A Phase III, Randomized, Multi-Center, Open-Label, Comparative Global Study to Determine the Efficacy of Durvalumab or Durvalumab and Tremelimumab in Combination With Platinum-Based Chemotherapy for First-Line Treatment in Patients With Metastatic Non Small-Cell Lung Cancer (NSCLC) (POSEIDON)
Phase: PHASE3
Conditions: Non Small Cell Lung Cancer NSCLC
Sponsor: AstraZeneca

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
This submission document contains confidential commercial information, disclosure of which is prohibited 
without providing advance notice to AstraZeneca and opportunity to object.
Clinical Study Protocol
Drug Substance
Durvalumab (MEDI4736) 
and tremelimumab
Study Code
D419MC00004
Version
6.0
Date
09 July 2021
EudraCT
2017-000920-81
A Phase III, Randomized, Multi-Center, Open-Label, Comparative Global 
Study to Determine the Efficacy of Durvalumab or Durvalumab and 
Tremelimumab in Combination With Platinum-Based Chemotherapy for 
First-Line Treatment in Patients With Metastatic Non-Small-Cell Lung 
Cancer (NSCLC) (POSEIDON) 
Sponsor:
AstraZeneca AB, S-151 85 Södertälje, Sweden
Local sponsor in Japan: AstraZeneca K.K., 3-1, Ofuka cho, Kita-ku Osaka 530-0011, Japan

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
2(225)
Version 6.0, 09 July 2021
SYNOPSIS [Study site(s) and number of patients planned], Section 9.3 [Study timetable 
and end of study]: To obtain long-term follow up OS data post final analysis of OS for 
superiority in line with the recent positive read-out from the study, “Estimated date of last 
patient completed in global cohort” was changed from Q2 2021 to Q4 2023 and detailed 
assessments during the long-term OS follow up period was highlighted.
SYNOPSIS [international Coordintating Investigators]:
 has been removed from 
ICI list.
Section 1.3.2.1 [Durvalumab]: This section was updated per durvalumab IB edition 16_08
Oct 2020
Section 1.4.1 [Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis]: This section was created to insert 
language describing study conduct mitigations during study disruptions due to a health crisis
per Oncology Late Phase Master Clinical Study Protocol v.1_Durvalumab +- Tremelimumab-
29 Jan 2021
SYNOPSIS [Post Final Data Cut Off(DCO)], Section 4.3 [Follow-up period], 
Section 7.2.2.3[Post Final Data Cut Off(DCO)], Section 9.3 [Study timetable and end of 
study], Section 9.4 [Data Management by AstraZeneca or delegate]: These sections were
updated to add detailed assessments to proceed Long-term follow-up post final analysis of OS 
for superiority.
Section 5.1.2 [Survival assessments]: This section was updated to provide clarification on 
how to assess patient survival post final analysis of OS for superiority.
Section 6.3.12 [Safety Data To Be Collected following the final DCO of the study]: 
This section was updated to provide clarification on how to collect safety data post final DCO 
of OS for superiority.
Section 6.9.1 [Specific toxicity management and dose modification information –
Durvalumab and durvalumab + tremelimumab]: Removal of TMG web-portal text due to 
portal shutdown per Oncology Late Phase Master Clinical Study Protocol v.1_Durvalumab +-
Tremelimumab-29 Jan 2021.
Section 7.2.2.2 [Treatment Arms 1 and 2: Criteria for treatment through progression 
and for retreatment]: This section was updated to provide clarification on “treatment 
through confirmed radiological PD”.
Section 7.8 [Post-study access to study treatment]: This section was updated to provide 
clarification on how to supply open-label drugs to patients receiving treatment.
PPD

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
3(225)
Appendix E [Guidelines for Evaluation of Objective Tumor Response]: This section was 
updated to clarify consultation is required before making a decision for patient to continue
treatment through confirmed radiological PD.
Appendix G [Changes Related to Mitigation of Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis, including COVID-19 Outbreak]:      
This section was created to insert language describing study conduct mitigations during study 
disruptions due to a health crisis per Oncology Late Phase Master Clinical Study Protocol 
v.1_Durvalumab +- Tremelimumab-29 Jan 2021.
Version 5.0, 20 April 2020
SYNOPSIS [Study site(s) and number of patients planned], Section 9.3 [Study timetable 
and end of study]: “Estimated date of last patient completed in global cohort” was changed 
from Q4 2019 to Q2 2021 according to study progress
SYNOPSIS [International Coordinating Investigators]: ICI name changed to 
 
SYNOPSIS [Safety Confirmation], Section 1.6.1 [Safety Confirmation]: Clarified 
language for IDMC after PFS analysis
Section 1.3.2.1[Durvalumab], 1.3.2.2[Tremelimumab]: Updates per durvalumab IB edition 
14_11 Feb 2019 and tremeliumab IB edition 9_27 Nov 2018
Section 6.3.12 [Specific toxicity management and dose modification information -
Durvalumab and durvalumab + tremelimumab], Section 6.5 [Treatment Arms 1 and 2 
adverse events of special interest], Section 6.9 [Manage of IP-related toxicities]:        
Term “Appendix E” was changed to “TMG Annex”
Section 6.5[Treatment Arms 1 and 2 adverse events of special interest]: Updated AESI 
list from Durvalumab IB edition 14_11 Feb 2019
Section 6.9.1 [specific toxicity management and dose modification information -
Durvalumab and durvalumab + tremelimumab: Updated language when applying TMGs 
as a separate clinical document
Appendix D [Hy’s Law]: This section was updated based on “The revised CSP Appendix 
Hys Law v3, dated 29March2019”. 
Appendix E [Dose Modification and Toxicity Management Guidelines]: This section was 
removed to have TMG as a standalone Annex. 
Appendix E [Guidelines for Evaluation of Objective Tumor Response]: This section was 
changed from Appendix F to Appendix E due to removal of Appendix E and a sentence was 
PPD

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
4(225)
taken out in regards to the need to consult with AZ, to add more clarity to the process. Very 
high recommended changed incorporated.
Appendix G [Patient Reported Outcomes]: This section was changed from Appendix G to 
Appendix F due to Appendix E removal.
Version 4.0, 25 September 2018
Synopsis [Study site(s) and number of patients planned, Statistical methods]: In these 
sections wording ‘up to’ was included to China patient numbers and word ‘mainland’ was 
removed to have flexibility for China patient recruitment.
Synopsis [Primary objectives]: This section was updated to be dual endpoint of overall 
survival (OS) (durvalumab + SoC chemotherapy).
Synopsis [Secondary objectives]: This section was updated to include patients with TMB-
high and PD-L1 TC<25% as a secondary endpoint in line with PD-L1 TC<50% and TC<1%. 
Also additional parameters were added for combo (durvalumab + tremelimumab combination 
therapy + SoC chemotherapy) and monotherapy (durvalumab monotherapy + SoC 
chemotherapy) compared with SoC chemotherapy.
Synopsis [Statistical methods]: OS included as dual primary endpoint in this section and 
other statistical considerations were updated. Also wording ‘up to’ was included to China 
patient numbers and word ‘mainland’ was removed to have flexibility for China patient 
recruitment.
List of abbreviations and definition of terms: Term 
 was included.
Section 1.2.4 [Rationale for endpoints]: Rationale for endpoints have been updated based on 
consideration of OS as dual primary endpoint and TMB-high as secondary endpoint.
Section 1.3.1.3 (Durvalumab + tremelimumab with chemotherapy): A typo error 
correction was made to number of patients involved in the DCO of Phase Ib study 
(NCT02537418) run by the CCTG.
Section 1.4 Study design, Section 8.2 Sample size estimate, and Section 8.6 China cohort:
In these sections wording ‘up to’ was included to China patient numbers and word ‘mainland’ 
was removed to have flexibility for China patient recruitment.
Figure 3 (overall study design): OS included as a secondary endpoint.
Section 2.1 [Primary objectives]: This section was updated to be dual endpoint of overall 
survival (OS) (durvalumab + SoC chemotherapy).
Section 2.2 [Secondary objectives]: This section was updated to include patients with TMB-
high and PD-L1 TC<25% as a secondary endpoint in line with PD-L1 TC<50% and TC<1%. 
Also additional parameters were added for combo (durvalumab + tremelimumab combination 
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
5(225)
therapy + SoC chemotherapy) and monotherapy (durvalumab monotherapy + SoC 
chemotherapy) compared with SoC chemotherapy.
Section 3.9 [Discontinuation of IP]: The wording in this section was updated to give more 
clarity on IP discontinuation criteria for treatment arm 1 and 2 patients.
Section 3.9.1 [Procedures for discontinuation of patient from IP]: A sentence in this 
section was deleted to clarify there is no necessity to notify AZ study Physician if any 
ongoing AE that may delay treatment or necessitate permanent discontinuation of treatment.
Section 4 [Study plan and timing of procedures]: Table 2: 
Footnote ‘y’ has been updated to provide more clarity on ePRO assessment window period.
Section 5.1 [Efficacy assessments]: The wording ‘co-primary endpoint’ has been changed to 
‘dual primary endpoint’ and the wordings are updated according to changes made into 
objectives in this amendment
Section 5.5.1 [Collection of patient samples for stratification by PD-L1 expression]: This 
section was updated to include TMB and provided more rationale for the same. Also it was 
clarified that plasm samples will also be used for tumor markers analysis.
Section 5.5.3 [Storage, re-use, and destruction of biological samples]: A note was added in 
this section to clarify the sample storage requirenments for China.
Section 7.2.2.2 [Treatment Arms 1 and 2: Criteria for treatment through progression 
and for retreatment]: The word ‘confirmed’ has been removed from this section to give 
more clarity on criteria for treatment through progression for treatment arm 1 and 2 patients. 
Other relavent sections in the protocol were also updated to maintain the consistency.
Section 8.1 [Statistical considerations]: The wording ‘co-primary endpoint’ has been 
changed to ‘dual primary endpoint’ and the wordings are updated according to changes made 
into objectives in this amendment.
Section 8.2 (Sample size estimate), Section 8.3 (Definition of analysis sets), Section 8.5
(Methods for statistical analyses) and Section 8.5.9 (Interim analysis): Multiple testing 
procedure is updated to reflect the updated primary/secondary endpoints. One additional OS 
interim analysis is added at the timepoint of PFS interim analysis. The protocol updated 
accordingly includes: power, critical values of hazard ratio for PFS and OS analyses, 
projected number and percentage of PFS and OS events at interim/final analyses, projected 
alpha allocation at interim/final analyses and projected study duration.
Section 8.3.3 (PD-L1 TC<25% analysis set): This section was removed in the version 2 of 
the protocol and now this section re-inserted.
References: References ‘Borghaei et al 2018’, ‘Gandara et al 2018’, and ‘Hellmann et al 
2018’ were added based on the update made to the main text.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
6(225)
Version 3.0, 16 March 2018
Synopsis [Study site(s) and number of patients planned]: Sample size increased from 801 
to 1000 to adequately power OS of PDL1<50% population.
Synopsis (Secondary objectives): This section was updated to provide clarity on key 
secondary objectives.
Synopsis (Survival): To provide clarity on survival follow up, word ‘randomized’ was 
inserted in this section.
Synopsis (Safety Confirmation): The paragraph concerning “safety confirmation for 
China” is included.
Synopsis (statistical methods): Sample size was increased from 801 to 1000 to adequately 
power OS of PDL1<50% population.
List of abbreviations and definition of terms: Terms DCO, SmPC and TMB were 
included.
Section 1.3 (Benefit/risk and ethical assessment): A new sub-section ‘1.3.2.4 Standard of 
Care’ was added to address MHRA recommendation to include warnings of ototoxicity, 
nephrotoxicity for chemotherapy regimens as per the SmPCs.
Section 1.4 (Study Design): Sample size number was updated from 801 to 1000.
Figure 3 (overall study design): Study sample size numbers are updated.
Section 1.6.1 (Safety Confirmation): Clarity provided on patient treatment exposure 
requirements for first and second global IDMCs, and Japan IDMC. The paragraph 
concerning “Safety confirmation for China” is included.
Section 2.2 (Secondary objectives): This section was updated to provide clarity on key 
secondary objectives.
Section 2.4
 
Section 3.1 (Inclusion criteria): Inclusion criterion 6 has been updated to include TMB and 
cross-referenced of section 5.5.2.
Section 3.2 (Exclusion criteria): Exclusion criterion 20 has been cross-referenced of 
Section 3.8 as per MHRA recommendation.
Section 3.3 (Patient enrollment and randomization): Points under this section were given 
in bullet format instead of numbers.
Section 3.8 (Restrictions): this section was updated as specified below as per MHRA 
recommendation:
• An additional note has been added to provide instruction to investigators to advise male 
patients to consider cryoconservation of sperm prior to treatment because of the 
possibility of infertility due to therapy with gemcitabine.
• Contraception duration for SoC regimens has been clarified
In addition to above, point number 5 was deleted under this section based on durvalumab 
project level CSP standard template to maintain consistency across the durvalumab program.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
7(225)
Section 4 (Study plan and timing of procedures): Table 2: 
• Schedule of assessments for Treatment Arms 1, 2, and 3): Tuberculosis (TB) was 
included in the table of assessment and footnote ‘i’ updated to provide clarity for TB 
assessment.
• Typo error occurred concerning Tremelimumab PK sample time point at cycle 5 was 
corrected.
• Footnote ‘j’, ‘s’, and ‘y’ have been updated to provide more clarity.
Section 4 (Study plan and timing of procedures): Table 3: A typo error correction was 
made to footnote ‘n’.
Section 4.2.1 (Safety Confirmation period): The paragraph concerning “safety 
confirmation for China” is included.
Section 5.2.1 (Laboratory safety assessments): A paragraph concerning screening 
laboratory assessment was deleted to avoid confusions. Clarity for screening laboratory 
assessment has already been given under Table 2 footnote ‘e’. Also word ‘urine’ was 
inserted to give clarity on pregnancy test.
Section 5.4.1.2 (Storage and destruction of pharmacokinetic/ADA samples): Further 
clarity was added to note concerning PK and ADA samples collected in China.
Section 5.5.1 (Collection of patient samples for stratification by PD-L1): Requirement of 
20 unstained sections has been included in case a tissue block is not submitted for PD-L1 
analysis.
Section 5.5.2
 
Section 5.5.5 (Chain of custody of biological samples): Clarity provided for keeping 
sample shipment documentation.
Section 6.9 (Management of IP-related toxicities): few bullets under this section were 
removed based on durvalumab project level CSP standard template to maintain consistency 
across the durvalumab program and avoid duplication.
Section 7.2.2.2 (Treatment Arms 1 and 2: Criteria for treatment through progression 
and for retreatment): The wording related to Criteria for treatment through progression 
(Treatment Arms 1 and 2) and retreatment (Treatment Arm 1) under this section was updated 
according to the durvalumab project level CSP standard template to maintain consistency 
across the durvalumab program.
Section 7.3 (Labeling): additional paragraph related to ‘Label text’ was introduced under 
this section to align with the durvalumab project level CSP standard template to maintain 
consistency across the durvalumab program.
Table 9 (Supportive medications): The wording related to Herbal and natural remedies was 
removed according to the durvalumab project level CSP standard template to maintain 
consistency across the durvalumab program.
Section 8.2 (Sample size estimate), Section 8.5 (Methods for statistical analyses) and 
Section 8.5.9 (Interim analysis): In these sections sample size was increased from 801 to 
1000 and OS final analysis maturity increased from 75% to 80% to adequately power OS 
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
8(225)
analyses of PDL1<50% population. The protocol updated accordingly includes: power, 
critical values of hazard ratio for PFS and OS analyses, projected number and percentage of 
PFS and OS events at interim/final analyses, projected alpha allocation at interim/final 
analyses and projected study duration.
Section 8.6 (China cohort): Global Cohort sample size was updated from 801 to 1000.
References: Reference ‘Carbone et al 2017’ was added based on the update made to the 
main text.
Version 2.0, 12 December 2017
Synopsis (Secondary objectives): This section was updated to provide clarity on key 
secondary objectives.
Synopsis (Safety objectives): A minor update has been made in this section to allow more 
flexibility for recruitment of patients from China and do not have to be Chinese.
Synopsis (Progression during treatment and retreatment): The wording in this section 
was updated according to the durvalumab project level CSP standard template to maintain 
consistency across the durvalumab program.
Synopsis (Follow-up of patients post discontinuation of study drug): A correction was 
made so that assessments for survival are collected every 2 months after Month 4 instead of 
every 2 weeks.
Synopsis (Post final Data Cut Off [DCO]): this section was introduced in synopsis to align 
with the durvalumab project level CSP standard template to maintain consistency across the 
durvalumab program.
Synopsis (Investigational product, dosage, and mode of administration): The 
maintenance schedule for pemetrexed has been changed to either every 3 weeks (q3w) or 
every 4 weeks (q4w) for Treatment Arm 3 (SoC), dependent on Investigator decision and 
local standards, to account for regional differences. A note was added under Figure 1 to 
clarify the same information and RECIST assessment schedule.
Synopsis (Safety confirmation): Clarity provided on patient treatment exposure 
requirements for first and second global IDMCs, and Japan IDMC.
List of abbreviations and definition of terms: Terms CFDA and SNP were included.
Section 1.1.1 (Immunotherapies): The wording in this section was updated based on 
durvalumab project level CSP standard template to maintain consistency across the 
durvalumab program.
Section 1.1.2 (Durvalumab): The wording in this section was updated based on durvalumab 
project level CSP standard template to maintain consistency across the durvalumab program.
Section 1.1.3 (Tremelimumab): The wording in this section was updated based on 
durvalumab project level CSP standard template to maintain consistency across the 
durvalumab program.
Section 1.1.4 (Durvalumab in combination with tremelimumab): The wording in this 
section was updated based on the durvalumab project level CSP standard template to 
maintain consistency across the durvalumab program.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
9(225)
Section 1.2.1.2 (Rationale for 4 cycles of combination therapy followed by durvalumab 
monotherapy): The wording in this section was updated based on durvalumab project level 
CSP standard template to maintain consistency across the durvalumab program.
Section 1.2.1.3 (Durvalumab monotherapy dose rationale): The wording in this section 
was updated based on durvalumab project level CSP standard template to maintain 
consistency across the durvalumab program.
Section 1.3.2 (Overall risks) and sub-sections: The wording in this section was updated 
based on durvalumab project level CSP standard template to maintain consistency across the 
durvalumab program.
Figure 3 (Overall study design): This figure is updated to reflect the schedule for 
pemetrexed has been changed to either every 3 weeks (q3w) or every 4 weeks (q4w) for 
Treatment Arm 3 (SoC), dependent on Investigator decision and local standards, to account 
for regional differences. Footnote ‘d’ deleted.
Figure 4 (Study flow chart): Footnote ‘a’ deleted.
Section 2.2  (Secondary objectives): This section was updated to provide clarity on key 
secondary objectives.
Section 2.4 
 
Section 3.1 (Inclusion criteria): ): Inclusion criterion 2 has been updated to align with 
durvalumab project level CSP standard template. Inclusion criterion 6 has been updated to 
provide more clarity for tumor lesion used for newly acquired biopsy. A new criterion (8) 
regarding patient life expectancy has been introduced. Below points were clarified in the 
inclusion criterion 11 (now updated to number 12): 
! The hemoglobin level in relation to blood transfusion prior to screening/randomization
! Total bilirubin value was updated to align to the durvalumab project level CSP standard 
template.
Section 3.2 (Exclusion criteria): Typo error was corrected in criterion 9. Exclusion 
criterion 15 has been divided into two criteria to provide more clarity on brain metastasis and 
spinal cord compression.
Section 3.3 (Patient enrollment and randomization): More clarity added on central and 
local EGFR/ALK testing. It was clarified that the 3-digit randomization number was 
corrected to a 4-digit number to match the IVRS.
Section 3.5 (Methods for assigning treatment arms): It was clarified that the IVRS/IWRS 
will provide the kit identification number to be allocated to the patient at subsequent 
dispensing visits also.
Section 3.8 (Restrictions): The wording in this section was updated based on durvalumab
project level CSP standard template to be consistent across program. A footnote ‘b’ has been 
added under Table 1 to provide clarity on approval status of contraception methods in Japan.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
10(225)
Section 3.9 (Discontinuation of IP) & sub-sections: The wording in these sections were 
updated based on durvalumab project level CSP standard template to maintain consistency 
across the durvalumab program.
Section 3.10.2.1 (Survival status for withdrawn consent and lost to follow-up patients): 
This section wordings were updated based on durvalumab project level CSP standard 
template to maintain consistency across the durvalumab program.
Section 4 (Study plan and timing of procedures): Table 2: Clarification was added to the 
schedule of assessments for the treatment and retreatment periods regarding which 
assessments should be done during retreatment. A row for medical/surgical history was 
added to the schedule of assessments. The maintenance schedule for pemetrexed has been 
changed to either every 3 weeks (q3w) or every 4 weeks (q4w) for Treatment Arm 3 (SoC), 
dependent on Investigator decision and local standards, to account for regional differences.
Folic acid/ Vitamin B12 pre-medication management was clarified. Footnote ‘e’, ‘h’, ‘j’, ‘n’, 
‘s’, and ‘t’ have been updated to provide more clarity.
Table 3: Tumor evaluation row has been updated to provide more clarity. Footnotes ‘c’ and 
‘n’ have been updated to provide more clarity on RECIST 1.1 assessments.
Section 4.1 (Screening/enrollment period): A typo error correction was made in this 
section.
Section 4.2 (Treatment period): This section was updated to provide clarity on RECIST 
assessments.
Section 4.2.1 (Safety confirmation period): Clarity provided on patient treatment exposure 
requirements for first and second global IDMCs, and Japan IDMC.
Section 4.3 (Follow-up period): The wording in this section was updated based on 
durvalumab project level CSP standard template to maintain consistency across the 
durvalumab program.
Section 5.1 (Efficacy assessments) and sub-sections: These sections wordings were 
updated based on durvalumab project level CSP standard template to maintain consistency 
across the durvalumab program.
Section 5.1.1 (Objective disease progression): The whole section has been deleted because 
this section needs to be simplified to RECIST 1.1.
Section 5.1.3 (Survival assessments): Now this is Section 5.1.2. A correction was made so 
that assessments for survival are collected every 2 months after Month 4 instead of every 
2 weeks.
Section 5.2.1 (Laboratory safety assessments): Table 4 (Clinical Chemistry) -
clarifications provided on creatinine clearance and TSH testing in footnote. 
Table 5 (Hematology) - Typo error corrected for Eosinophil count, clarification provided on 
assessment period and a footnote inserted to explain the absolute counts or percentages.
Section 5.2.4 (Vital signs): more clarity added on vital signs collections during first and 
subsequent infusion. A bullet point regarding treatment observation period was deleted to 
eliminate the observation time gap between tremelimumab, durvalumab and SoC, under first 
infusion paragraph.
Section 5.2.6 (WHO/ECOG performance status): Added “5 = Dead”

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
11(225)
Section 5.4.1.2 (Storage and destruction of pharmacokinetic/ADA samples): Sample 
disposition timelines has been clarified to align with Section 5.5.3 (Storage, re-use, and 
destruction of biological samples). A note added to clarify that PK and ADA samples 
collected in China will be stored and disposed according to local laws and regulations.
Section 5.5.1: (Collection of patient samples for stratification by PD-L1): Notes were 
added to clarify China will not take part in optional and additional biopsy samples.
Section 5.5.2:
 
Section 6.1 (Definition of adverse events): The wording in this section was updated based 
on durvalumab project level CSP standard template to maintain consistency across the 
durvalumab program.
Section 6.3 (Recording of adverse events) and sub-sections: The wording in these sections 
were updated based on durvalumab project level CSP standard template to maintain 
consistency across the durvalumab program.
Section 6.3.12 (Safety Data To Be Collected following the final DCO of the study): this 
section was introduced to align with the durvalumab project level CSP standard template to 
maintain consistency across the durvalumab program.
Section 6.5 (Treatment Arms 1 and 2 adverse events of special interest): The wording in 
this section was updated based on durvalumab project level CSP standard template to 
maintain consistency across the durvalumab program.
Section 6.7 (Pregnancy): The wording in this section was updated based on durvalumab
project level CSP standard template to maintain consistency across the durvalumab program.
Section 6.9.1 (Durvalumab and durvalumab + tremelimumab): The heading and wording 
in this section were updated based on durvalumab project level CSP standard template to 
maintain consistency across the durvalumab program.
Section 7.1.1 (Order of administration): The wording in this section was updated to 
eliminate the observation time gap between tremelimumab, durvalumab and SoC infusions.
Section 7.1.2 (Durvalumab [MEDI4736]): The wording in this section was updated based 
on durvalumab project level CSP standard template to maintain consistency across the 
durvalumab program.
Section 7.1.3 (Tremelimumab): This section wordings were updated based on durvalumab
project level CSP standard template to maintain consistency across the durvalumab program. 
Section 7.2.1 (Treatment regimens): The maintenance schedule for pemetrexed has been 
changed to every 3 weeks (q3w) or every 4 weeks (q4w) for Treatment Arm 3 (SoC), 
dependent on Investigator decision and local standards, to account for regional differences. 
A note was added under ‘Treatment Arm 3: SoC chemotherapy alone’ and Figure 5 to clarify 
the same information and RECIST assessment schedule.
Section 7.2.2 (Duration of treatment and criteria for treatment through progression 
and retreatment): Post final Data Cut Off information was introduced in this section to 
align with the durvalumab project level CSP standard template to maintain consistency 
across the durvalumab program.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
12(225)
Section 7.2.2.2 (Treatment Arms 1 and 2: Criteria for treatment through progression 
and for retreatment): Clarification was added regarding which assessments should be done 
during retreatment. To align to the treatment schedule, it was clarified that one of the 
eligibility criteria for retreatment is having completed 5 dosing cycles comprising the 
combination of durvalumab and tremelimumab portion of the regimen. To be consistent with 
the rest of the treatment regimens in the protocol, it was also clarified that a patient whose 
weight falls to 30 kg or below will receive weight-based dosing.
Section 7.7 (Concomitant medications and other treatments): Table 8 (Prohibited 
concomitant medications) was updated to align with the durvalumab project level CSP 
standard template to maintain consistency across the durvalumab program.
Section 8.3.3 (PD-L1 TC<25% analysis set): This section is now deleted. It was initially 
included for potential analysis but so far, no planned analysis is of interest.
Section 8.4.1
 
Section 8.4.2.1 (Co-primary endpoints): This section was updated to provide clarity on 
RECIST assessments.
Section 8.4.2.2 (Secondary endpoints): A paragraph related to best objective response 
deleted under this section because more information has already been provided in statistical 
analysis plan.
Section 8.4.3.1 (Adverse events): More clarity added to adverse events collection timelines.
Section 8.5.1.1 (Progression-free survival): Subgroup analyses that will be conducted 
comparing PFS (per RECIST 1.1) between experimental arms versus SoC arm were updated.
Section 8.6 (China cohort): Some updates were made to comply with new CFDA 
guidelines and allow more flexibility for recruitment of patients from China and do not have 
to be Chinese.
References: Few references are added and few references were deleted, all of which are not 
relevant based on the update made to the main text.
Appendix E (Guidelines for Evaluation of Objective Tumor Response): This appendix 
updated to align with durvalumab project level CSP standard template to maintain 
consistency across the durvalumab program
Version 1.0, 10 March 2017
Initial version
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
13(225)
PROTOCOL SYNOPSIS
A Phase III, Randomized, Multi-Center, Open-Label, Comparative Global 
Study to Determine the Efficacy of Durvalumab or Durvalumab and 
Tremelimumab in Combination With Platinum-Based Chemotherapy for 
First-Line Treatment in Patients With Metastatic Non-Small-Cell Lung 
Cancer (NSCLC) (POSEIDON)
International Coordinating Investigators
Sara Cannon Research Institute at Tennessee 
Oncology
Research Site Support
The SCRI Oncology
Tel: 
Study site(s) and number of patients planned
The study will randomize approximately 1000 patients in a 1:1:1 ratio to the following 
treatment arms: durvalumab + tremelimumab combination therapy + standard of care (SoC) 
chemotherapy, durvalumab monotherapy + SoC chemotherapy, or SoC chemotherapy alone 
(approximately 333 patients in each treatment arm), including at least approximately 
250 patients in each treatment arm with programmed cell death ligand 1 (PD-L1) expression 
on less than 50% of tumor cells (PD-L1 TC <50%). Once global enrollment is completed, 
recruitment may continue in mainland China only. A total of up to 180 patients, including up 
to 135 patients in total with PD-L1 TC <50%, from China will be randomized.
Study period
Phase of development
Estimated date of first patient enrolled
Q2 2017
III
Estimated date of last patient completed in global 
cohort*
Q4 2023
III
*
Estimated date of last China patient completed will be later than the estimated date of last patient completed 
in global cohort.
Study design
This is a randomized, open-label, multi-center, global, Phase III study to determine the 
efficacy and safety of durvalumab + tremelimumab combination therapy + SoC chemotherapy 
or durvalumab monotherapy + SoC chemotherapy versus SoC chemotherapy alone as 
first-line treatment in patients with metastatic non-small-cell lung cancer (NSCLC) with 
tumors that lack activating epidermal growth factor receptor (EGFR) mutations and anaplastic
lymphoma kinase (ALK) fusions.  Patients who fulfill all of the inclusion criteria and none of 
PPD
PPD
PPD

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
14(225)
the exclusion criteria will be randomized in a 1:1:1 ratio according to the following 
stratification scheme:
∀
PD-L1 tumor expression status (PD-L1 expression on at least 50% of tumor cells 
[PD-L1 TC ≥50%] versus PD-L1 TC <50%) 
∀
Disease stage (Stage IVA versus Stage IVB)
∀
Histology (non-squamous versus squamous)
Patients will be randomized in a 1:1:1 ratio to receive treatment every 3 weeks (q3w) with 
durvalumab + tremelimumab combination therapy + SoC chemotherapy, durvalumab 
monotherapy + SoC chemotherapy, or SoC chemotherapy alone in the ‘during chemotherapy’ 
phase.  During the ‘post-chemotherapy’ phase, patients in Treatment Arms 1 and 2 will 
receive durvalumab monotherapy every 4 weeks (q4w).  Non-squamous patients who received 
pemetrexed + carboplatin/cisplatin in the ‘during chemotherapy’ phase will receive 
pemetrexed maintenance therapy, unless contraindicated per the Investigator.  See Figure 1 for 
the dosing scheme.
The following are the definitions of the study treatment regimens in each treatment arm:
∀
Treatment Arm 1: durvalumab + tremelimumab combination therapy + SoC 
chemotherapy
∀
Treatment Arm 2: durvalumab monotherapy + SoC chemotherapy
∀
Treatment Arm 3: SoC chemotherapy alone
Tumor evaluation scans will be performed at screening (as baseline) with follow-ups at 
Week 6±1 week from the date of randomization, at Week 12±1 week from the date of 
randomization, and then every 8 weeks (q8w)±1 week until objective disease progression.  
Objectives 
All objectives will be evaluated for all patients, unless otherwise indicated.  The multiple 
testing procedure is described in detail in Section 8.5.
Primary objectives
Primary objectives
Outcome measure
∀
To assess the efficacy of durvalumab 
monotherapy + SoC chemotherapy compared 
with SoC chemotherapy alone in terms of 
PFS and OS in all patients 
∀
PFS in all patients using BICR assessments 
according to RECIST 1.1
∀
OS in all patients
Note: Sensitivity analyses of PFS will be performed based on the Investigator’s assessment according to 
RECIST 1.1.
BICR Blinded Independent Central Review; NSCLC Non-small-cell lung cancer; PFS Progression-free 
survival; RECIST 1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1; SoC Standard of care.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
15(225)
Secondary objectives
Secondary objectives
Outcome measures
∀
To assess the efficacy of 
durvalumab + tremelimumab combination 
therapy + SoC chemotherapy compared with 
SoC chemotherapy alone in terms of PFS and 
OS
∀
PFS in all patients using BICR assessments 
according to RECIST 1.1 (key secondary 
objective)
∀
OS in all patients (key secondary objective)
∀
To further assess the efficacy of 
durvalumab + tremelimumab combination 
therapy + SoC chemotherapy compared with 
SoC chemotherapy alone in terms of PFS, OS, 
ORR, BoR, DoR, APF12 and PFS2
∀
PFS in patients with PD-L1 TC <50%, patients 
with PD-L1 TC <25% and patients with PD-L1 
TC <1% using BICR assessments according to 
RECIST 1.1
∀
OS in patients with PD-L1 TC <50%, patients 
with PD-L1 TC <25% and patients with PD-L1 
<1%
∀
ORR, DoR, BoR and APF12 in patients with 
PD-L1 TC <50%, patients with PD-L1 TC 
<25%, patients with PD-L1 TC <1% and all 
patients using BICR assessments according to 
RECIST 1.1
∀
PFS2 in patients with PD-L1 TC <50%, patients 
with PD-L1 TC <25%, patients with PD-L1 
TC <1% and all patients using local standard 
clinical practice
∀
To further assess the efficacy of durvalumab 
monotherapy + SoC chemotherapy compared 
with SoC chemotherapy alone in terms of PFS, 
OS, ORR, DoR, BoR, APF12 and PFS2
∀
PFS in patients with PD-L1 TC <50%, patients 
with PD-L1 TC <25% and patients with PD-L1 
TC <1% using BICR assessments according to 
RECIST 1.1
∀
OS in patients with PD-L1 TC <50%, patients 
with PD-L1 TC <25% and patients with PD-L1 
TC <1%
∀
ORR, DoR, BoR and APF12 in patients with 
PD-L1 TC <50%, patients with PD-L1 TC 
<25%, patients with PD-L1 TC <1% and all 
patients using BICR assessments according to 
RECIST 1.1
∀
PFS2 in patients with PD-L1 TC <50%, patients 
with PD-L1 TC <25%, patients with PD-L1 
TC <1% and all patients using local standard 
clinical practice

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
16(225)
Secondary objectives
Outcome measures
∀
To assess the efficacy of 
durvalumab + tremelimumab combination 
therapy + SoC chemotherapy compared with 
durvalumab monotherapy + SoC chemotherapy 
in terms of PFS, OS and ORR
∀
PFS and ORR in patients with PD-L1 
TC <50%, patients with PD-L1 TC <25%, 
patients with PD-L1 TC <1% and all patients 
using BICR assessments according to 
RECIST 1.1
∀
OS in patients with PD-L1 TC <50%, patients 
with PD-L1 TC <25%, patients with PD-L1 
TC <1% and all patients
∀
To assess the association of tumor mutation 
burden (TMB) with the efficacy of durvalumab 
+ tremelimumab combination therapy + SoC 
chemotherapy compared with SoC 
chemotherapy alone in terms of PFS, OS, 
ORR, BoR, DoR, APF12 and PFS2
∀
PFS, ORR, BoR, DoR, APF12 in patients with 
TMB high using BICR assessments according 
to RECIST 1.1
∀
PFS2 in patients with TMB high using local 
standard clinical practice
∀
OS in patients with TMB high
∀
To assess the association of TMB with the 
efficacy of durvalumab + tremelimumab 
combination therapy + SoC chemotherapy 
compared with durvalumab 
monotherapy + SoC chemotherapy in terms of 
PFS, OS, ORR, BoR, DoR, APF12 and PFS2
∀
PFS, ORR, BoR, DoR, APF12 in patients with 
TMB high using BICR assessments according 
to RECIST 1.1
∀
PFS2 in patients with TMB high using local 
standard clinical practice
∀
OS in patients with TMB high
∀
To assess the association of TMB with the 
efficacy of durvalumab mono therapy + SoC 
chemotherapy compared with SoC 
chemotherapy in terms of PFS, OS, ORR, 
BoR, DoR, APF12 and PFS2
∀
PFS, ORR, BoR, DoR, APF12 in patients with 
TMB high using BICR assessments according 
to RECIST 1.1
∀
PFS2 in patients with TMB high using local 
standard clinical practice
∀
OS in patients with TMB high
∀
To assess the PK of durvalumab + 
tremelimumab combination therapy and 
durvalumab monotherapy
∀
Concentration of durvalumab and 
tremelimumab
∀
To investigate the immunogenicity of 
durvalumab and tremelimumab
∀
Presence of ADAs for durvalumab and 
tremelimumab
∀
To assess disease-related symptoms and 
HRQoL in patients treated with durvalumab + 
tremelimumab combination therapy + SoC 
chemotherapy and durvalumab monotherapy + 
SoC chemotherapy compared with SoC 
chemotherapy alone using the EORTC QLQ-
C30 v3, the QLQ-LC13 module, and 
WHO/ECOG performance status assessments
∀
EORTC QLQ-C30
∀
EORTC QLQ-LC13
∀
Changes in WHO/ECOG performance status 
will also be assessed.
ADA Anti-drug antibody; APF12 Proportion of patients alive and progression free at 12 months from 
randomization; BICR Blinded Independent Central Review; BoR Best objective response; DoR Duration of 
response; ECOG Eastern Cooperative Oncology Group; EORTC European Organisation for Research and 
Treatment of Cancer; HRQoL Health-related quality of life; NSCLC Non-small-cell lung cancer; 
ORR Objective response rate; OS Overall survival; PD-L1 Programmed cell death ligand 1; PFS Progression-

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
17(225)
free survival; PFS2 Time from randomization to second progression; PK Pharmacokinetic(s); QLQ-C30 v3 30-
item Core Quality of Life Questionnaire, version 3; QLQ-LC13 13-item Lung Cancer Quality of Life 
Questionnaire; RECIST 1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1; SoC Standard of care; 
TC Tumor cell; Definition of TMB High in tissue and/or ctDNA to be documented in the SAP ahead of DBL 
with data external to Poseidon; WHO World Health Organization.
Safety objectives
Safety objective
Outcome measure
∀
To assess the safety and tolerability profile of 
durvalumab + tremelimumab 
combination therapy + SoC chemotherapy and 
durvalumab monotherapy + SoC chemotherapy 
compared with SoC chemotherapy alone
∀
AEs, physical examinations, laboratory 
findings, and vital signs
AE Adverse event; SoC Standard of care.
A further objective to meet China Food and Drug Administration requirement is to evaluate 
consistency in efficacy and safety among patients in China for benefit-risk assessments of 
durvalumab + tremelimumab combination therapy + SoC chemotherapy compared with SoC 
chemotherapy alone and durvalumab monotherapy + SoC chemotherapy compared with SoC 
chemotherapy alone.
Target patient population
Adult patients (age ≥18 years; for those enrolled in Japan, age ≥20 years) with a histologically 
or cytologically documented metastatic NSCLC, with tumors that lack activating EGFR 
mutations and ALK fusions, are eligible for enrollment.  Patients must have had no prior 
chemotherapy or any other systemic therapy for metastatic NSCLC.  Prior to randomization, 
patients must have tumor PD-L1 status confirmed by a reference laboratory using the 
Ventana SP263 PD-L1 immunohistochemistry assay.  Patients must have a World Health 
Organization/Eastern Cooperative Oncology Group performance status of 0 or 1 at 
enrollment.
Duration of treatment
Treatment with SoC chemotherapy in Treatment Arms 1 and 2 will be limited to 4 cycles on a 
q3w schedule subsequent to randomization.  Patients in Treatment Arm 3 may receive an 
additional 2 doses of SoC chemotherapy at Weeks 12 and 15 (a total of 6 doses 
post-randomization), as clinically indicated, at the Investigator’s discretion.
Treatment with immunotherapy + SoC chemotherapy in Treatment Arms 1 and 2, as well as 
treatment with SoC chemotherapy alone in Treatment Arm 3, will be administered beginning 
on Cycle 1 Day 1.
For patients randomized to Treatment Arms 1 and 2, immunotherapy treatment with 
durvalumab monotherapy will continue until objective disease progression unless there is 
unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.  For 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
18(225)
patients in Treatment Arm 1, an additional dose of durvalumab + tremelimumab will be given 
at Week 16 post-chemotherapy.  In the case of dose delay(s), more than 1 durvalumab + 
tremelimumab combination dose can be given at and after Week 16 post-chemotherapy to 
ensure that up to 5 combination doses are administered in Treatment Arm 1.  If patients 
receive fewer than 4 cycles of platinum doublet chemotherapy, the remaining cycles of 
combined durvalumab/tremelimumab (up to a total of 5) should be given after combination of 
platinum doublet chemotherapy (with maintenance pemetrexed if applicable).  All 
non-squamous patients who received a pemetrexed doublet in the initial part of the study will 
receive pemetrexed maintenance in the ‘post-chemotherapy’ phase of the study, unless 
contraindicated per the Investigator.
For patients randomized to Treatment Arms 1 and 2, when SoC chemotherapy is discontinued 
due to treatment-related toxicity, durvalumab monotherapy or durvalumab + tremelimumab 
may continue at the Investigator’s discretion when toxicity resolves to at least Grade 2 or less.  
Note: if the Investigator feels a patient is ready to restart treatment prior to the toxicity 
resolving to Grade 2 or less, AstraZeneca should be consulted for an exception to this rule.
Progression during treatment and retreatment
Patients in Treatment Arms 1 and 2 with objective disease progression 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 progressive disease, may continue to receive 
durvalumab monotherapy for as long as they are gaining clinical benefit.  However, patients in 
the immunotherapy arms will not be permitted to continue immunotherapy if progression 
occurs after confirmed response (complete or partial response) (as defined by Response 
Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST 1.1]) to immunotherapy treatment 
in the target lesions (regardless of the appearance of new lesions), ie, the response and 
progression events both occurred in the target lesions while receiving immunotherapy during 
the same treatment period.
Patients in Treatment Arm 1 may undergo retreatment with the combination as described 
below:
∀
Patients who complete 5 dosing cycles comprising the combination of durvalumab 
and tremelimumab portion of the regimen (with clinical benefit per Investigator 
judgment), but subsequently have clinical progression or radiological PD during the 
durvalumab monotherapy portion of the combination regimen, may restart treatment 
with the combination of durvalumab + tremelimumab.
For patients randomized to Treatment Arm 3, treatment through progression and retreatment 
will not be permitted.
Follow-up of patients post-discontinuation of study drug
Patients who are permanently discontinued from further receipt of investigational product, 
regardless of the reason, will be identified as having permanently discontinued treatment and 
will enter follow-up.  Patients who have discontinued treatment due to toxicity or 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
19(225)
symptomatic deterioration, or who have commenced subsequent anticancer therapy, will be 
followed up until RECIST 1.1 defined radiological progression plus an additional subsequent 
scan and for survival.  This follow-up must be performed even if the patient begins another 
therapy to treat their NSCLC.  Assessments for survival must be made at Months 2, 3, and 4, 
and then every 2 months (8 weeks±2 weeks) following treatment discontinuation.  
Survival
All randomized patients will be followed for survival until the end of the study.
Post Data Cut Off (DCO) for final analysis of OS for superiority
For patients continuing to receive durvalumab/tremelimumab and/or SOC chemotherapy and 
patients on survival follow-up following the DCO for final analysis of OS for superiority, it is 
recommended that patients continue the scheduled site visits according to Table 12, Table 
13& Section 9.3 and investigators monitor the patient’s safety laboratory results prior to and 
periodically during treatment with durvalumab/tremelimumab and/or SOC chemotherapy in 
order to manage AEs in accordance with the durvalumab/tremelimumab toxicity management 
guidelines or as indicated in the local prescribing information for the relevant chemotherapy 
agent (please see Section 6.9.1 & 6.9.2).  
Post final Data Cut Off (DCO) 
Patients who continue to receive benefit from their assigned treatment
(durvalumab/tremelimumab and/or SOC chemotherapy) at the final DCO and database closure 
may continue to receive their assigned treatment for as long as they and their physician feel 
they are gaining clinical benefit. Investigators will monitor the patient’s safety laboratory 
results prior to and periodically during treatment with durvalumab/tremelimumab and/or SOC 
chemotherapy in order to manage AEs in accordance with the durvalumab/tremelimumab
toxicity management guidelines or as indicated in the local prescribing information for the 
relevant chemotherapy agent (please see Section6.9.1 &6.9.2).  
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, patients currently receiving treatment with durvalumab and/or SOC 
chemotherapy may be transitioned to such a study, and the current study would reach its end.  
The roll-over or safety extension study would ensure treatment continuation with visits 
assessment per its protocol.  Any patient that would be proposed to move to such study would 
be required to give consent to participation in the study via a new Informed Consent form.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
20(225)
Investigational product, dosage, and mode of administration
Patients will be randomized in a 1:1:1 ratio to receive treatment either with durvalumab + 
tremelimumab combination therapy + SoC chemotherapy, durvalumab monotherapy + SoC 
chemotherapy, or SoC chemotherapy alone.
∀
Durvalumab 1500 mg ± tremelimumab 75 mg will be administered via intravenous 
infusion concurrently with chemotherapy q3w starting on Week 0 for 4 cycles.  
Durvalumab monotherapy will be continued q4w post-chemotherapy.  In Treatment 
Arm 1, up to 5 combination doses of durvalumab + tremelimumab will be 
administered; the detailed dose and schedule is illustrated in Figure 1.
!
Note: If a patient’s weight falls to 30 kg or below, the patient should receive 
weight-based dosing equivalent to 20 mg/kg of durvalumab and 1 mg/kg 
tremelimumab until the weight improves to >30 kg, at which point the patient 
should start receiving the fixed dosing of durvalumab 1500 mg ± tremelimumab 
75 mg.  
∀
Standard of care chemotherapy: Patients will receive 1 of the following SoC 
regimens as part of their treatment regimen:
!
Abraxane + carboplatin (squamous and non-squamous patients): Abraxane 
100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle.  Carboplatin AUC 5 or 6 
via intravenous (IV) infusion on Day 1 of each 21-day cycle for 4 to 6 cycles 
(ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment 
Arm 3).
!
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 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles 
(ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment 
Arm 3).
!
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 (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for 
Treatment Arm 3).
!
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 (ie, 4 cycles for Treatment Arms 1 and 2 and 
4 to 6 cycles for Treatment Arm 3); then continue pemetrexed 500 mg/m2 
maintenance (i.e., q4w for Treatment Arms 1 and 2. For Treatment Arm 3, 
Pemetrexed maintenance therapy can be given either q3w or q4w dependent on 
Investigator decision and local standards) until objective disease progression, 
unless contraindicated per the Investigator.  

