, to promote the collection of additional scans after the first radiologic 
RECIST 1.1 assessment of progressive disease (PD) in order to distinguish pseudoprogression from true radiologic 
progression, also known as RECIST 1.1 modified for confirmation of progression
Confirmed objective disease progression refers to either of the following scenarios: (1). clinical progression/deterioration followed 
by a radiologic verification scan (PD by RECIST 1.1); or (2). in the absence of significant clinical deterioration, radiologic PD by 
RECIST 1.1 followed by a second radiologic confirmation scan with PD assessed according to the specific confirmation of 

Clinical Study Protocol Appendix D
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Version 9.0Date 20 Jan 2020
171 (174)
progression criteria listed below. RECIST 1.1 modified for confirmation of progression refers to the second scenario above. The 
confirmatory scan should occur preferably at the next scheduled imaging visit and no earlier than 4 weeks following the date of the 
immediate prior assessment of RECIST 1.1 PD.
Immediate prior radiologic progression would be considered confirmed if any the following criteria are met in the confirmatory 
scan:

≥20% increase in the sum diameters of TLs compared with the nadir at 2 consecutive visits, with an absolute increase of 
at least 5 mm in sum of diameters compared with nadir

and/or significant progression (worsening) of NTLs and/or pre-existing new lesions at the confirmatory scan time-point 
compared with the immediate prior time-point (Note: Pre-existing new lesions are evaluated as NTLs at the confirmatory 
scan time-point)

and/or additional new unequivocal lesions at the confirmatory scan timepoint
NOTE: In order to have confirmed objective disease progression, there should be two consecutive PD’s, the first PD by RECIST 
1.1 and the second PD using the confirmation of progression criteria (above). If the first PD by RECIST 1.1 is not confirmed,
continue with assessments until the next PD by RECIST 1.1, which in turn will need its own immediate subsequent confirmation 
scan.
In the absence of significant clinical deterioration, treatment with study drug may continue between the initial assessment of 
progression and the scan to confirm progression. 
If the confirmation scan confirms progression, then the date of the prior scan with PD should be declared as the date of progression.
If progression is not confirmed, in the absence of significant clinical deterioration, then the patient should continue study drug and 
on-treatment assessments until the next PD which will also require a follow-up confirmation scan. If the first PD is not confirmed 
by the immediate next scan, then the Investigator should not change the PD assessment of the first scan. 
If a patient discontinues treatment (and/or receives a subsequent cancer therapy) prior to progression, then the patient should still 
continue to be followed with imaging until confirmed objective disease progression.

Clinical Study Protocol Appendix D
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Version 9.0Date 20 Jan 2020
172 (174)
Central Review
Blinded Independent Central Review assessments are not planned for this study. However, all images will be collected, quality
checked, and stored centrally by an Imaging Contract Research Organization (CRO) appointed by AstraZeneca so that the scans 
will be available if such verification becomes necessary. Guidelines for image acquisition, anonymization, storage at the 
investigative site as source data, and transfer to the Imaging CRO will be provided in a separate document. The management of
patients will be based solely upon the local assessments conducted by the investigator. 
If central review is conducted, the Contract Research Organization appointed by AstraZeneca to perform the independent central 
review for this study will provide specification for radiological imaging protocols in standard acquisition guidelines documentation. 
Specifications for Radiological Imaging
These notes are recommendations for use in clinical studies. The use of standardized protocols for CT and MRI allows 
comparability both within and between different studies, irrespective of where the examination has been undertaken.
If specified, all images will be collected, quality checked and stored centrally by the imaging CRO appointed by AstraZeneca.
Guidelines for image acquisition, anonymization, storage at the investigative site as source data and transfer to the imaging CRO 
will be provided in a separate document. The management of patients will be based solely upon the local assessments conducted by 
the Investigator.
Also if specified, further details of the Blinded Independent Central Review (BICR) will be documented in the Independent Review 
Charter (also referred to as the ‘Imaging Charter’)
CT Scan
CT scans of the chest and abdomen (and pelvis when indicated) should be contiguous throughout all the anatomic region of interest.
The most critical CT image acquisition parameters for optimal tumour evaluation using RECIST 1.1 are anatomic coverage, 
contrast administration, slice thickness, and reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumours is the chest, abdomen and pelvis. 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 

Clinical Study Protocol Appendix D
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Version 9.0Date 20 Jan 2020
173 (174)
the extent of imaging coverage at baseline and at subsequent follow-up time points. This will enable better consistency not only of 
tumour measurements but also identification of new disease.
b. IV contrast administration: Optimal visualisation and measurement of metastases in solid tumours requires consistent 
administration (dose and rate) of IV contrast as well as timing of scanning. Typically, most abdominal imaging is performed during 
the portal venous phase and (optimally) about the same time frame after injection on each examination. An adequate volume of a 
suitable contrast agent should be given so that the metastases are demonstrated to best effect and a consistent method is used on 
subsequent examinations for any given patient. It is very important that the same technique be used at baseline and on follow- up 
examinations for a given patient. For patients who develop contraindications to contrast after baseline contrast CT is done, the 
decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) should be performed should also be based on the 
tumour type, anatomic location of the disease and should be optimised to allow for comparison to the prior studies if possible. Each 
case should be discussed with the radiologist to determine if substitution of these other approaches is possible and, if not, the patient 
should be considered not evaluable from that point forward. Care must be taken in measurement of target lesions on a different 
modality and interpretation of non-target disease or new lesions, since the same lesion may appear to have a different size using a 
new modality. Oral contrast is recommended to help visualise and differentiate structures in the abdomen. 
If iodine contrast media is medically contraindicated at baseline or at any time during the course of the study then the recommended 
methods are: CT thoracic (chest) examination without contrast and abdominal (and pelvis) MRI with contrast. If MRI cannot be 
performed then CT without IV contrast is an option for the thorax and abdomen (and pelvis) examination. For brain imaging, MRI 
with IV contrast is the preferred method.
c. Slice thickness and reconstruction interval: It is recommended that CT scans be performed at 5mm contiguous slice thickness 
and this guideline presumes a minimum 5 mm thickness in recommendations for measurable lesion definition. Exceptionally, 
particular institutions may perform medically acceptable scans at slice thicknesses greater than 5 mm. If this occurs, the minimum 
size of measurable lesions at baseline should be twice the slice thickness of the baseline scans.
All window settings should be included in the assessment, particularly in the thorax where lung and soft tissue windows should be 
considered. When measuring lesions, the TL should be measured on the same window setting for repeated examinations throughout 
the study. All images from each examination should be included in the assessment and not “selected” images of the apparent lesion.

Clinical Study Protocol Appendix D
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00003
Version 9.0Date 20 Jan 2020
174 (174)
MRI Scan
MRI has excellent contrast, spatial and temporal resolution; 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 measured/assessed on the 
same pulse sequence. Generally, axial imaging of the abdomen and pelvis (and other anatomies e.g. neck) with T1 and T2 weighted 
imaging along with gadolinium-enhanced imaging can be performed. The field of view, matrix, number of excitations, phase 
encoding steps, use of fat suppression and fast sequences should be optimised for the specific body part being imaged as well as the 
scanner utilised. CT of the chest is typically recommended over MRI due to significant motion artifacts (heart, major blood vessels, 
breathing) associated with MRI. It is beyond the scope of this appendix to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be 
followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques if possible.
For these reasons, CT is the imaging modality of choice.
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;45:228-47

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