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
21(225)
!
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 (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for 
Treatment Arm 3); then continue pemetrexed 500 mg/m2 maintenance (i.e., q4w 
for Treatment Arms 1 and 2. For Treatment Arm 3, Pemetrexed maintenance 
therapy can be given either q3w or q4w dependent on Investigator decision and 
local standards) until objective disease progression, unless contraindicated per 
the Investigator.  

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
22(225)
Figure 1
Dosing scheme
Treatment arms
During chemotherapy
1 cycle=3 weeks (21 days)
Post-chemotherapy
1 cycle=4 weeks (28 days)
Cycle 1
Week 0
Cycle 2
Week 3
Cycle 3
Week 6
Cycle 4
Week 9
Week 12
Week 16
Week 20 to PD
Durva + Treme + SoC 
(Treatment Arm 1)
Durva + Treme 
+ SoC
Durva + Treme 
+ SoC
Durva + Treme 
+ SoC
Durva + Treme 
+ SoC
Durva + 
Pemetrexed 
Maintenancea
Durva + Tremeb
Pemetrexed 
Maintenancea
Durva + 
Pemetrexed 
Maintenancea
Durva + SoC
(Treatment Arm 2)
Durva + SoC
Durva + SoC
Durva + SoC
Durva + SoC
Durva + 
Pemetrexed 
Maintenancea
Durva + 
Pemetrexed 
Maintenancea
Durva + 
Pemetrexed 
Maintenancea
SoC 
(Treatment Arm 3)
SoC
SoC
SoC
SoCc
Pemetrexed 
Maintenancea
Pemetrexed 
Maintenancea
Pemetrexed 
Maintenancea
a
Pemetrexed maintenance therapy is for non-squamous NSCLC patients who received treatment with pemetrexed and carboplatin/cisplatin during 
chemotherapy and did not progress after 4 to 6 cycles, unless contraindicated per the Investigator. Pemetrexed maintenance therapy can be given q4w 
for Treatment Arms 1 and 2. For Treatment Arm 3, Pemetrexed maintenance therapy can be given either q3w or q4w dependent on Investigator 
decision and local standards. Note: RECIST 1.1 assessment should be performed at Week 12 ±1 week from the date of randomization, and then q8w±1 
week thereafter until radiological progression (regardless of whether it chosen q3w or q4w)
b
For patients in Treatment Arm 1, an additional dose of durvalumab + tremelimumab will be given at Week 16 post-chemotherapy.  In the case of dose 
delay(s), more than 1 durvalumab + tremelimumab combination dose can be given at and after Week 16 post-chemotherapy to ensure that up to 
5 combination doses are administered in Treatment Arm 1.  If patients receive fewer than 4 cycles of platinum doublet chemotherapy, the remaining 
cycles of combined durvalumab/tremelimumab (up to a total of 5) should be given after combination of platinum doublet chemotherapy (with 
maintenance pemetrexed if applicable). 
c
In Treatment Arm 3, SoC chemotherapy can be given for an additional 2 cycles q3w on Weeks 12 and 15 (ie, total of 6 cycles post-randomization) if 
clinically indicated, at the investigator’s discretion before patients enter follow-up.  This does not alter the planned scan schedule q8w starting at 
Week 12 for patients in Treatment Arm 3.
Note: Patients whose weight falls to 30 kg or below must receive weight-based dosing-equivalent to 20 mg/kg of durvalumab and 1 mg/kg of tremelimumab 
until the weight improves to >30 kg, at which point the patient should start receiving the fixed dosing of durvalumab at 1500 mg and tremelimumab at 
75 mg.  Durvalumab dose will be 1500 mg during chemotherapy and 1500 mg post-chemotherapy; tremelimumab dose will be 75 mg. 
Durva Durvalumab; PD Progressive disease; q3w  Every 3 weeks; q4w  Every 4 weeks; SoC Standard of care; Treme Tremelimumab. 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
23(225)
Safety Confirmation
An independent data monitoring committee (IDMC) composed of independent experts will be 
convened to confirm the safety and tolerability of the proposed dose and schedule of 
durvalumab ± tremelimumab in combination with SoC chemotherapy at 2 early stages of 
enrollment.  A step-wise approach will be adopted.  The initial safety review will take place 
when the first 30 patients (10 in each arm) have completed the first cycle of treatment.  A 
second review will add an additional 30 patients (10 in each arm) who have completed the 
first cycle of treatment, making a total of 60 patients.  At the time of the second review, it is 
expected that the initial 30 patients would have had at least 6 weeks of follow-up, with some 
patients having longer follow-up.  These 2 reviews will be carried out by the IDMC in an 
unblinded manner.  After review of the unblinded data, the IDMC will make a 
recommendation on whether the study should continue recruitment as planned or hold 
recruitment.
Safety confirmation for Japan: An additional safety review for Japanese patients will take 
place when the first 3 patients in each treatment arm in Japan have completed the first cycle of 
treatment. This review will be carried out by the IDMC in an unblinded manner. After review 
of the unblinded data, the IDMC will make a recommendation on whether the study should 
continue recruitment as planned or hold recruitment in Japan.
Safety confirmation for China: An additional safety review for Chinese patients will take 
place when the first 10 patients in each treatment arm in China have completed the first cycle 
of treatment. This review will be carried out by the IDMC in an unblinded manner. After 
review of the unblinded data, the IDMC will make a recommendation on whether the study 
should continue recruitment as planned or hold recruitment in China.
In addition, the IDMC will review the unblinded interim analysis summaries of efficacy data. 
The IDMC meets approximately every 6 months thereafter to continue safety monitoring up to 
the decision to unblind the study.
Full details of the IDMC procedures, processes, and interim analyses can be found in the 
IDMC Charter.
Statistical methods
The dual primary aims of this study are to assess the efficacy of durvalumab monotherapy + 
SoC chemotherapy compared with SoC chemotherapy alone in terms of PFS and OS in all 
patients.   
The study will enroll approximately 2000 patients to randomize approximately 1000 patients 
in a 1:1:1 ratio to durvalumab + tremelimumab combination therapy + SoC chemotherapy, 
durvalumab monotherapy + SoC chemotherapy, or SoC chemotherapy alone (approximately 
333 patients in each treatment arm), including at least 250 patients in each treatment arm with 
PD-L1 TC <50%. Once global enrollment is completed, recruitment may continue in 
mainland China only. A total of up to 180 patients, including up to 135 patients in total with 
PD-L1 TC <50%, from China will be randomized (refer to Section 8.6 for more details). 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
24(225)
The study is sized for dual primary endpoints to characterize the PFS and OS benefits of 
durvalumab monotherapy + SoC chemotherapy versus SoC chemotherapy alone in the ITT 
population. Sample size and power analysis for the dual primary endpoints of final analysis 
are described below.
The final (primary) PFS analysis for superiority will be performed when the following 
conditions have been met: 
∀
Approximately 497 BICR PFS events from the global cohort have occurred across 
the durvalumab monotherapy + SoC chemotherapy and SoC chemotherapy alone 
treatment arms (75% maturity)
The final OS analysis for superiority will be performed when the following conditions have 
been met: 
∀
Approximately 532 OS events have occurred across the durvalumab monotherapy 
+ SOC chemotherapy and SoC chemotherapy alone treatment arms (80% maturity)
One interim analysis of PFS will be performed when approximately 80% of the target PFS 
events have occurred.  Three interim analyses of overall survival (OS) will be performed; the 
first at the time of the interim PFS analysis (approximately 45% of the target OS events), the 
second at the time of the primary PFS analysis (approximately 61% of the target OS events) 
and the third when approximately 84% of the target OS events have occurred.
Dual primary Endpoints:
Durvalumab monotherapy + SoC chemotherapy versus SoC chemotherapy alone 
(PFS in ITT population)
Assuming the true PFS HR is 0.67 and the median PFS in SoC chemotherapy alone arm is 
6 months, 497 PFS events from the global cohort (75% maturity) will provide greater than 
90% power to demonstrate statistical significance at the 2-sided alpha level of 0.9% (with 
overall alpha for PFS 1%), allowing for 1 interim analysis conducted at approximately 80% of 
the target events.  The smallest treatment difference that is statistically significant will be an 
HR of 0.79. Assuming a recruitment period of 16 months, this analysis is anticipated to be 
25 months from FPI.
Durvalumab monotherapy + SoC chemotherapy versus SoC chemotherapy alone
(OS in ITT population)
Assuming the true OS HR is 0.7 and the median OS in SoC arm is 12.9 months, 532 OS 
events (80% maturity) will provide greater than 90% power to demonstrate statistical 
significance at the 2-sided alpha level of a 3.3% (with overall alpha for OS 4%), allowing for 
3 interim analyses conducted at approximately 45%, 61% and 84% of the target events. The 
smallest treatment difference that is statistically significant will be an HR of 0.83. Assuming a 
recruitment period of 16 months, this analysis is anticipated to be 46 months from FPI.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
25(225)
PFS, based on the programmatically derived PFS from BICR, and OS will be analyzed using a 
stratified log-rank test.  The effect of treatment will be estimated by the HR together with 
corresponding 2-sided appropriately sized confidence interval (adjusted for interim analyses) 
and p-value. 
Safety data will be summarized descriptively.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
26(225)
TABLE OF CONTENTS
PAGE
PROTOCOL SYNOPSIS..................................................................................... 13
TABLE OF CONTENTS..................................................................................... 26
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS........................... 33
1.
INTRODUCTION ............................................................................................... 38
1.1
Background and rationale for conducting this study ............................................. 38
1.1.1
Immunotherapies ................................................................................................. 39
1.1.2
Durvalumab ......................................................................................................... 40
1.1.3
Tremelimumab..................................................................................................... 41
1.1.4
Durvalumab in combination with tremelimumab.................................................. 41
1.1.5
Rationale for the study ......................................................................................... 42
1.1.5.1
Rationale for the combination of durvalumab and tremelimumab with 
chemotherapy....................................................................................................... 42
1.2
Rationale for study design, doses, and control groups........................................... 44
1.2.1
Durvalumab and tremelimumab dose and treatment regimen justification ............ 44
1.2.1.1
Durvalumab+ tremelimumab combination therapy dose rationale......................... 44
1.2.1.2
Rationale for 4 cycles of combination therapy followed by durvalumab 
monotherapy........................................................................................................ 46
1.2.1.3
Durvalumab monotherapy dose rationale ............................................................. 46
1.2.1.4
Rationale for fixed dosing .................................................................................... 47
1.2.2
Rationale for proposed Phase III dose and schedule ............................................. 48
1.2.2.1
Safety confirmation of proposed doses................................................................. 52
1.2.3
Rationale for control treatment arm: standard care therapy................................... 52
1.2.4
Rationale for endpoints ........................................................................................ 52
1.3
Benefit/risk and ethical assessment ...................................................................... 53
1.3.1
Potential benefits.................................................................................................. 53
1.3.1.1
Durvalumab ......................................................................................................... 53
1.3.1.2
Durvalumab + tremelimumab............................................................................... 55
1.3.1.3
Durvalumab + tremelimumab with chemotherapy................................................ 55
1.3.2
Overall risks......................................................................................................... 56
1.3.2.1
Durvalumab ......................................................................................................... 56
1.3.2.2
Tremelimumab..................................................................................................... 57
1.3.2.3
Durvalumab + tremelimumab combination therapy.............................................. 57
1.3.2.4
Standard of Care .................................................................................................. 58
1.3.2.5
Durvalumab ± tremelimumab with chemotherapy ................................................ 58
1.3.3
Overall benefit-risk assessment ............................................................................ 61
1.4
Study design ........................................................................................................ 62
1.4.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................... 65
1.5
Study aim............................................................................................................. 66

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
27(225)
1.6
Study governance and oversight........................................................................... 66
1.6.1
Safety confirmation.............................................................................................. 66
2.
STUDY OBJECTIVES........................................................................................ 67
2.1
Primary objectives ............................................................................................... 67
2.2
Secondary objectives............................................................................................ 67
2.3
Safety objectives.................................................................................................. 69
2.4
Exploratory objectives ......................................................................................... 69
3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL...................... 72
3.1
Inclusion criteria .................................................................................................. 72
3.2
Exclusion criteria ................................................................................................. 74
3.3
Patient enrollment and randomization .................................................................. 77
3.4
Procedures for handling incorrectly enrolled or randomized patients.................... 78
3.5
Methods for assigning treatment arms.................................................................. 79
3.6
Methods for ensuring blinding (Not applicable) ................................................... 79
3.7
Methods for unblinding (Not applicable).............................................................. 79
3.8
Restrictions.......................................................................................................... 79
3.9
Discontinuation of IP ........................................................................................... 81
3.9.1
Procedures for discontinuation of patient from IP................................................. 82
3.10
Criteria for withdrawal......................................................................................... 83
3.10.1
Screen failures ..................................................................................................... 83
3.10.2
Withdrawal of the informed consent..................................................................... 83
3.10.2.1
Survival status for withdrawn consent and lost to follow-up patients.................... 83
3.11
Discontinuation of the study................................................................................. 84
4.
STUDY PLAN AND TIMING OF PROCEDURES............................................. 84
4.1
Screening/enrollment period ................................................................................ 96
4.2
Treatment period.................................................................................................. 96
4.2.1
Safety confirmation period................................................................................... 97
4.3
Follow-up period.................................................................................................. 97
5.
STUDY ASSESSMENTS.................................................................................... 98
5.1
Efficacy assessments............................................................................................ 98
5.1.1
Central reading of scans ....................................................................................... 98
5.1.2
Survival assessments............................................................................................ 99
5.2
Safety assessments............................................................................................... 99
5.2.1
Laboratory safety assessments.............................................................................. 99

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
28(225)
5.2.2
Physical examination ......................................................................................... 101
5.2.3
Electrocardiogram.............................................................................................. 102
5.2.4
Vital signs.......................................................................................................... 102
5.2.5
Early patient review for safety............................................................................ 103
5.2.6
WHO/ECOG performance status........................................................................ 103
5.2.7
Other safety assessments.................................................................................... 103
5.3
Other assessments.............................................................................................. 104
5.3.1
Clinical outcome assessments/patient-reported outcomes................................... 104
5.3.1.1
EORTC QLQ-C30 ............................................................................................. 104
5.3.1.2
EORTC QLQ-LC13........................................................................................... 105
5.3.1.3
..................................................................................................... 105
5.3.1.4
105
5.3.1.5
105
5.3.2
Administration of the patient-reported outcome questionnaires .......................... 106
5.3.3
107
5.4
Pharmacokinetics ............................................................................................... 107
5.4.1
Collection of samples......................................................................................... 107
5.4.1.1
Collection of samples to measure for the presence of ADAs............................... 108
5.4.1.2
Storage and destruction of pharmacokinetic/ADA samples................................. 108
5.5
Biomarkers Analysis .......................................................................................... 109
5.5.1
Collection of patient samples for stratification by PD-L1 and for expression 
of PD-L1 and Tumor Mutation Burden (TMB)................................................... 109
5.5.2
111
5.5.3
Storage, re-use, and destruction of biological samples........................................ 113
5.5.4
Labeling and shipment of biological samples ..................................................... 113
5.5.5
Chain of custody of biological samples .............................................................. 113
5.5.6
Withdrawal of informed consent for donated biological samples........................ 114
5.6
114
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 114
6.1
Definition of adverse events............................................................................... 115
6.2
Definitions of serious adverse event ................................................................... 115
6.3
Recording of adverse events............................................................................... 115
6.3.1
Time period for collection of adverse events ...................................................... 115
6.3.2
Follow-up of unresolved adverse events............................................................. 115
6.3.3
Variables............................................................................................................ 116
6.3.4
Causality collection............................................................................................ 117
6.3.5
Relationship to protocol procedures ................................................................... 117
6.3.6
Adverse events based on signs and symptoms .................................................... 117
6.3.7
Adverse events based on examinations and tests ................................................ 118
6.3.8
Hy’s law ............................................................................................................ 118
6.3.9
Disease progression............................................................................................ 118
6.3.10
New cancers....................................................................................................... 118
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
29(225)
6.3.11
Deaths................................................................................................................ 119
6.3.12
Safety Data To Be Collected following the final DCO of the study .................... 119
6.4
Reporting of serious adverse events ................................................................... 120
6.5
Treatment Arms 1 and 2 adverse events of special interest ................................. 120
6.6
Overdose............................................................................................................ 121
6.6.1
Durvalumab or tremelimumab............................................................................ 121
6.6.2
Standard of care ................................................................................................. 122
6.7
Pregnancy .......................................................................................................... 122
6.7.1
Maternal exposure.............................................................................................. 122
6.7.2
Paternal exposure............................................................................................... 123
6.8
Medication Error................................................................................................ 123
6.9
Management of IP-related toxicities................................................................... 125
6.9.1
Specific toxicity management and dose modification information -
Durvalumab and durvalumab + tremelimumab................................................... 125
6.9.2
Standard of care agents ...................................................................................... 126
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 126
7.1
Identity of investigational products .................................................................... 126
7.1.1
Order of administration...................................................................................... 127
7.1.2
Durvalumab (MEDI4736).................................................................................. 128
7.1.3
Tremelimumab................................................................................................... 129
7.1.4
Standard of care ................................................................................................. 130
7.2
Dose and treatment regimens ............................................................................. 130
7.2.1
Treatment regimens............................................................................................ 130
7.2.2
Duration of treatment and criteria for treatment through progression and 
retreatment......................................................................................................... 137
7.2.2.1
Duration of treatment ......................................................................................... 137
7.2.2.2
Treatment Arms 1 and 2: Criteria for treatment through progression and for 
retreatment......................................................................................................... 137
7.2.2.3
Treatment Arm 3: No treatment through progression.......................................... 140
7.3
Labeling............................................................................................................. 141
7.4
Storage............................................................................................................... 141
7.5
Compliance........................................................................................................ 141
7.6
Accountability.................................................................................................... 141
7.7
Concomitant medications and other treatments................................................... 142
7.7.1
Other concomitant treatment .............................................................................. 144
7.7.2
Durvalumab drug-drug interactions.................................................................... 144
7.8
Post-study access to study treatment................................................................... 144
8.
STATISTICAL ANALYSES............................................................................. 145

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
30(225)
8.1
Statistical considerations.................................................................................... 145
8.2
Sample size estimate .......................................................................................... 145
8.3
Definitions of analysis sets................................................................................. 147
8.3.1
Full analysis set.................................................................................................. 147
8.3.2
PD-L1 TC <50% analysis set ............................................................................. 147
8.3.3
PD-L1 TC <25% analysis set ............................................................................. 148
8.3.4
PD-L1 TC <1% analysis set ............................................................................... 148
8.3.5
TMB high analysis set........................................................................................ 148
8.3.6
Safety analysis set.............................................................................................. 148
8.3.7
Pharmacokinetic analysis set.............................................................................. 148
8.4
Outcome measures for analyses.......................................................................... 148
8.4.1
Calculation or derivation of efficacy variables.................................................... 148
8.4.2
RECIST 1.1-based endpoints ............................................................................. 148
8.4.2.1
Dual primary endpoints...................................................................................... 149
8.4.2.2
Secondary endpoints .......................................................................................... 150
8.4.3
Calculation or derivation of safety variables....................................................... 152
8.4.3.1
Adverse events................................................................................................... 152
8.4.3.2
Other significant adverse events......................................................................... 152
8.4.3.3
Safety assessments............................................................................................. 152
8.4.4
Calculation or derivation of patient-reported outcome variables ......................... 153
8.4.4.1
EORTC QLQ-C30 ............................................................................................. 153
8.4.4.2
Lung cancer module (EORTC QLQ-LC13)........................................................ 154
8.4.4.3
............................. 155
8.4.5
Calculation or derivation of pharmacokinetic variables ...................................... 156
8.4.5.1
Pharmacokinetic analysis ................................................................................... 156
8.4.5.2
Immunogenicity analysis.................................................................................... 156
8.4.6
................................................ 156
8.5
Methods for statistical analyses.......................................................................... 156
8.5.1
Analysis of the primary and key secondary variable(s)....................................... 161
8.5.1.1
Progression-free survival.................................................................................... 161
8.5.1.2
Overall survival.................................................................................................. 163
8.5.2
Analysis of the secondary variable(s) ................................................................. 164
8.5.2.1
Objective response rate ...................................................................................... 164
8.5.2.2
Duration of response .......................................................................................... 164
8.5.2.3
Proportion of patients alive and progression free at 12 months ........................... 165
8.5.2.4
Patient-reported outcomes.................................................................................. 165
8.5.3
167
8.5.4
Safety data ......................................................................................................... 167
8.5.5
Pharmacokinetic data ......................................................................................... 167
8.5.6
Immunogenicity analysis.................................................................................... 167
8.5.7
.............................................. 168
8.5.8
168
8.5.9
Interim analysis.................................................................................................. 168
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
31(225)
8.6
China cohort ...................................................................................................... 169
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA......................... 170
9.1
Training of study site personnel ......................................................................... 170
9.2
Monitoring of the study...................................................................................... 170
9.2.1
Source data ........................................................................................................ 170
9.2.2
Study agreements............................................................................................... 170
9.2.3
Archiving of study documents............................................................................ 171
9.3
Study timetable and end of study........................................................................ 171
9.4
Data management by AstraZeneca or delegate ................................................... 174
10.
ETHICAL AND REGULATORY REQUIREMENTS....................................... 174
10.1
Ethical conduct of the study ............................................................................... 174
10.2
Patient data protection........................................................................................ 175
10.3
Ethics and regulatory review .............................................................................. 175
10.4
Informed consent ............................................................................................... 175
10.5
Changes to the protocol and informed consent form........................................... 176
10.6
Audits and inspections ....................................................................................... 177
11.
LIST OF REFERENCES ................................................................................... 178
LIST OF TABLES
Table 1
Highly effective methods of contraception (<1% failure rate)........................ 81
Table 2
Study treatment and retreatment periods: Schedule of assessments for 
Treatment Arms 1, 2, and 3 ........................................................................... 87
Table 3
Follow-up period: Schedule of assessments for patients in Treatment 
Arms 1, 2, and 3 who have completed/discontinued treatment....................... 93
Table 4
Clinical chemistry ....................................................................................... 100
Table 5
Hematology................................................................................................. 101
Table 6
Urinalysis.................................................................................................... 101
Table 7
List of investigational products for this study .............................................. 126
Table 8
Prohibited concomitant medications............................................................ 142
Table 9
Supportive medications ............................................................................... 144
Table 10
Summary of outcome variables and analysis populations............................. 147
Table 11
Pre-planned statistical and sensitivity analyses to be conducted................... 158

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
32(225)
Table 12
Schedule of study assessments and relevant eCRF pages to be 
completed during Long-term follow-up (up to approximately 12 
months after DCO for final analysis of OS for superiority).......................... 172
Table 13
Schedule of study assessments and relevant eCRF pages to be 
completed during long-term follow-up (12 months after DCO for final 
analysis of OS for superiority)..................................................................... 173
Table 14
Summary of methods of assessment ............................................................ 202
Table 15
Evaluation of target lesions ......................................................................... 206
Table 16
Evaluation of non-target lesions .................................................................. 206
Table 17
Overall visit response .................................................................................. 207
LIST OF FIGURES
Figure 1
Dosing scheme.............................................................................................. 22
Figure 2
Study schematic for the CCTG study............................................................. 50
Figure 3
Overall study design...................................................................................... 63
Figure 4
Study flow chart............................................................................................ 64
Figure 5
Dosing scheme............................................................................................ 136
Figure 6
Multiple testing procedures for controlling the type 1 error rate................... 161
LIST OF APPENDICES
Appendix A
Additional Safety Information..................................................................... 188
Appendix B
IATA 6.2 Guidance Document.................................................................... 190
Appendix C
191
Appendix D
Hy’s Law .................................................................................................... 194
Appendix E
Guidelines for Evaluation of Objective Tumor Response............................. 200
Appendix F
Patient Reported Outcomes ......................................................................... 212
Appendix G
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis, including 
COVID-19 Outbreak................................................................................... 221
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
33(225)
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
AESI
Adverse event of special interest
ALK
Anaplastic lymphoma kinase
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
APF12
Proportion of patients alive and progression free at 12 months from 
randomization
AST
Aspartate aminotransferase
AUC0-16wk
Area under the plasma drug concentration-time curve from time 0 to Week 16
AUC
Area under the plasma drug concentration-time curve
AUCss
Area under the plasma drug concentration-time curve at steady state
BICR
Blinded Independent Central Review
BoR
Best objective response
BP
Blood pressure
C
Cycle
CCTG
Canadian Cancer Trials Group
CD
Cluster of differentiation
CFDA
China Food and Drug Administration
CI
Confidence interval
CL
Calculated creatinine clearance
Cmax
Maximum plasma concentration
Cmax,ss
Maximum plasma concentration at steady state
Cmin
Minimum plasma concentration
CR
Complete response
CRO
Clinical Research Organization
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CT
Computed tomography
CTC
Common toxicity criteria
CTCAE
Common Terminology Criteria for Adverse Events
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
34(225)
Abbreviation or 
special term
Explanation
CTLA-4
Cytotoxic T-lymphocyte-associated antigen 4
Ctrough,ss
Trough concentration at steady state
DCO
Data Cut Off
DCR
Disease control rate
DILI
Drug induced liver injury
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
DoR
Duration of response
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDoR
Expected duration of response
EGFR
Epidermal growth factor receptor
EORTC
European Organisation for Research and Treatment of Cancer
ePRO
Electronic patient-reported outcome (device)
ESMO
European Society for Medical Oncology
EU
European Union
FAS
Full analysis set
FDA
Food and Drug Administration
FPI
First patient in
GCP
Good Clinical Practice
Unless otherwise noted, ‘GCP’ shall mean ‘the International Council for 
Harmonisation Tripartite Guideline for Good Clinical Practise’ (ICH GCP) 
and the Japanese ‘Good Clinical Practice for Trials on Drugs (Ministry of 
Health, Labour and Welfare [MHLW] Ordinance No. 28, 27 March 1997, 
partially revised by MHLW Ordinance and their related notifications’ (GCP 
Ordinance).
GMP
Good Manufacturing Practice
HbsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
35(225)
Abbreviation or 
special term
Explanation
HIV
Human immunodeficiency virus
HL
Hy’s Law
HR
Hazard ratio
HRCT
High-resolution computed tomography
HRQoL
Health-related quality of life
IASLC
International Association for the Study of Lung Cancer
IB
Investigator’s Brochure
IC
Immune cell
ICF
Informed consent form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IgG
Immunoglobulin
IHC
Immunohistochemistry
ILD
Interstitial lung disease
imAE
Immune-mediated adverse event
IMP
Investigational medicinal product
IP
Investigational product 
IRB
Institutional Review Board, synonymous to Ethics Committee (EC) and 
Independent Ethics Committee (IEC)
IO
Immuno-oncology
ITT
Intent-to-treat
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LPFV
Last patient first visit
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MTP
Multiple testing procedure
NAB
Nanoparticle albumin-bound
NCI
National Cancer Institute
NE
Not evaluable
NSCLC
Non-small-cell lung cancer
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
36(225)
Abbreviation or 
special term
Explanation
NTL
Non-target lesion
OAE
Other significant adverse events
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 TC <1%
PD-L1 expression on less than 1% of tumor cells
PD-L1 TC ≥25%
PD-L1 expression on at least 25% of tumor cells
PD-L1 TC <25%
PD-L1 expression on less than 25% of tumor cells
PD-L1 TC ≥50%
PD-L1 expression on at least 50% of tumor cells
PD-L1 TC <50%
PD-L1 expression on less than 50% of tumor cells
PD-L1 TC ≥90%
PD-L1 expression on ≥90% of tumor cells
PD-L2
Programmed cell death ligand 2
PFS
Progression-free survival
PFS2
Time from randomization to second progression
PHL
Potential Hy’s Law
PK
Pharmacokinetic(s)
PR
Partial response
PRO
Patient-reported outcome
q2w
Every 2 weeks
q3w
Every 3 weeks
q4w
Every 4 weeks
q6w
Every 6 weeks
q8w
Every 8 weeks
q12w
Every 12 weeks
QC
Quality Control
QLQ-C30 v3
30-item Core Quality of Life Questionnaire, version 3
QLQ-LC13
13-item Lung Cancer Quality of Life Questionnaire
QoL
Quality of life
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, Version 1.1
RT-QPCR
Reverse transcription quantitative polymerase chain reaction
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
37(225)
Abbreviation or 
special term
Explanation
SAE
Serious adverse event 
SAP
Statistical analysis plan
SCCHN
Squamous cell carcinoma of the head and neck
SCLC
Small-cell lung cancer
SD
Stable disease
SmPC
Summary of Product Characteristics
SoC
Standard of care
sPD-L1
Soluble programmed cell death ligand 1
TB
Tuberculosis
TBL
Total bilirubin
TC
Tumor cells
TL
Target lesion
TMB
Tumor Mutational Burden
TNBC
Triple-negative breast cancer
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States
WBDC
Web-Based Data Capture
WHO
World Health Organization
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
38(225)
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 
5-year overall survival (OS) 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 OS of 10 to 12 months (Bonomi 2010).  
Patients without a targetable mutation (ie, 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 
(Sandler et al 2006, 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.
Common first-line treatment regimens for advanced NSCLC in major global markets are 
typically platinum-based doublets and include carboplatin and paclitaxel (eg, nanoparticle 
albumin-bound [nab] paclitaxel [Abraxane®]), carboplatin and gemcitabine (squamous only), 
carboplatin and pemetrexed (non-squamous only), cisplatin and gemcitabine (squamous only), 
and cisplatin and pemetrexed (non-squamous only).  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 (Ciuleanu et al 2009, Paz-Ares et al 2013).  Although 
platinum-based doublets are interchangeable in terms of efficacy when used alone, these 
doublets 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. 
Recently, pembrolizumab, a programmed cell death 1 (PD-1) inhibitor, gained Food and Drug 
Administration (FDA) approval for the first-line treatment of metastatic NSCLC in patients 
with high programmed cell death ligand 1 (PD-L1) expression and without EGFR or ALK 
genomic tumor aberrations.  Regulatory approval was based on safety and efficacy data from 
the KEYNOTE-024 study.  Results from the KEYNOTE-024 study, which included patients 
with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells (TC) and with no 
activating EGFR mutations or ALK fusions, demonstrated that patients treated with 
pembrolizumab had longer PFS (10.3 versus 6.0 months) and OS (hazard ratio [HR] for death, 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
39(225)
0.60) and higher objective response rate (ORR; 44.8% versus 27.8%) compared with patients 
treated with platinum-based therapy (Reck et al 2016).  The KEYNOTE-021 21G cohort is an 
expansion cohort of a Phase I/II study that compared the efficacy and safety of 
pembrolizumab plus carboplatin and pemetrexed to carboplatin and pemetrexed alone as 
first-line therapy for patients with advanced NSCLC of non-squamous histology.  Patients 
who were treated with first-line pembrolizumab in combination with chemotherapy had higher 
ORR (55%) compared with patients receiving chemotherapy alone (29%) (Langer et al 2016).  
Both of these studies have shown that pembrolizumab alone or in combination with
chemotherapy can be an effective first-line treatment option for patients with advanced 
NSCLC.
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 part of a complex system of receptors and ligands that are involved in controlling 
T-cell activation. The PD-1 receptor (CD279) is expressed on the surface of activated T cells 
(Keir et al 2008).  It has 2 known ligands: PD-L1 (B7 H1; CD274) and PD-L2 (B7 DC; 
CD273) (Okazaki and Honjo 2007).  The PD-1 and PD-L1/PD-L2 belong to the family of 
immune checkpoint proteins that act as co inhibitory factors, which can halt or limit the 
development of T cell response.  When PD-L1 binds to PD-1, an inhibitory signal is 
transmitted into the T cell, which reduces cytokine production and suppresses T cell 
proliferation. Tumor cells exploit this immune checkpoint pathway as a mechanism to evade 
detection and inhibit immune response.
PD-L1 is constitutively expressed by B cells, dendritic cells, and macrophages (Qin et 
al 2016).  Importantly, PD-L1 is commonly over expressed on tumor cells or on non 
transformed cells in the tumor microenvironment (Pardoll 2012).  PD-L1 expressed on the 
tumor cells binds to PD-1 receptors on the activated T cells leading to the inhibition of 
cytotoxic T cells.  These deactivated T cells remain inhibited in the tumor microenvironment.  
The PD-1/PD-L1 pathway represents an adaptive immune resistance mechanism that is 
exerted by tumor cells in response to endogenous antitumor activity.
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way 
of evading immune detection and elimination.  The binding of an anti-PD-L1 agent to the 
PD-L1 receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed 
on ICs.  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.  
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 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
40(225)
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 (Bonomi 2010, Brahmer et al 2012, Hirano et al 2005, 
Howlander et al 2014, 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 2015a, Schiller et al 2002, Segal et al 2015). In 
addition, a high mutational burden (eg, in bladder carcinoma) (Alexandrov et al 2013) may 
contribute to the responses seen with immune therapy. 
In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is constitutively 
expressed by regulatory T cells and upregulated on activated T cells.  CTLA-4 delivers a 
negative regulatory signal to T cells upon binding of CD80 (B7.1) or CD86 (B7.2) ligands on 
antigen-presenting cells (FDA Guidance 2011, Fife and Bluestone 2008).  A block 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 have now been added with a wealth of clinical data showing that blockade of 
negative regulatory signals to T-cells such as CTLA-4 and PD-L1 has promising clinical 
activity.  Ipilimumab was granted US FDA approval for the treatment of metastatic melanoma 
and is currently under investigation for several other malignancies, while nivolumab and 
pembrolizumab, 2 anti-PD-1 agents, and atezolizumab, an anti-PD-L1 agent, have been 
granted approvals by agencies such as the US FDA and the European Medicines Agency 
approval for the treatment of a number of malignancies including metastatic melanoma, 
squamous and non-squamous cell NSCLC, squamous cell carcinoma of the head and neck 
(SCCHN), and urothelial carcinoma.  In addition, there are data from agents in the anti-
PD-1/PD-L1 class showing clinical activity in a wide range of tumor types.
1.1.2
Durvalumab
Durvalumab (MEDI4736) is a human mAb of the immunoglobulin G (Ig) G1 kappa subclass 
that blocks the interaction of PD-L1 (but not programmed cell death ligand 2 [PD-L2]) with 
PD-1 on T cells and CD80 (B7.1) on immune cells (ICs).  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). The proposed mechanism of action (MOA) for durvalumab is 
interference in the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-
1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including those 
that may result in tumor elimination.  In vitro studies demonstrate that durvalumab 
antagonizes the inhibitory effect of PD-L1 on primary human T cells resulting in the restored 
proliferation of IFN-γ (Stewart et al 2015).  In vivo studies have shown that durvalumab 
inhibits tumor growth in xenograft models via a T cell dependent mechanism 
(Stewart et al 2015).  Based on these data, durvalumab is expected to stimulate the patient’s 
antitumor immune response by binding to PD-L1 and shifting the balance toward an antitumor 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
41(225)
response. Durvalumab has been engineered to reduce antibody-dependent cellular cytotoxicity 
and complement-dependent cytotoxicity. 
To date, durvalumab has been given to more than 6000 patients as part of ongoing studies 
either as monotherapy or in combination with other anticancer agents.  Details on the safety 
profile of durvalumab monotherapy are summarized in Section 1.2.1.3 and Section 6.5.  Refer 
to the current durvalumab Investigator’s Brochure (IB) for a complete summary of non-
clinical and clinical information including safety, efficacy, and pharmacokinetics.
1.1.3
Tremelimumab
Tremelimumab (MEDI1123, formerly CP-675,206) is a human 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-2 and 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 1500 patients as part of ongoing studies 
either as monotherapy or in combination with anticancer agents other than durvalumab. 
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
Durvalumab 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 durvalumab + tremelimumab 
combination therapy for the treatment of cancer.
Study D4190C00006 is a Phase Ib dose-escalation study to establish the safety, 
pharmacokinetics (PK)/pharmacodynamics, and preliminary anti-tumor activity of 
durvalumab + tremelimumab combination therapy in patients with advanced NSCLC.  
 
 
 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 3000 patients have received the combination using a number of doses and 
dosing schedules.  Details on the safety profile of durvalumab + tremelimumab combination 
therapy are summarized in Sections 1.2.1.1 and 1.3.2.3.  Refer to the current editions of the 
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
42(225)
durvalumab and tremelimumab IBs for a complete summary of non-clinical and clinical 
information including safety, PK, and efficacy.
1.1.5
Rationale for the study
Current therapies for advanced NSCLC have poor outcomes (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 (Bonomi 2010, 
D’Addario et al 2010, Sandler et al 2006, Scagliotti et al 2008, Schiller et al 2002).  Systemic 
chemotherapy is associated with significant side effects, including neutropenia, nausea, 
vomiting and dehydration, and alopecia (Sandler et al 2006, Scagliotti et al 2008).  Recent 
progress in immunotherapy for first-line NSCLC has been mixed.  While previously untreated 
patients with PD-L1 expression on at least 50% of tumor cells (PD-L1 TC ≥50%) NSCLC 
receiving the PD-1 inhibitor pembrolizumab had a 44.8% response rate and median PFS of 
10.3 months (Reck et al 2016), nivolumab failed to meet its primary endpoint of PFS in a 
similar population (Socinski et al 2016).  These facts indicate that there is still a significant 
unmet medical need for additional treatment options for use in this patient population.  In
addition, patients with NSCLC may be particularly susceptible to these immunotherapies 
given the high mutational burden of this disease.  Novel therapies are urgently needed to 
improve clinical outcomes, irrespective of PD-L1 status. 
1.1.5.1
Rationale for the combination of durvalumab and tremelimumab with 
chemotherapy
Non-clinical and clinical studies have indicated that blockade of immune checkpoints 
(PD-1/PD-L1 and CTLA-4) can have a positive effect on antitumor immunity.  One potential 
strategy is to combine these non-redundant and potential synergistic single-agent immune 
checkpoint inhibitors, thereby producing an additive improvement in tumor response 
(Larkin et al 2015, Pisters and LeChevalier 2005, Postow et al 2015).  
The use of combination chemotherapy is a mainstay of oncology therapy.  The goal of 
combination chemotherapy is to utilize agents that affect cancer cells by different 
mechanisms, thus reducing the risk of developing resistance.  Current studies are now adding 
immunotherapeutics to chemotherapeutics to broaden antitumor responses.
Checkpoint inhibitors have been tested in NSCLC, either used alone or in combination with 
chemotherapy.  Preliminary efficacy data from Study D4190C00006 have demonstrated that 
durvalumab + tremelimumab combination therapy is clinically active and well tolerated.  As 
of 1 June 2015, in 63 patients with at least 24 weeks of follow-up, 17% achieved objective 
response and disease control at 24 weeks is 29%.  Responses in both patients with PD-L1 
TC ≥25% and those with PD-L1 TC <25% demonstrated evidence of clinical activity.  
Investigator-reported confirmed objective responses were achieved by 23% of patients in the 
combined tremelimumab 1 mg/kg cohort, including 22% of patients with PD-L1 TC ≥25%  
and 29% of patients with PD-L1 TC <25% (Antonia et al 2016a).
Nivolumab (PD-1 inhibitor) in combination with platinum-based doublet chemotherapy 
(Rizvi et al 2016) and nivolumab in combination with ipilimumab (anti-CTLA-4 mAb) 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
43(225)
(Hellmann et al 2017) as first-line treatment for advanced NSCLC have been studied in 
CheckMate 012.  The antitumor activity of first-line nivolumab in combination with platinum 
doublets appeared highly promising, and the safety profile of nivolumab in combination with 
either ipilimumab or with chemotherapy was tolerable (Sections 1.3.1.2 and 1.3.1.3, 
respectively).
The safety and efficacy of checkpoint inhibitors combined with chemotherapy have also been 
demonstrated across multiple tumor types.  Data for durvalumab ± tremelimumab with 
standard platinum-based chemotherapy in advanced cancers are being generated from 
2 ongoing Phase I studies: the internal Study D419SC00001 (n=6) and a Phase Ib study 
(NCT02537418) run by the Canadian Cancer Trials Group (CCTG; n=111 as of an 
October 2016 cut-off).  The combinations tested are tolerable and toxicities manageable; 
details on the safety profile found in these studies are summarized in Sections 1.2.2 and 
1.3.2.5.  Preliminary results from the CCTG study were presented for the NSCLC cohorts at 
the International Association for the Study of Lung Cancer (IASLC) 2016 meeting; the overall 
ORR in NSCLC cohort (n=26) was 61.5%. 
In addition, KEYNOTE-021 is a multi-cohort Phase I/II study comparing pembrolizumab in 
combination with various chemotherapy regimens to chemotherapy alone as first-line 
treatment for NSCLC.  In the cohort of patients receiving pembrolizumab in combination with 
chemotherapy (carboplatin and pemetrexed), the objective response was 55% (95% 
confidence interval [CI]: 42 to 68) compared with 29% (95% CI: 18 to 41) in patients 
receiving chemotherapy (carboplatin and pemetrexed) alone.  Objective response was 
significantly improved in patients receiving pembrolizumab with chemotherapy compared 
with those receiving chemotherapy alone (estimated treatment difference 26% [95% CI: 9% to 
42%]; p=0.0016).  In patients receiving pembrolizumab with chemotherapy, the response rate 
was 57% (95% CI: 34 to 79) in patients who had a PD-L1 tumor proportion score of less than
1% and was 54% (95% CI: 37 to 70) in patients with a PD-L1 tumor proportion score of ≥1%.  
In patients receiving pembrolizumab with chemotherapy, median time to response was 
1.5 months compared with 2.7 months in patients receiving chemotherapy alone.  Kaplan-
Meier estimates of response duration of at least 6 months were 92% (95% CI: 73 to 98) in the 
pembrolizumab with chemotherapy group and 81% (95% CI: 51 to 93) in the chemotherapy 
alone group.  In patients receiving pembrolizumab with chemotherapy, the most common 
Grade 3 or worse treatment-related adverse events (AEs) were anemia (12%); decreased 
neutrophil count (5%); and acute kidney injury, decreased lymphocyte count, fatigue, 
neutropenia, sepsis, and thrombocytopenia (3% each).  Additional results on tolerability of 
pembrolizumab in combination with chemotherapy are discussed in Section 1.3.2.5
(Langer et al 2016).
In addition to these completed studies, a number of studies of immunotherapies in 
combination with chemotherapy in first-line NSCLC are ongoing.  These include 
CheckMate 227 (nivolumab plus platinum doublet in PD-L1-negative NSCLC; 
NCT02477826); KEYNOTE-189 (pembrolizumab plus pemetrexed in non-squamous 
NSCLC; NCT02578680); KEYNOTE-407 (carboplatin and paclitaxel or nab-paclitaxel with 
or without pembrolizumab in first-line metastatic NSCLC; NCT02775435); and 
IMpower 130, IMpower 131, and IMpower 150 (atezolizumab plus carboplatin, 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
44(225)
nab-paclitaxel, or paclitaxel with or without bevacizumab in squamous and non-squamous 
NSCLC; NCT02367781, NCT02367794, and NCT02366143, respectively) (reviewed in 
Gainor 2016 and Langer et al 2016).
In summary, the preliminary efficacy, safety, and tolerability data of 
durvalumab ± tremelimumab generated to date, together with early positive signals with other 
immunotherapies in combination with chemotherapy, support the continued development of 
these treatments in combination with standard of care (SoC) chemotherapy in NSCLC.
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
Durvalumab and tremelimumab dose and treatment regimen justification
1.2.1.1
Durvalumab+ tremelimumab combination therapy dose rationale
The durvalumab + tremelimumab combination therapy doses and regimen selected for this 
study are based on the goal of selecting an optimal combination dose of durvalumab and 
tremelimumab that would yield sustained target suppression (PD-L1 and CTLA-4, 
respectively), demonstrate promising efficacy, and have an acceptable safety profile. 
Pharmacokinetics/Pharmacodynamics data
Study D4190C00006 included dose cohorts with both a 
 schedule of 
durvalumab in combination with a 
 schedule of tremelimumab. The 
 schedule was 
included to align with the 
 dosing of tremelimumab. PK simulations from durvalumab 
monotherapy data indicated that a similar area under the serum drug concentration-time curve 
at steady state (AUCss; 4 weeks) was expected following both 
 
 dosing with durvalumab. The observed durvalumab PK data from the 
Study D4190C00006 were in line with the predicted monotherapy PK data developed pre-
clinically and in line with that seen in the first-time-in-human, single-agent study 
(CD-ON-durvalumab-1108) in patients with advanced solid tumors. This demonstrates similar 
exposure of durvalumab 
 with no alterations in PK when 
durvalumab and tremelimumab (doses ranging from 
 are dosed together. While 
the median maximum serum concentration at steady state (Cmax,ss) is expected to be higher 
with 
 (approximately 1.5-fold) and median trough concentration at steady state 
(Ctrough,ss) is expected to be higher with 
 (approximately 1.25-fold), this is not 
expected to impact the overall safety and efficacy profile, based on existing pre-clinical and 
clinical data.
Monotonic increases in pharmacodynamic activity were observed with increasing doses of 
tremelimumab relative to the activity observed in patients treated with durvalumab 
monotherapy.  There was evidence of augmented pharmacodynamic activity relative to 
durvalumab monotherapy with combination doses containing 
 tremelimumab, 
including both the 
 durvalumab + 
 tremelimumab combinations.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
45(225)
Clinical data
In Study D4190C00006, various dose combinations have been explored, with doses of 
tremelimumab ranging from 
 and doses of durvalumab ranging from 
 
  Tremelimumab was given on a 
 schedule, while durvalumab was explored in 
both a 
 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 AEs, 
including discontinuations due to AEs, serious adverse events (SAEs), and severe AEs.  
Between the 
 durvalumab + 
 tremelimumab and 
 durvalumab + 
 tremelimumab cohorts treated at the 
 schedule, the number of patients reporting 
any AE, Grade ≥3 AEs, SAEs, and treatment-related AEs was higher in the 
 
durvalumab + 
 tremelimumab cohort than the 
 durvalumab + 
 
tremelimumab cohort.  A similar pattern was noted in the 
 regimens, suggesting that, as 
the dose of tremelimumab increased above 
 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 
 of tremelimumab compared to the 
 dose cohorts.  Together, 
these data suggest that a combination using a tremelimumab dose of 
 appeared to 
minimize the rate of toxicity when combined with durvalumab.  As a result, all combination 
doses utilizing either the 
 doses of tremelimumab were eliminated in the final 
dose selection.
In contrast, cohorts assessing higher doses of durvalumab with a constant dose of 
tremelimumab did not show an increase in the rate of AEs.  The data suggested that increasing 
doses of durvalumab may not impact the safety of the combination as much as the 
tremelimumab dose.  Further, safety data between the 
 cohorts were 
similar, with no change in safety events with increasing dose of durvalumab.
In Study D4190C00006, of all treatment cohorts, the cohort of patients treated in the 
 
durvalumab + 
 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 durvalumab and tremelimumab combination did not appear 
to change with increasing doses of tremelimumab.  The 
 durvalumab 
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 
 durvalumab + 
 tremelimumab dose cohort 
may demonstrate equivalent clinical activity to those of other dose combinations.  
Altogether, the data suggested that a 
 durvalumab + 
 tremelimumab dose 
combination should be selected for further development.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
46(225)
Refer to the current durvalumab IB for a complete summary of non-clinical and clinical 
information on the durvalumab + tremelimumab combination, including safety, efficacy, and 
pharmacokinetics.  
1.2.1.2
Rationale for 4 cycles of combination therapy followed by durvalumab 
monotherapy
Long-term follow-up on melanoma patients treated with ipilimumab, an anti-CTLA-4 
targeting antibody (dosed 
 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 (Sandler et al 2006, 
Schadendorf et al 2013).  
Data from Study D4190C00006 (Phase I trial in NSCLC patients using the combination of 
durvalumab and tremelimumab) also show an approximately dose-proportional increase in PK 
exposure for durvalumab over the dose range of 
 durvalumab 
 or 
 (For 
further information on PK observations in Study D4190C00006, please see the current IB). 
The observed durvalumab PK data from the combination study were well in line with the 
predicted monotherapy PK data (5th median and 95th percentiles) for a 
 regimen.  
The durvalumab + tremelimumab combination regimen will be administered for 4 doses q3w 
in combination with chemotherapy followed by durvalumab monotherapy q4w until disease 
progression or unless other specific discontinuation criteria are met.  One additional 
combination dose will be administered post-chemotherapy (see Section 1.2.2).  This is to 
account for the possibility that the ability of T cells to respond to tremelimumab may be 
dampened in the presence of cytotoxic chemotherapy.
1.2.1.3
Durvalumab monotherapy dose rationale
A durvalumab dose of 
 is supported by in-vitro data, non-clinical activity, 
clinical PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in patients 
with advanced solid tumors and from a Phase I study performed in Japanese patients with 
advanced solid tumor (D4190C00002).
PK/pharmacodynamic data
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging 
from 
 durvalumab exhibited non-linear 
(dose-dependent) PK consistent with target-mediated drug disposition.  The PK approached 
linearity at 
 suggesting near-complete target saturation (membrane-bound and 
soluble programmed cell death ligand 1 [sPD-L1]), and further shows that the durvalumab 
dosing frequency can be adapted to a particular regimen given the linearity seen at doses 
higher than 
  The expected half-life with doses 
 is approximately 
21 days.  A dose-dependent suppression in peripheral sPD-L1 was observed over the dose 
range studied, consistent with the engagement of durvalumab with PD-L1.  A low level of 
immunogenicity has been observed.  No patients have experienced immune-complex disease 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
47(225)
following exposure to durvalumab. (For further information on immunogenicity, please see 
the current IB.)    
A population PK model was developed using the data from Study 1108 (doses 
 
 (Fairman et al 2014).  Multiple simulations indicate that a similar 
overall exposure is expected following both 
 regimens, as 
represented by AUCss (4 weeks).  Median Cmax,ss is expected to be higher with
(~1.5-fold) and median Ctrough,ss is expected to be higher with
(~1.25-fold).  
Clinical activity with the 
 dosing regimen is anticipated to be consistent with 
 with the proposed similar dose of 
 expected to (a) achieve 
complete target saturation in majority of patients; (b) account for anticipated variability in PK, 
pharmacodynamics, and clinical activity in diverse cancer populations; (c) maintain sufficient 
PK exposure in case of anti-drug antibody (ADA) impact; and (d) achieve PK exposure that 
yielded maximal antitumor activity in animal models.
Given the similar area under the serum drug concentration-time curve (AUC) and modest 
differences in median peak and trough levels at steady state, the observation that both 
regimens maintain complete sPD-L1 suppression at trough, and the available clinical data, the 
 regimens are expected to have similar efficacy and safety 
profiles, supporting further development with a dose of 
 
Clinical data
Refer to the current durvalumab IB for a complete summary of clinical information including 
safety, efficacy, and pharmacokinetics at the 
 regimen.
1.2.1.4
Rationale for fixed dosing
A population PK model was developed for durvalumab using monotherapy data from a 
Phase I study (Study 1108; N=292; doses 
 solid 
tumors).  Population PK analysis indicated only minor impact of body weight on the PK of 
durvalumab (coefficient of ≤0.5).  The impact of body weight-based 
 and 
fixed dosing 
 of durvalumab was evaluated by comparing predicted steady-state 
PK concentrations (5th, median, and 95th percentiles) using the population PK model.  A 
fixed dose of 
 was selected to approximate 
 (based on median body weight of 
~75 kg).  A total of 1000 patients were simulated using body weight distribution of 40 to 
120 kg.  Simulation results demonstrate that body weight-based and fixed dosing regimens 
yield similar median steady-state PK concentrations with slightly less overall between-patient 
variability with fixed dosing regimen.  
Similarly, a population PK model was developed for tremelimumab using data from Phase I 
through Phase III (N=654; doses 
 metastatic 
melanoma) (Wang et al 2014).  Population PK model indicated minor impact of body weight 
on PK of tremelimumab (coefficient of ≤0.5).  The weight-based 
 and fixed 
dosing 
 based on median body weight of ~75 kg) regimens were compared 
using predicted PK concentrations (5th, median, and 95th percentiles) using population PK 
model in a simulated population of 1000 patients with body weight distribution of 40 to 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
48(225)
120 kg.  Similar to durvalumab, simulations indicated that both body weight-based and fixed 
dosing regimens of tremelimumab yield similar median steady-state PK concentrations with 
slightly less between-patient variability with fixed dosing regimen.
Similar findings have been reported by others (NCCN 2014, Ng et al 2006, Wang et al 2009, 
Zhang et al 2012, Narwal et al 2013).  Wang and colleagues investigated 12 mAbs and found 
that fixed and body size-based dosing perform similarly, with fixed dosing being better for 
7 of 12 antibodies (Wang et al 2009).  In addition, they investigated 18 therapeutic proteins 
and peptides and showed that fixed dosing performed better for 12 of 18 in terms of reducing 
the between-patient variability in pharmacokinetic/pharmacodynamic parameters 
(Zhang et al 2012). 
 
 
 
 
1.2.2
Rationale for proposed Phase III dose and schedule 
The proposed dosing schedule is aligned with the standard fixed dosing of 
 
durvalumab + 
 tremelimumab for 
 followed by durvalumab monotherapy 
 which is supported by efficacy and safety as well as tolerability data across 
multiple studies in multiple tumor types.  To conform to the chemotherapy schedule in the 
study, we propose to use standard durvalumab + tremelimumab combination therapy dose and 
ratio at a 
 dosing interval for the 
 rather than the standard 
 schedule. 
The safety of a 
 dosing schedule in combination with chemotherapy has been explored in 
the ongoing Study D419SC00001 (described below), where tremelimumab is administered at 
 in combination with 
 durvalumab 
 followed by 
 durvalumab 
  
The combination has been declared tolerable and manageable (see below for more detail).  
The 
 dose of durvalumab is the 
 equivalent of the standard 
 dose.  
The tremelimumab dose was not lowered proportionally to 
 because 
 is the lowest 
tested biologically effective dose. 
In this study, AstraZeneca proposes to use the Phase III fixed dose of durvalumab, so this study 
will combine 75 mg tremelimumab with 1500 mg durvalumab q3w in combination with 
chemotherapy.  The relative increase in dose density of durvalumab (ie, 1500 mg q3w instead 
of 
 is supported by the fact that toxicities attributable to durvalumab do not appear dose 
dependent, and PK modeling reveals no meaningful differences in drug levels between 
 
 dosing.  After chemotherapy, the dose will be 1500 mg durvalumab q4w.  
Study BR.34 is a Phase II randomized trial of durvalumab and tremelimumab 
± platinum-based chemotherapy in patients with metastatic (Stage IV) squamous or 
non-squamous NSCLC.  Both Study BR.34 and the CCTG (NCT02537418) described below 
are assessing 
 tremelimumab with 
 durvalumab 
 in combination with 
platinum-based chemotherapy.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
49(225)
Supportive clinical data
The safety and tolerability data that support the proposed combination and schedule are based 
on 2 ongoing Phase I/IB studies investigating the safety and tolerability of 
durvalumab + tremelimumab in combination with various chemotherapy regimens in solid 
tumors, an AstraZeneca internal study (D419SC00001) and a CCTG study (NCT02537418).
AstraZeneca Phase I study (D419SC00001)
This Phase I open-label study is evaluating the safety and tolerability of durvalumab + 
tremelimumab combination therapy in combination with first-line chemotherapy regimens in 
patients with locally advanced or metastatic solid tumors.  The tumor types originally included 
ovarian/peritoneal/fallopian tube cancer, SCCHN, triple-negative breast cancer (TNBC), small 
cell lung carcinoma (SCLC), and gastric/gastroesophageal junction cancer. 
As of 6 December 2016, 6 patients with SCLC had completed 
 of treatment with 
durvalumab 
 + tremelimumab 
 given concurrently with carboplatin AUC 
 and etoposide 
 followed by durvalumab 
 monotherapy 
  No DLT was reported during the first cycle of treatment (a 21-day period).  One patient 
developed Grade 4 hepatitis with elevation of alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and gamma-glutamyl transferase at Cycle 5 Day 1.  Although the 
onset of this event was 1 day after the protocol-defined DLT period of 4 cycles, it was 
considered as a DLT following discussion with the Investigator.  The liver enzymes were 
normalized within 16 days after steroid use and was confirmed as not a Hy’s law case.  As 
there was only 1 DLT reported in 6 patients, the safety profile of this combination with 
chemotherapy at the q3w schedule is declared tolerable and manageable.
Additional details on safety are provided in Section 1.3.2.5.
CCTG study (NCT02537418)
This is an ongoing multi-center, Phase I study of single or double immunotherapy 
(durvalumab ± tremelimumab) in combination with multiple standard platinum-based 
chemotherapy regimens in patients with incurable advanced or metastatic cancer and is 
sponsored and conducted by the CCTG.  Chemotherapy regimens assessed in the study 
include cisplatin + pemetrexed, cisplatin + gemcitabine, cisplatin + etoposide, carboplatin + 
pemetrexed, carboplatin + gemcitabine, nab-paclitaxel + carboplatin, and etoposide + 
carboplatin at standard doses for each regimen.
The dose escalation and dose regimen are outlined below (Figure 2).  Another dose level 
(DL3, durvalumab 
 + tremelimumab 
 [maximum 6 doses of tremelimumab] 
 with chemotherapy) was added after the protocol was initiated.  A total of 4 dose levels 
of durvalumab ± tremelimumab are being assessed.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
50(225)
Figure 2
Study schematic for the CCTG study
As of an October 2016 data cut-off, a total of 111 patients have been dosed with 
7 chemotherapy regimens across multiple tumor types; the majority of patients enrolled have 
metastatic/advanced NSCLC (44%), followed by SCLC (16%) and then bladder cancer (7%), 
and most have had no prior chemotherapy (71%).  SCLC patients enrolled into the etoposide-
carboplatin cohorts started immuno-oncology (IO) treatment in Cycle 3 of chemotherapy; all 
other chemotherapy regimens assessed the IO combination starting at Cycle 1. 
Overall, toxicities related to the chemotherapy core regimen appeared as expected in severity 
and frequency (see Section 1.3.2.5 for more detail on the safety profile from this study).  
Overall, across all dose levels, there was no clear dose dependency in any of the reported AEs, 
and there was no DLT reported per protocol-defined criteria (DLT period of 21 days).  
Toxicities related to durvalumab and tremelimumab were also those expected for these agents, 
although a number of potential IO-related toxicities such as diarrhea, skin rash, hepatic 
function changes, or pneumonitis were difficult to differentiate from those reported from 
cytotoxic agents.  As expected, there were more IO-related toxicities reported for dose levels 
containing tremelimumab.  In general, all regimens were tolerable and toxicities were 
manageable at all dose levels.  There was no discernible difference in the tolerability profile 
when IO treatment was administered in Cycle 1 (including SCLC patients) versus Cycle 3 of 
chemotherapy for SCLC patients only.
In general, the overall safety profile from these 2 studies with regard to the IO+IO treatment 
appears to be consistent with available safety and tolerability data for durvalumab in 
combination with tremelimumab. 
PK modeling
PK modeling and simulation have been conducted to evaluate the switch from q4w dosing to 
q3w dosing for both durvalumab and tremelimumab.  Simulated PK profiles of both drug 
components based on the study design (
 dosing regimen of 
 durvalumab in 
combination with 
 tremelimumab given at 
 durvalumab as a single 
agent in 
 a combination dose given at 
 followed by durvalumab 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
51(225)
monotherapy 
 were compared with simulated PK profiles of the 
 dosing regimen 
 dosing regimen of 
 durvalumab in combination of 
 tremelimumab given 
at 
 followed by durvalumab monotherapy 
 
Results suggest that tremelimumab exposure is similar between the 
 dosing regimen of the 
study (tremelimumab given at 
 and the 
 dosing 
regimen (tremelimumab given at 
 For the 
 dosing 
regimen versus the 
 dosing regimen, median maximum serum concentration (Cmax) 
following 4th dose were 26.2 μg/mL versus 24.5 μg/mL, median trough concentration 
following 4th dose at Week 16 was 3.56 μg/mL versus 5.62 μg/mL, and area under the plasma 
drug concentration-time curve from time 0 to Week 16 (AUC0-16wk) was 1045 μg*day/mL 
versus 982 μg*day/mL for the q3w and q4w schedules, respectively.
For durvalumab, median Cmax following the 5th dose of the 
 regimen and the 4th dose of 
the 
 regimen was 689 and 624 μg/mL, median trough concentration at Week 16 was 
125 and 94.5 μg/mL, and AUC0-16wk was 28726 and 22772 μg*day/mL for the 
schedule, respectively. 
Therefore, PK modeling suggests that a 
 schedule does not impose a significant increased 
safety risk based on expected durvalumab and tremelimumab exposures.
Taken together, the totality of data provides sufficient safety data to support the combination 
of 
 durvalumab + 
 tremelimumab with chemotherapy.  There is supportive 
safety data for the combination of 
 durvalumab + 
 tremelimumab 
 followed by 
 durvalumab 
 from Study D419SC00001.  The safety
of the combination of 
 durvalumab 
 plus tremelimumab
 
with 
chemotherapy has been assessed in more than 100 patients in the CCTG Phase I study.  
Clinical data from NSCLC patients in Study 006 suggest that increasing the dose of 
durvalumab has no significant impact on the safety and tolerability of the durvalumab and 
tremelimumab combination.  In addition, PK modeling data suggest that there will be a 
minimal impact on investigational product (IP) exposure if the standard doses 
 are 
given on a 
regimen. 
Additional dose of tremelimumab
Patients in Treatment Arm 1 will receive an additional dose of durvalumab + tremelimumab 
after chemotherapy at Week 16 if they tolerate the combination and complete all 4 doses of 
durvalumab + tremelimumab combination therapy during chemotherapy.  The rationale to 
have an additional dose of tremelimumab after chemotherapy is based on the possibility that 
chemotherapy may limit the responsiveness of T cells to tremelimumab and that 
tremelimumab given after chemotherapy will help control rapid progression that is inherent to 
the clinical course of NSCLC, thereby sustaining the responses that may have been achieved 
during induction.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
52(225)
1.2.2.1
Safety confirmation of proposed doses 
To better support the use of the 1500 mg durvalumab ± 75 mg tremelimumab q3w in this 
study and to ensure safety and tolerability in this larger Phase III study, an evaluation and 
confirmation of safety of the combination using the proposed dose and schedule will be 
conducted by an independent data monitoring committee (IDMC) (see Section 1.6).
1.2.3
Rationale for control treatment arm: standard care therapy 
The choice of SoC chemotherapy options provided in this study includes abraxane + 
carboplatin, gemcitabine + cisplatin (squamous patients only), gemcitabine + carboplatin 
(squamous patients only), pemetrexed + carboplatin (non-squamous patients only), and 
pemetrexed + cisplatin (non-squamous patients only).  Patients in the SoC treatment arm 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, Reck et al 2014).
1.2.4
Rationale for endpoints 
The dual primary aims of this study are to assess the efficacy of durvalumab monotherapy + 
SoC chemotherapy compared with SoC chemotherapy alone in terms of PFS and OS in all 
patients. The key secondary aims of the study are to assess the efficacy of durvalumab + 
tremelimumab combination therapy + SoC chemotherapy compared with SoC chemotherapy 
alone in terms of PFS and OS in all patients. PFS may serve as a surrogate endpoint for OS 
when differences between treatment arms are of sufficient magnitude and clinical importance 
(FDA Guidance 2011, Paz-Ares et al 2013, Pazdur 2008). In certain settings, the utility of 
survival as an endpoint may potentially be confounded by subsequent therapies. Specifically, 
there are a number of molecules that target the PD-1/PD-L1 pathway, including 
pembrolizumab, nivolumab, and atezolizumab that are now available for the treatment of 
NSCLC. Access to these agents creates challenges in being able to fully characterize the 
effects of study treatment on OS if patients subsequently receive these immunotherapeutic 
agents. 
Secondary aims of the study also include evaluation of the efficacy endpoints OS, PFS and 
ORR in biomarker defined populations, to further evaluate the antitumor effect and survival 
benefit of durvalumab + tremelimumab + SoC chemotherapy compared with SoC 
chemotherapy alone in such biomarker selected patient population. The biomarker defined 
populations are those patients with high tumor mutational burden (TMB high detected in 
tumor tissue and/or ctDNA, cut-offs to be detailed in the SAP), those patients with PD-L1 
expression on less than 50% of tumor cells (PD-L1 TC <50%), patients with PD L1 
expression on less than 25% of tumor cells (PD L1 TC <25%) and patients with PD-L1 
expression on less than 1% of tumor cells (PD-L1 TC <1%). 
In addition to the comparisons of durvalumab ± tremelimumab + SoC chemotherapy treatment 
arms to the SoC chemotherapy alone treatment arm, the comparison of the 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
53(225)
durvalumab + tremelimumab combination therapy + SoC chemotherapy and the 
durvalumab monotherapy + SoC chemotherapy treatment arms will provide information as to 
the relative contribution of adding tremelimumab to the established benefit-risk profile of 
durvalumab monotherapy+ SoC chemotherapy.  This comparison is not currently included in 
the multiplicity-controlled statistical testing procedure because the proposed study is not 
powered for the comparison.  However, the treatment difference will be summarized 
descriptively to evaluate the relative benefit-risk difference between the 2 experimental 
treatment arms.
Antitumor activity will be assessed according to Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST 1.1) guidelines.  The interim and primary analysis of PFS will 
be based on programmatically derived PFS calculated from the tumor scan assessments 
according to RECIST 1.1 by Blinded Independent Central Review (BICR).  
 
Secondary efficacy endpoints of proportion of patients alive and progression free at 12 months 
from randomization (APF12), ORR, DoR, best objective response (BoR), and time from 
randomization to second progression (PFS2) will be examined to further evaluate the 
antitumor effect and survival benefit of durvalumab ± tremelimumab + SoC chemotherapy 
compared with SoC chemotherapy alone in all patients.  
The secondary endpoints of health-related quality-of-life (HRQoL), patient-reported 
outcome (PRO) assessments, the European Organisation for Research and Treatment of 
Cancer [EORTC] 30-item Core Quality of Life Questionnaire, version 3 [QLQ-C30 v3], and 
the 13-item Lung Cancer Quality of Life Questionnaire [QLQ-LC13]) will show the overall 
influence of the benefits and toxicity of the treatment from the patient’s perspective and will 
aid in assessing of the benefit-risk evaluation.  These PRO questionnaires are well-established 
instruments that have been previously included in lung cancer clinical studies.  
The PK and immunogenicity of durvalumab and tremelimumab are being examined to assess 
any potential impact on PK, pharmacodynamics, safety, and efficacy parameters. 
 
 
1.3
Benefit/risk and ethical assessment
The following sections include summaries of the potential benefits and risks associated with 
durvalumab and tremelimumab prior to the overall benefit-risk assessment.
1.3.1
Potential benefits
1.3.1.1
Durvalumab
The majority of the safety and efficacy data currently available for durvalumab are based on 
the first-in-human, single-agent study (Study 1108) in patients with advanced solid tumors and 
the study of durvalumab monotherapy in NSCLC (Study D4191C00003 [ATLANTIC]).  In 
Study 1108, as of 7 May 2015, 456 of 694 patients treated with durvalumab 10 mg/kg q2w 
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
54(225)
were evaluable for response (defined as having ≥24 week follow-up, measurable disease at 
baseline, and ≥1 follow-up scan or discontinued because of disease progression or death 
without any follow-up scan).  Data from treatment-naïve patients with NSCLC in this study 
(n=59) showed a favorable disease control rate (DCR) at ≥12 weeks of 56% when durvalumab 
was given 10 mg/kg q2w (Antonia et al 2016b).
In PD-L1 unselected patients, the ORR, based on Investigator’s assessment per RECIST 1.1, 
ranged from 0% in uveal melanoma to 20.0% in bladder cancer, and DCR at 24 weeks ranged 
from 4.2% in triple-negative breast cancer to 39.1% in advanced cutaneous melanoma.  
PD-L1 status was known for 383 of the 456 response evaluable patients.  Across the 
PD-L1-positive tumors (defined as PD-L1 TC ≥25%), ORR was highest (>10%) for bladder 
cancer, advanced cutaneous melanoma, and hepatocellular carcinoma (33.3% each); NSCLC 
(26.7%); and SCCHN (18.2%).  Moreover, in the PD-L1-positive subset, DCR at 24 weeks 
was highest (>10%) in advanced cutaneous melanoma (66.7%), NSCLC (36.0%), 
hepatocellular carcinoma and bladder cancer (33.3% each), and SCCHN (18.2%).
A total of 444 patients with locally advanced or metastatic NSCLC were treated in 
ATLANTIC.  As of the data cut-off of 03 June 2016, in Cohort 2 (EGFR/ALK 
wild type/unknown, PD-L1 expression on ≥25% of TCs), durvalumab monotherapy showed 
clinically meaningful activity based on ORR in patients with locally advanced or metastatic 
NSCLC who had received at least 2 prior systemic treatment regimens.  The responses were 
numerically greater in the PD-L1 TC ≥25% group (16.4%) compared with the PD-L1 
expression on less than 25% of tumor cells (PD-L1 TC <25%) group (7.5%).  The DCR at 
6 months was 28.8% in the PD-L1 TC ≥25% group and 20.4% in the PD-L1 TC <25% group.  
The median OS was 10.9 months in the PD-L1 TC ≥25% patients and 9.3 months in the 
PD-L1 TC <25% patients.  For the PD-L1 TC ≥25% patients, the OS rate at 6 and 12 months 
was 67.4% and 47.7%, respectively.  For the PD-L1 TC <25% patients, the OS rate at 6 and 
12 months was 60.3% and 34.5%, respectively.  Observed PFS was numerically longer in the 
PD-L1 TC ≥25% group compared with the PD-L1 TC <25% group.  In Cohort 3 (EGFR/ALK 
wild type/unknown, PD-L1 expression on ≥90% of TCs [PD-L1 TC ≥90%]), the ORR was 
30.9%.  The DCR at 6 months was 38.2%.  Observed PFS and OS were similar to 
PD-L1 TC ≥25% patients in Cohort 2.  For patients with PD-L1 ≥90% in the combined 
Cohorts 2 and 3, the ORR was 23.2%.  The DCR at 6 months was 34.1%.  Observed PFS and 
OS were similar to PD-L1 TC ≥25% patients in Cohort 2.  For patients who responded, the 
response was durable across various subgroups (median DoR of 12.3 months in the PD-L1 
TC ≥25% group in Cohort 2).  In Cohort 2, 66.7% of responders in the PD-L1 TC ≥25% 
group had their first response at the time of the first on-treatment tumor assessment (Week 8).  
The median time to response was 1.9 months.  In Cohort 1 (EGFR/ALK positive), the ORR 
was numerically lower than in the EGFR/ALK wild type/unknown cohorts.  The responses 
were numerically greater in the PD-L1 TC ≥25% group (12.2%) compared with the 
PD-L1 TC <25% group (3.6%).  The DCR at ≥6 months was 28.8% in the PD-L1 TC ≥25% 
group, 20.4% in the PD-L1 TC <25% group, and 38.2% in the PD-L1 TC ≥90% group.  
Observed PFS and OS were numerically longer in the PD-L1 TC ≥25% group compared with 
the PD-L1 TC <25% group (Garassino et al 2016; AstraZeneca internal data).

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
55(225)
1.3.1.2
Durvalumab + tremelimumab
Preliminary efficacy data from Study 006 have demonstrated that this combination is 
clinically active and well tolerated in NSCLC.  As of 1 June 2015, 63 patients with at least 
24 weeks of follow-up were evaluable for response across various 
durvalumab + tremelimumab combination therapy dose regimens.  Of these, 11 patients 
(17%) had achieved an objective response, and 18 patients (29%) had achieved disease control 
at 24 weeks (Antonia et al 2016a).  
Nivolumab as monotherapy or in combination with ipilimumab (anti-CTLA-4 mAb) has also 
been investigated as first-line treatment for NSCLC in the CheckMate 012 study.  The ORRs 
reported were similar, 47% in nivolumab 3 mg/kg q2w plus ipilimumab 1 mg/kg q12w and 
38% nivolumab 3 mg/kg q2w plus ipilimumab 1 mg/kg q6w.  Median DoR was not reached in 
either cohort.  The safety profile of the combination was tolerable (Hellmann et al 2017). 
1.3.1.3
Durvalumab + tremelimumab with chemotherapy
Studies evaluating agents targeting PD-L1 or CTLA-4 in combination with chemotherapy 
have yielded encouraging results (see Section 1.1.5.1). 
Durvalumab ± tremelimumab with standard platinum-based chemotherapy in advanced 
cancers are being generated from an ongoing Phase Ib study (NCT02537418) run by the 
CCTG.  Preliminary results were presented in IASLC 2016.  Up to the October 2016 cut-off, a 
total of 111 patients have been dosed with various chemotherapy regimens and different tumor 
type.  The overall ORR in the NSCLC cohort (n=26) was 61.5% (NSCLC data based on a data 
cut-off of July 2016) (Juergens et al 2016).
CheckMate 012 (NCT01454102) is a multi-arm Phase I study of nivolumab in combination 
with various anticancer agents or as monotherapy in chemotherapy-naïve patients with 
NSCLC.  The results published in the Journal of Clinical Oncology showed that the ORRs for 
nivolumab 10 mg/kg plus gemcitabine-cisplatin, nivolumab 10 mg/kg plus pemetrexed-
cisplatin, nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 5 mg/kg plus 
paclitaxel-carboplatin were 33%, 47%, 47%, and 43%, respectively; 24-week PFS rates were 
51%, 71%, 38%, and 51%, respectively.  On the basis of these results, the antitumor activity 
of first-line nivolumab in combination with platinum-based doublets is highly promising 
(Rizvi et al 2016). 
In addition, the Phase II KEYNOTE-021 study showed that the addition of pembrolizumab to 
SoC carboplatin and pemetrexed followed by pembrolizumab for 2 years and indefinite 
pemetrexed maintenance therapy significantly improved the proportion of patients who 
achieved an objective response compared with carboplatin and pemetrexed alone in patients 
with chemotherapy-naïve, advanced non-squamous NSCLC.  In the study, 123 patients with
Stage IIIB/IV, chemotherapy-naïve, non-squamous NSCLC were randomized to receive 
4 cycles of carboplatin and pemetrexed (500 mg/m2 q3w), with or without 24 months of 
treatment with pembrolizumab (200 mg q3w).  Of 60 patients, 33 (55%; 95% CI: 42 to 68) in
the pembrolizumab plus chemotherapy group achieved an objective response compared with 
18 of 63 patients (29%; 95% CI: 18 to 41) in the chemotherapy alone group (estimated 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
56(225)
treatment difference 26% [95% CI: 9% to 42%]; p=0.0016) (Langer et al 2016).  PFS was 
significantly longer in patients treated with pembrolizumab plus chemotherapy compared with 
chemotherapy alone (HR 0.53 [95% CI: 0.31 to 0.91]; p=0.010).  Median PFS was 
13.0 months (95% CI: 8.3 to not reached) for pembrolizumab plus chemotherapy and 
8.9 months (95% CI: 4.4 to 10.3 months) for chemotherapy alone.  No difference in survival 
was noted between treatment arms (22% of patients died in both treatment arms).  On the 
basis of these clinical data, the antitumor activity of PD-L1/CTLA-4 in combination with first-
line platinum-based doublets is highly promising.  Given the synergistic potential of 
durvalumab and tremelimumab, the combination of both these drugs with chemotherapy has 
the potential to further improve the response rates and response durability.
1.3.2
Overall risks
Monoclonal antibodies directed against immune checkpoint proteins, such as PD-L1 as well as 
those directed against PD-1 or CTLA-4, aim to boost endogenous immune responses directed 
against TC.  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 mechanism and which may require more 
frequent monitoring and/or unique interventions such as immunosuppressants and/or 
endocrine replacement 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.
1.3.2.1
Durvalumab
Risks with durvalumab include, but are not limited to diarrhea/colitis, pneumonitis/ILD, 
endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency), 
hyper- and hypo-thyroidism, type I diabetes mellitus and diabetes insipidus), hepatitis/ 
increases in transaminases, nephritis/increases in creatinine, rash/ dermatitis(including 
pemphigoid), myocarditis, myositis/polymyositis, immune thrombocytopenia, 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 durvalumab please always refer to 
the current version of the durvalumab IB.
In monotherapy clinical studies, AEs at an incidence of > 20% include events such as fatigue, 
cough, decreased appetite, dyspnea and nausea. Approximately 10% of patients discontinued 
the drug due to an AE. Please see the current version of the IB for a detailed summary of the 
monotherapy data including AEs, SAEs, and CTC Grade 3 to 5 events reported across the 
durvalumab program.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
57(225)
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 see Section 6.9.1).
A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab IB.
1.3.2.2
Tremelimumab
Risks with tremelimumab monotherapy include, but are not limited to, gastrointestinal 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-Barre 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 and 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. 
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
Durvalumab + tremelimumab combination therapy
The safety of durvalumab + tremelimumab combination therapy was initially evaluated in the 
ongoing dose escalation and dose expansion Study 006, in patients with NSCLC, and is being 
studied in a number of other ongoing clinical studies in a number of different indications and 
has so far shown a manageable safety and tolerability profile.  
The types of risks with the combination of durvalumab + tremelimumab (based on an 
equivalent durvalumab dose of 20m/kg and a tremelimumab dose of 1mg/kg) are similar to 
those for durvalumab and tremelimumab monotherapy.  Emerging data from Study 006, 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.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
58(225)
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 (all grades) reported very commonly (≥10% of patients) are 
fatigue, diarrhea, nausea, dyspnea, decreased appetite, pruritus, vomiting, anemia, 
constipation, cough, abdominal pain, pyrexia, back pain, arthralgia, hypothyroidism, asthenia, 
edema peripheral, weight, decreased hyponatremia and rash. 
Approximately 15% of patients experienced an AE that resulted in permanent discontinuation 
of study drug and approximately 15% of patients experienced an SAE that was considered to 
be 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.
1.3.2.4
Standard of Care
Risks associated with SoC are described in  the local prescribing information (i.e., SmPC, etc). 
In addition to the local prescribing information and associated risks with SoC, the investigator 
should be cognizant that ototoxicity and nephrotoxicity have been observed with carboplatin 
and cisplatin.
1.3.2.5
Durvalumab ± tremelimumab with chemotherapy
Two ongoing studies are evaluating the safety and tolerability of combining durvalumab and 
tremelimumab with different chemotherapy regimens in patients with solid tumors.  One study 
is an AstraZeneca internal study (D419SC00001) and the other is CCTG Study NCT02537418
(see Section 1.2.2 for details on the designs of these studies).
In the AstraZeneca internal study (D419SC00001), 6 patients with SCLC were evaluable for 
safety as of 6 December 2016.  Common adverse events reported were neutropenia (6 
patients), nausea (4 patients), decreased appetite (4 patients), rash (3 patients), diarrhea (2 
patients) and pyrexia (2 patients).  Diarrhea, skin rash were generally low grade, with the 
exception of 1 Grade 3 erythroderma that responded to topical steroids.  One patient with 
intermittent Grade 1 diarrhea required steroid treatment and resolved.  Cycle 4 was modified 
in this patient where immunotherapy was held and chemotherapy was dose reduced to 75% 
due to Grade 4 neutropenia.  Grade 3 and above events were febrile neutropenia (2 patients), 
platelet decrease (1 patient), and lung infection (1 patient) which were considered to be 
chemotherapy related, hepatitis (1 patient), and erythroderma (1 patient) which were 
considered to be immune related.  Febrile neutropenia, lung infection, hepatitis were reported 
as SAE.  Two patients had Grade 3/4 lipase/amylase elevation at baseline and were considered 
not drug related; these were due to pancreatic metastasis at baseline confirmed by imaging.  
One patient died due to disease progression as primary cause and a secondary cause of lung 
infection.  Two patients discontinued treatment due to immune-related hepatitis and persistent 
skin rash.  Two patients continue on active study treatment and are being followed up for long 
term safety.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
59(225)
In the CCTG study (NCT02537418), a total of 488 cycles have been administered up to the 
data cut-off of October 2016, with 103 patients evaluable for non-hematologic AEs.  Overall, 
all patients experienced at least 1 AE; 96% were considered by the Investigator as causally 
related to chemotherapy, 75% were considered as causally related to durvalumab, and 55% 
were considered as causally related to tremelimumab.  A total of 69 events (26% of all events) 
were Grade ≥3, regardless of causality.  Of these, 20 events were considered by the 
Investigators as causally related to durvalumab treatment, and 15 events were considered as 
causally related to tremelimumab treatment.  SAEs were reported in 38% of patients (39/103) 
regardless of causality; 19% was related to chemotherapy, 15% was considered by the 
Investigator as related to durvalumab, while 11% was related to tremelimumab treatment.  
Note that some events considered related to durvalumab and tremelimumab treatment may be 
reported in the same patient(s).
Overall, the common AEs reported were Grade 1 to 2 with the most commonly reported being 
fatigue (93%), nausea (72%), dyspnea (63%), constipation (59%), and cough (52%) regardless 
of causality.  The most common chemotherapy-related AEs were fatigue (62%), 
nausea (58%), vomiting (32%), anorexia (28%), alopecia (27%), and peripheral sensory 
neuropathy (24%).  The most common durvalumab-related AEs were fatigue (42%), rash 
maculo-papular (17%), nausea (16%), and diarrhea (12%).  The most common tremelimumab-
related AEs were fatigue (26%), rash maculo-papular (13%), and diarrhea (11%).  The most 
common CTC Grade >3 events were fatigue (11 events), thrombotic events (9), dyspnea (7), 
lung infection (7), and diarrhea (7).  Transient elevations in amylase and lipase were seen, but 
no patient had clinical or radiological evidence of pancreatitis.  Thyroid-stimulating hormone 
(TSH) elevations of ≥5× upper limit of normal (ULN) were documented in 10 patients (10%), 
and 6 patients required initiation of thyroid replacement therapy on study.  Three of these 
patients with elevated TSH had a previous history of hypothyroidism. 
In all dose levels, dose delays of durvalumab were mostly for administrative reasons/patient 
request and neutropenia related to chemotherapy, while those for durvalumab ± tremelimumab 
were interrupted in 4 patients because of pneumonitis, colitis, or rash. 
Seven patients (6.7%) discontinued durvalumab ± tremelimumab due to the following AEs: 
pneumonitis (3 patients), hepatitis (1 patient), myocarditis (1 patient), hyperthyroidism 
(1 patient), and limbic encephalitis (1 patient). 
There were 7 deaths within 30 days of the last dose of protocol therapy.  Two of these were 
considered to be at least possibly related to durvalumab or tremelimumab; 1 patient (Case 
No.
 had diarrhea, hyperthyroidism, and myocarditis, which was steroid 
responsive but later declined active therapy.  The cause of death has not yet been determined.  
The final post-mortem examination has not been reported.  One patient (Case 
No.
 had confusion and possible encephalitis. 
The 2 possibly related fatal cases are briefly described as follows: 
Case Report No. 
 - An event of myocarditis (Grade 5) occurred in a 
 with metastatic SCLC who on Cycle 1 Day 12 presented with s/s of fever, 
PPD
PPD
PPD
PPD

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
60(225)
nausea, vomiting, and decreased neutrophil count of 0.68 for which patient was eventually 
admitted.  
 developed diarrhea.  Computed tomography (CT) abdomen showed liver 
metastasis, with inflammatory changes of duodenum suggestive of uncomplicated duodenitis 
or ulcer.  The patient also developed acute renal failure and pulmonary edema.  On Cycle 1 
Day 16, the patient presented with s/s of Grade 4 heart failure and myocarditis as well as 
Grade 3 thyroiditis that initially responded to steroid administration.  
 was sent home only 
to be readmitted with weakness, fever, dizziness, and dehydration.  The patient’s condition 
deteriorated despite steroids and supportive treatment (inotropic support, use of ace inhibitors) 
and eventually died.  Preliminary autopsy report showed multiple metastases in the involved 
lungs (effusions), liver, and lymph nodes.  Except for atherosclerosis, there was no evidence 
of myocardial infarction or pulmonary emboli.
Case Report No. 
 – An event of limbic encephalitis (Grade 5) 
occurred in a 
 with metastatic SCLC who on Cycle 2 Day 27 presented 
with s/s of limbic encephalitis (eg, cognitive decline, restlessness, agitation, 
electroencephalogram findings suggestive of encephalopathy, CSF findings of increased white 
blood cells and protein, magnetic resonance imaging [MRI] finding of no intra-cranial mass), 
and despite treatment with antibiotics and steroids, the patient eventually died.  Confounding 
factors that may likely also provide alternative cause/explanation for this event include the 
following: 1) a possible paraneoplastic effect of underlying SCLC, 2) concomitant 
medications that included treatment with phenobarbitone and midazolam, 3) underlying 
diabetes mellitus for which the patient had insulin/oral hypoglycemic treatment, and 
4) possible central nervous system infection.
Overall, toxicities related to the chemotherapy core regimen and to durvalumab and 
tremelimumab were as expected for these agents.  In general, the combination of durvalumab 
+ tremelimumab with chemotherapy appears tolerable and manageable. 
External clinical data also support these findings.  In a randomized Phase III study in patients 
with extensive-stage SCLC treated with etoposide-platinum ± ipilimumab, the overall 
incidence of treatment-related Grade 3/4 AEs was 48% for chemotherapy plus ipilimumab and 
44% for chemotherapy plus placebo.  The most common irAEs in patients treated with 
chemotherapy plus ipilimumab involved skin (rash and pruritus) and gastrointestinal tract 
(diarrhea) (Reck et al 2014).  In the CheckMate 012 study, in patients with NSCLC treated 
with nivolumab 10 mg/kg or 5 mg/kg plus platinum-based doublet chemotherapy concurrently 
q3w for 4 cycles, the overall incidences of treatment-related Grade 3/4 AEs were 50% and 
29%, respectively.  Overall, the most common (≥5% of patients) treatment-related Grade 3/4 
AEs were pneumonitis (7%), fatigue (5%), and acute renal failure (5%) (Rizvi et al 2016).  In 
KEYNOTE-021, in patients with NSCLC treated with pembrolizumab and chemotherapy or 
chemotherapy alone, the incidence of treatment-related Grade 3 or worse AEs was 39% and 
26%, respectively.  In the pembrolizumab plus chemotherapy group, the most common 
treatment-related Grade 3 or worse AEs were anemia (12%); decreased neutrophil count (5%); 
and acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, sepsis, and 
thrombocytopenia (3% each).  In the chemotherapy alone group, the most common 
treatment-related Grade 3 or worse AEs were anemia (15%) and decreased neutrophil count, 
pancytopenia, and thrombocytopenia (3% each).  There were 3 treatment-related deaths, 
PPD
PPD
PPD
PPD

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
61(225)
2 deaths due to sepsis (1 patient in each treatment arm) and 1 death due to pancytopenia in a 
patient in the chemotherapy alone group (Langer et al 2016).
1.3.3
Overall benefit-risk assessment
Platinum-based chemotherapies have been considered the standard treatment regimens for 
NSCLC for the past 2 decades; however, OS remains poor with a 5-year survival rate between 
11% and 17% (D’Addario et al 2010, Howlander et al 2014).  Patients presenting with 
advanced NSCLC have a median OS of 10 to 12 months (Bonomi 2010), and patients without 
targetable mutations (EGFR and ALK) show responses to treatment of approximately 20% to 
30% and PFS of 4 to 5 months (Sandler et al 2006, Scagliotti et al 2008, Schiller et al 2002).  
The poor prognosis reflects the limited treatment options available, highlighting the need for 
the development of newer therapeutic options.
There remains a significant unmet medical need for additional treatment options for patients 
with metastatic NSCLC, irrespective of PD-L1 status, whose tumors lack activating EGFR 
mutations and ALK fusions and who have not received prior chemotherapy or any systemic 
therapy for metastatic NSCLC.
Treatment with durvalumab and/or tremelimumab has shown activity in several tumor types in 
a subset of patients deriving meaningful and durable benefit.  Efficacy data for patients treated 
with durvalumab monotherapy have shown clinical activity across several tumor types.  
Preliminary data generated from patients with NSCLC treated with 
durvalumab + tremelimumab combination therapy have also shown early signs of clinical 
activity, and data from the literature indicate that the combination may act synergistically 
(Wolchok et al 2013).  Thus, these agents may potentially offer benefit to this patient 
population.  Also as presented in Section 1.1.5.1, the studies evaluating agents targeting 
PD-L1 or CTLA-4 in combination with chemotherapy have yielded encouraging efficacy data, 
with a seemingly tolerable toxicity profile.
The study design also aims to minimize potential risks.  For example, intensive monitoring, 
including early safety assessment, is in place for those risks deemed to be most likely based on 
prior experience with the IPs (ie, durvalumab + tremelimumab combination therapy, 
durvalumab monotherapy) and SoC.
Therefore, the rationale for this study is supported by 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 
durvalumab alone and in combination with tremelimumab in a number of tumor types, the 
preliminary data on the efficacy and tolerability of the combination of PD-L1 or CTLA-4 with 
chemotherapy, and the strength of the scientific hypotheses evaluating the safety and 
tolerability of adding durvalumab and tremelimumab to first-line standard platinum-based 
chemotherapy for the treatment of NSCLC.
Based on these considerations, the proposed treatments may have the potential to provide 
meaningful clinical benefit by generating durable clinical responses, thereby potentially 
extending survival.  Therefore, the overall benefit-risk assessment supports the proposed study 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
62(225)
to evaluate the safety and tolerability of the combination of durvalumab and tremelimumab 
with standard platinum-based chemotherapy regimens.
1.4
Study design 
This is a randomized, open-label, multi-center, global, Phase III study to determine the 
efficacy and safety of durvalumab + tremelimumab combination therapy + SoC chemotherapy 
or durvalumab monotherapy + SoC chemotherapy versus SoC chemotherapy alone as 
first-line treatment in patients with metastatic NSCLC with tumors that lack activating EGFR 
mutations and ALK fusions.  A schematic diagram of the overall study design is presented in 
Figure 3, and a detailed study flow chart is presented in Figure 4.  SoC chemotherapy will be 
one of the following regimens: abraxane + carboplatin, pemetrexed + cisplatin or carboplatin, 
or gemcitabine + cisplatin or carboplatin.  
This study will randomize approximately 1000 eligible patients at sites worldwide. Once 
global enrollment is complete, enrollment may continue in mainland China only. A total of up 
to 180 patients, including up to 135 patients in total with PD-L1 TC <50%, from China will be 
randomized.  
Patients who fulfill all of the inclusion criteria and none of the exclusion criteria will be 
randomized in a 1:1:1 ratio in a stratified manner according to the following:
∀
PD-L1 tumor expression status (PD-L1 expression on at least 50% of tumor cells 
[PD-L1 TC ≥50%] versus PD-L1 TC <50%) 
∀
Disease stage (Stage IVA versus Stage IVB)
∀
Histology (non-squamous versus squamous)
Crossover will not be permitted as part of this study.  Study treatment doses and regimens are 
described in Section 7.2.  Assessments will be conducted as indicated in Table 2 and Table 3.
Tumor evaluation scans will be performed at screening (as baseline) with follow-ups at 
Week 6±1 week from the date of randomization, at Week 12±1 week from the date of 
randomization, and then every 8 weeks (q8w)±1 week until radiological progression.  The 
management of patients will be based solely upon the results of the tumor evaluation scans 
conducted by the Investigator.  The BICR of all radiologic scans will be performed to derive 
the PFS, ORR, DoR, BoR, and APF12 endpoints according to RECIST 1.1.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
63(225)
Figure 3
Overall study design
Stratified randomization factors:
1. PD-L1 tumor expression status (TC ≥50% versus <50%)
2. Disease stage (Stage IVA versus Stage IVB)
3. Histology (non-squamous or squamous)
STUDY TREATMENT
FOLLOW-UP
During chemotherapy
Post-chemotherapy
Treatment Arm 1
Durva + Treme + SoC
4 cycles
N = 333
Metastatic NSCLC
•
EGFR activating 
mutation negative
•
ALK fusion negative
•
No prior therapy for 
metastatic
•
NSCLC
•
ECOG PS 0-1
•
N = 2000
R
A
N
D
O
M
I
Z
A
T
I
O
N
Treatment Arm 2
Durva + SoC
4 cycles
N = 333
Treatment Arm 3
SoC
4-6 cycles
N = 333
Treatment Arm 1a
Durva 
Pemetrexed maintenanceb
q4w up to PD
Treatment Arm 2
Durva 
Pemetrexed maintenanceb
q4w up to PD
Treatment Arm 3c
Pemetrexed maintenanceb
q4w or q3w up to PD
Primary endpoint: 
PFS and OS
Objective disease 
progression
Secondary endpoint: OS
Subsequent therapy
a
One additional durvalumab + tremelimumab combination therapy dose will be given at Week 16 post-chemotherapy.  In the case of dose delay(s), more than 1 
durvalumab + tremelimumab combination dose can be given at and after Week 16 post-chemotherapy to ensure that up to 5 combination doses are administered 
in Treatment Arm 1.  If patients receive fewer than 4 cycles of platinum doublet chemotherapy, the remaining cycles of combined durvalumab/tremelimumab 
(up to a total of 5) should be given after combination of platinum doublet chemotherapy (with maintenance pemetrexed, if applicable) (see Section 7.2).
b
Pemetrexed maintenance therapy from Week 12 to clinical progression or radiological progression for non-squamous NSCLC patients who initially received 
treatment with pemetrexed and carboplatin/cisplatin, unless contraindicated per the Investigator.
c
SoC chemotherapy will be given q3w up to 4 doses; extension into Weeks 12 and 15 is as clinically indicated, at the Investigator’s discretion.  
Durva Durvalumab; ECOG Eastern Cooperative Oncology Group; EGFR Epidermal growth factor receptor; NSCLC Non-small-cell lung cancer; OS Overall survival; 
PD Progressive disease; PFS Progression-free survival; q4w Every 4 weeks; q3w - Every 3 weeks; SoC Standard of care; TC Tumor cell; Treme Tremelimumab.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
64(225)
Figure 4
Study flow chart
Screening Visit: Screening to complete eligibility assessments (Days -28 to -1)
Day 1: First day of treatment for randomized patients
Treatment Arm 1: Durvalumab + tremelimumab combination therapy + SoC chemotherapy followed by
durvalumab monotherapy
-or-
Treatment Arm 2: Durvalumab monotherapy + SoC chemotherapy followed by durvalumab monotherapy
-or-
Treatment Arm 3: SoC chemotherapy alone
All Treatment Arms: After chemotherapy, non-squamous patients who received 4-6 cycles of
carboplatin/cisplatin plus pemetrexed and who do not have evidence of disease progression will receive
pemetrexed maintenance therapy
Assessments per Table 2 with tumor evaluation scans using RECIST 1.1 performed at screening as
baseline, then q6w (±1 week) for the first 12 weeks, and then q8w (±1 week)
until objective disease progression
Discontinuation of treatment either due to objective disease
progression or another reason
Follow-up assessments per Table 3
Treatment may be offered by physician
q6w - Every 6 weeks; q8w - Every 8 weeks; RECIST 1.1 - Response Evaluation Criteria in Solid Tumors, 
Version 1.1; SoC -Standard of care.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
65(225)
1.4.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster or public health crisis 
(eg, during quarantines and resulting site closures, regional travel restrictions and 
considerations if site personnel or study participants become infected with severe acute 
respiratory syndrome coronavirus 2 [SARS-CoV-2] or similar pandemic infection), which 
would prevent the conduct of study-related activities at study sites, thereby compromising the 
study site staff or the participant’s ability to conduct the study. The investigator or designee 
should contact the study sponsor to discuss whether the mitigation plans below should be 
implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with GCP, and minimise risks to study integrity. Where allowable by local health 
authorities, ethics committees, health care provider guidelines (eg, hospital policies) or local 
government, these changes may include the following options: 
∀
Obtaining consent/reconsent for the mitigation procedures (note, in the case of verbal 
consent/reconsent, the informed consent form [ICF] should be signed at the participant’s next 
contact with the study site).
∀
Rescreening: Additional rescreening for screen failure and to confirm eligibility to participate in 
the clinical study can be performed in previously screened participants. The investigator should 
confirm this with the designated study clinical lead. 
∀
Home or Remote visit: Performed by a site qualified health care professional (HCP) or HCP 
provided by a third-party vendor (TPV).
∀
Telemedicine visit: Remote contact with the participants using telecommunications technology 
including phone calls, virtual or video visits, and mobile health devices. 
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix G. 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
66(225)
1.5
Study aim
This is a Phase III, randomized, open-label, comparative, multi-center, global study that aims 
to determine the efficacy and safety of durvalumab + tremelimumab combination 
therapy + SoC chemotherapy versus SoC chemotherapy alone and to assess the efficacy of 
durvalumab monotherapy + SoC chemotherapy versus SoC chemotherapy alone as first-line 
treatment in patients with metastatic NSCLC with tumors that lack activating EGFR mutations 
or ALK fusions.
1.6
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.
1.6.1
Safety confirmation
An IDMC composed of independent experts will be convened to confirm the safety and 
tolerability of the proposed dose and schedule of durvalumab ± tremelimumab in combination 
with SoC chemotherapy at 2 early stages of enrollment.  A step-wise approach will be 
adopted.  The initial safety review will take place when the first 30 patients (10 in each arm) 
have completed the first cycle of treatment. A second review will add an additional 30 patients 
(10 in each arm) who have completed the first cycle of treatment, making a total of 
60 patients.  At the time of the second review, it is expected that the initial 30 patients would 
have had at least 6 weeks of follow-up, with some patients having longer follow-up.  These 
2 reviews will be carried out by the IDMC in an unblinded manner. After a review of the 
unblinded data, the IDMC will make a recommendation on whether the study should continue 
recruitment as planned or hold recruitment.
Safety confirmation for Japan: An additional safety review for Japanese patients will take 
place when the first 3 patients in each treatment arm in Japan have completed the first cycle of 
treatment. This review will be carried out by the IDMC in an unblinded manner. After review 
of the unblinded data, the IDMC will make a recommendation on whether the study should 
continue recruitment as planned or hold recruitment in Japan.
Safety confirmation for China: An additional safety review for Chinese patients will take 
place when the first 10 patients in each treatment arm in China have completed the first cycle 
of treatment. This review will be carried out by the IDMC in an unblinded manner. After 
review of the unblinded data, the IDMC will make a recommendation on whether the study 
should continue recruitment as planned or hold recruitment in China.
In addition, the IDMC will review the unblinded interim analysis summaries of efficacy data. 
The IDMC meets approximately every 6 months thereafter to continue safety monitoring up to 
the decision to unblind the study.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
67(225)
Full details of the IDMC procedures, processes, and interim analyses can be found in the 
IDMC Charter.
2.
STUDY OBJECTIVES
All objectives will be evaluated for all patients, unless otherwise indicated.  
2.1
Primary objectives
Primary objectives
Outcome measure
∀
To assess the efficacy of durvalumab
monotherapy + SoC chemotherapy 
compared with SoC chemotherapy alone in 
terms of PFS and OS in all patients 
∀
PFS in all patients using BICR assessments 
according to RECIST 1.1
∀
OS in all patients
Note: Sensitivity analyses of PFS will be performed based on the Investigator’s assessment according to 
RECIST 1.1.
BICR Blinded Independent Central Review; NSCLC Non-small-cell lung cancer; PFS Progression-free 
survival; RECIST 1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1; SoC Standard of care.
2.2
Secondary objectives
Secondary objectives
Outcome measures
∀
To assess the efficacy of 
durvalumab + tremelimumab combination 
therapy + SoC chemotherapy compared with 
SoC chemotherapy alone in terms of PFS and 
OS
∀
PFS in all patients using BICR assessments 
according to RECIST 1.1 (key secondary 
objective)
∀
OS in all patients (key secondary objective)
∀
To further assess the efficacy of 
durvalumab + tremelimumab combination 
therapy + SoC chemotherapy compared with 
SoC chemotherapy alone in terms of PFS, 
OS, ORR, BoR, DoR, APF12 and PFS2
∀
PFS in patients with PD-L1 TC <50%, patients 
with PD-L1 TC <25% and patients with PD-L1 
TC <1% using BICR assessments according to 
RECIST 1.1
∀
OS in patients with PD-L1 TC <50%, patients 
with PD-L1 TC <25% and patients with PD-L1 
TC <1%
∀
ORR, DoR, BoR and APF12 in patients with 
PD-L1 TC <50%, patients with PD-L1 TC 
<25%, patients with PD-L1 TC <1% and all 
patients using BICR assessments according to 
RECIST 1.1
∀
PFS2 in patients with PD-L1 TC <50%, patients 
with PD-L1 TC <25%, patients with PD-L1 
TC <1% and all patients using local standard 
clinical practice

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
68(225)
Secondary objectives
Outcome measures
∀
To further assess the efficacy of durvalumab 
monotherapy + SoC chemotherapy compared 
with SoC chemotherapy alone in terms of 
PFS, OS, ORR, DoR, BoR, APF12 and PFS2
∀
PFS in patients with PD-L1 TC <50%, patients 
with PD-L1 TC <25% and patients with PD-L1 
TC <1% using BICR assessments according to 
RECIST 1.1
∀
OS in patients with PD-L1 TC <50%, patients 
with PD-L1 TC <25% and patients with PD-L1 
TC <1%
∀
ORR, DoR, BoR and APF12 in patients with 
PD-L1 TC <50%, patients with PD-L1 TC 
<25%, patients with PD-L1 TC <1% and all 
patients using BICR assessments according to 
RECIST 1.1
∀
PFS2 in patients with PD-L1 TC <50%, patients 
with PD-L1 TC <25%, patients with PD-L1 
TC <1% and all patients using local standard 
clinical practice
∀
To assess the efficacy of 
durvalumab + tremelimumab combination 
therapy + SoC chemotherapy compared with 
durvalumab monotherapy + SoC 
chemotherapy in terms of PFS, OS and ORR
∀
PFS and ORR in patients with PD-L1 TC <50%, 
patients with PD-L1 TC <25%, patients with 
PD-L1 TC <1% and all patients using BICR 
assessments according to RECIST 1.1
∀
OS in patients with PD-L1 TC <50%, patients 
with PD-L1 TC <25%, patients with PD-L1 
TC <1% and all patients
∀
To assess the association of tumor mutation 
burden (TMB) with the efficacy of 
durvalumab + tremelimumab combination 
therapy + SoC chemotherapy compared with 
SoC chemotherapy alone in terms of PFS, 
OS, ORR, BoR, DoR, APF12 and PFS2
∀
PFS, ORR, BoR, DoR, APF12 in patients with 
TMB high using BICR assessments according to 
RECIST 1.1
∀
PFS2 in patients with TMB high using local 
standard clinical practice
∀
OS in patients with TMB high
∀
To assess the association of TMB with the 
efficacy of durvalumab + tremelimumab 
combination therapy + SoC chemotherapy 
compared with durvalumab 
monotherapy + SoC chemotherapy in terms 
of PFS, OS, ORR, BoR, DoR, APF12 and 
PFS2
∀
PFS, ORR, BoR, DoR, APF12 in patients with 
TMB high using BICR assessments according to 
RECIST 1.1
∀
PFS2 in patients with TMB high using local 
standard clinical practice
∀
OS in patients with TMB high
∀
To assess the association of TMB with the 
efficacy of durvalumab mono therapy + SoC 
chemotherapy compared with SoC 
chemotherapy in terms of PFS, OS, ORR, 
BoR, DoR, APF12 and PFS2
∀
PFS, ORR, BOR, DoR, APF12 in patients with 
TMB high using BICR assessments according to 
RECIST 1.1
∀
PFS2 in patients with TMB high using local 
standard clinical practice
∀
OS in patients with TMB high

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
69(225)
Secondary objectives
Outcome measures
∀
To assess the PK of durvalumab + 
tremelimumab combination therapy and 
durvalumab monotherapy
∀
Concentration of durvalumab and tremelimumab
∀
To investigate the immunogenicity of 
durvalumab and tremelimumab
∀
Presence of ADAs for durvalumab and 
tremelimumab
∀
To assess disease-related symptoms and 
HRQoL in patients treated with durvalumab 
+ tremelimumab combination therapy + SoC 
chemotherapy and durvalumab monotherapy 
+ SoC chemotherapy compared with SoC 
chemotherapy alone using the EORTC QLQ-
C30 v3, the QLQ-LC13 module, and 
WHO/ECOG performance status assessments
∀
EORTC QLQ-C30
∀
EORTC QLQ-LC13
∀
Changes in WHO/ECOG performance status 
will also be assessed.
ADA Anti-drug antibody; APF12 Proportion of patients alive and progression free at 12 months from 
randomization; BICR Blinded Independent Central Review; BoR Best objective response; DoR Duration of 
response; ECOG Eastern Cooperative Oncology Group; EORTC European Organisation for Research and 
Treatment of Cancer; HRQoL Health-related quality of life; NSCLC Non-small-cell lung cancer; 
ORR Objective response rate; OS Overall survival; PD-L1 Programmed cell death ligand 1; PFS Progression-
free survival; PFS2 Time from randomization to second progression; PK Pharmacokinetic(s); 
QLQ-C30 v3 30-item Core Quality of Life Questionnaire, version 3; QLQ-LC13 13-item Lung Cancer Quality 
of Life Questionnaire; RECIST 1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1; SoC Standard 
of care; TC Tumor cell; Definition of TMB High in tissue and/or ctDNA to be documented in the SAP ahead of 
DBL with data external to Poseidon; WHO World Health Organization.
2.3
Safety objectives
Safety objective
Outcome measure
∀
To assess the safety and tolerability profile of 
durvalumab + tremelimumab combination 
therapy + SoC chemotherapy and durvalumab 
monotherapy + SoC chemotherapy compared 
with SoC chemotherapy alone
∀
AEs, physical examinations, laboratory findings, 
and vital signs
AE Adverse event; SoC Standard of care.
2.4
Exploratory objectives
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
70(225)
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
71(225)
A further objective to meet China FDA (CFDA) requirement is to evaluate consistency in 
efficacy and safety among patients in China for benefit-risk assessments of durvalumab + 
tremelimumab combination therapy + SoC chemotherapy compared with SoC chemotherapy 
alone and durvalumab monotherapy + SoC chemotherapy compared with SoC chemotherapy 
alone.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
72(225)
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.  In Japan, patients must be ≥20 years at the 
time of screening.
2.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol. Written informed consent and any locally required authorization (eg, 
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 amenable to 
curative surgery or radiation (according to Version 8 of the IASLC Staging Manual 
in Thoracic Oncology 2016).
4.
Patients must have tumors that lack activating EGFR mutations 
(eg, exon 19 deletion or exon 21 L858R, exon 21 L861Q, exon 18 G719X, or 
exon 20 S768I mutation) and ALK fusions.  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 metastatic NSCLC.  
Patients who have received prior platinum-containing adjuvant, neoadjuvant, or 
definitive chemoradiation for advanced disease are eligible, provided that 
progression has occurred >12 months from end of last therapy (see exclusion 
criterion 7). 
6.
Tumor PD-L1 status, confirmed by a reference laboratory using the Ventana SP263 
PD-L1 immunohistochemistry (IHC) assay, 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 tumor sample taken <3 months prior to enrollment.  
Tumor lesions used for newly acquired biopsies during screening period should not 
be the same lesions used as RECIST target lesions, unless there are no other lesions 
suitable for biopsy; and in this instance only core needle (not excisional/incisional) 
biopsy is allowed.  For patients with a single target lesion, if biopsy is collected 
prior to screening imaging for baseline tumor assessment, allow approximately 2 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
73(225)
weeks before imaging scans are acquired.  Samples with limited tumor content and 
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, TMB and other 
 analyses 
(also see Section 5.5.2) and is preferred in formalin-fixed paraffin-embedded
blocks. 
7.
World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1 at enrollment and randomization.
8.
Life expectancy ≥12 weeks at randomization (Day 1).
9.
Body weight >30 kg
10.
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 CT or MRI and that is suitable for accurate repeated 
measurements as per RECIST 1.1 guidelines.
11.
No prior exposure to immune-mediated therapy including, but not limited to, other 
anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding 
therapeutic anticancer vaccines.
12.
Adequate organ and marrow function as defined below:
!
Hemoglobin ≥9.0 g/dL without transfusion 4 weeks prior to the screening and 
randomization
!
Absolute neutrophil count ≥1.5 × 109/L
!
Platelet count ≥100 × 109/L
!
Serum bilirubin ≤1.5 × ULN. This will not apply to patients with confirmed 
Gilbert’s syndrome, who will be allowed in consultation with their physician
!
ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST 
≤5 × ULN
!
Calculated creatinine clearance (CL) ≥40 mL/min as determined by 
Cockcroft-Gault (using actual body weight) or 24-hour urine collection
!
For patients receiving cisplatin: 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)
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
74(225)
13.
Evidence of post-menopausal status or negative urinary or serum pregnancy test for 
female premenopausal 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 last menses >1 year 
ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy, or hysterectomy). 
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.
Previous IP assignment in the present study.
3.
Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional 
study.
4.
Participation in another clinical study with an IP during the last 12 months. 
5.
Mixed small-cell lung cancer and NSCLC histology, sarcomatoid variant.
6.
Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer 
treatment.  Concurrent use of hormonal therapy for non-cancer-related conditions 
(eg, hormone replacement therapy) is acceptable.
7.
No radiation therapy is allowed, unless it is 1) definitive radiation that had been 
administered at least 12 months prior, 2) palliative radiation to brain, with 
associated criteria for stability or lack of symptoms (see also exclusion 
criterion 16), or 3) palliative radiation to painful bony lesions (this must comprise 
less than 30% of the bone marrow).
8.
Major surgical procedure (as defined by the Investigator) within 28 days prior to the 
first dose of the IP.  Note: Local surgery of isolated lesions for palliative intent is 
acceptable.
9.
History of allogeneic organ transplantation.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
75(225)
10.
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, 
or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, 
rheumatoid arthritis, hypophysitis, uveitis, etc]).  The following are exceptions to 
this criterion:
!
Patients with vitiligo or alopecia
!
Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement 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
11.
Uncontrolled intercurrent illness, including but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, ILD, serious chronic gastrointestinal conditions 
associated with diarrhea, or psychiatric illness/social situations that would limit 
compliance with study requirement, that substantially increase risk of incurring AEs 
or compromise the ability of the patient to give written informed consent.
12.
Medical contraindication to platinum-based doublet chemotherapy.
13.
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 the IP and of low potential risk for recurrence
!
Adequately treated nonmelanoma skin cancer or lentigo maligna without 
evidence of disease
!
Adequately treated carcinoma in situ without evidence of disease (eg, cervical 
cancer in situ)
14.
History of leptomeningeal carcinomatosis.
15.
Spinal cord compression.
16.
Brain metastases. Patients with suspected brain metastases at screening should have 
an intravenous (IV) contrast-enhanced MRI (preferred) or IV contrast-enhanced CT 
of the brain prior to study entry. If brain metastases are detected patients must be 
treated before randomization.  Randomization is only permitted if patients with 
brain metastases have:

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
76(225)
!
Confirmed stable condition 4 weeks after the intervention using imaging
!
Returned neurologically to baseline
!
Completed associated steroids at least 5 days prior to randomization
Brain metastases will not be recorded as RECIST Target Lesions at baseline. 
17.
History of active primary immunodeficiency. 
18.
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.
19.
Current or prior use of immunosuppressive medication within 14 days before the 
first dose of durvalumab or tremelimumab.  The following are exceptions to this 
criterion:
!
Intra-nasal, inhaled, topical steroids, or local steroid injections 
(eg, intra-articular injection)
!
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or its equivalent
!
Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication, cytotoxic chemotherapy premedication)
20.
Receipt of live, attenuated vaccine within 30 days prior to the first dose of the IP.  
Note: Patients, if enrolled, should not receive live vaccine during the study and up 
to 30 days after the last dose of the IP.
21.
Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 90 days after the last dose of durvalumab monotherapy or 180 days 
after the last dose of durvalumab + tremelimumab combination therapy. Also see 
Section 3.8.
22.
Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients.
23.
Prior randomization or treatment in a previous durvalumab and/or tremelimumab 
clinical study regardless of treatment arm assignment.
24.
Judgment by the Investigator that the patient is unsuitable to participate in the study 
and the patient is unlikely to comply with study procedures, restrictions, and 
requirements.
For procedures for withdrawal of incorrectly enrolled patients, see Section 3.4.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
77(225)
3.3
Patient enrollment and randomization
Investigators should keep a record (ie, the patient screening log) of patients who entered 
screening.
At screening (Days -28 to -1), the Investigators or the suitably trained delegate will do the 
following:
∀
Obtain signed informed consent from the potential patient 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 imaging results must have been obtained 
within 28 days of randomization (Appendix E).  For patients with a single TL, if 
screening biopsy is collected prior to the screening imaging for baseline tumor 
assessment, allow approximately 2 weeks before imaging scans are acquired. 
(Informed consent of study procedures may be obtained prior to the 28-day 
screening window to permit tumor biopsy sample acquisition, which must be 
analyzed prior to randomization.)  
∀
Obtain a unique 
 enrollment number (E-code) through the Interactive Voice 
Response System (IVRS)/Interactive Web Response System (IWRS) in the 
following format: 
 
  This number is 
the patient’s unique identifier and is used to identify the patient on the electronic 
case report forms (eCRFs).
∀
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) to permit analysis prior 
to randomization.  See Section 5.5.1 for details on tumor samples.  
The sample for centralized PD-L1 testing should be sent only for patients 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 be used first for local EGFR mutation and ALK 
fusion testing or, if not feasible, be sent directly to be EGFR/ALK tested centrally 
concomitantly with PD-L1, in accordance with inclusion criterion 4. 
Tumor samples will be used to determine PD-L1 expression status (defined by the 
Ventana SP263 PD-L1 IHC assay) in which: 
!
≥50% of TC with membrane staining for PD-L1 at any intensity (PD-L1 
TC ≥50%)
!
<50% of TC with membrane staining for PD-L1 at any intensity (PD-L1 
TC <50%)
PPD
PPD

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
78(225)
∀
Determine patient eligibility (see Sections 3.1 and 3.2).
∀
At randomization, eligibility criteria will be confirmed on Cycle 1 Day 1, prior to the first 
dose of IP.  At randomization, once the patient is confirmed to be eligible, the Investigator or 
suitably trained delegate will do the following:
1.
Define the SoC treatment (based on the most appropriate option for the patient) that 
the patient will receive.  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 scheduled to receive 
pemetrexed, folic acid and vitamin B12 should commence prior to randomization 
for up to 7 days, in line with local practice.  This is to ensure 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 
3 treatment arms (PD-L1 expression status results must be received from the central 
laboratory by the IVRS/IWRS prior to randomization).
Patients will be randomized in a 1:1:1 ratio in a stratified manner according to the following:
∀
PD-L1 tumor expression status (PD-L1 TC ≥50% versus PD-L1 TC <50%)
∀
Disease stage (Stage IVA versus Stage IVB)
∀
Histology (non-squamous versus squamous)
If the patient is ineligible and not randomized, the IVRS/IWRS status should be changed to 
screen failure.
Patients will begin treatment on Cycle 1 Day 1.  Treatment should start no more than 
3 working days after being randomized.  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 or randomized 
patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive study medication.  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.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
79(225)
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 AstraZeneca 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.  In situations where an agreement cannot be 
reached, the patient should have their study therapy stopped and be withdrawn from the study.
3.5
Methods for assigning treatment arms
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 stratum.  A blocked 
randomization will be generated, and all centers will use the same list to minimize any 
imbalance in the number of patients assigned to each treatment arm. 
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 
randomization.  The IVRS/IWRS will provide the kit identification number to be allocated to 
the patient at the randomization visit and subsequent treatment dispensing visits.
3.6
Methods for ensuring blinding (Not applicable)
Not applicable; this study is not blinded.
3.7
Methods for unblinding (Not applicable)
Not applicable; this study is not blinded.
3.8
Restrictions
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after:
1.
Female patient of childbearing potential
!
Female patients of childbearing potential who are not abstinent and 
intend to be 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 throughout the total duration of the drug treatment and the 
drug washout period (180 days after the last dose of durvalumab + 
tremelimumab combination therapy or 90 days after the last dose of 
durvalumab monotherapy). Nonsterilized male partners of a female 
patient of childbearing potential must use male condom plus spermicide 
throughout this period. Cessation of birth control after this point should 
be discussed with a responsible physician. Periodic abstinence, the 
rhythm method, and the withdrawal method are not acceptable methods 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
80(225)
of birth control. Female patients should also refrain from breastfeeding 
throughout this period.
2.
Male patients with a female partner of childbearing potential
!
Nonsterilized male patients who are not abstinent and intend to be 
sexually active with a female partner of childbearing potential must use a 
male condom plus spermicide from the time of screening throughout the 
total duration of the drug treatment and the drug washout period (180 
days after the last dose of durvalumab + tremelimumab combination 
therapy or 90 days after the last dose of durvalumab monotherapy). 
However, periodic abstinence, the rhythm method, and the withdrawal 
method are not acceptable methods of contraception.  Male patients 
should refrain from sperm donation throughout this period.
!
Female partners (of childbearing potential) of male patients must also use 
a highly effective method of contraception throughout this period 
(Table 1).  
Note 1: Females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-
menopausal.  
Note 2: For male patients receving gemcitabine SoC chemotherapy, in addition to referring to 
the current local prescribing information, cryopreservation of male sperm should be 
considered due to the risk of infertility. 
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. 
∀
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.
Highly effective methods of contraception, defined as those that result in a low failure rate 
(ie, 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 (eg, male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non-copper-containing intra-uterine 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).

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
81(225)
All patients: Follow the local prescribing information relating to contraception, the time 
limits for such precautions (6 months following discontinuation of SoC treatment), and any 
additional restrictions for agents in the SoC group.
Table 1
Highly effective methods of contraception (<1% failure rate)
Barrier/Intra-uterine methods
Hormonal methods
∀
Copper T intra-uterine device
∀
Levonorgesterel-releasing intra-uterine 
system (eg, Mirena®)a
∀
Implants: Etonogestrel-releasing implants (eg, 
Implanon® or Norplan®) b
∀
Intra-vaginal devices: 
Ethinylestradiol/etonogestrel-releasing intra-
vaginal devices (eg, NuvaRing®) b
∀
Injection: Medroxyprogesterone injection (eg, 
Depo-Provera®) b
∀
Combined pill: Normal and low dose combined 
oral contraceptive pill
∀
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Ortho Evra®) b
∀
Minipill: Progesterone-based oral contraceptive pill 
using desogestrel (Cerazette® is currently the only 
highly effective progesterone-based pill) b
a
This is also considered a hormonal method.
b
Not approved in Japan.
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 
durvalumab + tremelimumab combination therapy or 90 days after receipt of the 
final dose of durvalumab or until alternate anticancer therapy is started.
4.
Restrictions relating to concomitant medications are described in Section 7.7.
3.9
Discontinuation of IP
An individual patient will not receive any further IP (durvalumab + tremelimumab 
combination therapy, durvalumab monotherapy 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.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
82(225)
∀
An AE that meets criteria for discontinuation as defined in the Dosing Modification 
and Toxicity Management Guidelines (please see Section 6.9.1) or as defined in the 
local prescribing information for the SoC agent.
∀
Pregnancy or intent to become pregnant.
∀
Noncompliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from treatment with IP (eg, refusal to adhere to 
scheduled visits).
∀
Initiation of alternative anticancer therapy including another investigational agent.
∀
Treatment Arms 1 and 2: Clinical progression, i.e. Investigator determination that
the patient is no longer benefiting from treatment with IP, or radiological 
progressive disease (PD) based on RECIST 1.1 criteria and Investigator 
determination that the patient is no longer benefiting from treatment with the IP.
∀
Treatment Arm 3: Clinical progression, i.e. Investigator determination that the 
patient is no longer benefiting from treatment with IP,  or RECIST 1.1 defined 
radiological progression.
For patients in Treatment Arms 1 and 2, when SoC chemotherapy is discontinued due to 
treatment-related toxicity, durvalumab monotherapy or durvalumab + tremelimumab may 
continue at the Investigator’s discretion when toxicity resolves to at least Grade 2 or less.  
Note: if the Investigator feels that a patient is ready to restart treatment prior to the toxicity 
resolving to Grade 2 or less, AstraZeneca should be consulted for an exception to this rule.
3.9.1
Procedures for discontinuation of patient from IP
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 AEs. If possible, they will be seen and assessed by an 
Investigator(s). AEs will be followed up (see Section 6).
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 the follow-up period (see Table 3).  
Patients who permanently discontinue drug for reasons other than objective disease 
progression should continue to have RECIST scans performed at Week 6±1 week from the 
date of randomization, Week 12±1 week from the date of randomization, and then 
q8w±1 week thereafter until RECIST 1.1 defined radiological progression plus an additional 
subsequent scan or death (whichever comes first) as defined in Table 3.
All patients will be followed for survival until the end of the study.  This follow-up must be 
performed even if the patient begins another therapy to treat their NSCLC.
Patients who decline to return to the site for evaluations should be contacted by telephone as 
indicated in Table 3 as an alternative.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
83(225)
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IVRS/IWRS.
If a patient is withdrawn from study, see Section 3.10.
3.10
Criteria for withdrawal
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” (ie, patient does not meet the required inclusion/meets 
exclusion criteria).  This reason for study withdrawal is only valid for screen failures (ie, not 
randomized patients).  Patients may be rescreened a single time, but they cannot be 
re-randomized.  Patients may not be rescreened after enrollment to the study has closed.
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 (eg, 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 patients’ status at that time.  Patients who refuse to continue participation in the 
study, including telephone contact, should be documented as “withdrawal of consent” rather 
than “lost to follow-up.”  Investigators should document attempts to re-establish contact with 
missing patients throughout the study period.  If contact with a missing patient is 
re-established, the patient should not be considered lost to follow-up and evaluations should 
resume according to the protocol.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
84(225)
In order to support key endpoints of PFS and OS analyses, 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.”
∀
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. (The applicable eCRF moduleswill be updated.)
∀
Withdrawal of consent: 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 resources where it is possible to 
do so under applicable local laws to obtain a current survival status. (The applicable 
eCRF 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 study drug
∀
Are not considered to be consistent with continuation of the study
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 1.6).
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 
durvalumab 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 study treatment periods in this study are presented in 
Table 2, and the procedures for the follow-up period are presented in Table 3.  
The following are the definitions of the study treatment regimens in each treatment arm:
∀
Treatment Arm 1: durvalumab + tremelimumab combination therapy + SoC 
chemotherapy
∀
Treatment Arm 2: durvalumab monotherapy + SoC chemotherapy

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
85(225)
∀
Treatment Arm 3: SoC chemotherapy alone
The study treatment period of this study includes the following 2 phases (Table 2):
∀
‘During chemotherapy’: during which patients receive durvalumab ± tremelimumab 
+ SoC chemotherapy or SoC chemotherapy alone
∀
‘Post-chemotherapy’: during which patients in Treatment Arms 1 and 2 receive 
durvalumab monotherapy, and non-squamous patients in all treatment arms who 
received pemetrexed + carboplatin/cisplatin in the ‘during chemotherapy’ phase and 
who have not progressed after 4 to 6 cycles will receive pemetrexed maintenance 
therapy, unless contraindicated per the Investigator.
Patients who continue study treatment beyond Week 20 will continue with all Week 20 
assessments defined in Table 2 until discontinuation of study treatment. Patients who 
discontinue study treatment will follow assessments as defined in Table 3.  All patients must 
follow the tumor evaluation scan schedule, which is at screening (as baseline), 
Week 6±1 week from the date of randomization, Week 12±1 week from the date of 
randomization, and q8w±1 week, thereafter, until RECIST 1.1 defined radiological 
progression plus an additional subsequent scan or until death, for those patients who 
discontinue study treatment for reasons other than objective disease progression.  Follow-up 
visits for tumor evaluation scans should be planned to align to this schedule where possible.
For all treatment arms
PRO and tumor efficacy (RECIST) assessment dates will not be affected by dose delays since 
they will be based on the date of randomization (not the date of therapy); hence, the 
assessment dates will remain as originally scheduled.
All other scheduled assessments must be performed relative to the start of the dosing cycle, 
such that all laboratory procedures required for dosing should be performed within 3 days 
prior to dosing.
For durvalumab + tremelimumab combination arms or durvalumab monotherapy 
(Treatment Arms 1 and 2)
∀
Patients may delay dosing under certain circumstances.
!
Dosing may be delayed per Toxicity Management Guidelines, due to either an 
immune or a non-immune-related 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 (during chemotherapy, the interval is 
21 days and during post-chemotherapy, the interval is 28 days) may be 
shortened as clinically feasible in order to gradually align treatment cycles with 
the schedule of tumor efficacy (RECIST) and PRO assessments.  For 
subsequent cycles the time between 2 consecutive doses cannot be less than 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
86(225)
21 days, based on the half-lives of durvalumab and tremelimumab (see current 
Investigator’s Brochures for durvalumab and tremelimumab).  If there is a 
dosing delay while on the q3w schedule, all future dosing days should be 
delayed to ensure that the intervals between dosing study treatment are always 
at least 21 days.  
For standard of care therapy arm (Treatment Arm 3)
∀
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 D419MC00004
Version 6.0
Date 09 July 2021
87(225)
Table 2
Study treatment and retreatment periods: Schedule of assessments for Treatment Arms 1, 2, and 3
Screening
During chemotherapy
1 cycle = 3 weeks (21 days)
Post-chemotherapy
1 cycle = 4 weeks (28 days)
For details, 
see Section
C1/
D1
C1/
D8
C2/
D1
C2/
D8
C3/
D1
C3/
D8
C4/
D1
C4/
D8
C5
C6
C7 to PD (q4w)
Week
0
1
3
4
6
7
9
10
12
16
20 to PD
Day
-28 to -1
1
8
22
29
43
50
64
71
Window (days)*
NA
+3
±2
+3
±2
+3
±2
+3
±2
+3
±3
±3
Informed consent 
X
3.3, 4.1, 10.4
X
Appendix C
Study procedures
Full physical 
examination
X
5.2.2
Targeted physical 
examination
X
X
X
X
X
X
X
X
X
X
X
5.2.2
Vital signsb
X
X
X
X
X
X
X
X
X
X
X
X
5.2.4
12-lead ECGc
X
As clinically indicated
5.2.3
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
7.7
Demography
X
4.1
Eligibility criteria
X
X
3.1, 3.2
Medical/ surgical history
X
Laboratory assessments
Clinical chemistryd
X
Xe
X
X
X
X
X
X
X
X
X
X
5.2.1
Hematologyd
X
Xe
X
X
X
X
X
X
X
X
X
X
5.2.1
APTT and INRd
X
As clinically indicated
5.2.1
TSH, free T3, and free 
T4d,f
X
Xe
X
X
X
X
X
X
5.2.1
Urinalysis
X
Xe
X
X
X
X
X
X
X
X
X
X
5.2.1
TB (in line with local 
standards), Hepatitis B, 
Hepatitis C, and HIV
X
5.2.1
Pregnancy testg
X
Xe
X
X
X
X
X
X
5.2.1
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
88(225)
Table 2
Study treatment and retreatment periods: Schedule of assessments for Treatment Arms 1, 2, and 3
Screening
During chemotherapy
1 cycle = 3 weeks (21 days)
Post-chemotherapy
1 cycle = 4 weeks (28 days)
For details, 
see Section
C1/
D1
C1/
D8
C2/
D1
C2/
D8
C3/
D1
C3/
D8
C4/
D1
C4/
D8
C5
C6
C7 to PD (q4w)
Week
0
1
3
4
6
7
9
10
12
16
20 to PD
Day
-28 to -1
1
8
22
29
43
50
64
71
Window (days)*
NA
+3
±2
+3
±2
+3
±2
+3
±2
+3
±3
±3
Efficacy assessments
Tumor evaluation (CT or 
MRI) (RECIST 1.1)h
Xi
X
X
Xj
5.1
PK assessments
Durvalumab PK sample 
(serum; Treatment Arms 
1 and 2 only)
Xk
Xl
Xl
5.4.1
Tremelimumab PK 
sample (serum; 
Treatment Arm 1 only)
Xk
Xl
Xl
X (3 months after 
tremelimumab 
discontinuation)m
5.4.1
Abraxane PK sample 
(plasma; selected sites 
only)
Xn
5.4.1
Gemcitabine PK sample 
(plasma; selected sites 
only)
Xn
5.4.1
Safety monitoring
WHO/ECOG 
performance status
X
X
X
X
X
X
X
X
X
X
X
X
5.2.6
AE/SAE assessment
X
X
X
X
X
X
X
X
X
X
X
X
6.3.1
Drug accountability
X
X
X
X
X
X
X
7.6
Pre-randomization medication
Folic acid/
Vitamin B12o
X
Continue in line with local practice
3.3

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
89(225)
Table 2
Study treatment and retreatment periods: Schedule of assessments for Treatment Arms 1, 2, and 3
Screening
During chemotherapy
1 cycle = 3 weeks (21 days)
Post-chemotherapy
1 cycle = 4 weeks (28 days)
For details, 
see Section
C1/
D1
C1/
D8
C2/
D1
C2/
D8
C3/
D1
C3/
D8
C4/
D1
C4/
D8
C5
C6
C7 to PD (q4w)
Week
0
1
3
4
6
7
9
10
12
16
20 to PD
Day
-28 to -1
1
8
22
29
43
50
64
71
Window (days)*
NA
+3
±2
+3
±2
+3
±2
+3
±2
+3
±3
±3
IP administration (Interval between 2 consecutive doses must be at least 21 days)
Treatment Arm 1: durvalumab + tremelimumab combination therapy + SoC chemotherapy
Durvalumabd,p
X
X
X
X
X
X
Xq
7.2.1
Tremelimumabd,p
X
X
X
X
Xdd
7.2.1
Abraxaner,s
X
X
X
X
X
X
X
X
7.2.1
Gemcitabiner
X
X
X
X
X
X
X
X
7.2.1
Pemetrexedr,t
X
X
X
X
Xt
Xt
Xt
7.2.1
Carboplatin or 
cisplatinr,u
X
X
X
X
7.2.1
Treatment Arm 2: durvalumab monotherapy + SoC chemotherapy
Durvalumabd,p
X
X
X
X
X
X
Xq
7.2.1
Abraxaner,s
X
X
X
X
X
X
X
X
7.2.1
Gemcitabiner
X
X
X
X
X
X
X
X
7.2.1
Pemetrexedr,t
X
X
X
X
Xt
Xt
Xt
7.2.1
Carboplatin or 
cisplatinr,u
X
X
X
X
7.2.1
Treatment Arm 3: SoC chemotherapy alone
Abraxaner,s,v
X
X
X
X
X
X
X
X
7.2.1
Gemcitabiner,v
X
X
X
X
X
X
X
X
7.2.1
Pemetrexedr,t,v
X
X
X
X
Xt
Xt
Xt
7.2.1
Carboplatin or 
cisplatinr,u,v
X
X
X
X
7.2.1

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
90(225)
Table 2
Study treatment and retreatment periods: Schedule of assessments for Treatment Arms 1, 2, and 3
Screening
During chemotherapy
1 cycle = 3 weeks (21 days)
Post-chemotherapy
1 cycle = 4 weeks (28 days)
For details, 
see Section
C1/
D1
C1/
D8
C2/
D1
C2/
D8
C3/
D1
C3/
D8
C4/
D1
C4/
D8
C5
C6
C7 to PD (q4w)
Week
0
1
3
4
6
7
9
10
12
16
20 to PD
Day
-28 to -1
1
8
22
29
43
50
64
71
Window (days)*
NA
+3
±2
+3
±2
+3
±2
+3
±2
+3
±3
±3
PRO assessments
EORTC QLQ-C30 v3, 
EORTC QLQ-LC13, 
, and 
X
X
X
X
X
X
X
X
5.3.1.1, 
5.3.1.2, 
5.3.1.3,
5.3.1.5
X
X
X
X
X
X 
5.3.1.4
Other laboratory assessments and assays
Immunogenicity 
assessment (ADA 
sampling)z
Xl
Xl
Xl
X (3 months after 
tremelimumab 
discontinuation)l,aa 5.4.1.1
Tumor biopsy (newly 
acquired or archived 
<3 months old)
X
5.5.1
Archival tumor sample 
≥3 months old, where 
available 
X
5.5.1
X
Appendix C
Xl
X
X
5.5.2
EGFR and ALK testcc
Xcc
3.3
PD-L1 test
X
5.5.1
X
5.5.2
X
X
5.5.2
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
91(225)
Table 2
Study treatment and retreatment periods: Schedule of assessments for Treatment Arms 1, 2, and 3
Screening
During chemotherapy
1 cycle = 3 weeks (21 days)
Post-chemotherapy
1 cycle = 4 weeks (28 days)
For details, 
see Section
C1/
D1
C1/
D8
C2/
D1
C2/
D8
C3/
D1
C3/
D8
C4/
D1
C4/
D8
C5
C6
C7 to PD (q4w)
Week
0
1
3
4
6
7
9
10
12
16
20 to PD
Day
-28 to -1
1
8
22
29
43
50
64
71
Window (days)*
NA
+3
±2
+3
±2
+3
±2
+3
±2
+3
±3
±3
X
X
X
X
X
X
X
X
5.3.3
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated. Every effort should be made to minimize the time 
between randomization and starting treatment. (i.e. within one day after randomization)
Note: For retreatment, the same assessments should be done as in the first treatment period, with the exception of the hepatitis B, hepatitis C and HIV tests. In 
addition, PK, ADA, 
 EGFR/ALK, PD-L1, and 
 which do not need 
to be collected a second time.
*
Visit windows: For durvalumab and tremelimumab treatment schedules: If there is a dosing delay while on the q3w schedule, all future dosing days should be delayed 
to ensure that the intervals between dosing study treatment are always at least 21 days.  For SoC: Dosing delays should be managed as per local prescribing guidelines.
a
 
b
Body weight will be recorded along with vital signs.
c
Any clinically significant cardiovascular findings require confirmation by ECG.
d
Results for urea and electrolytes, full blood count, and liver function tests must be available before commencing an infusion (samples must have been obtained within 
3 days prior to the infusion).
e
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. Serum or plasma 
chemistry, hematology, and/or LFT monitoring may be performed more frequently if clinically indicated.  If TSH is measured within 14 days prior to Day 1 (first 
infusion day), it does not need to be repeated at day 1.
f
Free T3 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.
g
Pregnancy test will be performed in women of childbearing potential only.  A urine or serum pregnancy test is acceptable.
h
Baseline assessments should be performed no more than 28 days before the date of randomization and, ideally, should be performed as close as possible to and prior to 
the date of randomization. RECIST 1.1 assessments will be performed on images from CT scans (preferred) or MRI scans, each preferably with IV contrast, of the 
chest and abdomen (including the entire liver and both adrenal glands). Additional anatomy (e.g., pelvis, brain) should be scanned based on signs and symptoms of 
individual patients at baseline and during follow-up period. Scheduled on-study scans should be collected within ±1 week of the scheduled imaging visit.  For patients 
who reach a RECIST 1.1-defined PD, a subsequent scan should be performed preferably at the next scheduled imaging visit and no earlier than 4 weeks after the prior
assessment of radiological PD and Confirmation of Radiological Progression criteria should be used to evaluate this subsequent scan (please refer to Appendix E).  If an 
unscheduled assessment has been performed and the patient has not reached PD, every attempt should be made to perform the subsequent assessments at his or her next 
scheduled visit.  
i
Patients’ diagnostic scan may be used as a baseline scan if taken within 28 days of randomization and provides assessment of any radiologic findings that would 
indicate active infectious processes includinge TB status and, if it is in accordance with the requirements outlined in Appendix E.
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
92(225)
j
Patients will have tumor evaluation scans performed at Week 6±1 week from the date of randomization, Week 12 ±1 week from the date of randomization, and then 
q8w±1 week thereafter until radiological progression
k
PK sampling should be performed within 10 minutes of the end of infusion.
l
Pre-dose samples; should collected within 60 minutes pre-dose (same day of infusion).
m
For patients in Treatment Arm 1 only, a sample for tremelimumab PK will be collected 3 months after the last tremelimumab dose.  This will be Week 28, assuming the 
last dose of tremelimumab was at Week 16.  If there are dose delays and the last tremelimumab dose was after Week 16, the tremelimumab PK should be collected 
3 months after the last tremelimumab dose.
n
Abraxane PK sample- collect at end of infusion, 8 hours post-infusion, and 48 hours post-infusion; gemcitabine PK sample- collect at end of infusion, 1 hour 
post-infusion, 3 hours post-infusion, and 8 hours post-infusion. Window period for PK samples collection is ±5 minutes.
o
To be administered in line with local practice for patients with non-squamous tumors who will receive pemetrexed.
p
During the combination portion of treatment, tremelimumab will be administered first; the durvalumab infusion will start approximately 1 hour (maximum 2 hours) 
after the end of the tremelimumab infusion.  If there are no clinically significant infusion reactions with the first cycle, and at the discretion of the investigator, then for 
all other cycles, the durvalumab can be given immediately after the tremelimumab infusion has finished
q
In Treatment Arms 1 and 2, durvalumab treatment will be continued until clinical progression or radiological progression. Scenarios for treatment through progression, 
including with the combination for Treatment Arm 1, are discussed in Section 7.2.2.2.
r
The immunotherapy agents will be infused first followed by the SoC chemotherapy regimen.
s
Abraxane will be dosed at Days 1 (±3), 8 (±2), and 15 (±2). The Day 15 assessements are similar to Day 8.
t
Non-squamous patients who received carboplatin/cisplatin + pemetrexed and who have not progressed after 4 to 6 cycles of carboplatin/cisplatin + pemetrexed will 
receive pemetrexed maintenance therapy, unless contraindicated per the Investigator. Pemetrexed maintenance therapy can be given q4w for Treatment Arms 1 and 2. 
For Treatment Arm 3, Pemetrexed maintenance therapy can be given either q3w or q4w dependent on Investigator decision and local standards. Note: RECIST 1.1 
assessment should be performed at Week 12 ±1 week from the date of randomization, and then q8w±1 week thereafter until radiological progression (regardless of 
whether it chosen q3w or q4w).
u
If cisplatin: infuse over 1 to 2 hours.  If carboplatin: infuse over 0.5 to 1 hour.
v
For Treatment Arm 3, SoC chemotherapy will be given q3w up to 4 doses; extension into Weeks 12 and 15 is as clinically indicated, at the Investigator’s discretion.  
Note: tumor evaluation at Week 12±1 week and q8w thereafter and PRO collection q4w until objective disease progression are required irrespective of the number of 
cycles of SoC given.
w
For the PRO collection, the research nurse or study coordinator should ensure that the patient completes the questionnaire prior to any other study procedures and 
before discussion of PD to avoid introducing bias to the patient’s responses to the questions.  The EORTC QLQ-C30 should always be completed prior to the EORTC 
QLQ-LC13 module.
x
y
 
z
ADA for tremelimumab will be assessed for Treatment Arm 1 patients only; ADA for durvalumab will be assessed for Treatment Arms 1 and 2 patients only.
aa
A sample to look for antibodies to tremelimumab will be taken 90 days±7 days after last dose of tremelimumab for Treatment Arm 1.  
bb
 
 
cc
For patients with unknown status of ALK and/or EGFR NSCLC.  If EGFR and ALK status is unknown, then the tumor sample (archive or fresh, primary or metastatic) 
should be used first for (local or central) EGFR mutation and ALK fusion testing in accordance to inclusion criterion 4.  (If patients have squamous histology or are 
known to have a tumor with a KRAS mutation, then EGFR and ALK testing is not required.)
dd
For patients in Treatment Arm 1, an additional dose of durvalumab + tremelimumab will be given at Week 16 post-chemotherapy.  In the case of dose delay(s), more 
than 1 durvalumab + tremelimumab combination dose can be given at and after Week 16 post-chemotherapy to ensure that up to 5 combination doses are administered 
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
93(225)
in Treatment Arm 1.  If patients receive fewer than 4 cycles of platinum doublet chemotherapy, the remaining cycles of combined durvalumab/tremelimumab (up to a 
total of 5) should be given after combination of platinum doublet chemotherapy (with maintenance pemetrexed, if applicable).
ADA Anti-drug antibody; AE Adverse event; ALK Anaplastic lymphoma kinase; APTT Activated partial thromboplastin time; C Cycle; CT Computed tomography; 
 D Day; 
 ECG Electrocardiogram; ECOG Eastern Cooperative Oncology Group; 
EGFR Epidermal growth factor receptor; EORTC European Organisation for Research and Treatment of Cancer; 
 
 HIV Human immunodeficiency virus; 
 INR International normalized ratio; IP Investigational product; 
 IV Intravenous; MRI Magnetic resonance imaging; NA Not available; PD Progressive disease; 
PD-L1 Programmed cell death ligand 1; 
 PK Pharmacokinetic(s); 
 
 q3w Every 3 weeks; q4w Every 4 weeks; QLQ-C30 v3 30-item Core Quality of Life Questionnaire, version 3; QLQ-LC13 13-item Lung Cancer Quality of Life 
Questionnaire; RECIST 1.1 Response Evaluation Criteria in Solid Tumors, version 1.1; RNA SAE Serious adverse event; SoC Standard of care; 
 
 T3 Triiodothyronine; T4 Thyroxine; TSH Thyroid-stimulating hormone; WHO World Health Organization.
Table 3
Follow-up period: Schedule of assessments for patients in Treatment Arms 1, 2, and 3 who have 
completed/discontinued treatment
Evaluation
Time since last dose of IP
For details, see 
Section
Day (±3)
Months (±1 week)
Every 
2 months 
(±2 weeks)
28
2
3
4
6
8
10
12
Full physical examinationa
X
5.2.2
Vital signs
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
Follow-up of ongoing AEs
6.3.1
Concomitant medications
X
X
X
7.7
WHO/ECOG performance statusd
At timepoints consistent with tumor assessments, at 30, 60, and 90 days and at initiation of subsequent 
anticancer therapy
5.2.6
Subsequent anticancer therapye
X
5.1
Survival statusf
X
X
X
X
X
X
X
X
5.1.2
Hematology
X
X
X
5.2.1
Clinical chemistry
X
X
X
5.2.1
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
94(225)
Table 3
Follow-up period: Schedule of assessments for patients in Treatment Arms 1, 2, and 3 who have 
completed/discontinued treatment
Evaluation
Time since last dose of IP
For details, see 
Section
Day (±3)
Months (±1 week)
Every 
2 months 
(±2 weeks)
28
2
3
4
6
8
10
12
TSH, free T3, and free T4g
X
X
X
5.2.1
Durvalumab PK sample (serum; 
Treatment Arms 1 and 2 only)
X (3 months after 
durvalumab 
discontinuation)h
5.4.1
Tremelimumab PK sample (serum; 
Treatment Arm 1 only)
X (3 months after 
tremelimumab 
discontinuation)h
5.4.1
Immunogenicity assessment (ADA 
sampling)i
X (3 months after 
durvalumab 
discontinuation for 
Treatment Arms 1 and 2; 
3 months after 
tremelimumab 
discontinuation for 
Arm 1)j
5.4.1.1
EORTC QLQ-C30 v3,k
EORTC QLQ-LC13,k
X
q4w until PD and then q8w until second progression/death (whichever comes first)
5.3.1.1, 5.3.1.2, 
5.3.1.3, 5.3.1.4, 
5.3.1.5
X
5.3.3
Tumor evaluation (CT or MRI)n
(RECIST 1.1)
RECIST 1.1 tumor assessments should be performed at Week 6±1 week, at Week 12±1 week, and then 
q8w±1 week until RECIST 1.1 defined radiological progression plus an additional subsequent scan or 
death.
5.1
Second progression assessmento
Assessment will be performed by the Investigator and defined according to local standard clinical 
practice and may involve any of the following: objective radiologic imaging, symptomatic progression, 
or death (using the patient’s status at first progression as the reference for assessment of second 
progression).
a
Physical examinations are described in Section 5.2.2.
b
Pregnancy test will be performed in women of childbearing potential only.  A urine or serum pregnancy test is acceptable.
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
95(225)
c
AEs and SAEs will be collected until 90 days following discontinuation of study treatment (ie, the last dose of durvalumab, durvalumab + tremelimumab, or SoC 
chemotherapy)
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 performance status should be provided when information on subsequent anticancer therapy is provided, where possible.
e
Details of any treatment for NSCLC (including surgery) after the last dose of study treatment must be recorded in the eCRF.
f
Patients may be contacted in the week following the data cut-off to confirm survival status.  Details of any treatment for NSCLC (including surgery) after the last dose of 
study treatment must be recorded in the eCRF.  Every effort should be made to contact patients by telephone to follow and record survival status.
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
The 3-month follow-up samples for each molecule are relative to the respective last dose: the tremelimumab sample will be collected 3 months after the last 
tremelimumab dose (Treatment Arm 1).  The durvalumab sample will be collected 3 months after the last durvalumab dose (Treatment Arms 1 and 2).
i
ADA for tremelimumab will be assessed for Treatment Arm 1 patients only; ADA for durvalumab will be assessed for Treatment Arms 1 and 2 patients only.
j
A sample to look for antibodies to tremelimumab will be taken 90 days±7 days after last dose of tremelimumab.  A sample to look for antibodies to durvalumab will be 
taken 90 days±7 days after last dose of durvalumab.
k
For the PRO data collection, the research nurse or study coordinator should ensure that the patient completes the questionnaire prior to any other study procedures and 
before discussion of PD to avoid introducing bias to the patient’s responses.  The EORTC QLQ-C30 should always be completed prior to the EORTC QLQ-LC13 
module.
l
m
  
 
n
Only for patients yet to progress, RECIST 1.1 assessments will be performed on images from CT (preferred) or MRI, each preferably with IV contrast, of the chest and 
abdomen (including the entire liver and both adrenal glands). Additional anatomy should be imaged based on signs and symptoms of individual patients.  For Treatment 
Arms 1 and 2 scans subsequent to a prior radiological PD should be performed preferably at the next scheduled imaging visit and no earlier than 4 weeks after the 
immediate prior assessment of radiological PD. If an unscheduled assessment has been performed and the patient has not progressed, every attempt should be made to 
perform the subsequent assessments at his or her scheduled visits (relative to the date of randomization).
o
For patients who discontinue durvalumab + tremelimumab combination therapy + SoC chemotherapy, durvalumab monotherapy + SoC chemotherapy, or SoC 
chemotherapy alone following objective disease progression, available readings of CT/MRI from local practice will be collected from the patients’ medical charts while 
information on subsequent anticancer treatment and/or PFS2 is collected.
ADA Anti-drug antibody; AE Adverse event; CT Computed tomography; 
 eCRF electronic case report form; 
ECOG Eastern Cooperative Oncology Group; EORTC European Organisation for Research and Treatment of Cancer; 
 
 IP Investigational product; IV Intravenous; MRI Magnetic resonance imaging; NSCLC Non-
small cell lung cancer; PD Progressive disease; PFS2 Time from randomization to second progression; 
 
PK Pharmacokinetic(s); 
 q4w Every 4 weeks; q8w every 8 weeks; QLQ-C30 v3 30-item Core Quality of 
Life Questionnaire, version 3; QLQ-LC13 13-item Lung Cancer Quality of Life Questionnaire; RECIST 1.1 Response Evaluation Criteria in Solid Tumors, version 1.1; 
SAE Serious adverse event; SoC Standard of care; T3 Triiodothyronine; T4 Thyroxine; TSH Thyroid-stimulating hormone; WHO World Health Organization.
  
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
96(225)
4.1
Screening/enrollment period
All screening and enrollment procedures will be performed according to the assessment 
schedules in Table 2.  Demographic data and other characteristics will be recorded including 
date of birth or age, sex, 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 
evaluations.  If 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 imaging results must have been obtained within 28 days of randomization 
(Appendix E).  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 will be 
included in the main patient informed consent form (ICF).  
Screening/baseline evaluations may be performed over more than 1 visit.  If the 
screening/baseline evaluations are spread across more than 1 visit, the screening visit date will 
be the date that screening started.
The timing of vital signs assessments should be such that it allows the blood draw (eg, PK 
blood sample) to occur at the timepoints indicated in Table 2.
4.2
Treatment period
All procedures to be conducted during the study treatment period will be performed according 
to the assessment schedule (see Table 2).
Treatment with immunotherapy + SoC chemotherapy in Treatment Arms 1 and 2, as well as 
treatment with SoC chemotherapy alone in Treatment Arm 3, will be administered beginning 
on Cycle 1 Day 1.
All patients will receive study treatment until clinical progression or radiological progression 
(Arm 1 and Arm 2) or RECIST 1.1 defined radiological progression (Arm 3).
Patients in Treatment Arms 1 and 2 who are treated beyond progression (see Section 7.2.2) 
will be expected to follow the assessment schedule in Table 2.
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 vital signs assessments should be such that it allows the 
blood draw (eg, PK blood sample) to occur at the timepoints indicated in Table 2.
Patients in Treatment Arm 3 only:
Patients who receive additional cycles of SoC chemotherapy at Weeks 12 and 15 will be 
expected to follow the assessment schedule in Table 2 after 4 to 6 cycles of SoC 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
97(225)
chemotherapy; additional visits or scans due to the optional extension of SoC chemotherapy 
will be recorded in applicable eCRF modules.
4.2.1
Safety confirmation period
This applies to the first 60 patients randomized to the study and will be split into 2 parts; an 
unblinded safety review carried out by the IDMC will be conducted after the initial 30 patients 
have completed the first cycle of treatment and again after an additional 30 patients have been 
randomized and  have completed the first cycle of treatment.  More details on the IDMC are 
provided in Section 1.6.1. 
Safety confirmation for Japan: An additional unblinded safety review for Japanese patients 
will take place when the first 3 patients in each treatment arm in Japan have completed the 
first cycle of treatment (see Section 1.6.1 for details).
Safety confirmation for China: An additional unblinded safety review for Chinese patients 
will take place when the first 10 patients in each treatment arm in China have completed the 
first cycle of treatment (see Section 1.6.1 for details).
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 study treatment and will enter follow-up 
(see Table 3).  
Patients in Treatment Arms 1, 2, and 3 who permanently discontinue study treatment for 
reasons other than objective RECIST 1.1 disease progression should continue to have tumor 
evaluation scans performed q6w±1 week for the first 12 weeks (relative to the date of 
randomization), and then q8w±1 week thereafter until RECIST 1.1 defined radiological 
progression plus an additional subsequent scan or death (whichever comes first) as defined 
Table 3. All scans will be read centrally (Section 5.1.1).
Patients in Treatment Arms 1 and 2 who discontinue study treatment for unconfirmed 
progression should also continue to have tumor evaluation scans performed q6w±1 week for 
the first 12 weeks (relative to the date of randomization), and then q8w±1 week thereafter 
until confirmed objective disease progression or death (whichever comes first) as defined in 
Table 3.  All scans will be read centrally (Section 5.1.1).
All procedures to be conducted during the follow-up period will be performed according to 
the assessment schedule (see Table 3).
Whenever vital signs, 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 (eg, PK blood 
sample) to occur at the timepoints indicated in Table 3.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
98(225)
All patients will be followed for survival until the end of the study. The schedule of study 
procedures for patients in long-term follow up is presented in Table 12, Table 13 in Section 
9.3 Study timetable and end of study.
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 will ensure 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
The dual primary aims of this study are to assess the efficacy of durvalumab monotherapy + 
SoC chemotherapy compared with SoC chemotherapy alone in terms of PFS and OS in all 
patients. Efficacy assessments of PFS, APF12, DoR, BoR, and ORR will be derived (by 
AstraZeneca) using BICR assessments according to RECIST 1.1. A sensitivity analysis of 
PFS and OS will be performed using Investigator assessments. Secondary objectives will 
include OS and PFS of durvalumab + tremelimumab combination therapy + SoC 
chemotherapy compared with SoC chemotherapy as well as APF12, DoR, BoR, ORR and 
PFS2. 
Tumor evaluations utilize images from CT [preferred] or MRI, each preferably with IV 
contrast, of the chest and abdomen (including the entire liver and both adrenal glands), 
collected during screening/baseline and at selected timepoints during the 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 E) 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 the date of randomization and ideally should be performed as close as 
possible to and prior to the date of randomization.  The RECIST 1.1 assessments of baseline
images identify target lesions (TLs [defined as measurable]) and non-target lesions (NTLs), 
and each lesion (and any new lesion) is evaluated in subsequent, on-treatment follow-up 
images.  This allows the determination of follow-up TL response, NTL response, New 
Lesions, and overall timepoint tumor responses (complete response [CR], partial response 
[PR], stable disease [SD], progressive disease [PD], or not evaluable [NE]).
5.1.1
Central reading of scans
All images, including unscheduled visit scans, will be collected on an ongoing basis and sent 
to an AstraZeneca-appointed imaging Contract Research Organization for quality 
control (QC) and storage.  A BICR of images will be performed at the direction of 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
99(225)
AstraZeneca.  Results of these independent reviews will not be communicated to 
Investigators, and the management of patients will be based solely upon the results of the 
RECIST 1.1 assessment conducted by the Investigator.  The BICR of all radiological scans 
will be performed to derive the ORR, PFS, DoR, BoR, and APF12 endpoints according to 
RECIST 1.1. The BICR will include assessment by RECIST 1.1 and 
  Only 
Investigator assessments will be captured in the RAVE system in RECIST folders. 
5.1.2
Survival assessments
Assessments for survival must be made at Months 2, 3, and 4, and then every 2 months 
(8 weeks±2 weeks) following treatment discontinuation.  Survival information may be 
obtained via telephone contact with the patient or the patient’s family, or by contact with the 
patient’s current physician.  These assessments must be performed even if the patient begins 
another therapy to treat their NSCLC.  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 analyses to provide complete 
survival data.  These contacts should generally occur within 7 days of the data cut-off.  
Survival assessments may continue as per protocol (every 2 months) post the final analysis of 
OS for superiority.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken at the times indicated in the assessment schedules and as clinically indicated (see 
Table 2 and Table 3). 
Clinical laboratory safety tests, including serum/urine pregnancy tests (on women of 
childbearing potential), thyroid-stimulating hormone, free triiodothyronine, and free 
thyroxine, according to Table 2 and Table 3, 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.  Clinically 
significant abnormal 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 (Table 2 and Table 3).  
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.  
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
100(225)
The laboratory variables to be measured are presented in Table 4 (clinical chemistry), Table 5
(hematology), and Table 6 (urinalysis).
Other safety tests to be performed at screening will include assessment for HbsAg, HCV 
antibodies, and HIV antibodies.
The following laboratory variables will be measured:
Table 4
Clinical chemistry
Albumin
Lipaseb
Alkaline phosphatasea
Magnesiumc
ALTa
Potassium
Amylaseb
Sodium
ASTa
Total bilirubina
Bicarbonatec
Total protein
Calcium
TSHe
Chloridec
T3 freef (reflex)
Creatinined
T4 freef (reflex)
Gamma-glutamyl transferasec
Urea or blood urea nitrogen, depending on local practice
Glucose
Lactate dehydrogenase
a
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently.  
If total bilirubin is ≥2 × upper limit of normal (and no evidence of Gilbert’s syndrome), then the fractions of 
direct and indirect bilirubin should be determined.
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-glutamyl transferase, and magnesium 
testing are to be performed at baseline and on Day 1 (unless all screening laboratory clinical chemistry 
assessments are performed within 3 days prior to Day 1), and if clinically indicated.
d
Creatinine Clearance will be calculated by derivation (data management) using Cockcroft-Gault (using 
actual body   weight).
e
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at 
day 1.
f
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE 
related to the endocrine system.
ALT - Alanine aminotransferase; AST - Aspartate aminotransferase; T3 - Triiodothyronine; T4 - Thyroxine; 
TSH - Thyroid-stimulating hormone.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
101(225)
Table 5
Hematology
Absolute lymphocyte counta
Hemoglobin
Absolute neutrophil counta
Platelet count
Absolute eosinophil counta
Total white blood cell count
Note: For coagulation parameters, activated partial thromboplastin time and international normalized ratio are to 
be assessed at baseline on Day 1 (unless all screening laboratory hematology assessments are performed 
within 3 days prior to Day 1), and as clinically indicated. 
a
Can be recorded as absolute counts or as percentages. Absolute counts will be calculated by data 
management if entered as percentage. Total white cell count therefore has to be provided.
Table 6
Urinalysis
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 D for further instructions on cases of increases in liver biochemistry and evaluation 
of Hy’s Law.  These cases should be reported as SAEs if, after evaluation, they meet the 
criteria for a Hy’s Law case or if any of the individual liver function test parameters fulfill any 
of the SAE criteria.  
All patients should have further hematology and clinical chemistry profiles performed at 
28 days (±3 days), 2 months (±1 week), and 3 months (±1 week) after permanent 
discontinuation of IP (see Table 3).
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF.  Situations in which laboratory safety results should be 
reported as AEs are described in Section 6.3.7.
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from study treatment 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 (Table 2 and 
Table 3).  Full physical examinations will include assessments of the head, eyes, ears, nose, 
and throat, and the respiratory, cardiovascular, gastrointestinal, urogenital, musculoskeletal, 
neurological, dermatological, hematologic/lymphatic, and endocrine systems.  Height will be 
measured at screening only.  Targeted physical examinations are to be utilized by the 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
102(225)
Investigator on the basis of clinical observations and symptomatology.  Situations in which 
physical examination results should be reported as AEs are described in Section 6.3.6.
5.2.3
Electrocardiogram
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study (see Table 2).  ECGs should be obtained after the patient has been in a supine position 
for 5 minutes and recorded while the patient remains in that position. 
In case of clinically significant ECG abnormalities, including a QT interval corrected for heart 
rate using Fridericia’s formula (QTcF) value >470 ms, 2 additional 12-lead ECGs should be 
obtained over a brief period (eg, 30 minutes) to confirm the finding.  
Situations in which ECG results should be reported as AEs are described in Section 6.3.7.
5.2.4
Vital signs
Vital signs (blood pressure [BP], pulse rate, temperature, and respiration rate) will be 
evaluated according to the assessment schedules (Table 2 and Table 3).  Body weight is also 
recorded at each visit along with vital signs.
First infusion
On the first infusion day, patients in Treatment Arms 1 and 2 will be monitored and vital signs 
will be collected/recorded in the eCRF prior to, during, and after infusion of IP as presented in 
the bulleted list below.  Patients in Treatment Arm 3 will be monitored pre-dose and as 
clinically indicated before every infusion or administration.  
BP, pulse rate, temperature and respiratory rate will be collected from patients in Treatment 
Arms 1 and 2 prior to, during, and after each infusion at the following times (based on a 60-
minute infusion):
∀
Prior to the beginning of each infusion (measured once from approximately 
30 minutes before up to 0 minutes [ie, the beginning of the infusion]) 
∀
Approximately 30 minutes during the infusion (halfway through infusion) 
∀
At the end of the infusion (after approximately 60 minutes ±5 minutes)
If the infusion takes longer than 60 minutes, then BP and pulse rate measurements should 
follow the principles as described above or be taken more frequently if clinically indicated.  A 
1-hour observation period is recommended after the first infusion of durvalumab and 
tremelimumab.  Additional monitoring with assessment of vital signs will be at the discretion 
of the Investigator per standard clinical practice or as clinically indicated.  
Subsequent infusions
BP, pulse rate, and other vital signs should be measured and collected/recorded in the eCRF 
prior to the start of the every subsequent infusion.  Patients should be carefully monitored, and 
BP and other vital signs should be measured during and after infusion as per institution 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
103(225)
standard and as clinically indicated. Any clinically significant changes in vital signs should be 
entered onto an unscheduled vital signs eCRF.
Situations in which vital signs results should be reported as AEs are described in 
Section 6.3.7.  For any AEs of infusion reactions, please enter the vital signs values into the 
eCRF.
5.2.5
Early patient review for safety
Patients will be evaluated 7 days after the first dose of each cycle of chemotherapy across all 
treatment arms to ensure early identification and management of toxicities.  It is strongly 
recommended for any patient experiencing Grade 3 or 4 neutropenia that granulocyte 
colony-stimulating factor is administered according to local practice.
5.2.6
WHO/ECOG performance status
WHO/ECOG performance status will be assessed at the times specified in the assessment 
schedules (see Table 2 and Table 3) based on the following:
∀
0 = Fully active; able to carry out all usual activities without restrictions
∀
1 = Restricted in strenuous activity, but ambulatory and able to carry out light work 
or work of a sedentary nature (eg, light housework or office work)
∀
2 = Ambulatory and capable of self-care, but unable to carry out any work 
activities; up and about more than 50% of waking hours
∀
3 = Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours
∀
4 = Completely disabled; unable to carry out any self-care and totally confined to 
bed or chair
∀
5 = Dead
Any significant changes from baseline or screening must be reported as an AE.
5.2.7
Other safety assessments
If new or worsening pulmonary symptoms (eg, dyspnea) 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 6.9.1), will be applied.  The results of the full diagnostic workup (including 
high-resolution computed tomography (HRCT) scans, blood and sputum culture, 
hematological parameters, etc) will be captured in the eCRF.  It is strongly recommended to 
perform a full diagnostic workup, to exclude alternative causes such as lymphangitic 
carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage.  In the 
presence of confirmatory HRCT scans where other causes of respiratory symptoms have been 
excluded, a diagnosis of pneumonitis (ILD) should be considered and the Dosing Modification 
and Toxicity Management Guidelines should be followed.  

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
104(225)
Pneumonitis/ILD investigation
The following assessments, and additional assessments if required, will be performed to 
enhance the investigation and diagnosis of potential cases of pneumonitis.  The results of the 
assessment will be collected.
∀
Physical examination
!
Signs and symptoms (cough, shortness of breath, and pyrexia, etc.), including 
auscultation for lung field will be assessed.
∀
SpO2
!
Saturation of peripheral oxygen (SpO2)
∀
Other items
!
When pneumonitis/ILD is suspected during study treatment, the following 
markers should be measured, where possible:
(i)
ILD markers (KL-6, SP-D) and β-D-glucan
(ii) Tumor markers: particular tumor markers which are related to disease 
progression
(iii) Additional clinical chemistry: C-reactive protein, lactate dehydrogenase
5.3
Other assessments
5.3.1
Clinical outcome assessments/patient-reported outcomes
Patient-reported outcomes (PRO) is an umbrella term referring to all outcomes and symptoms 
that are directly reported by the patient.  PROs have become a significant endpoint when 
evaluating effectiveness of treatments in clinical studies.  The following PROs will be 
administered in this study: EORTC QLQ-C30 v3 (core questionnaire), EORTC QLQ-LC13 
(lung cancer module),
 
 
(see Appendix F).
The PRO instruments will be completed by the patients using a handheld electronic 
patient-reported outcome (ePRO) device.  All assessments should be completed without 
assistance from anyone according to the assessment schedules (see Table 2 and Table 3).  It 
will take approximately 30 minutes for patients to complete the questionnaires; therefore, the 
burden to the patient should be moderate.
5.3.1.1
EORTC QLQ-C30
The EORTC QLQ-C30 v3 questionnaire is included for the purpose of assessing HRQoL and 
is a well-established measure of HRQoL/health status and is commonly used as an endpoint in 
cancer clinical studies.  It assesses HRQoL/health status through 9 multi-item scales: 
5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales 
(fatigue, pain, and nausea and vomiting), and a global health and quality of life (QoL) scale.  
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
105(225)
It also includes 6 single-item symptom measures: dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties (see Appendix F).  For each of the 
15 domains, final scores are transformed such that they range from 0 to 100, where higher 
scores indicate greater functioning, greater HRQoL, or greater level of symptoms 
(Aaronson et al 1993).
5.3.1.2
EORTC QLQ-LC13
For patients with NSCLC, a disease-specific 13-item self-administered questionnaire for lung 
cancer was developed (EORTC QLQ-LC13; Appendix F) to be used in conjunction with the 
EORTC QLQ-C30 (Bergman et al 1994).  It comprises both multi-item and single-item 
measures of lung cancer-associated symptoms (ie, coughing, hemoptysis, dyspnea, and pain) 
and treatment-related symptoms from conventional chemotherapy and radiotherapy (ie, hair 
loss, neuropathy, sore mouth, and dysphagia).  Similar to the EORTC QLQ-C30, all questions 
except 1 have a 4-point scale: “not at all,” “a little,” “quite a bit,” and “very much”.  One 
question (no. 43: “Did you take any medicine for pain?”) has a response option of “yes” or 
“no.”  The scoring approach for the EORTC QLQ-LC13 is similar to the EORTC QLQ-C30.
5.3.1.3
 
5.3.1.4
5.3.1.5
CCI
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
106(225)
5.3.2
Administration of the patient-reported outcome questionnaires
Patients will complete the PRO assessments by using an electronic tablet (ePRO) during clinic 
visits.
Each center must allocate the responsibility for the administration of the PRO instruments to a 
specific individual (eg, a research nurse or study coordinator) and, if possible, assign a 
back-up person to cover if that individual is absent.  The PRO questionnaires must be 
administered and completed at the clinic as per the schedule of assessments.  The PRO 
questionnaires will be administered on the days specified in the schedules of assessments (see 
Table 2 and Table 3).  The EORTC QLQ-C30 should always be completed prior to the 
EORTC QLQ-LC13 module.
It is important that the significance and relevance of the data are explained carefully to 
participating patients so that they are motivated to comply with data collection.  The following 
best practice guidelines should be followed when collecting PRO data via an electronic 
device:
∀
It is preferred that PRO questionnaires are completed prior to any other study 
procedures (following informed consent) and before discussion of disease 
progression to avoid biasing the patient’s responses to the questions.
∀
PRO questionnaires must be completed in private by the patient.
∀
Patients should be given sufficient time to complete the PRO questionnaires at their 
own speed.
∀
The research nurse or appointed site staff should stress that the information is 
confidential.  Therefore, if the patient has any medical problems, he or she should 
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
107(225)
discuss them with the doctor or research nurse separately from the ePRO 
assessment.
∀
The research nurse or appointed site staff must train the patient on how to use the 
ePRO device using the materials and training provided in the ePRO device.  The 
research nurse or appointed site staff must remind patients that there are no right or 
wrong answers and avoid introducing bias by not clarifying items.  The patient 
should not receive help from relatives, friends, or clinic staff to answer the PRO 
questionnaires. 
5.3.3
5.4
Pharmacokinetics
5.4.1
Collection of samples 
Blood samples for determination of gemcitabine, abraxane, durvalumab, and tremelimumab 
concentrations in serum or plasma will be obtained according to the assessment schedules (see 
Table 2 and Table 3).  Samples for gemcitabine and abraxane PK determination will be 
collected from selected sites only and will include approximately 12 patients per treatment 
arm dosed with abraxane and carboplatin and approximately 12 patients per treatment arm 
dosed with either gemcitabine regimen (approximately 6 patients per gemcitabine + cisplatin 
and approximately 6 patients per gemcitabine + carboplatin).  AstraZeneca will inform the 
selected sites once this requirement has been fulfilled.
Blood samples for determination of durvalumab and tremelimumab concentrations in serum 
will be obtained according to the assessment schedules (see Table 2 and Table 3).  Note that 
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
108(225)
for patients in Treatment Arms 1 and 2, the 3-month (90-day) follow-up samples for each 
molecule are relative to the respective last dose: 
∀
Treatment Arm 1: The tremelimumab PK sample will be collected 3 months after 
the last tremelimumab dose. 
∀
Treatment Arms 1 and 2: The durvalumab PK sample will be collected 3 months 
after the last durvalumab dose.
Samples for determination of durvalumab and tremelimumab concentrations 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.  
5.4.1.1
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 3). 
Samples will be measured for the presence of ADAs and ADA neutralizing antibodies for 
both IPs (durvalumab and tremelimumab) using validated assays.  
ADA for tremelimumab will be assessed for Treatment Arm 1 patients only; ADA for 
durvalumab will be assessed for Treatment Arms 1 and 2 patients only.  
Note that for patients in Treatment Arms 1 and 2, the 3-month (90-day) follow-up samples for 
each molecule are relative to the respective last dose: 
∀
A sample to look for antibodies to tremelimumab will be taken 90 days±7 days after 
the last dose of tremelimumab.  
∀
A sample to look for antibodies to durvalumab will be taken 90 days±7 days after 
the last dose of durvalumab.  
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. 
5.4.1.2
Storage and destruction of pharmacokinetic/ADA samples
Durvalumab and tremelimumab PK and ADA samples will be disposed after a maximum of 
15 years after the IPs are approved for marketing.  SoC PK samples will be disposed after a 
maximum of 15 years from the end of study.
PK and ADA samples may be disposed of or destroyed or anonymized by pooling.  Additional 
analyses may be conducted on the anonymized, pooled PK samples to further evaluate and 
validate the analytical method.  Results from such analyses may be reported separately from 
the clinical study report (CSR).  

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
109(225)
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will be reported separately in a 
Bioanalytical Validation Report and not in the CSR.
 
For China: PK and ADA samples collected in China will be stored and disposed according to 
local laws and regulations. PK and ADA samples collected in China will be destroyed after 
finalization of bioanalytical report or completion of CSR.
5.5
Biomarkers Analysis
By participating in this study, the patient is mandatorily consenting to the collection and use 
of donated biological samples as described here.  Tumor tissue samples will be obtained from 
all screened patients.  
 
 Samples will be obtained according to the 
assessment schedules provided in Table 2 and Table 3.
Details for collection, volumes, storage, and shipment of biologic samples are presented 
separately in the Laboratory Manual.
All samples collected for biomarker analyses will be stored at the study site, a reference 
laboratory, or at AstraZeneca facilities and may be used for subsequent research relevant to 
evaluating biological and/or clinical response to immunotherapy.
The results may be pooled with biomarker data from other durvalumab and 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 provisions of tissue to be used for determination of 
eligibility.  There is 1 subsequent mandatory provision of tissue at progression if retreatment 
is planned (Treatment Arm 1).
∀
MANDATORY: Provision of a tumor biopsy that is 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.
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
110(225)
!
When tissue is newly obtained for the purpose of entry into this study, 3 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 and TMB analyses (see the Laboratory 
Manual). Tumor tissue block is preferred. If a tissue block is unavailable, 20 
unstained sections from the tissue block may be submitted. Please consult the 
Laboratory Manual for specific instructions and guidelines regarding sample 
collection and handling. Newly acquired or archived specimens with limited 
tumor content and fine-needle aspirates are inadequate for defining tumor 
PD-L1 status and TMB determination.
!
Tumor lesions used for fresh biopsies should not be the same lesions used as 
RECIST 1.1 TLs, unless there are no other lesions suitable for biopsy.  If a 
RECIST 1.1 TL is used for biopsy (preferably core needle biopsy), the lesion 
must be imaged after biopsy prior to randomization (see inclusion criterion 6). 
∀
MANDATORY: The collection of additional archived tumor tissue block 
(formalin-fixed and 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. Note: These samples will not be collected in China.
∀
MANDATORY: For patients in Treatment Arm 1, 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. Note: These 
samples will not be collected in China.
∀
 
 
∀
Additional tumor biopsies collected as part of clinical care (eg, for mixed responses 
or upon PD) can be submitted for further analysis. Note: These samples will not be 
collected in China.
See the Laboratory Manual for further details of requirements including sample QC and 
shipping.
 
 
 
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
111(225)
To meet the requirement of FDA approval of a companion diagnostic, sections of the tumor 
will be retained at Ventana or a Ventana-approved laboratory for potential additional studies, 
as requested by the FDA, to support potential test approval.
5.5.2
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
112(225)
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
113(225)
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.  The results of this biomarker research may be pooled with biomarker data from 
other studies involving durvalumab or tremelimumab to generate hypotheses to be tested in 
future research.
Note: Tumor samples collected in China 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 are not shipped, and no further 
samples will be taken from the patient unless agreed 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.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
114(225)
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.
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 AZ-assigned 
biobank and will be registered by the AstraZeneca Biobank Team during the entire life cycle.
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 or destroyed and the action is documented.  If samples have already been analyzed,
AstraZeneca is not obliged to destroy the results of this research. 
The Principal Investigator will perform the following:
∀
Ensure that AstraZeneca is immediately notified of the patient’s withdrawal of 
informed consent to the use of donated samples.
∀
Ensure that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of, or destroyed and the action is documented.
∀
Ensure that the organization(s) holding the samples is/are immediately informed 
about the withdrawn consent and that samples are disposed of or destroyed, the 
action is documented, and a copy is returned to the clinical study team for 
communication to the study site.
∀
Ensure that the patient and AstraZeneca are informed about the sample disposal.
AstraZeneca will ensure that the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and a copy is returned to clinical study team for communication to the study site.
5.6
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.
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
115(225)
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 
following or during exposure to a pharmaceutical product, whether or not considered causally 
related to the product.  An undesirable medical condition can be symptoms (eg, nausea, chest 
pain), signs (eg, tachycardia, enlarged liver), or the abnormal results of an investigation 
(eg, laboratory findings, 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 study 
treatment has been administered.
The term AE is used to include both SAEs and non-serious AEs.
For cases where it could be suspected that a tissue-derived medicine has been contaminated by 
a pathogen, information about any of the above conditions (including infection) should be 
collected.
6.2
Definitions of serious adverse event
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), which fulfils one or more of the following criteria:
∀
Results in death
∀
Is immediately life-threatening
∀
Requires in-patient hospitalization or prolongation of existing hospitalization 
∀
Results in persistent or significant disability/incapacity 
∀
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 durvalumab ± 
tremelimumab or SoC). 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 (for all arms) 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 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
116(225)
for all events, even if the events continue after the patient has discontinued study drug or the 
study 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)
∀
Date when the AE started and stopped
∀
Maximum CTCAE grade reported
∀
Changes in CTCAE grade (report only the maximum CTCAE grade for a calendar 
day)
∀
Whether the AE is serious or not
∀
Investigator causality rating against the IPs (yes or no)
∀
Action taken with regard to IPs
∀
Administration of treatment for the AE
∀
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 SAE
∀
Seriousness of criteria 
∀
Date of hospitalization
∀
Date of discharge
∀
Probable cause of death
∀
Date of death
∀
Whether an autopsy was performed
∀
Causality assessment in relation to study procedure(s)
∀
Causality assessment in relation to other medication, as explained in Section 6.3.4
∀
Description of SAE

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
117(225)
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 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 SAEs 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 
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.
6.3.4
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.
6.3.5
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 
(ie, SAEs that occur prior to the administration of IP) and treatment-emergent SAEs.  A 
protocol-related SAE may occur as a result of a procedure or intervention required during the 
study (eg, 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.
6.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study 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.  

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
118(225)
When collecting AEs, the recording of diagnoses is preferred when possible, to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
6.3.7
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 with 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 term rather than the laboratory term (eg, anemia versus 
low hemoglobin value).  In the absence of clinical signs or symptoms, clinically relevant 
deteriorations in non-mandated parameters should be reported as 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.
6.3.8
Hy’s law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need 
to be reported as SAEs.  Please refer to Appendix D for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s law.
6.3.9
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.
6.3.10
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 study treatment and have 
been identified after the patient’s inclusion in this study.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
119(225)
6.3.11
Deaths
All deaths that occur during the study treatment period, or within the protocol-defined 
follow-up period after the administration of the last dose of study treatment, 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 in the Statement of Death page.  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.  It should also be documented in the Statement of Death 
page in the eCRF.  The report should contain a comment regarding the 
co-involvement of PD, if appropriate, and should assign main and contributory 
causes of death.
∀
Deaths with an unknown cause should always be reported as an SAE.  It should also 
be documented in the Statement of Death page in the eCRF. A post-mortem may be
helpful in the assessment of the cause of death, and if performed, a copy of the 
post-mortem results should be forwarded to AstraZeneca Patient Safety or its 
representative within the usual timeframes.
Deaths occurring after the protocol defined safety follow-up period after the administration of 
the last dose of study drug should be documented in the Statement of Death page.  If the death 
occurred as a result of an event that started after 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.
6.3.12
Safety Data To Be Collected following the final DCO of the study
For patients continuing to receive durvalumab/tremelimumab treatment and/or SOC 
chemotherapy after final DCO and database closure, 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 durvalumab/tremelimumab in order to 
manage AEs in accordance with the durvalumab/tremelimumab toxicity management 
guidelines (TMG Annex) and per label information of chemotherapy.  All data post the final 
DCO and database closure will be recorded in the patient notes but, with the exception of 
Serious Adverse Events, will not otherwise be reported for the purposes of this study.
All SAEs that occur in patients still receiving durvalumab/tremelimumab treatment and/or 
SOC chemotherapy (or within the 90 days following the last dose of 
durvalumab/tremelimumabs treatment and/or SOC chemotherapy) post the final DCO and 
database closure must be reported as detailed in Section 6.4.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
120(225)
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s).  All SAEs will be recorded in the eCRF.
If any SAE occurs during the course of the study, then the Investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1 day, ie, immediately, but 
no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative 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, ie, 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 the SAE to the appropriate AstraZeneca representative by telephone.
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 
durvalumab and tremelimumab and the EU Summary of Product Characteristics for the active 
comparator product (including any AstraZeneca comparator).
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.
6.5
Treatment Arms 1 and 2 adverse events of special interest
An adverse event of special interest (AESI) is one of the scientific and medical interests 
specific to understanding the IP 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 IP.
AESIs for durvalumab ± tremelimumab include, but are not limited to, events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
121(225)
monitoring and/or interventions such as steroids, immunosuppressants, and/or hormone 
replacement therapy.  These AESIs are being closely monitored in clinical studies with 
durvalumab 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 etiology.  
Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to 
support an imAE diagnosis.  Appropriate efforts should be made to rule out neoplastic, 
infectious, metabolic, toxin, or other etiologic causes of the imAE. 
If the Investigator has any questions in regards to an AE being an imAE, the Investigator 
should promptly contact the Study Physician.
AESI/imAEs observed with anti PD-L/PD-1 agents such as durvalumab and durvalumab in 
combination with tremlimumab 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 
etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and other events 
involving the eye, skin, hematological, rheumatological events, vasculitis, non-infectious 
meningitis and non-infectious encephalitis. It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all organs
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology are also considered AESIs.
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the durvalumab and tremelimumab IB.  More specific guidelines for their 
evaluation and treatment are described in detail in the Dosing Modification and Toxicity 
Management Guidelines (please see Section 6.9.1 and TMG Annex.  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.  In the event of 
an AESI or suspected AESI, the AstraZeneca study team may request relevant clinical 
information (including images) for those patients who demonstrate the event and may request 
the independent review.  
6.6
Overdose
6.6.1
Durvalumab or tremelimumab
Use of durvalumab or tremelimumab 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 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
122(225)
overdose of durvalumab or tremelimumab, 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 during 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.
6.6.2
Standard of care
For patients randomized to the SoC (Treatment Arm 3) group, refer to the local prescribing 
information for treatment of cases of overdose.  If any overdose is associated with an AE or 
SAE, record the AE/SAE diagnosis or symptoms only in the relevant AE modules of the 
eCRF.
6.7
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:
∀
Pregnancy discovered before the study patient has received any study drugs.
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 
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.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
123(225)
If any pregnancy occurs during the course of the study, then the Investigator or other site 
personnel should inform the appropriate AstraZeneca representatives within 1 day, 
ie, immediately, but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative 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 durvalumab + tremelimumab combination therapy + SoC 
chemotherapy, 90 days after the last dose of durvalumab monotherapy + SoC chemotherapy, 
or 90 days after receipt of the final dose of durvalumab, 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 durvalumab + tremelimumab combination therapy, 90 days after the last dose of 
durvalumab monotherapy + SoC chemotherapy, or 90 days after the last dose of durvalumab 
monotherapy, 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
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 patient 
or has the potential to cause harm to the patient. 
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 patient.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
124(225)
Medication error includes situations where an error:
∀
Occurred;
∀
Was identified and intercepted before the patient received the drug;
∀
Did not occur, but circumstances were recognized that could have led to an error.
Examples of events to be reported in clinical studies as medication errors:
∀
Drug name confusion
∀
Dispensing error, eg, medication prepared incorrectly, even if it was not actually 
given to the patient
∀
Drug not administered as indicated, for example, wrong route or wrong site of 
administration
∀
Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as 
a solid tablet
∀
Drug not stored as instructed, eg, kept in the fridge when it should be at room 
temperature 
∀
Wrong patient received the medication (excluding IVRS/IWRS errors)
∀
Wrong drug administered to patient (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 that lead to one of 
the above-listed events that would otherwise have been a medication error
∀
Patient accidentally missed drug dose(s), eg, forgot to take medication
∀
Accidental overdose (will be captured as an overdose)
∀
Patient failed to return unused medication or empty packaging
∀
Errors related to background and rescue medication, or SoC medication in 
open-label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
If an 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 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 6.4) and within 30 days for all other medication errors.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
125(225)
6.9
Management of IP-related toxicities
The following general guidance should be followed for the management of toxicities (see 
TMG Annex):
∀
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.
∀
In the event that durvalumab ± tremelimumab is discontinued or delayed as part of 
the toxicity management guidance SoC may still be administered as scheduled.
All toxicities will be graded according to NCI CTCAE, Version 4.03.
6.9.1
Specific toxicity management and dose modification information - Durvalumab 
and durvalumab + tremelimumab
Comprehensive toxicity management guidelines (TMG) have been developed to assist 
investigators with the recognition and management of toxicities associated with the use of the 
immune-checkpoint inhibitors durvalumab [Medi4736] (PD-L1 inhibitor) <<and 
tremelimumab (CTLA-4 inhibitor)>.  Given the similar underlying mechanisms of toxicities 
observed with these two compounds, these guidelines are applicable to the management of 
patients receiving either drug as monotherapy or in combination.  Additionally, these 
guidelines are applicable when either drug is used alone or in combination and is administered 
concurrently or sequentially with other anti-cancer drugs (i.e. antineoplastic chemotherapy, 
targeted agents), as part of a protocol specific treatment regimen.  The TMGs provide 
information for the management of immune-mediated reactions, infusion-related reactions, 
and non-immune mediated reactions that may be observed with checkpoint inhibitor 
monotherapy or combination checkpoint inhibitor regimens, with specific instructions for dose 
modifications (including discontinuations) and treatment interventions.  Investigators are 
advised however to use local practice guidelines and consult local references for the 
management of toxicities observed with other cancer treatment The most current version of 
the TMGs entitled “Dosing Modification and Toxicity Management Guidelines for Immune-
Mediated, Infusion-Related, and Non-Immune Mediated Reactions (MEDI4736) Monotherapy 
or Combination Therapy with Tremelimumab or Tremelimumab Monotherapy” is provided to 
the investigative site as an Annex document and is maintained within the Site Master File. 
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE.  Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
126(225)
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 Dosing Modification and 
Toxicity Management Guidelines in TMG Annex).
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 in TMG Annex. 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 combination therapy regimen by the 
reporting Investigator.
Dose reductions are not permitted.  In case of doubt, the Investigator should consult with 
the Study Physician.
6.9.2
Standard of care agents
Chemotherapies are associated with a number of unwanted effects.  SoC-related toxicity 
management and dose adjustment, including dose delays and reductions, should be performed 
as indicated in the local prescribing information for the relevant agent.  In the event of 
unfavorable tolerability, patients can switch between cisplatin and carboplatin therapy at any 
point on study (assuming eligibility for the switched therapy is met).
In the event that an AE can reasonably be attributed to SoC, dose adjustment of SoC should be 
attempted before modifying the administration of durvalumab ± tremelimumab.
In the event that SoC is delayed, durvalumab ± tremelimumab should also be delayed.  Every 
effort should be made to ensure patients receive at least 4 cycles of SoC across all treatment 
arms in the study, if conditions allow.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational products
AstraZeneca will supply durvalumab (MEDI4736) and tremelimumab, while the SoC 
chemotherapies will be supplied locally (Table 7).  Under certain circumstances when local 
sourcing is not feasible, SoC treatment may be supplied centrally through AstraZeneca.
Table 7
List of investigational products for this study
Investigational product
Dosage form and strength
Durvalumab (MEDI4736)
50 mg/mL, solution for infusion after dilution
Tremelimumab
20 mg/mL, solution for infusion after dilution
Standard of care

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
127(225)
Abraxanea
IV (as sourced locally)
Carboplatina
IV (as sourced locally)
Cisplatina
IV (as sourced locally)
Gemcitabinea
IV (as sourced locally)
Pemetrexeda
IV (as sourced locally)
a
Under certain circumstances when local sourcing is not feasible, SoC treatment may be supplied centrally 
through AstraZeneca.
IV
Intravenous.
7.1.1
Order of administration
Treatment Arm 1: 
Patients will receive 1 dose of tremelimumab (75 mg) via IV infusion over 1 hour, which will 
be followed by durvalumab (MEDI4736; 1500 mg) via IV infusion over 1 hour, starting 
approximately 1 hour (maximum 2 hours) after the end of the tremelimumab infusion.
SoC chemotherapy will start approximately 1 hour (maximum 2 hours) after the end of the 
Durvalumab infusion.  
If there is no clinically significant concerns after the first cycle, then at the Investigator’s 
discretion, durvalumab (MEDI4736) can be given immediately after tremelimumab in 
subsequent cycles. 
If there is no clinically significant concerns after the first cycle, reducing the observation 
period after durvalumab (MEDI4736) administration to 30 minutes is recommended, at the 
Investigator’s discretion.
Immunotherapy administration will then be followed by SoC chemotherapy via IV infusion as 
indicated in Section 7.2.2.
Treatment Arm 2: 
Patients will receive durvalumab (MEDI4736; 1500 mg) via IV infusion over 1 hour.
SoC chemotherapy will start approximately 1 hour (maximum 2 hours) after the end of the 
Durvalumab infusion.  
If there is no clinically significany concerns after the first cycle, reducing the observation 
period after durvalumab (MEDI4736) administration to 30 minutes is recommended, at the 
Investigator’s discretion.
Immunotherapy administration will then be followed by SoC chemotherapy via IV infusion as 
indicated in Section 7.2.2.
Treatment Arm 3:
Patients will receive SoC chemotherapy via IV infusion as indicated in Section 7.2.2.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
128(225)
7.1.2
Durvalumab (MEDI4736)
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for 
infusion after dilution. The solution contains 50 mg/mL durvalumab (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.  The nominal fill volume is 
10.0 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 secondary packaging until use to prevent excessive 
light exposure.
Preparation of durvalumab (MEDI4736) doses for administration with an IV bag
The dose of durvalumab (MEDI4736) for administration must be prepared by the 
Investigator’s or site’s designated IP manager using aseptic technique. Total time from needle 
puncture of the durvalumab (MEDI4736) vial to the start of administration should not exceed:
∀
24 hours at 2°C to 8°C (36°F to 46°F)
∀
4 hours at room temperature
Infusion solution must be allowed to equilibrate to room temperature prior to commencement 
of administration.
A dose of 1500 mg (for patients >30 kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 20 mg/mL, and delivered through an IV administration set 
with a 0.2- or 0.22-μm in-line filter. Add 30.0 mL of durvalumab (MEDI4736) (ie, 1500 mg 
of durvalumab [MEDI4736]) to the IV bag. The IV bag size should be selected such that the 
final concentration is within 1 to 20 mg/mL. Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag.
If weight falls to ≤ 30 kg during the study, weight-based dosing at 20 mg/kg will be 
administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final 
durvalumab (MEDI4736) concentration ranging from 1 to 20 mg/mL, and delivered through 
an IV administration set with a 0.2- or 0.22-μm in-line filter.
Standard infusion time is 60 minutes (±5 minutes). In the event that there are interruptions 
during infusion, the total allowed infusion time should not exceed 8 hours at room 
temperature. 
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and document 
if the line was not flushed.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
129(225)
If either preparation time or infusion time exceeds the time limit, a new dose must be prepared 
from new vials.  Durvalumab (MEDI4736) does not contain preservatives, and any unused 
portion must be discarded.  
Preparations are to be in accordance with the study-specific drug handling instructions.
7.1.3
Tremelimumab 
Tremelimumab will be supplied by AstraZeneca as a 400-mg vial concentrate 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.  The nominal fill volume is 
20.0 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 secondary container until use to prevent excessive 
light exposure.
Preparation of tremelimumab doses for administration with an IV bag
The dose of tremelimumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique.  Total time from needle puncture of the 
tremelimumab vial to the start of administration should not exceed:
∀
24 hours at 2°C to 8°C (36°F to 46°F)
∀
4 hours at room temperature
Infusion solution must be allowed to equilibrate to room temperature prior to commencement 
of administration.
A dose of 75 mg (for patients >30 kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final tremelimumab concentration 
ranging from 0.10 to 10 mg/mL, and delivered through an IV administration set with a 0.2- or 
0.22-μm in-line filter.  Add 3.8 mL (ie, 75 mg of tremelimumab, with the dose volume 
rounded to the nearest 10th mL) to the IV bag.  The IV bag size should be selected such that 
the final concentration is within 0.10 to 10 mg/mL.  Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag.
If weight falls to  ≤ 30 kg during the study, weight-based dosing will be administered using an 
IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final tremelimumab 
concentration ranging from 0.10 to 10 mg/mL, and delivered through an IV administration set 
with a 0.2- or 0.22-μm in-line filter.
Standard infusion time is 60 minutes (±5 minutes).  Less than 55 minutes is considered a 
protocol deviation. In the event that there are interruptions during infusion, the total allowed 
infusion time should not exceed 8 hours at room temperature. 
Do not co-administer other drugs through the same infusion line. 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
130(225)
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and document 
if the line was not flushed.  
If either preparation time or infusion time exceeds the time limit, a new dose must be prepared 
from new vials.  Tremelimumab does not contain preservatives, and any unused portion must 
be discarded.
Preparations are to be in accordance with the study-specific drug handling instructions.
7.1.4
Standard of care
SoC chemotherapy will be locally sourced and will be administered according to prescribing 
information or treatment guidance in general use by the investigating site.  Under certain 
circumstances when local sourcing is not feasible, AstraZeneca will centrally source the drug, 
which will be labeled with text translated to local language in accordance with regulatory 
guidelines.
7.2
Dose and treatment regimens
Patients will be randomized in a 1:1:1 ratio to receive treatment q3w with durvalumab 
(MEDI4736) + tremelimumab combination therapy+ SoC chemotherapy, durvalumab 
(MEDI4736) monotherapy + SoC chemotherapy, or SoC chemotherapy alone in the ‘during 
chemotherapy’ phase.  During the ‘post-chemotherapy’ phase, patients in Treatment Arms 1 
and 2 receive durvalumab (MEDI4736) monotherapy q4w.  Non-squamous patients who 
received pemetrexed + carboplatin/cisplatin in the ‘during chemotherapy’ phase will receive 
pemetrexed maintenance therapy, unless contraindicated per the Investigator.  See Figure 5 for 
the dosing scheme.
The following are the definitions of the study treatment regimens in each treatment arm:
Treatment Arm 1: durvalumab (MEDI4736) + tremelimumab combination therapy + SoC 
chemotherapy
Treatment Arm 2: durvalumab (MEDI4736) monotherapy + SoC chemotherapy
Treatment Arm 3: SoC chemotherapy alone
During the ‘post-chemotherapy’ phase of the study, patients in Treatment Arms 1 and 2 will 
receive durvalumab (MEDI4736) monotherapy until disease progression.  See Section 7.2.2
for the duration of treatments and criteria for treatment through progression and retreatment.
7.2.1
Treatment regimens
Standard of care chemotherapy: Patients will receive 1 of the following SoC regimens as 
part of their treatment regimen:

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
131(225)
∀
Abraxane + carboplatin (squamous and non-squamous patients): Abraxane 
100 mg/m2 on Days 1, 8, and 15 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 (ie, 4 cycles for 
Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3).
∀
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 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles 
(ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3).
∀
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 
(ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3).
∀
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 (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment 
Arm 3); then continue pemetrexed 500 mg/m2 maintenance (i.e., q4w for Treatment 
Arms 1 and 2. For Treatment Arm 3, Pemetrexed maintenance therapy can be given 
either q3w or q4w dependent on Investigator decision and local standards) until 
objective disease progression, unless contraindicated per the Investigator.  
∀
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 
(ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3); 
then continue pemetrexed 500 mg/m2 maintenance (i.e., q4w for Treatment Arms 1 
and 2. For Treatment Arm 3, Pemetrexed maintenance therapy can be given either 
q3w or q4w dependent on Investigator decision and local standards) until objective 
disease progression, unless contraindicated per the Investigator.  
Treatment Arm 1: Durvalumab (MEDI4736) + tremelimumab combination therapy 
+ SoC chemotherapy 
During chemotherapy
NSCLC type
Agent and dose
Route
Duration
Schedule
Squamous and 
non-squamous 
patients
Durvalumab (MEDI4736; 
1500 mg)
IV
60 min
4 doses q3w 
Weeks 0, 3, 6, and 9
Squamous and 
non-squamous 
patients
Tremelimumab (75 mg)
IV
60 min
4 doses q3w 
Weeks 0, 3, 6, and 9
Squamous and 
non-squamous 
patients
SoC (abraxane 
[100 mg/m2] with 
carboplatin [AUC 5 or 6])
IV
Days 1, 8, and 15 of each 21-day 
cycle (abraxane) and on Day 1 of 
each 21-day cycle (carboplatin) for 
4 cycles

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
132(225)
NSCLC type
Agent and dose
Route
Duration
Schedule
Squamous patients 
only
SoC (gemcitabine 
[1000 mg/m2 or 
1250 mg/m2] with 
cisplatin [75 mg/m2])
IV
Days 1 and 8 of each 21-day cycle 
(gemcitabine) and on Day 1 of 
each 21-day cycle (cisplatin) for 
4 cycles
Squamous patients 
only
SoC (gemcitabine 
[1000 mg/m2 or 
1250 mg/m2] with 
carboplatin [AUC 5 or 6])
IV
Days 1 and 8 of each 21-day cycle 
(gemcitabine) and on Day 1 of 
each 21-day cycle (carboplatin) for 
4 cycles
Non-squamous 
patients only
SoC (pemetrexed 
[500 mg/m2] with 
carboplatin [AUC 5 or 6])
IV
Day 1 of each 21-day cycle for 
4 cycles
Non-squamous 
patients only
SoC (pemetrexed 
[500 mg/m2] and cisplatin 
[75 mg/m2])
IV
Day 1 of each 21-day cycle for 
4 cycles
Note: Patients whose weight falls to 30 kg or below should receive weight-based dosing—equivalent to 
20 mg/kg of durvalumab and 1 mg/kg of tremelimumab q3w until the weight improves to >30 kg, at 
which point the patient should start receiving the fixed dosing of durvalumab at 1500 mg and 
tremelimumab at 75 mg. 
Note: If there is a dosing delay during chemotherapy while on the q3w schedule, all future dosing days should 
be delayed to ensure that the intervals between dosing study treatment are always at least 21 days.  
AUC Area under the curve; IV Intravenous; q3w Every 3 weeks; SoC Standard of care.
Post-chemotherapy
Agent
Dose
Route
Duration
Schedule
Durvalumab 
(MEDI4736)
1500 mg
IV
60 min
q4w 
Week 12 to PDa
Tremelimumab
75 mg 
IV
60 min
1 dose at Week 16b
Pemetrexedc
500 mg/m2
IV
q4w
Week 12 to PDd
a
Patients are treated until clinical progression or radiological progression unless there is unacceptable 
toxicity, withdrawal of consent, or another discontinuation criterion is met.  For criteria for treatment 
through progression and for retreatment with the combination, see Section 7.2.2.2.
b
For patients in Treatment Arm 1, an additional dose of durvalumab + tremelimumab will be given at 
Week 16 post-chemotherapy.  In the case of dose delay(s), more than 1 durvalumab + tremelimumab 
combination dose can be given at and after Week 16 post-chemotherapy to ensure that up to 
5 combination doses are administered in Treatment Arm 1.  If patients receive fewer than 4 cycles of 
platinum doublet chemotherapy, the remaining cycles of combined durvalumab/tremelimumab (up to a 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
133(225)
total of 5) should be given after combination of platinum doublet chemotherapy (with maintenance 
pemetrexed, if applicable).
c
Non-squamous patients who received carboplatin/cisplatin + pemetrexed and who have not progressed 
after 4 cycles of carboplatin/cisplatin + pemetrexed will receive pemetrexed maintenance therapy, unless 
contraindicated per the Investigator.
d
Patients are treated until clinical progression or RECIST1.1 defined radiological progression unless there 
is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.
Note: Patients whose weight falls to 30 kg or below should receive weight-based dosing-equivalent to 20 mg/kg 
of durvalumab and 1 mg/kg of tremelimumab q4w until the weight improves to >30 kg, at which point the 
patient should start receiving the fixed dosing of durvalumab at 1500 mg and tremelimumab at 75 mg.
IV
Intravenous; NSCLC Non-small-cell lung cancer; PD Progressive disease; q4w Every 4 weeks.
Note: Dose reductions of durvalumab (MEDI4736) and tremelimumab are not 
permitted.
Treatment Arm 2: Durvalumab (MEDI4736) monotherapy + SoC chemotherapy
During chemotherapy
NSCLC type
Agent and dose
Route
Duration
Schedule
Squamous and 
non-squamous 
patients
Durvalumab (MEDI4736; 
1500 mg)
IV
60 min
4 doses q3w 
Weeks 0, 3, 6, and 9
Squamous and 
non-squamous 
patients
SoC (abraxane [100 mg/m2] 
with carboplatin [AUC 5 or 
6])
IV
Days 1, 8, and 15 of each 21-
day cycle (abraxane) and on 
Day 1 of each 21-day cycle 
(carboplatin) for 4 cycles
Squamous patients 
only
SoC (gemcitabine 
[1000 mg/m2 or 
1250 mg/m2] with cisplatin 
[75 mg/m2])
IV
Days 1 and 8 of each 21-day 
cycle (gemcitabine) and on 
Day 1 of each 21-day cycle 
(cisplatin) for 4 cycles
Squamous patients 
only
SoC (gemcitabine 
[1000 mg/m2 or 
1250 mg/m2] with 
carboplatin [AUC 5 or 6])
IV
Days 1 and 8 of each 21-day 
cycle (gemcitabine) and on 
Day 1 of each 21-day cycle 
(carboplatin) for 4 cycles
Non-squamous 
patients only
SoC (pemetrexed [500 
mg/m2] with carboplatin 
[AUC 5 or 6])
IV
Day 1 of each 21-day cycle for 
4 cycles
Non-squamous 
patients only
SoC (pemetrexed 
[500 mg/m2] and cisplatin 
[75 mg/m2])
IV
Day 1 of each 21-day cycle for 
4 cycles
Note: Patients whose weight falls to 30 kg or below should receive weight-based dosing-equivalent to 20 mg/kg 
of durvalumab q3w until the weight improves to >30 kg, at which point the patient should start receiving 
the fixed dosing of durvalumab at 1500 mg. 
Note: If there is a dosing delay during chemotherapy while on the q3w schedule, all future dosing days should 
be delayed to ensure that the intervals between dosing study treatment are always at least 21 days.  
IV
Intravenous; NSCLC Non-small-cell lung cancer; q3w Every 3 weeks; SoC Standard of care.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
134(225)
Post-chemotherapy
Agent
Dose
Route
Duration
Schedule
Durvalumab 
(MEDI4736)
1500 mg
IV
60 min
q4w 
Week 12 to PDa
Pemetrexedb
500 mg/m2
IV
q4w
Week 12 to PDc
a
Patients are treated until clinical progression or radiological progression unless there is unacceptable 
toxicity, withdrawal of consent, or another discontinuation criterion is met.  For criteria for treatment 
through progression, see Section 7.2.2.2.
b
Non-squamous patients who received carboplatin/cisplatin + pemetrexed and who have not progressed 
after 4 cycles of carboplatin/cisplatin + pemetrexed will receive pemetrexed maintenance therapy, unless 
contraindicated per the Investigator.
c
Patients are treated until clinical progression or RECIST1.1 defined radiological progression unless there 
is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.
Note: Patients whose weight falls to 30 kg or below should receive weight-based dosing—equivalent to 
20 mg/kg of durvalumab q4w until the weight improves to >30 kg, at which point the patient should start 
receiving the fixed dosing of durvalumab at 1500 mg. 
IV
Intravenous; PD Progressive disease; q4w Every 4 weeks.
Note: Dose reductions of durvalumab (MEDI4736) are not permitted.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
135(225)
Treatment Arm 3: SoC chemotherapy alone
NSCLC type
Agent and dose
Route
Duration
Schedule
Squamous and 
non-squamous 
patients 
SoC (abraxane [100 mg/m2] 
with carboplatin [AUC 5 or 
6])
IV
Days 1, 8, and 15 of each 21-
day cycle (abraxane) and on 
Day 1 of each 21-day cycle 
(carboplatin) for 4 cyclesa
Squamous patients 
only
SoC (gemcitabine 
[1000 mg/m2 or 
1250 mg/m2] with cisplatin 
[75 mg/m2])
IV
Days 1 and 8 of each 21-day 
cycle (gemcitabine) and on 
Day 1 of each 21-day cycle 
(cisplatin) for 4 cyclesa
Squamous patients 
only
SoC (gemcitabine 
[1000 mg/m2 or 
1250 mg/m2] with 
carboplatin [AUC 5 or 6])
IV
Days 1 and 8 of each 21-day 
cycle (gemcitabine) and on 
Day 1 of each 21-day cycle 
(carboplatin) for 4 cyclesa
Non-squamous 
patients only
SoC (pemetrexed 
[500 mg/m2] with 
carboplatin [AUC 5 or 6])b
IV
Day 1 of each 21-day cycle for 
4 cyclesa
Non-squamous 
patients only
SoC (pemetrexed 
[500 mg/m2] and cisplatin 
[75 mg/m2])b
IV
Day 1 of each 21-day cycle for 
4 cyclesa
a
An additional 2 doses of SoC (Weeks 12 and 15) can be given at the Investigator’s discretion, if clinically 
indicated.  
b
Non-squamous patients who received carboplatin/cisplatin + pemetrexed and who have not progressed 
after 4 to 6 cycles of carboplatin/cisplatin + pemetrexed will receive pemetrexed maintenance therapy can 
be given q3w or q4w, dependent on Investigator decision and local standards, unless contraindicated per 
the Investigator. Note: RECIST 1.1 assessment should be performed at Week 12 ±1 week from the date of 
randomization, and then q8w±1 week thereafter until radiological progression (regardless of whether it
chosen q3w or q4w).
Note: Patients who receive extra cycles of SoC will still be expected to follow the planned scan schedule visits 
as detailed in Table 2 and Table 3. 
Note: If there is a dosing delay during chemotherapy while on the q3w schedule, all future dosing days should 
be delayed to ensure that the intervals between dosing study treatment are always at least 21 days.  
IV
Intravenous; NSCLC Non-small-cell lung cancer; q3w Every 3 weeks; q4w Every 4 weeks; 
SoC Standard of care.
The full dosing scheme is provided below in Figure 5.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
136(225)
Figure 5
Dosing scheme
Treatment arms
During chemotherapy
1 cycle=3 weeks (21 days)
Post-chemotherapy
1 cycle=4 weeks (28 days)
Cycle 1
Week 0
Cycle 2
Week 3
Cycle 3
Week 6
Cycle 4
Week 9
Week 12
Week 16
Week 20 to PD
Durva + Treme + SoC 
(Treatment Arm 1)
Durva + Treme 
+ SoC
Durva + Treme 
+ SoC
Durva + Treme 
+ SoC
Durva + Treme 
+ SoC
Durva + 
Pemetrexed 
Maintenancea
Durva + Tremeb
Pemetrexed 
Maintenancea
Durva + 
Pemetrexed 
Maintenancea
Durva + SoC
(Treatment Arm 2)
Durva + SoC
Durva + SoC
Durva + SoC
Durva + SoC
Durva + 
Pemetrexed 
Maintenancea
Durva + 
Pemetrexed 
Maintenancea
Durva + 
Pemetrexed 
Maintenancea
SoC 
(Treatment Arm 3)
SoC
SoC
SoC
SoCc
Pemetrexed 
Maintenancea
Pemetrexed 
Maintenancea
Pemetrexed 
Maintenancea
a
Pemetrexed maintenance therapy is for non-squamous NSCLC patients who received treatment with pemetrexed and carboplatin/cisplatin during 
chemotherapy and did not progress after 4 to 6 cycles, unless contraindicated per the Investigator. Pemetrexed maintenance therapy can be given q3w 
or q4w (i.e., q4w for Treatment Arms 1 and 2. For Treatment Arm 3, Pemetrexed maintenance therapy can be given either q3w or q4w dependent on 
Investigator decision and local standards). Note: RECIST 1.1 assessment should be performed at Week 12 ±1 week from the date of randomization, 
and then q8w±1 week thereafter until radiological progression (regardless of whether it chosen q3w or q4w).
b
For patients in Treatment Arm 1, an additional dose of durvalumab + tremelimumab will be given at Week 16 post-chemotherapy.  In the case of dose 
delay(s), more than 1 durvalumab + tremelimumab combination dose can be given at and after Week 16 post-chemotherapy to ensure that up to 
5 combination doses are administered in Treatment Arm 1.  If patients receive fewer than 4 cycles of platinum doublet chemotherapy, the remaining 
cycles of combined durvalumab/tremelimumab (up to a total of 5) should be given after combination of platinum doublet chemotherapy (with 
maintenance pemetrexed, if applicable).
c
In Treatment Arm 3, SoC chemotherapy can be given for an additional 2 cycles q3w on Weeks 12 and 15 (ie, total of 6 cycles post-randomization) if 
clinically indicated, at the Investigator’s discretion before patients enter follow-up.  This does not alter the planned scan schedule q8w starting at 
Week 12 for patients in Treatment Arm 3.
Note: Patients whose weight falls to 30 kg or below must receive weight-based dosing—equivalent to 20 mg/kg of durvalumab and 1 mg/kg of 
tremelimumab until the weight improves to >30 kg, at which point the patient should start receiving the fixed dosing of durvalumab at 1500 mg and 
tremelimumab at 75 mg.  Durvalumab dose will be 1500 mg during chemotherapy and 1500 mg post-chemotherapy; tremelimumab dose will be 
75 mg.
Durva Durvalumab (MEDI4736); PD Progressive disease; q3w Every 3 weeks; q4w Every 4 weeks; SoC Standard of care; Treme Tremelimumab.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
137(225)
7.2.2
Duration of treatment and criteria for treatment through progression and 
retreatment
7.2.2.1
Duration of treatment
Treatment with SoC chemotherapy in Treatment Arms 1 and 2 will be limited to 4 cycles on a 
q3w schedule subsequent to randomization.  Patients in Treatment Arm 3 may receive an 
additional 2 doses of SoC chemotherapy at Weeks 12 and 15 (a total of 6 doses 
post-randomization), as clinically indicated, at the Investigator’s discretion.
Treatment with immunotherapy + SoC chemotherapy in Treatment Arms 1 and 2, as well as 
treatment with SoC chemotherapy alone in Treatment Arm 3, will be administered beginning 
on Cycle 1 Day 1.
For patients randomized to Treatment Arms 1 and 2, immunotherapy treatment with 
durvalumab monotherapy will continue until clinical progression or radiological progression 
unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation 
criterion is met.  For patients in Treatment Arm 1, an additional dose of durvalumab + 
tremelimumab will be given at Week 16 post-chemotherapy.  In the case of dose delay(s), 
more than 1 durvalumab + tremelimumab combination dose can be given at and after Week 16 
post-chemotherapy to ensure that up to 5 combination doses are administered in Treatment 
Arm 1.   If patients receive fewer than 4 cycles of platinum doublet chemotherapy, the 
remaining cycles of combined durvalumab/tremelimumab (up to a total of 5) should be given 
after combination of platinum doublet chemotherapy (with maintenance pemetrexed if 
applicable).  All non-squamous patients who received a pemetrexed doublet in the initial part 
of the study will receive pemetrexed maintenance in the ‘post-chemotherapy’ phase of the 
study, unless contraindicated per the Investigator.
For patients randomized to Treatment Arms 1 and 2, when SoC chemotherapy is discontinued 
due to treatment-related toxicity, durvalumab monotherapy or durvalumab + tremelimumab 
may continue at the Investigator’s discretion when toxicity resolves to at least Grade 2 or less.  
Note: if the Investigator feels a patient is ready to restart treatment prior to the toxicity 
resolving to Grade 2 or less, AstraZeneca should be consulted for an exception to this rule.
For patients randomized to Treatment Arm 3, treatment through progression and retreatment 
will not be permitted.
7.2.2.2
Treatment Arms 1 and 2: Criteria for treatment through progression and for 
retreatment
Treatment through progression (Treatment Arms 1 and 2)
During the treatment period, patients in Treatment Arms 1 and 2 may continue receiving their 
assigned therapy in the setting of unconfirmed radiological progressive disease (PD) 
according to Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1), at the 
Investigator’s discretion, until progressive disease is confirmed (Appendix E). A confirmatory
scan is required following a RECIST 1.1 overall timepoint assessment of progression (PD),

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
138(225)
preferably at the next scheduled imaging visit and no earlier than 4 weeks after the prior 
assessment of PD.
For patients in Treatment Arms 1 and 2 with confirmed objective radiological progression 
who, in the Investigator’s opinion continue to receive benefit from their assigned treatment 
and following consultation with AstraZeneca, may continue to receive durvalumab 
monotherapy for as long as they are gaining clinical benefit providing they meet the criteria 
for treatment in the setting of PD (see section on Criteria for treatment through progression 
(Treatment Arms 1 and 2) and retreatment (Treatment Arm 1).
Retreatment (Treatment Arm 1)
Patients in Treatment Arm 1 with radiological progression who, in the Investigator’s opinion, 
continue to receive benefit from their assigned treatment and who meet the criteria for 
retreatment in the setting of PD (below), may start retreatment with durvalumab + 
tremelimumab combination therapy. For retreatment, the same assessments should be done as 
in the first treatment period, with the exception of the hepatitis B, hepatitis C and HIV tests. In 
addition, PK, ADA, 
 
EGFR/ALK, PD-L1, and whole blood for gene expression, which do not need to be collected 
a second time.
Patients with rapid tumor progression or with symptomatic progression that requires urgent 
medical intervention (eg, central nervous system metastasis, respiratory failure due to tumor
compression, or spinal cord compression) will not be eligible for starting retreatment with 
durvalumab + tremelimumab combination therapy. 
For all patients in Treatment Arm 1 who begin retreatment, the Investigator should ensure the 
patients do not have any significant, unacceptable, or irreversible toxicities that indicate 
restarting treatment would not further benefit the patient.
Patients in Treatment Arm 1 meeting the retreatment criteria below will follow the same 
treatment guidelines followed during the original ‘post-chemotherapy’ q4w treatment period 
(Table 2):
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 + tremelimumab combination therapy arm (Treatment 
Arm 1) may undergo retreatment with the combination as described below:
∀
Patients who complete the 5 dosing cycles of the combination of durvalumab and 
tremelimumab portion of the regimen (with clinical benefit per Investigator 
judgment), but subsequently have evidence of clinical progression or radiological 
PD during the durvalumab monotherapy portion of the combination regimen (see 
Appendix E), may restart treatment with the combination.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
139(225)
∀
During the retreatment period, patients in the durvalumab + tremelimumab 
combination therapy group (Treatment Arm 1) will continue durvalumab dosing at 
1500 mg q4w with 75 mg of tremelimumab q4w for 4 doses/cycles each.  Patients 
will then continue with durvalumab monotherapy at 1500 mg q4w.
Note: If a patient’s weight falls to 30 kg or below, the patient should receive weight-based 
dosing equivalent to 20 mg/kg of durvalumab and 1 mg/kg tremelimumab until the weight 
improves to >30 kg, at which point the patient should start receiving the fixed dosing of 
durvalumab 1500 mg ± tremelimumab 75 mg.
Criteria for treatment through progression (Treatment Arms 1 and 2) and retreatment
(Treatment Arm 1)
For all patients who are treated through progression and for patients who are restarting 
durvalumab + tremelimumab combination therapy, 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 (eg, 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 Sections 3.1 and 
3.2) with the exception of inclusion criteria 5, 9, and 11 and exclusion criteria 2, 19, 
and 23.
Patients in Treatment Arms 1 and 2 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), 
ie, 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 RECIST 1.1 defined radiological progression plus an additional subsequent 
scan and for survival.
The investigator may offer other therapies to patients who AstraZeneca and the Investigator 
determine may not continue treatment following objective disease progression.  

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
140(225)
7.2.2.3
Treatment Arm 3: No treatment through progression
For patients randomized to Treatment Arm 3, treatment through progression will not be 
permitted, and crossover to durvalumab + tremelimumab combination therapy + SoC 
chemotherapy or durvalumab monotherapy + SoC chemotherapy following objective disease 
progression will not be permitted.
Following objective disease progression, the Investigator may offer other therapies to the 
patient.  
Following objective disease progression, patients in Treatment Arm 3 will continue to be 
followed for survival, even if another therapy to treat NSCLC is started.
Post Data Cut Off (DCO) for final analysis of OS for superiority
For patients continuing to receive durvalumab/tremelimumab treatment and/or SOC 
chemotherapy and patients on survival follow-up following the DCO for final analysis of OS 
for superiority, it is recommended that the patients continue the scheduled site visits according 
to Table 12, Table 13 & Section 9.3 and investigators monitor the patient’s safety laboratory 
results prior to and periodically during treatment with durvalumab/tremelimumab and/or SOC 
chemotherapy in order to manage AEs in accordance with the durvalumab/tremelimumab
toxicity management guidelines or as indicated in the local prescribing information for the 
relevant chemotherapy agent(please see Section6.9.1 & 6.9.2).
Post final Data Cut Off (DCO) 
Patients who continue to receive benefit from their assigned treatment (durvalumab and/or 
SOC chemotherapy) at the final DCO and database closure may continue to receive their 
assigned treatment as long as they and their physician feel they are gaining clinical 
benefit(See section 7.8). Investigators will monitor the patient’s safety laboratory results prior 
to and periodically during treatment with durvalumab/tremelimumab and/or SOC 
chemotherapy in order to manage AEs in accordance with the durvalumab/tremelimumab 
toxicity management guidelines or as indicated in the local prescribing information for the 
relevant chemotherapy agent (please see Section 6.9.1 & 6.9.2).
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, patients currently receiving treatment with durvalumab and/or SOC 
chemotherapy may be transitioned to such a study, and the current study would reach its end. 
The roll-over or safety extension study would ensure treatment continuation with visits 
assessment per its protocol. Any patient that would be proposed to move to such study would 
be given a new Informed Consent.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
141(225)
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.
Label text prepared for durvalumab (MEDI4736) will show the product name as “MEDI4736” 
or “durvalumab (MEDI4736)” or ‘durvalumab’ depending upon the agreed product name used 
in the approved study master label document.  All naming conventions are correct during this 
transitional period.
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 (eg, pharmacist), will ensure that all IP is 
stored in a secured area, in refrigerated temperatures (2°C to 8°C) and in accordance with 
applicable regulatory requirements.  A temperature log will be used to record the temperature 
of the storage area.  Temperature excursions outside the permissible range listed in the clinical 
supply packaging are to be reported to the monitor upon detection.  A calibrated temperature 
monitoring device will be used to record the temperature conditions in the drug storage 
facility.  Storage conditions stated in the IB may be superseded by the label storage.
The IP label on the pack/bottle/carton for SoC specifies the appropriate storage for these 
agents.  
7.5
Compliance
The administration of all study drugs (including IP) should be recorded in the appropriate 
sections of the eCRF.
Treatment compliance will be assured by reconciliation of site drug accountability logs.
7.6
Accountability
The study drug provided for this study will be used only as directed in the study protocol.
The study personnel will account for all study drugs dispensed to and returned from the 
patient.
Study drug will not be distributed to the study site until the contract is concluded between the 
study site and AstraZeneca.  The Investigational Product Storage Manager is responsible for 
managing the study drug from receipt by the study site until the return of all unused study 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
142(225)
drug to AstraZeneca.  AstraZeneca will provide the study documents ‘Procedures for drug 
accountability’ and ‘Procedures for drug storage’ which describes the specific requirements.  
The Investigator(s) is responsible for ensuring that the patient has returned all unused study 
drug.
7.7
Concomitant medications 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 (final study visit), 
including the 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.
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the Investigator.
Restricted, prohibited, and permitted concomitant medications are described in Table 8 and 
Table 9.  Refer also to the Dosing Modification and Toxicity Management Guidelines (please 
see Section 6.9.1.
For chemotherapy agents, please refer to the local prescribing information with regard to 
warnings, precautions, and contraindications.
Table 8
Prohibited concomitant medications
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 while 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 while the 
patient is on study treatment
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal therapy for 
cancer treatment other than those under investigation 
in this study
Should not be given concomitantly while the 
patient is on study treatment.  (Concurrent use of 
hormones for non-cancer-related conditions 
[eg, insulin for diabetes and hormone 
replacement therapy] is acceptable. Local 
treatment of isolated lesions, excluding target 
lesions, for palliative intent is acceptable [eg, by 
local surgery or radiotherapy])
Live attenuated vaccines 
Should not be given through 30 days after the last 
dose of IP
For the durvalumab (MEDI4736) ± tremelimumab treatment arms only
Immunosuppressive medications including, but not 
limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or 
Should not be given concomitantly, or used for 
premedication prior to the immuno-oncology 
infusions.  The following are allowed exceptions:

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
143(225)
Prohibited medication/class of drug:
Usage:
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-α blockers
∀
Use of immunosuppressive medications for 
the management of IP-related AEs. 
∀
Short-term premedication for patients 
receiving combination agents SoC, in which 
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 intra-
nasal corticosteroids is permitted.
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential 
for the management of non-immunotherapy 
related events experienced by the patient 
(eg, chronic obstructive pulmonary disease, 
radiation, nausea, etc).
Drugs with laxative properties and herbal or natural 
remedies for constipation
Should be used with caution through to 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 
combination therapy of tremelimumab and 
sunitinib)
EGFR TKIs 
Should not be given concomitantly. 
Should be used with caution in the 90 days 
post-last dose of durvalumab. 
Increased incidences of pneumonitis (with third 
generation EGFR TKIs) and increased incidence 
of transaminase increases (with 1st generation 
EGFR TKIs) has been reported when durvalumab 
has been given concomitantly.
Herbal and natural remedies which may have 
immune-modulating effects
Should not be given concurrently unless agreed 
by the Sponsor
AE Adverse event; CTLA-4 Cytotoxic T-lymphocyte-associated antigen 4; EGFR Epidermal growth factor 
receptor; IP Investigational product; PD-1 Programmed cell death 1; PD-L1 Programmed cell death ligand 
1; SoC Standard of care; TKI Tyrosine kinase inhibitor.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
144(225)
Table 9
Supportive medications
Supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) 
deemed necessary to provide adequate prophylactic 
or supportive care, except for those medications 
identified as “prohibited,” as listed above 
To be administered as prescribed by the 
Investigator
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy to 
non-target lesions, etc])
Should be used, when necessary, for all patients
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
Durvalumab drug-drug interactions
There is no information to date on drug-drug interactions with durvalumab either pre-
clinically or in patients.  As durvalumab is a mAb and therefore a protein, it will be degraded 
to small peptides and amino acids and will be eliminated by renal and reticuloendothelial 
clearance.  It is therefore not expected that durvalumab will induce or inhibit the major drug 
metabolizing cytochrome P450 pathways.  As a result, there are no expected pharmacokinetic 
drug-drug interactions.  The mechanism of action of durvalumab involves binding to PD-L1, 
and therefore significant pharmacodynamic drug interactions with the commonly administered 
concomitant medications are not expected.  Despite this, appropriate clinical monitoring in all 
of the planned clinical studies will be conducted to evaluate any potential drug-drug 
interactions.
7.8
Post-study access to study treatment
Patients receiving study treatment at the time of study completion (ie, after final data cut-off 
date) may continue to receive study treatment up to meeting discontinuation criteria(see 
section 3.9) if, in the opinion of the Investigator, they are continuing to receive benefit from 
treatment.
The provision of durvalumab/tremelimumab treatment at study completion may include, but is 
not limited to, transition to a roll-over study, continuous supply within this trial (for example 
in countries where regulatory approval is not obtained for a roll-over study) or switching to 
commercial drug as permitted by local regulations. SOC chemotherapy will not be provided 
unless it is not locally available as standard of care.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
145(225)
After discontinuation of study treatment, the Investigator will be at liberty to define further the 
most appropriate anticancer treatment.
8.
STATISTICAL ANALYSES
8.1
Statistical considerations
All statistical analyses will be performed by AstraZeneca or its representatives.  
A comprehensive statistical analysis plan (SAP) will be prepared and finalized within 
3 months of the first randomized patient, and any subsequent amendments will be 
documented, with final amendments completed prior to the reporting of the data. The dual 
primary aims of this study are to assess the efficacy of durvalumab monotherapy + SoC 
chemotherapy compared with SoC chemotherapy alone in terms of PFS and OS in all patients.   
8.2
Sample size estimate
The study will enroll approximately 2000 patients to randomize approximately 1000 patients 
in a 1:1:1 ratio to durvalumab + tremelimumab combination therapy + SoC chemotherapy, 
durvalumab monotherapy + SoC chemotherapy, or SoC chemotherapy alone (approximately 
333 patients in each treatment arm), including at least 250 patients in each treatment arm with 
PD-L1 TC <50%. Once global enrollment is completed, the recruitment may continue in 
mainland China only. A total of up to 180 patients, including up to 135 patients in total with 
PD-L1 TC <50%, from China will be randomized (refer to Section 8.6 for more details). 
The study is sized for dual primary endpoints to characterize the PFS and OS benefits of 
durvalumab monotherapy + SoC chemotherapy versus SoC chemotherapy alone in the intent-
to-treat (ITT) population. Sample size and power analysis for the dual primary endpoints are 
described below. Refer to Section 8.5 for the multiple testing procedure and Section 8.5.9 for 
alpha allocation and alpha spending.
One interim analysis of PFS will be performed when approximately 80% of the target PFS 
events have occurred.  Three interim analyses of overall survival (OS) will be performed; the 
first at the time of the interim PFS analysis (approximately 45% of the target OS events), the 
second at the time of the primary PFS analysis (approximately 61% of the target OS events) 
and the third when approximately 84% of the target OS events have occurred.  The alpha will 
be split between the interim and final analyses using the Lan and DeMets 
(Lan and DeMets 1983) spending function that approximates an O’Brien Fleming approach, 
with the boundaries for the treatment comparison derived based upon the exact number of 
events at the time of analysis.
The final (primary) PFS analysis for superiority will be performed when the following 
conditions have been met: 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
146(225)
∀
Approximately 497 BICR PFS events from the global cohort have occurred across 
the durvalumab monotherapy + SoC chemotherapy and SoC chemotherapy alone 
treatment arms (75% maturity)
The final OS analysis for superiority will be performed when the following conditions have 
been met: 
∀
Approximately 532 OS events have occurred across the durvalumab monotherapy 
+ SOC chemotherapy and SoC chemotherapy alone treatment arms (80% maturity)
Dual primary Endpoints:
Durvalumab monotherapy + SoC chemotherapy versus SoC chemotherapy alone
(PFS in ITT population)
Assuming the true PFS HR is 0.67 and the median PFS in SoC chemotherapy alone arm is 
6 months, 497 PFS events from the global cohort (75% maturity) will provide greater than 
90% power to demonstrate statistical significance at the 2-sided alpha level of 0.9% (with 
overall alpha for PFS 1%), allowing for 1 interim analysis conducted at approximately 80% of 
the target events.  The smallest treatment difference that is statistically significant will be an 
HR of 0.79. Assuming a recruitment period of 16 months, this analysis is anticipated to be 
25 months from FPI.
Durvalumab monotherapy + SoC chemotherapy versus SoC chemotherapy alone
(OS in ITT population)
Assuming the true OS HR is 0.7 and the median OS in SoC arm is 12.9 months, 532 OS 
events (80% maturity) will provide greater than 90% power to demonstrate statistical 
significance at the 2-sided alpha level of a 3.3% (with overall alpha for OS 4%), allowing for 
3 interim analyses conducted at approximately 45%, 61% and 84% of the target events. The 
smallest treatment difference that is statistically significant will be an HR of 0.83. Assuming a 
recruitment period of 16 months, this analysis is anticipated to be 46 months from FPI.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
147(225)
8.3
Definitions of analysis sets
Definitions of the analysis sets for each outcome variable are provided in Table 10.
Table 10
Summary of outcome variables and analysis populations
Outcome variable
Population
Efficacy data
PFS and OS
PD-L1 TC <50% analysis set
PFS and OS
Full analysis set (ITT population)
ORR, DoR, BoR, APF12, PFS2, PROs, and 
symptom endpoints
PD-L1 TC <50% analysis set
ORR, DoR, BoR, APF12, PFS2, PROs, and 
symptom endpoints
Full analysis set (ITT population)
PFS, OS, ORR, BoR, DoR, APF12, and PFS2
PD-L1 TC <25% analysis set
PFS, OS, ORR, BoR, DoR, APF12, and PFS2
PD-L1 TC <1% analysis set
PK data
PK analysis set
PFS, OS, ORR, BoR, DoR, APF12, and PFS2
TMB high analysis set
Safety data
Exposure
Safety analysis set
AEs
Safety analysis set
Laboratory measurements
Safety analysis set
Vital signs
Safety analysis set
ECGs
Safety analysis set
AE Adverse event; APF12 Proportion of patients alive and progression free at 12 months from randomization; 
BoR Best objective response; DoR Duration of response; ECG Electrocardiogram; ITT Intent-to-treat; 
ORR Objective response rate; OS Overall survival; PD-L1 Programmed cell death ligand 1; 
PFS Progression-free survival; PFS2 Time from randomization to second progression; 
PK Pharmacokinetic(s); PRO Patient-reported outcome; TC Tumor cell.
8.3.1
Full analysis set
The full analysis set (FAS) will include all randomized patients.  Treatment arms will be 
compared on the basis of randomized study treatment, regardless of the treatment actually
received.  Patients who were randomized but did not subsequently go on to receive study 
treatment are included in the analysis in the treatment arm to which they were randomized.
8.3.2
PD-L1 TC <50% analysis set
The PD-L1 TC<50% analysis set will include the subset of patients in the FAS whose PD-L1 
status is PD-L1 TC <50% as defined by the Ventana SP263 PD-L1 IHC assay (ie, <50% 
PD-L1-membrane expression in tumoral tissue).

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
148(225)
8.3.3
PD-L1 TC <25% analysis set
The PD-L1 TC<25% analysis set will include the subset of patients in the FAS whose PD L1 
status is PD-L1 TC <25% as defined by the Ventana SP263 PD-L1 IHC assay (ie, <25% PD 
L1 membrane expression in tumoral tissue).
8.3.4
PD-L1 TC <1% analysis set
The PD-L1 TC <1% analysis set will include the subset of patients in the FAS whose PD-L1 
status is PD-L1 TC <1% as defined by the Ventana SP263 PD-L1 IHC assay (ie, <1% 
PD-L1-membrane expression in tumoral tissue).
8.3.5
TMB high analysis set
The TMB high analysis set will include the subset of patients in the FAS defined as per cut-
off/threshold included in the final SAP prior to DBL with data external to Poseidon.
8.3.6
Safety analysis set
The safety analysis set will consist of all patients who received at least 1 dose of study 
treatment.  Safety data will not be formally analyzed but summarized, according to the 
treatment received, that is, erroneously treated patients (eg, those randomized to treatment A 
but actually given treatment B) will be summarized according to the treatment they actually
received.
8.3.7
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 analyses will be included in the PK analysis set.  The population 
will be defined by the Study Physician, Pharmacokineticist, and Statistician prior to any 
analyses being performed.
8.4
Outcome measures for analyses
8.4.1
Calculation or derivation of efficacy variables
The analysis of PFS, ORR, DoR, BoR, and APF12 will be based on BICR tumor assessments 
according to RECIST 1.1.  OS will be evaluated from all-cause mortality.  Additionally, PFS2 
will be defined by local clinical practice.
A sensitivity analysis of PFS will be performed using the Investigator tumor assessments. 
8.4.2
RECIST 1.1-based endpoints
Blinded Independent Central Review of RECIST 1.1-based assessments
The BICR will be performed on all radiological scans of all patients.  All images will be 
collected centrally. Prior radiotherapy reports will also be provided to the BICR to allow the 
selection of appropriate target lesions.  The imaging scans will be reviewed by 2 independent 
radiologists using RECIST 1.1 and will be adjudicated, if required, by a third independent 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
149(225)
radiologist who will choose the assessments of 1 of the 2 primary reviewers.  For each patient, 
the BICR will define the overall visit response data (CR, PR, SD, PD, or NE).  If a patient has 
had a tumor assessment that cannot be evaluated, then the patient will be assigned a visit 
response of NE (unless there is evidence of progression, in which case the response will be 
assigned as PD).  Endpoints (of PFS) will be derived from the scan dates.
Further details of the BICR will be documented in the Imaging Charter.
Investigator RECIST 1.1-based assessments
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations.  This is also regardless of whether a patient discontinues study treatment or 
receives another anticancer therapy.
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 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 E.
8.4.2.1
Dual primary endpoints
PFS and OS comparing durvalumab monotherapy +SoC versus SoC alone are the dual 
primary endpoints.
Progression-free survival
PFS (per RECIST 1.1 using BICR 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.  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:
∀
The date of progression will be determined based on the earliest of the scan dates of 
the component that triggered the progression for the adjudicated reviewer selecting 
PD or of reviewer, where both select PD as a timepoint response and there is no 
adjudication for central review (BICR).

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
150(225)
∀
For investigational assessments, the date of progression will be determined based on 
the earliest of the RECIST 1.1 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 will be recorded out of all scans performed 
at that assessment for the target lesions.  Similarly, for non-target lesions, only the latest scan 
date will be recorded out of all scans performed at that assessment for the non-target lesions.  
For Treatment Arms 1 and 2, patients with a single disease progression and with no further 
tumor assessment scans will be treated as PD in the analysis.  In the absence of significant 
clinical deterioration, the investigational site will be advised to have the patient continue in 
their randomized experimental arms until radiological progression is confirmed (Appendix E).  
If progression is not confirmed, the patient should continue in their randomized experimental 
arms and on-treatment assessments.
For Treatment Arm 3, at least 1 scan documenting unequivocal radiographic progression.
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 after 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.
8.4.2.2
Secondary endpoints
Objective response rate
ORR (per RECIST 1.1 using BICR 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.
ORR will also be obtained using the algorithm described above for the RECIST 1.1 site 
Investigator tumor data.
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
151(225)
Duration of response
DoR (per RECIST 1.1 using BICR 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 a documented response.
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 it may involve any of the following: objective radiological 
imaging, symptomatic progression, or death.  Second progression status will be reviewed 
(q6w for the first 12 weeks relative to the date of randomization and q8w thereafter) following 
the progression event used for the primary variable PFS (the first progression) and status 
recorded.  Patients who are alive and in whom a second disease progression has not been 
observed should be censored at the last time known to be alive, 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. 
Proportion of patients alive and progression free at 12 months
The APF12 will be defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed 
using BICR assessments) at 12 months.
Best objective response
BoR will be calculated based on the overall visit responses from each RECIST 1.1 
assessment, described in Appendix E. 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 1.1 progression, as determined by BICR.
Categorization of BoR will be based on RECIST (Appendix E) using the following response 
categories: CR, PR, SD, PD, and NE.
BoR will be determined programmatically based on RECIST 1.1 using all BICR assessments 
up until the first progression event.  For patients whose progression event is death, BoR will 
be calculated based upon all evaluable RECIST 1.1 assessments prior to death.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
152(225)
8.4.3
Calculation or derivation of safety variables
8.4.3.1
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 in all treatment arms, may be included in the AE summaries, but the majority
of those summaries will omit those AEs observed after a patient has received further systemic 
non-protocol therapy for cancer. Further details will be provided in the SAP. Any events in the 
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 study drug 
in all treatment arms will be produced. These events will not be included in AE summaries.
8.4.3.2
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 as other significant 
adverse events (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.
8.4.3.3
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 study 
treatment. 
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.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
153(225)
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, evaluable patients 
need only have 1 post-dose value recorded.
The denominator in vital signs data should include only those patients with recorded data.
8.4.4
Calculation or derivation of patient-reported outcome variables
PRO questionnaires, a secondary endpoint of interest, will be assessed using the EORTC 
QLQ-C30 with the QLQ-LC13 module (HRQoL and lung cancer specific symptoms),
  All items/questionnaires will be scored according to 
published scoring guidelines or the developer’s guidelines, if published guidelines are not 
available.  All PRO analyses will be based on the full analysis set (FAS; ITT population) and 
the PD-L1<50% analysis sets, unless otherwise stated.  The clinical meaningfulness threshold 
of the PRO analyses described below will be provided in the SAP.
8.4.4.1
EORTC QLQ-C30
The EORTC QLQ-C30 consists of 30 questions that can be combined to produce 5 functional 
scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and 
nausea/vomiting), 5 individual items (dyspnea, insomnia, appetite loss, constipation, and 
diarrhea), and a global measure of health status.  The EORTC QLQ-C30 will be scored 
according to the EORTC QLQ-C30 Scoring Manual (Fayers et al 2001).  An outcome variable 
consisting of a score from 0 to 100 will be derived for each of the symptom scales/symptom 
items, each of the functional scales, and the global health status scale in the EORTC QLQ-
C30 according to the EORTC QLQ-C30 Scoring Manual.  Higher scores on the global health 
status and functioning scales indicate better health status/function, but higher scores on 
symptom scales/items represent greater symptom severity.
Changes in score compared with baseline will be evaluated.  For each subscale, if <50% of the 
subscale items are missing, then the subscale score will be divided by the number of 
non-missing items and multiplied by the total number of items on the subscales 
(Fayers et al 2001). If at least 50% of the items are missing, then that subscale will be treated 
as missing.  Missing single items are treated as missing.  The reason for any missing 
questionnaire will be identified and recorded. If there is evidence that the missing data are 
systematic, missing values will be handled to ensure that any possible bias is minimized.
Time to HRQoL/function deterioration
For the following HRQoL items of the EORTC QLQ-C30, time to deterioration will be 
analyzed:
∀
The Global Health Status/ QoL scale consisting of items 29 and 30 of the EORTC 
QLQ-C30.  Item 29: How would you rate your overall health during the past week? 
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
154(225)
Item 30: How would you rate your overall quality of life during the past week?  
Patients are asked to rate their overall health and overall quality of life on a scale 
from 1 (very poor) to 7 (excellent).
Time to deterioration will be defined as the time from the date of randomization until the date 
of the first clinically meaningful deterioration that is confirmed at a subsequent visit or death 
(by any cause) in the absence of a clinically meaningful deterioration, regardless of whether 
the patient withdraws from study treatment or receives another anticancer therapy prior to 
HRQoL/function deterioration.  Patients with a single deterioration and with no further 
assessments will be treated as deteriorated in the analysis.
Death will be included as an event only if the death occurs within 2 visits of the last PRO 
assessment where the HRQoL/function change could be evaluated.
Patients whose HRQoL (as measured by EORTC QLQ-C30) has not shown a clinically 
meaningful deterioration and who are alive at the time of the analysis will be censored at the 
time of their last PRO assessment where the HRQoL/function could be evaluated.  Also, if 
HRQoL deteriorates after 2 or more missed PRO assessment visits or if the patient dies after 
2 or more missed PRO assessment visits, the patient will be censored at the time of the last 
PRO assessment where HRQoL/function could be evaluated.  If a patient has no evaluable 
visits or does not have baseline data they will be censored at 0 days.
Symptom improvement rate
The symptom improvement rate will be defined as the number (%) of patients with 
2 consecutive assessments at least 14 days apart that show a clinically meaningful 
improvement in that symptom from baseline.
HRQoL/function improvement rate
The HRQoL/function improvement rate will be defined as the number (%) of patients with 
2 consecutive assessments at least 14 days apart that show a clinically meaningful 
improvement in that scale from baseline.
8.4.4.2
Lung cancer module (EORTC QLQ-LC13)
The QLQ-LC13 is a lung cancer specific module from the EORTC for lung cancer comprising 
13 questions to assess lung cancer symptoms (cough, hemoptysis, dyspnea, and site-specific 
pain), treatment-related symptoms (sore mouth, dysphagia, peripheral neuropathy, and 
alopecia), and pain medication.  Changes in score compared with baseline will be evaluated.
Time to symptom deterioration
For each of the following key symptom scales/items in the QLQ-LC13 and QLQ-C30, time to 
deterioration will be analyzed:
∀
Dyspnea: multi-item scale based on 3 questions: (“Were you short of breath when 
you rested; walked; climbed stairs?”), LC13,

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
155(225)
∀
Cough: 1 item (“How much did you cough?”), LC13
∀
Pain: 3 individual items (“Have you had pain in your chest; your arm or shoulder; 
other parts of your body?”), LC13
∀
Appetite loss: 1 item (“Have you lacked appetite?”), C30
∀
Fatigue: 3 individual items (“Have you felt weak?”, “Did you need to rest?”, “Were 
you tired?”), C30
The dyspnea scale will only be used if all 3 items have been scored; otherwise the items are 
treated as single-item measures.  The scoring approach for the QLQ-LC13 is identical in 
principle to that for the symptom scales/single items of the EORTC QLQ-C30.
Time to symptom deterioration will be defined as the time from the date of randomization 
until the date of the first clinically meaningful symptom deterioration that is confirmed at a 
subsequent visit or death (by any cause) in the absence of a clinically meaningful symptom 
deterioration, regardless of whether the patient withdraws from study treatment or receives 
another anticancer therapy prior to symptom deterioration.  Patients with single deterioration 
and no further assessments will be treated as deteriorated in the analysis.
Death will be included as an event only if the death occurs within 2 visits of the last PRO 
assessment where the symptom change could be evaluated.
Patients whose symptoms (as measured by QLQ-LC13) have not shown a clinically 
meaningful deterioration and who are alive at the time of the analysis will be censored at the 
time of their last PRO assessment where the symptom could be evaluated.  Also, if symptoms 
deteriorate after 2 or more missed PRO assessment visits or the patient dies after 2 or more 
missed PRO assessment visits, the patient will be censored at the time of the last PRO 
assessment where the symptom could be evaluated.  If a patient has no evaluable visits or does 
not have baseline data they will be censored at 0 days.
Symptom improvement rate
The symptom improvement rate will be defined as the number (%) of patients with 
2 consecutive assessments at least 14 days apart that show a clinically meaningful 
improvement in that symptom from baseline.
8.4.4.3
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
156(225)
8.4.5
Calculation or derivation of pharmacokinetic variables
8.4.5.1
Pharmacokinetic analysis
The PK analyses 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.  Samples below the 
lower limit of quantification will be treated as missing in the analyses.  The PK data collected 
in this study may be utilized with data from other studies for population PK and/or PKPD 
analyses.
8.4.5.2
Immunogenicity analysis
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADAs against durvalumab 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.
8.4.6
8.5
Methods for statistical analyses
The formal statistical analysis will be performed to test the following main hypotheses:
∀
H0: No difference between durvalumab monotherapy + SoC chemotherapy and SoC 
chemotherapy alone
∀
H1: Difference between durvalumab monotherapy + SoC chemotherapy and SoC 
chemotherapy alone
The dual primary endpoints are PFS and OS (durvalumab monotherapy +SoC chemotherapy 
versus SoC chemotherapy alone) in the ITT population (with PFS using BICR assessments per 
RECIST 1.1). 
The final (primary) PFS analysis for superiority will be performed when the following 
conditions have been met: 
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
157(225)
∀
Approximately 497 BICR PFS events from the global cohort have occurred across 
the durvalumab monotherapy + SoC chemotherapy and SoC chemotherapy alone 
treatment arms (75% maturity)
The final OS analysis for superiority will be performed when the following conditions have 
been met: 
∀
Approximately 532 OS events have occurred across the durvalumab monotherapy 
+ SOC chemotherapy and SoC chemotherapy alone treatment arms (80% maturity)
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment arm.  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 arm.
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 by treatment 
arm based on the FAS, the PD-L1 TC <50% analysis set, the PD-L1 TC <25% analysis set, 
the PD-L1 TC <1% analysis set, and TMB high analysis set. PK data will be summarized and 
analyzed based on the PK analysis set. Safety data will be summarized on the safety analysis 
set.
Results of all statistical analysis will be presented using appropriately sized CIs and 2-sided
p-values, unless otherwise stated.
Table 11 details which endpoints are to be subjected to formal statistical analysis, together 
with pre-planned sensitivity analyses, making it clear which analysis is regarded as primary
for that endpoint.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
158(225)
Table 11
Pre-planned statistical and sensitivity analyses to be conducted
Endpoints analyzed
Notes
Progression-free survival
Stratified log-rank tests for:
Dual primary analyses using BICR RECIST 1.1 assessments:
- Durvalumab monotherapy + SoC chemotherapy and SoC 
chemotherapy alone for the ITT population 
Secondary analysis using BICR RECIST 1.1 assessments:
- Durvalumab + tremelimumab combination therapy + SoC 
chemotherapy and SoC chemotherapy alone for the ITT 
population
- Durvalumab + tremelimumab combination therapy + SoC 
chemotherapy and SoC chemotherapy alone for PD-L1 TC <50% 
population (stratified only for disease stage and histology), PD-L1 
TC <25% population, PD-L1 TC <1% population and TMB high 
population
- Durvalumab monotherapy + SoC chemotherapy and SoC 
chemotherapy alone for PD-L1 TC <50% population (stratified 
only for disease stage and histology), PD-L1 TC <25% 
population, PD-L1 TC <1% population and TMB high population
Sensitivity analyses using Investigator assessments (RECIST 1.1)
Overall survival
- Stratified log-rank tests for:
Dual primary analysis
- Durvalumab monotherapy + SoC chemotherapy and SoC 
chemotherapy alone for the ITT population 
Key secondary analysis
- Durvalumab + tremelimumab combination therapy + SoC 
chemotherapy and SoC chemotherapy alone for the ITT 
population 
- Durvalumab + tremelimumab combination therapy + SoC 
chemotherapy and SoC chemotherapy alone for PD-L1<50% 
(stratified only for disease stage and histology), PD-L1 TC <25%, 
PD-L1<1% and TMB high population 
- Durvalumab monotherapy + SoC chemotherapy and SoC 
chemotherapy alone for PD-L1<50% (stratified only for disease 
stage and histology), PD-L1 TC <25%, PD-L1<1% and TMB high 
population
Objective response rate
Logistic regression for:
Secondary analysis for the ITT, PD-L1<50%, PD-L1 <25%, PD-L1 
<1% and TMB high population using BICR RECIST 1.1 assessments
Sensitivity analysis for the ITT, PD-L1<50%, PD-L1 <25%, PD-L1 
<1% and TMB high population using Investigator RECIST 1.1 
assessments
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
159(225)
Endpoints analyzed
Notes
Duration of response
Analysis methods as described by Ellis et al 2008 for:
Secondary analysis using BICR assessments (RECIST 1.1)
Proportion of patients alive and 
progression free at 12 months
Hazard ratio using the Kaplan Meier estimates of progression-free 
survival at 12 months (following method described by 
Klein et al 2007)
Time from randomization to 
second progression
Stratified log-rank test
Time to deterioration (EORTC 
QLQ-C30 and QLQ-LC13 
endpoints)
Stratified log-rank test
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 be used across the dual primary endpoints and the 
secondary endpoints included in MTP.
∀
The dual primary endpoints: PFS and OS (durvalumab monotherapy +SoC 
chemotherapy versus SoC chemotherapy alone) in the ITT population (with PFS 
using BICR assessments per RECIST 1.1). 
∀
The key secondary endpoints: PFS and OS (durvalumab + tremelimumab 
combination therapy + SoC chemotherapy and SoC chemotherapy alone) in the ITT 
population (with PFS using BICR assessments per RECIST 1.1).
Hypotheses will be tested using a multiple testing procedure with an alpha-exhaustive 
recycling strategy (Burman et al 2009).  With this approach, hypotheses will be tested in a 
pre-defined order as outlined in Figure 6.  According to alpha (test mass) splitting and alpha 
recycling, if the higher level hypothesis in the MTP is rejected for superiority, the next lower 
level hypothesis will then be tested.  The test mass that becomes available after each rejected 
hypothesis is recycled to lower level hypotheses not yet rejected.  This testing procedure stops 
when the entire test mass is allocated to non- rejected hypotheses.  Implementation of this 
pre-defined ordered testing procedure, including recycling, will strongly control type I error at 
5% (2-sided), among all the dual primary endpoints and the secondary endpoints included in 
MTP.
The overall 5% type 1 error will be first split between the dual primary endpoints of PFS and 
OS so an alpha level of 1% will be allocated to the primary PFS analysis and 4% will be 
allocated to the primary OS analysis. If PFS primary endpoint is significant, the 1% alpha 
level will be recycled to the key secondary PFS comparison of Arm 1 vs Arm 3. If OS primary 
endpoint is significant, the 4% alpha level will be recycled to the key secondary OS 
comparison of Arm 1 vs Arm 3. If PFS comparison of Arm 1 vs Arm 3 is significant, the 1% 
alpha level will be recycled to OS comparison of Arm 1 vs Arm 3. If OS comparison of Arm 1 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
160(225)
vs Arm 3 is significant, the 4% alpha level will be recycled to PFS comparison of Arm 1 vs 
Arm 3. 
If both PFS and OS comparisons of Arm 1 vs Arm 3 are significant, the available alpha level 
may be recycled to other comparisons. The recycle scheme of these additional compariosns, if 
included in MTP, will be specified in SAP prior to DBL.
The primary and secondary PFS endpoints are tested at 2 timepoints, 1 interim analysis and 1 
final analysis. The primary and the key secondary OS endpoints are tested at 4 timepoints: 3 
interim analyses and 1 final analysis.  The tests including the interim and the final analyses 
that are for the same comparison/endpoint (ie, shown in 1 rectangle box in Figure 6) will be 
considered as 1 test family.  As long as 1 test in the family can be rejected, the family is 
rejected.  Thus, the assigned total alpha to the family will be recycled to next MTP level.  
So, if the interim or final analyses indicate superiority in the tested hypothesis, then 
subsequent analyses of endpoints will be performed hierarchically in accordance with the 
MTP strategy.  The alpha level allocated to the interim or final analyses will be determined by
the Lan DeMets (Lan and DeMets 1983) spending function that approximates an O’Brien 
Fleming approach, where the alpha level applied at the interim depends upon the proportion of 
information available at time of the analysis.  A separate Lan DeMets (O’Brien Fleming) 
spending function will be used to determine the alpha level at the interim and final analyses 
for the next lower level of hypothesis testing under MTP based on the information proportion 
of that lower level of hypothesis.
If the interim results do not meet the criterion of stopping for superiority for a given 
hypothesis, then follow-up will continue until the next target number of events for that 
comparison has been observed, following which the hypothesis will be re-tested.  If the 
hypothesis is then rejected, subsequent testing will continue hierarchically in accordance with 
the MTP strategy. 
Assuming that 1% alpha level is available to a PFS hypothesis testing, if exactly 80% of the 
final target PFS events are available at the time of the interim, the 2 sided alpha level to be 
applied for the interim and final analyses of PFS would be 0.0034 and 0.009, respectively.
Assuming that 4% alpha level is available to a OS hypothesis testing, and if exactly 45%, 61% 
and 84% of the OS events required at the time of the final OS analysis are available at the 
times of the interim analyses, the 2-sided alpha level to be applied for the first interim, second 
interim, third interim and final analyses of OS would be 0.001, 0.0055, 0.0204 and 0.033 
respectively. Refer Section 8.5.9 for details of interim analysis.
The details of the multiple testing procedure will be provided in the SAP prior to DBL.
Figure 6 shows the multiple testing framework.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
161(225)
Figure 6
Multiple testing procedures for controlling the type 1 error rate
Combo durvalumab + tremelimumab combination therapy + SoC chemotherapy; Mono durvalumab 
monotherapy + SoC chemotherapy; ITT Intent-to-treat; OS Overall survival; PFS Progression-free survival; 
SoC Standard of care; vs versus.
8.5.1
Analysis of the primary and key secondary variable(s)
8.5.1.1
Progression-free survival
The dual primary PFS analyses will be based on the programmatically derived RECIST 1.1 
using the BICR tumor assessments.  The dual primary analysis uses a stratified log-rank test 
adjusting for PD-L1 tumor expression (PD-L1≥ 50% versus PD-L1 <50%), histology 
(squamous versus non-squamous), and disease stage (Stage IVA and Stage IVB).  The effect 
of experimental arms versus SoC arm will be estimated by the HR together with its 
corresponding 95% CI and p-value.
The HR and its CI can be estimated from the Cox proportional hazards model (Cox 1972).
All of the secondary analyses will be performed using the same methodology as for the 
primary analyses described above.
Kaplan-Meier plots of PFS will be presented by treatment arm and PD-L1 tumor status and 
TMB subgroup, where appropriate.  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.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
162(225)
Sensitivity analyses 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.
Ascertainment bias will be assessed by analyzing the site Investigator data.  The stratified 
log-rank test will be repeated on the programmatically derived PFS using the site Investigator 
data based upon RECIST 1.1.  The HR and CI will be presented.  
If there is an important discrepancy between the primary analysis using the BICR assessments 
and this sensitivity analysis using Investigator assessments, the proportion of patients with site 
but no central confirmation of progression will be summarized; such patients have the 
potential to introduce bias in the central review due to informative censoring.  An approach 
that imputes an event at the next visit in the central review analysis may help inform the most 
likely HR value (Fehrenbacher et al 2016, Fleischer et al 2011), but only if an important 
discrepancy exists.
 
 
  
Subgroup analyses will be conducted comparing PFS (per RECIST 1.1) between experimental 
arms versus SoC arm in the following subgroups of the FAS (but not limited to):  
∀
Sex (male versus female)
∀
Age at randomization (<65 versus ≥65 years of age)
∀
PD-L1 status (PD-L1 TC ≥50% versus TC <50%)
∀
Histology (squamous versus non-squamous)
∀
Chemotherapy (abraxane doublet versus pemetrexed doublet versus gemcitabine 
doublet)
∀
Smoking (current smoker, former smoker, never smoker)
∀
Race (Asian versus non-Asian)
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
163(225)
∀
PD-L1 using cutpoints of 1% and 25% tumor expression (<1% versus ≥1%, and 
<25% versus ≥25%)
∀
TMB (high vs low)
∀
PS status (0 versus 1)
∀
Brain metastasis (Yes vs No)
∀
Disease stage (stage IVa versus stage IVb)
Other baseline variables may also be assessed if there is clinical justification or an imbalance 
is observed between the treatment arms.  The purpose of the subgroup analyses is to assess the 
consistency of treatment effect across expected prognostic and/or predictive factors.
No adjustment to the significance level for testing of the subgroup and sensitivity analyses 
will be made since all these analyses will be considered supportive of the analysis of PFS.
Unless there is a marked difference between the results of the statistical analyses of the PFS 
from the BICR data and that of the site Investigator tumor data, these subgroup analyses will 
only be performed on the PFS endpoint using the BICR data.
Cox proportional hazards modeling will be employed to assess the effect of covariates on the 
HR estimate.  Before embarking on more detailed modeling, an initial model will be 
constructed containing treatment and the stratification factors alone to ensure that any output 
from the Cox modeling is likely to be consistent with the results of the stratified log-rank test.
Interactions between treatment and stratification factor will also be tested to rule out any 
qualitative interaction using the approach of Gail and Simon (Gail and Simon 1985).
Additionally, for each subgroup, the HR (for the treatment comparisons of interest) and 
95% CI will be calculated from a single model that contains treatment and subgroup.  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 analyses where there are less than 20 events in a 
subgroup), the relationship between that subgroup and PFS will not be formally analyzed.  In 
this case, only descriptive summaries will be provided.
Censoring rules will be provided in the SAP.
8.5.1.2
Overall survival
OS will be analyzed using a stratified log-rank tests, using the same methodology as described 
for the primary PFS endpoint.  The effect of experimental arms versus SoC arm will be 
estimated by the HR together with its corresponding CI and p-value.  Kaplan-Meier plots will 
be presented by treatment arm and PD-L1 tumor status and TMB subgroup, where 
appropriate. Summaries of the number and percentage of patients who have died, those still in 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
164(225)
survival follow-up, those lost to follow-up, and those who have withdrawn consent will be 
provided along with the median OS for each treatment.
The boundaries (ie, adjusted alpha levels) for the treatment comparison at the interim and final 
analyses for OS will be derived based upon the exact number of OS events using the Lan and 
DeMets approach that approximates the O’Brien Fleming spending function (see Section 8.2).  
8.5.2
Analysis of the secondary variable(s)
8.5.2.1
Objective response rate
The ORR will be based on the programmatically derived RECIST 1.1 using the BICR tumor 
data. The ORR will be compared between experimental arms versus SoC arm using logistic 
regression models adjusting for the same factors as the primary endpoint. 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 ITT, 
PD-L1 <50%, PD-L1 <25%, PD-L1 <1%, and TMB high populations. 
This analysis of ORR will be repeated using the results of the programmatically derived ORR 
using the site Investigator tumor data based upon RECIST 1.1 as a sensitivity analysis to 
confirm the results of the primary analysis derived from the eCRFs.
 
 
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 (ie, the FAS).  For 
each treatment arm, best overall response (BoR) will be summarized by n (%) for each 
category (CR, PR, SD, PD, and NE).  No formal statistical analyses are planned for BoR.
8.5.2.2
Duration of response
In order to analyze the DoR between the experimental arms and the SoC arm, the expected 
duration of response (EDoR) will be derived for each treatment arm (Ellis et al 2008) using 
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
165(225)
the BICR 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 
arms or p-value attached). Further details will be provided in SAP.
8.5.2.3
Proportion of patients alive and progression free at 12 months
The APF12 will be summarized (using the Kaplan-Meier curve) and presented by treatment 
arm.  APF12 will be compared between experimental arms and SoC arm by using the Kaplan-
Meier estimator of PFS at 12 months 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 
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 strata will be estimated and combined by weighting 
inversely proportionately according to each within stratum variance (Whitehead 
and Whitehead 1991).
8.5.2.4
Patient-reported outcomes
EORTC QLQ-C30
Time to deterioration will be analyzed using a stratified log-rank test, using the same 
methodology as described for the primary PFS endpoint.
The effect of experimental arms versus SoC arm will be estimated by the HR together with its 
corresponding CI and p-value.  Kaplan-Meier plots will be presented by treatment arm.  
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.
A summary of the symptom improvement rate for each of the 3 symptom scales and the 
5 individual symptom items will be produced.  Similarly, a summary of QoL/function 
improvement rate for each of the 5 function scales (physical, role, emotional, cognitive, and 
social) and global health status/QoL will be produced.  
)
(
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
#
#
∃
%
&
!
∋
t
t
i
i
i
i
i
i
d
n
n
d
t
)
(
)
(
ˆ
2
#

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
166(225)
Summaries of the original and the change from baseline values of each symptom scale/item, 
the global HRQoL score, and each functional domain will be reported by visit for each 
treatment arm.  Graphical presentations may also be produced as appropriate.  Summaries of 
the number and percentage of patients in each response category at each visit for each ordinal 
item will also be produced for each treatment arm. 
EORTC QLQ-LC13
Time to deterioration in the ITT population will be analyzed using a stratified log-rank test, 
using the same methodology as described for the primary PFS endpoint.
The effect of experimental arms versus SoC arm will be estimated by the HR together with its 
corresponding CI and p-value.  Kaplan-Meier plots will be presented by treatment arm.  
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.
A summary of the symptom improvement rate for each of the 6 individual-symptom items 
will be produced.  
Summaries of the original and the change from baseline values of each symptom (dyspnea, 
cough, hemoptysis, chest pain, arm/shoulder pain, and/or other pain) and each 
treatment-related symptom (sore mouth, dysphagia, peripheral neuropathy, and alopecia) will 
be reported by visit for each treatment arm.  Graphical presentations may also be produced as 
appropriate.  Summaries of the number and percentage of patients in each response category at 
each visit for each ordinal-symptom item will also be produced for each treatment arm.  
For PRO symptoms and HRQoL endpoints, the overall type I error (5% [2-sided]) will be 
controlled across the 5 primary PRO measures of cough, dyspnea, and pain as assessed by the 
EORTC QLQ-LC13 and fatigue and appetite loss as assessed by the EORTC QLQ-C30 using 
the Bonferroni-Holm procedure (Holm 1979).
The physical functioning and overall health status domains of the EORTC QLQ-C30 are 
furthermore pre-specified endpoints of interest.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
167(225)
8.5.3
 
8.5.4
Safety data
Safety and tolerability data will be presented by treatment arm using the safety population.
Data from all cycles of treatment will be combined in the presentation of safety data.  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 arm 
and CTCAE grade.  Additionally, data presentations of the rate of AEs per person-years at risk 
may be produced.  Any safety summaries examining retreatment with durvalumab + 
tremelimumab combination therapy will 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 durvalumab + tremelimumab combination 
therapy, durvalumab monotherapy, and SoC alone will be summarized.  Time on study; 
durvalumab + tremelimumab combination therapy, durvalumab monotherapy, and SoC dose 
delays/interruptions; and SoC 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. 
8.5.5
Pharmacokinetic data
PK concentration data will be listed for each patient and each dosing day, and a summary will 
be provided for all evaluable patients in the PK analysis population.
8.5.6
Immunogenicity analysis
Immunogenicity results will be listed by patient, and a summary of the number and percentage 
of patients who develop detectable anti-durvalumab and anti-tremelimumab antibodies will be 
provided.  The immunogenicity titer and neutralizing ADA data will be listed for samples 
confirmed positive for the presence of anti-durvalumab and anti-tremelimumab antibodies.  
 
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
168(225)
8.5.7
8.5.8
8.5.9
Interim analysis
Interim monitoring for safety will be conducted by the IDMC.  Details of the plan and 
communication process will be provided in the SAP and the IDMC Charter.
In addition, one interim analysis of PFS will be performed when approximately 80% of the 
target PFS events have occurred.  Three interim analyses of overall survival (OS) will be 
performed; the first at the time of the interim PFS analysis (approximately 45% of the target 
OS events), the second at the time of the primary PFS analysis (approximately 61% of the 
target OS events) and the third when approximately 84% of the target OS events have 
occurred. The interim analyses will be performed for the analyses specified in multiple testing 
procedure, refer to Section 8.5. It is expected that global recruitment will have completed prior 
to the results of the interim analyses being available.
The Lan DeMets spending function that approximates an O’Brien Fleming approach will be 
used to account for multiplicity introduced by including the interim analysis for superiority 
(Lan and DeMets 1983).
The alpha level that is spent at the interim and final analyses for the PFS analyses will be 
calculated using the Lan DeMets spending function separately.  If exactly 80% of the target 
events are available at the time of each interim comparison (368 out of 465 events occurred in 
Arm1 and 3, ITT population;397 out of 497 events occurred in Arm 2 and 3, ITT population), 
with overall 2-sided alpha levels of 0.01, the 2-sided alpha level to be applied for the interim 
and final analyses of each PFS would be 0.0034 and 0.009, respectively.
The alpha level that is spent at the interim and final analyses for the OS analyses will be 
calculated using the Lan DeMets spending function separately. If exactly 45% of the target 
events are available at the time of the first interim comparison (243 out of 532 events occurred 
in Arm 1 and 3 or Arm 2 and 3, ITT population and if exactly 61% of the target events are 
available at the time of the second interim comparison (328 out of 532 events occurred in Arm 
1 and 3 or Arm 2 and 3, ITT population), and if exactly 84% of the target events are available 
at the time of the third interim comparison (449 out of 532 events occurred in Arm 1 and 3 or 
Arm 2 and 3, ITT population), with overall 2-sided alpha levels of 0.04, the 2-sided alpha 
level to be applied for the first interim, second interim, third interim and final analyses of each 
OS analysis would be 0.001, 0.0055, 0.0204 and 0.033 respectively.
If the interim analyses indicate superiority, subsequent analyses of other endpoints will be 
performed in accordance with the hierarchical multiple testing strategy described in Section 8.5.
CCI
CCI
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
169(225)
8.6
China cohort
It is planned to randomize up to 180 patients from China, including up to 135 patients with 
PD-L1 TC <50%, before global enrollment completion. This is to ensure adequate Chinese 
patient participation to satisfy CFDA requirements to evaluate consistency in safety and 
efficacy in Chinese patients. If China enrollment cannot complete prior to the last patient first 
visit (LPFV) of the global cohort, then the following portion of this section will be applied.
The global cohort will enroll approximately 2000 patients to randomize approximately 
1000 patients. The China cohort consists of all patients from sites in China and enrolled prior 
to the last patient last visit of the global cohort. The China cohort has up to 180 randomized 
patients, including up to totally 135 patients with PD-L1 TC <50%. The global cohort consists 
of all patients recruited by the documented date of LPFV of the global cohort. Global 
recruitment will be complete once approximately 1000 patients have been randomized. The 
recruitment across all sites will then be closed except for those sites in China, where 
recruitment of patients will continue. Hence, a patient randomized in the China cohort prior to 
the LPFV of the global cohort enrollment will be included in both the global 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 CFDA 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 Chinese 
and Asian populations is required to facilitate the benefit-risk assessment for Chinese patients. 
Hence, the safety and efficacy data in the China cohort will be analyzed separately where the 
same endpoint definitions (as described in Section 8.4) and the same analysis methods (as 
detailed in Section 8.5) are applied.
The China FAS will include all patients randomized in the China cohort and will be used for 
all China-only efficacy analyses.
The China safety analysis set will consist of all patients recruited in the China cohort who 
received at least 1 dose of study treatment and for whom post-dose data are available.
Efficacy analyses for the China cohort will be performed when the PFS and/or OS data from 
the patients from China are of similar maturity at which significant clinical efficacy is 
established in the global cohort, eg, if PFS efficacy is established at the PFS interim analysis, 
a similar maturity will be used for the consistency evaluation.
All statistical analyses will be considered exploratory and only performed if sufficient 
numbers of events or patients are available (eg, ≥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. 
PFS and OS efficacy evaluation for the China cohort will be performed once, respectively.
Details of the China cohort and Asian population analyses, including the vendor to perform 
the analyses, will be specified in the China supplementary SAP, which is to be finalized 
before the global cohort data locks for analysis.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
170(225)
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, WBDC, 
and any ePRO 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).
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 study drug 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 (eg, 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 location of source data.
9.2.2
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 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
171(225)
Study Protocol and the CSA, the terms of the Clinical Study Protocol shall prevail with 
respect to 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.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the CSA.
9.3
Study timetable and end of study
The Investigator will be notified by AstraZeneca when recruitment is complete.
The end of the study is defined as “the last visit of the last patient undergoing the study”.    
The study started in Quarter 2 2017 (first patient enrolled).  The last patient in the global 
cohort was enrolled in Quarter 3 2018.  The estimated date of last patient completed in the 
China cohort will be later than the estimated date of last patient completed in global cohort.  
The study is expected to end by Quarter 4 2023.  The end of the study is defined as “the last 
visit of the last patient undergoing the study”. 
Data collection during long-term follow up until study end:
After the final analysis of OS for superiority is conducted, ongoing patients in the study will 
continue to be followed for long-term data collection
1) Following DCO for the final analysis of superiority for OS for approximately 12 
months:
There will be reduced schedule of assessments to allow collection of safety data (for safety 
reporting) and survival data for long-term follow-up (as per Table 12)  
2) Subsequent to safety reporting :
There will be only limited assessments to allow collection of safety data and survival data for 
long-term follow-up (as per Table 13)
!
Subjects continuing Durvalumab and Tremelimumab with or without pemetrexed
maintenance therapy (Arms 1 and 2) & subject receiving pemetrexed maintenance therapy
(Arm 3) should continue to receive study treatment until objective disease progression, 
unless contraindicated per the Investigator (see Section 3.9, 7.2.2)
!
Subjects in survival follow-up should continue further visits for survival assessment (see 
section 5.1.2). 
!
All AEs/SAEs collection (see section 6).

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
172(225)
Table 12
Schedule of study assessments and relevant eCRF pages to be completed 
during Long-term follow-up (up to approximately 12 months after DCO
for final analysis of OS for superiority)
(* Visit windows and timepoints for assessments should be performed as per details outlined in Table 2 
for patients ongoing study treatment and in Table 3 for patients in follow-up period.)
Assessment
Relevant eCRF page
Durvalumab, Tremelimumab & Pemetrexed Exposure 
(applicablefor patients continuing Durvalumab, Tremelimumab or
Pemetrexed treatment post final analysis of OS for superiority)
EX, EX4, EX7, EX8
Discontinuation (applicable for patients
continuing Durvalumab, Tremelimumab & Pemetrexed treatment
post final analysis of OS for superiority)
DOSDISC, DOSDISC1, DOSDISC4, 
DOSCDISC7, DOSDISC8
Survival assessment
SURVIVE
Statement of death
DEATH
Subsequent anti-cancer therapy
CAPRX1, CAPRXR2
All AEs/SAEs experienced by patients whilst receiving treatment 
or within 90 days of treatment discontinuing.
If SAE is reported then all data relevant to the SAE (e.g. 
concomitant medications, laboratory data, dosing data, new 
medical or surgical history) should be submitted under 
"Description of AE" as part of the SAE report 
AE, SERAE
WHO/ECOG Performance Status
PSTAT
Vital signsa
VS
Full physical examination
PE
12-lead ECGb
EG
Laboratory assessments Including
1) Clinical Chemistryc
2) Hematologyc
3) APTT and INRc
4) TSH, free T3, and free T4 c, d
5) Urinalysis
6) Pregnancy Teste
LB, LB3, LB4, LB5, LB6, PREG
a
Body weight will be recorded along with vital signs.
b
Any clinically significant cardiovascular findings require confirmation by ECG.
c
Results for urea and electrolytes, full blood count, and liver function tests must be available before commencing an infusion
(samples must have been obtained within 3 days prior to the infusion).
d
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.
e
Pregnancy test will be performed in women of childbearing potential only.  A urine or serum pregnancy test is acceptable.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
173(225)
Table 13
Schedule of study assessments and relevant eCRF pages to be completed 
during long-term follow-up (12 months after DCO for final analysis of OS 
for superiority)
(* Visit windows and timepoint for assessment should be performed as per details outlined in Table 2 for 
patients onoing study treatment and in table 3 for patients in follow-up period.)
Assessment
Relevant eCRF page
Durvalumab, Tremelimumab & Pemetrexed Exposure (applicable
for patients continuing Durvalumab, Tremelimumab or 
Pemetrexed treatment post final analysis of OS for superiority)
EX,  EX4, EX7, EX8
Discontinuation (applicable for patients
continuing Durvalumab, Tremelimumab & Pemetrexed treatment 
post final analysis of OS for superiority)
DOSDISC, DOSDISC1, DOSDISC4, 
DOSCDISC7, DOSDISC8
Survival assessment 
SURVIVE
Statement of death
DEATH
Subsequent anti-cancer therapy 
CAPRX1, CAPRXR2
All SAEs experienced by patients whilst receiving treatment or 
within 90 days of treatment discontinuing.
If SAE is reported then all data relevant to the SAE (e.g. 
concomitant medications, laboratory data, dosing data, new 
medical or surgical history) should be submitted under 
"Description of AE" as part of the SAE report 
SERAE
WHO/ECOG Performance Status
PSTAT
The study may be terminated at individual centres once there are no longer any patients being 
treated or in overall survival follow up or once the final DCO for the study has cored and all 
queries at that centre have been resolved. 
Also, The study may be terminated at individual centers if the study procedures are not being 
performed according to 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 durvalumab and/or tremelimumab.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
174(225)
9.4
Data management by AstraZeneca or delegate
Data management will be performed by AstraZeneca Data Management Centre staff 
according to the Data Management Plan.  
The data collected through third-party sources will be obtained and reconciled against study 
data. 
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 WHO Drug Dictionary.  
Classification coding will be performed by the Medical Coding Team at the AstraZeneca Data 
Management Centre.
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.
Data collection per section 9.3 will continue post DCO for final analysis of OS for superiority
for collection of limited data in long term survivors.
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.
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory(ies) 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 Council for Harmonisation 
(ICH)/GCP, applicable regulatory requirements, and the AstraZeneca policy on Bioethics and 
Human Biological Samples.  

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
175(225)
10.2
Patient data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
10.3
Ethics and regulatory review
An EC/IRB should approve the final study protocol, including the final version of the 
Informed Consent Form 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 EC/IRB, and the Principal Investigator to the Investigator and study site staff.
The opinion of the EC/IRB should be given in writing.  The head of the study site should 
submit a notification of direction/determination as well as the EC/IRB written approval to 
AstraZeneca and the Principal Investigator before enrollment of any patient should into the 
study.
The EC/IRB should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
The head of the study site should seek the opinion of the EC/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 one year.  The Principal Investigator should submit progress reports to 
the EC/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, should be approved by the national regulatory authority with notification 
provided, according to local regulations.  AstraZeneca will handle the distribution of any of 
these documents to the national regulatory authorities.
AstraZeneca will provide Regulatory Authorities, EC/IRB, the head of the study site and the 
Principal Investigator with safety updates/reports according to local requirements.
The head of the study site should submit a written report to the EC/IRB providing the details 
of all safety relative 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
∀
Ensure that each patient is notified that he or she is free to discontinue from the 
study at any time

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
176(225)
∀
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.
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 (revised clinical study protocol).
The amendment 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 
revised protocols.
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.
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. 
If required by local regulations, any administrative change will be communicated to or 
approved by each EC/IRB.
For sites in Japan: 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 center's Informed Consent Form, then 
AstraZeneca and the center’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.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
177(225)
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 purposes of an audit 
or inspection are to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and to determine whether 
data were recorded, analyzed, and accurately reported according to the Clinical Study 
Protocol, GCP, guidelines of the ICH, and any applicable regulatory requirements.  The 
Investigator will contact AstraZeneca immediately if contacted by a regulatory agency about 
an inspection at the center.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
178(225)
11.
LIST OF REFERENCES
Aaronson et al 1993
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst 1993;85(5):365-76.
Alexandrov et al 2013
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Blankin AV et al. 
Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415-21.
Antonia et al 2016a
Antonia S, Goldberg SB, Balmanoukian A, Chaft JE, Sanborn RE, Gupta A et al. Safety and 
antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a 
multicentre, phase 1b study. Lancet Onc 2016;17(6):299-308.
Antonia et al 2016b
Antonia SJ, Kim SW, Spira AI, Ahn MJ, SHI Ou, Stjepanovic N et al. Safety and clinical 
activity of durvalumab (MEDI4736), an anti-PD-L1 antibody, in treatment-naïve patients with 
advanced non‒small-cell lung cancer. J Clin Oncol 2016;34(suppl; abstr 9029).
Bergman et al 1994
Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M; EORTC Study Group on 
Quality of Life. The EORTC QLQ-LC13: a modular supplement to the EORTC Core Quality 
of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials. 
Eur J Cancer 1994;30A(5):635-42.
Bonomi 2010
Bonomi PD. Implications of key trials in advanced nonsmall cell lung cancer. 
Cancer 2010;116(5):1155-64.
Borghaei et al 2018
Borghaei H, Hellmann MD, Paz-Ares L, Ramalingam SS, Reck M, O’Byrne KJ et al. 
Nivolumab + Ipilimumab, Nivolumab + Chemotherapy, and Chemotherapy in Chemo-Naïve 
Patients With Advanced Non-Small Cell Lung Cancer and <1% Tumor PD-L1 Expression: 
Results From CheckMate 227. J Clin Oncol 36, 2018 (Suppl: abstr 9001).
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
179(225)
Brahmer et al 2012
Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, Topalian SL, Hwu P et al. Safety and activity 
of anti-PD-L1 antibody in patients with advanced cancer. 
N Engl J Med 2012;366(26):2455-65.
Burman et al 2009
Burman CF, Sonesson C, Guilbaud O. A recycling framework for the construction of 
Bonferroni-based multiple tests. Stat Med 2009;28(5):739-61.
Carbone et al 2017
Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M et al. First-line nivolumab in 
stage IV or recurrent non-small-cell lung cancer. N Engl J Med 2017;376(25):2415-26.
Ciuleanu et al 2009
Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E et al. Maintenance 
pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-
cell lung cancer: a randomized, double-blind, phase 3 study. Lancet 2009;374(9699):1432-40.
Cox 1972
Cox DR. Regression models and life-tables. J Royal Stat Society 1972;Series B 34(2):187-
220.
D’Addario et al 2010
D’Addario G, Fruh M, Reck M, Baumann P, Klepetko W, Felip E et al. Metastatic non-small-
cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. 
Ann Oncol 2010;21(Suppl 5):116-9.
Dunn et al 2004
Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. 
Annu Rev Immunol 2004;22:329-60.
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al. New response 
evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). 
Eur J Cancer 2009;45(2):228-47.
Ellis et al 2008
Ellis S, Carroll KJ, Pemberton K. Analysis of duration of response in oncology trials. 
Contemp Clin Trials 2008;29(4):456-65.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
180(225)
Fayers et al 2001
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A; EORTC Quality 
of Life Group. The EORTC QLQ-C30 Scoring Manual. 3rd ed. Brussels: European 
Organisation for Research and Treatment of Cancer; 2001.
Fairman et al 2014
Fairman D, Narwal R, Liang M, Robbins PB, Schneider A, Chavez C et al. Pharmacokinetics 
of durvalumab, a fully human anti-PDL1 monoclonal antibody, in patients with advanced 
solid tumours. Journal of Clinical Oncology, 2014 ASCO Annual Meeting Abstracts;32(5s): 
(suppl; abstr 2602).
FDA Guidance 2011
Food and Drug Administration. Guidance for Industry: Clinical trial endpoints for the 
approval of non-small-cell lung cancer drugs and biologics. June 2011. Available from: URL: 
http://www.fda.gov/downloads/Drugs/Guidances/UCM259421.pdf. Accessed 21 May 2014.
Fehrenbacher et al 2016
Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J et al. 
Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer 
(POPLAR): a multicentre, open-label, Phase 2, randomised, controlled trial. 
Lancet 2016;387(10030):1837-46.
Fife and Bluestone 2008
Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the 
CTLA-4 and PD-1 pathways. Immunol Rev 2008;224:166-82.
Fleischer et al 2011
Fleischer F, Gaschler-Markefski B, Bluhmki E. How is retrospective independent review 
influenced by investigator-introduced informative censoring: a quantitative approach. 
Stat Med 2011;30(29):3373-86.
Gail and Simon 1985
Gail M, Simon R. Tests for qualitative interactions between treatment effects and patient 
subsets. Biometrics 1985;41(2):361–72.
Gainor 2016
Gainor JF. Moving programmed death-1 inhibitors to the front lines in non-small-cell lung 
cancer. J Clin Oncol. 2016;34(25):2953-5.
Garassino et al 2016
Garassino MC, Vansteenkiste J, Kim JH, Lena H, Mazieres J, Powderly J et al. Durvalumab in 
≥3rd-line locally advanced or metastatic, EGFR/ALK wild-type NSCLC: results from the 
Phase 2 ATLANTIC study. IASLC 17th World Conference on Lung Cancer. 2016.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
181(225)
Garon et al 2015
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP et al. KEYNOTE-001 
Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. 
N Engl J Med 2015;372(21):2018-28.
Gettinger et al 2015
Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA et al. Overall survival and 
long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) 
in patients with previously treated advanced non-small-cell lung cancer. 
J Clin Oncol 2015;33(18):2004-12.
Glimm et al 2009
Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group-sequential 
trials. Stat Med 2009;29(2):219-28.
GLOBOCAN 2012
GLOBOCAN. Lung cancer, estimated incidence, mortality and prevalence worldwide in 
2012. International Agency for Research on Cancer, World Health Organization; Lyon, 2012 
[cited 16 April 2015]. Available from: URL: 
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx.
Gandara et al 2018
Gandara DR, Paul SM, Kowanetz M, Schleifman E, Zou W, Li Y, Rittmeyer A et al. Blood-
based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer 
patients treated with atezolizumab. Nature Medicine 2018, Available from: URL: 
https://doi.org/10.1038/s41591-018-0134-3.
Hellmann et al 2017
Hellmann MD, Rizvi NA, Goldman JW, Gettinger SN, Borghaei H, Brahmer JR et al. 
Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer 
(CheckMate 012): results of an open-label, phase 1, multicohort study. 
Lancet Oncol 2017;18(1):31-41.
Hellmann et al 2018
Hellmann MD, Ciuleanu T-E, Pluzanski A, Lee JS, Otterson GA, Audigier‑Valette C et al. 
Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. 
NEJM.org (posted on April 16, 2018, DOI: 10.1056/NEJMoa1801946).
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
182(225)
Hirano et al 2005
Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and 
PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. 
Cancer Res 2005;65(3):1089-96.
Holm 1979
Holm S. A simple sequentially rejective multiple test procedure. 
Scand J Statistics 1979;6:65-70.
Howlander et al 2014
Howlander N, Noone AM, Krapcho M, Garshell J, Neyman N, Altekruse SF, et al. SEER 
cancer statistics review, 1975-2011. Bethesda (MD): National Cancer Institute. Available 
from: URL:http://seer.cancer.gov/csr/1975_2011/. Based on November 2013 SEER data 
submission (posted to the SEER web site, April 2014).
IASLC Staging Manual in Thoracic Oncology 2016
Rami-Porta R, ed. Staging manual in thoracic oncology (2nd edition; includes 8th edition 
tumor, node, and metastasis classification (TNM) information for lung cancer, plural 
mesothelioma, thymic malignancies, and carcinoma of the oesophagus and of 
oesophagogastric Junction). IASLC 2016. (Available on request).
Iwai et al 2002
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor 
cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. 
Proc Natl Acad Sci USA 2002;99(19):12293-7.
Juergens et al 2016
Juergens RA, Hao D, Laurie SA, Mates M, Tehfe M, Bradbury P, et al. Pemetrexed / cisplatin 
+ durvalumab +/- tremelimumab in patients with advanced non-squamous NSCLC: A CCTG 
phase IB study - IND.226 Cohort 1. IASLC 17th World Conference on Lung Cancer. 2016.
Keir et al 2008
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. 
Annu Rev Immunol 2008;26:677-704.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
183(225)
Klein et al 2007
Klein JP, Logan B, Harhoff M, Andersen PK. Analyzing survival curves at a fixed point in 
time. Stat Med 2007;26(24):4505-19.
Lan and DeMets 1983
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. 
Biometrika 1983;70:659-63.
Langer et al 2016
Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF et al. 
Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous 
non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 
study. Lancet Oncol 2016;17(11):1497-1508.
Larkin et al 2015
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD et al. Combined 
nivolumab and ipilimumab or monotherapy in untreated melanoma. 
N Engl J Med 2015;373(1):23-34.
Narwal et al 2013
Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an 
investigational anti-interferon-α monoclonal antibody, in systemic lupus erythematosus. 
Clin Pharmacokinet 2013;52(11):1017-27.
NCCN 2014
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN 
Guidelines®). Non-Small Cell Lung Cancer. Version 4.2014. Available from: URL: 
www.nccn.org.
Ng et al 2006
Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of pertuzumab 
in cancer patients based on population pharmacokinetic analysis. 
Pharm Res 2006;23(6):1275-84.
Nishino et al 2013
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a 
common language for tumor response to immunotherapy: Immune-related response criteria 
using unidimensional measurements. Clin Cancer Res 2013;19(14):3936-43.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
184(225)
Okazaki and Honjo 2007
Okazaki T and Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application.
Int Immunol 2007;19(7):813-24.
Okudaira et al 2009
Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, et al. Blockade of B7-
H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model. 
Int J Oncol 2009;35(4):741-9.
Pardoll 2012
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. 
Nat Rev Cancer 2012;12(4):252-64.
Paz-Ares et al 2013
Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P et al. PARAMOUNT: 
Final overall survival results of the phase III study of maintenance pemetrexed versus placebo 
immediately after induction treatment with pemetrexed plus cisplatin for advanced 
nonsquamous non-small-cell lung cancer. J Clin Oncol 2013;31(23):2895-902.
Pazdur 2008
Pazdur R. Endpoints for assessing drug activity in clinical trials. 
Oncologist 2008;13(Suppl 2):19-21.
Pisters and LeChevalier 2005
Pisters KM, LeChevalier T. Adjuvant chemotherapy in completely resected non-small-cell 
lung cancer. J Clin Oncol 2005;23(14):3270-8.
Postow et al 2015
Postow MA, Chesney J, Pavlick AC, Robert C, Grossman K, McDermott D et al. Nivolumab 
and ipilimumab versus ipilimumab in untreated melanoma. 
N Engl J Med 2015;372(1):2006-17.
Powles et al 2014
Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) 
treatment leads to clinical activity in metastatic bladder cancer. 
Nature 2014;515(7528):558-62.
CCI
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
185(225)
Qin et al 2016
Qin A, Coffey DG, Warren EH, Ramnath N. Mechanisms of immune evasion and current 
status of checkpoint inhibitors in non-small cell lung cancer. 
Cancer Med 2016;5(9):2567-78.
Reck et al 2014
Reck M, Popat S, Reinmuth N, De Ruysscher D, Kerr KM, Peters S; ESMO Guidelines 
Working Group. Metastatic non-small-cell lung cancer (NSCLC): ESMO clinical practice 
guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014;25(Suppl 3):iii27-39.
Reck et al 2016
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A et al. Pembrolizumab 
versus chemotherapy for PD-L1–positive non–small-cell lung cancer. 
N Engl J Med. 2016;375(19):1823-33.
Rizvi et al 2015a
Rizvi N, Brahmer J, Ou S-H, Segal NH, Khleif SN, Hwu WJ. Safety and clinical activity of 
MEDI4736, an anti-programmed cell death-ligand-1 (PD-L1) antibody, in patients with 
nonsmall cell lung cancer (NSCLC). J Clin Oncol 2015;33:Abstract 8032.
Rizvi et al 2015b
Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ et al. Mutational 
landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. 
Science 2015;348(6230):124-8
Rizvi et al 2016
Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S et al. 
Nivolumab in combination with platinum‐based doublet chemotherapy for first-line treatment 
of advanced non-small-cell lung cancer. J Clin Oncol 2016;34(25):2969-79.
Sandler et al 2006
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A et al. Paclitaxel-carboplatin 
alone or with bevacizumab for non-small-cell lung cancer. 
N Engl J Med 2006;355(24):2524-50.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
186(225)
Scagliotti et al 2008
Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C et al. Phase III 
study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-
naive patients with advanced-stage non-small-cell lung cancer. 
J Clin Oncol 2008;26(21):3543-51.
Schadendorf et al 2013
Schadendorf D, Hodi FS, Robert C et al. Pooled analysis of long-term survival data from 
phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable 
melanoma [abstract 24]. Presented at European Cancer Congress 2013 (ECCO-ESMO-
ESTRO); 27 September to 01 October 2013; Amsterdam, The Netherlands. 
Schiller et al 2002
Schiller JH, Harringdon D, Belani CP, Langer C, Sandler A, Krook J et al. Comparison of 
four chemotherapy regimens for advanced non-small-cell lung cancer. 
N Engl J Med 2002;346(2):92-8.
Segal et al 2015
Segal NH, Ou S-HI, Balmanoukian AS, Fury MG, Massarelli E, Brahmer JR et al. Safety and 
efficacy of MEDI4736, an anti-PD-L1 antibody, in patients from a squamous cell carcinoma 
of the head and neck (SCCHN) expansion cohort. J Clin Oncol 2015;33:Abstract 3011.
Socinski et al 2016
Socinski MA, Creelan B, Horn L, Reck M, Paz-Ares L, Steins M et al. CheckMate026: A 
phase 3 trial of nivolumab vs investigator's choice of platinum-based doublet chemotherapy as 
first-line therapy for stage IV/recurrent programmed death ligand 1–positive NSCLC. 
ESMO 2016.
Stewart et al 2015
Stewart R, Morrow M, Hammond SA, Mulgrew K, Marcus D, Poon E et al. Identification and 
characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. 
Cancer Immunol Res 2015;3(9):1052-62.
Sun and Chen 2010
Sun X, Chen C. Comparison of Finkelstein's Method with the conventional approach for 
interval-censored data analysis. Stat Biopharm Res 2010;2(1):97-108.
Tarhini and Kirkwood 2008
Tarhini AA, Kirkwood JM. Tremelimumab (CP-675,206): a fully human anticytotoxic 
T lymphocyte-associated antigen 4 monoclonal antibody for treatment of patients with 
advanced cancers. Expert Opin Biol Ther 2008;8(10):1583-93.
CCI

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 6.0
Date 09 July 2021
187(225)
Topalian et al 2012
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. 
N Engl J Med 2012;366(26):2443-54.
Wang et al 2009
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size based dosing 
of monoclonal antibodies in adult clinical trials. J Clin Pharmacol 2009;49(9):1012-24.
Wang et al 2014
Wang E, Kang D, Bae KS, Marshall MA, Pavlov D, Parivar K. Population pharmacokinetic 
and pharmacodynamics analysis of tremelimumab in patients with metastatic melanoma. 
J Clin Pharmacol 2014;54(10):1108-16.
Whitehead and Whitehead 1991
Whitehead A, Whitehead J. A general parametric approach to the meta-analysis of 
randomized clinical trials. Stat Med 1991;10(11):1665-77.
Wolchok et al 2013
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM et al. Nivolumab 
plus ipilimumab in advanced melanoma. N Engl J Med 2013;369(2):122-33
Zhang et al 2008
Zhang C, Wu S, Xue X, Li M, Qin X, Li W et al. Anti-tumor immunotherapy by blockade of 
the PD-1/PD-L1 pathway with recombinant human PD-1-IgV. 
Cytotherapy. 2008;10(7):711-9.
Zhang et al 2012
Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing of 
therapeutic peptides and proteins in adults. J Clin Pharmacol 2012;52(1):18-28.

Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 10 March 2017
188(225)
Appendix A
Additional Safety Information
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS 
ADVERSE EVENT 
Life threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, 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 judgment 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 
judgment must be used. 
∀
Angioedema not severe enough to require intubation but requiring IV 
hydrocortisone treatment
∀
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine
∀
Intensive treatment in an emergency room or at home for allergic bronchospasm
∀
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization
∀
Development of drug dependency or drug abuse

Clinical Study Protocol Appendix A
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 10 March 2017
189(225)
A guide to interpreting the causality question
When making an assessment of causality, consider the following factors when deciding if 
there is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
∀
Time Course.  Exposure to suspect drug.  Has the patient actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?
∀
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
∀
De-challenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?
∀
No alternative cause.  The AE cannot be reasonably explained by another 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.

Clinical Study Protocol Appendix B
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 10 March 2017
190(225)
Appendix B
IATA 6.2 Guidance Document
LABELING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories.  For transport purposes the classification of infectious substances according to 
risk groups was removed from the Dangerous Goods Regulations in the 46th edition (2005).  
Infectious substances are now classified either as Category A, Category B, or Exempt.  There 
is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening, or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are, for example, 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, for example, Hepatitis A, B, C, D, and E 
viruses and human immunodeficiency virus types 1 and 2.  They are assigned the following 
UN number and proper shipping name:
∀
UN3373 - Biological Substance, Category B
∀
Are to be packed in accordance with UN3373 and IATA 650
Exempt are 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.

Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 10 March 2017
191(225)
Appendix C
CCI
CCI

Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 10 March 2017
192(225)
CCI

Clinical Study Protocol Appendix C
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 10 March 2017
193(225)
CCI

Clinical Study Protocol Appendix D
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 29 March 2019
194(225)
Appendix D
Hy’s Law
ACTIONS REQUIRED IN CASES OF INCREASES IN LIVER 
BIOCHEMISTRY AND EVALUATION OF HY’S LAW
D1. 
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 biochemistry.  Specific guidance on managing liver abnormalities can be 
found in Sections 5.2.1 and 6.3.8 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.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory.
The Investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in the 
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 AEs and SAEs according to the outcome of the review and assessment in line with 
standard safety reporting procedures.
D2.
Definitions
Potential Hy’s Law (PHL)
AST or ALT ≥3 × 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). 

Clinical Study Protocol Appendix D
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 29 March 2019
195(225)
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 (eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug).  
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
D3.
Identification of Potential Hy’s Law cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:
∀
ALT ≥3 × ULN
∀
AST ≥3 × ULN
∀
TBL ≥2 × ULN
Local laboratories being used:
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
∀
Notify the AstraZeneca representative
∀
Determine whether the patient meets PHL criteria (see 2 definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits
∀
Promptly enter the laboratory data into the laboratory eCRF
D4.
Follow-up
a. Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:
∀
Inform the AstraZeneca representative that the patient has not met PHL criteria
∀
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol
b. Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:
Determine whether PHL criteria were met at any study visit prior to starting study treatment 
(see Section 6.3.8)

Clinical Study Protocol Appendix D
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 29 March 2019
196(225)
Notify the AstraZeneca representative who will then inform the central Study Team 
∀
Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting.
∀
For subjects that met PHL criteria prior to starting IMP, the investigator is not required to 
submit a PHL SAE unless there is a significant change# in the subject’s condition
∀
The Study Physician contacts the Investigator, to provide guidance, discuss and agree 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 3 Liver eCRF Modules as information becomes available
∀
# A ‘significant’ change in the subject’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.
D5.
Review and assessment of Potential Hy’s Law cases
The instructions in this section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from date PHL criteria was met.  The AstraZeneca Global Clinical Lead or equivalent and 
Global Safety Physician will also be involved in this review together with other subject matter 
experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.

Clinical Study Protocol Appendix D
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 29 March 2019
197(225)
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for 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: update the previously submitted 
Potential Hy’s Law SAE and AE CRFs accordingly with the new 
information(reassessing event term: causality and seriousness criteria) following the 
AZ standra proess.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:
∀
Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
process. 
!
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 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:
∀
Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP 
and seriousness criteria is medically important, according to CSP process for SAE 
reporting.
∀
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are still met.  Update the previously submitted PHL 
SAE report following CSP process for SAE reporting, according to the outcome of 
the review and amending the reported term if an alternative explanation for the liver 
biochemistry elevations is determined.
D6.
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:

Clinical Study Protocol Appendix D
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 29 March 2019
198(225)
∀
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 TBL) 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.
D7.
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 (eg, 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 Appendix D, Section D4 for reporting PHL as a n SAE.
∀
If Yes:
Determine if there has been a significant change in the patient’s condition# compared with 
when PHL criteria were previously met
∀
If there is no significant change no action is required
∀
If there is a significant change follow the process described in Section D4 for 
reporting PHL as a n SAE.
# 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 TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 

Clinical Study Protocol Appendix D
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 29 March 2019
199(225)
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
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’

Clinical Study Protocol Appendix E
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 09 July 2021
200(225)
Appendix E
Guidelines for Evaluation of Objective Tumor Response 
GUIDELINES FOR EVALUATION OF OBJECTIVE TUMOR 
RESPONSE USING RECIST 1.1 CRITERIA (RESPONSE EVALUATION 
CRITERIA IN SOLID TUMORS, VERSION 1.1)
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 radiological 
progression.
Definition of measurable, non-measurable, target and non-target lesions
Only patients with measurable target disease at baseline should be included in the study.  
Measurable disease is defined by the presence of at least one measurable lesion which has not 
been previously irradiated.  
Tumor lesions selected for screening biopsy should not be selected as target lesions (TLs), 
unless imaging occurred at least ~2 weeks after biopsy, allowing time for healing.
Measurable:
A lesion that can be accurately measured at baseline as ≥10 mm in the longest diameter 
(except lymph nodes which must have short axis1diameter of ≥15 mm) with computed 
tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate 
repeated measurements.
Non-measurable:
∀
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis diameter at baseline2).
∀
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.
∀
Previously irradiated lesions3 (see exception below for Target lesions)
                                               
1   The short axis is defined as the longest axis perpendicular to long axis
2   Nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded or 
followed as non-target lesions (NTLs).
3.  Localised post-radiation changes which affect lesion sizes may occur.  Therefore, lesions that have been 
previously irradiated are typically considered non-measurable and should be selected as NTL at baseline and 
followed up as part of the NTL assessment.

Clinical Study Protocol Appendix E
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 09 July 2021
201(225)
∀
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 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 (local/regional and distant), are collectively 
considered as a single organ, with a maximum of 2 lymph nodes as TLs.  A bilateral organ 
(eg, adrenal glands), a segmented organ (eg, liver), or multilobed organ (eg, lung) is each 
considered as a single organ.
If there are no other target lesions available, previously irradiated lesions may be considered 
measurable and selected as TLs provided they fulfil the other criteria for measurability. Tumor 
lesions selected for screening biopsy should not be selected as TLs, unless imaging occurred 
at least ~2 weeks after biopsy, allowing time for healing.
Non-target lesions:
Additional measurable lesions not recorded as TL and non-measurable lesions (or sites of 
disease) should be identified as NTLs at baseline.
Methods of assessment
∀
The same method of assessment on the same imaging 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 1.1 assessment is provided in 
Table 14, and those excluded from tumor assessments for this study are highlighted 
with the rationale provided.

Clinical Study Protocol Appendix E
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 09 July 2021
202(225)
Table 14
Summary of methods of assessment
Target lesions 
Non-target lesions
New lesions
CT (preferred)
MRI
CT (preferred)
MRI
Plain X-ray
Chest X-ray
CT (preferred)
MRI
Plain X-ray
Chest X-ray
Bone scan
FDG-PET
CT  Computed tomography; FDG-PET  18F-Fluoro-deoxyglucose positron emission tomography; MRI  Magnetic 
resonance imaging. 
CT and MRI 
CT and MRI, each preferably with intravenous (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 CT examinations of the chest and abdomen (including the entire liver 
and both adrenal glands) will be used to assess tumor burden at baseline and follow-up visits.  
Any other areas of disease involvement (eg, pelvis, brain) 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 examination of the chest and an MRI with IV contrast of the 
abdomen (and pelvis) is appropriate.  In patients with severely compromised renal function a 
non-contrast CT examination of the chest and abdomen is appropriate.  For brain lesion 
assessment, MRI with IV contrast is the preferred method over IV 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.
Clinical examination 
Clinical examination of tumors (by visual inspection or manual palpation) will not be used for 
RECIST 1.1 assessments. Tumors identified by clinical examination will need to be assessed 
by correlative CT or MRI anatomical scans.
Chest X-ray
Chest X-ray assessment will not be used for assessment of TL.  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 RECIST 1.1 assessment of tumors as it is not a 
reproducible method, does not provide an accurate assessment of tumor size, and it is 

Clinical Study Protocol Appendix E
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 09 July 2021
203(225)
subjective and operator dependent.  Tumors identified by ultrasound will need to be assessed 
by correlative CT or MRI anatomical scan.
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 on cytological or histological (biopsy) samples will not be used for tumor 
response assessments as per RECIST 1.1.
Histology and Cytology 
Histology on tumor biopsy samples will not be used as part of the tumor response assessment 
as per RECIST 1.1.  
Results of cytological examination for the neoplastic origin of any fluid accumulation/effusion 
(e.g. ascites, pericardial effusion, pleural effusion) that appears or worsens during the study 
will not be used as part of the tumor response assessment in this study. An effusion that 
appears or significantly worsens (from trace to large) radiologically by CT/MRI anatomical 
scans will be considered to be disease progression due to New Lesions or progression of 
NTLs, respectively.
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 may be recorded in case positive hot-spots 
appear on a bone scan that were not present on a previous bone scan; however, a newly 
observed equivocal hot-spot on a bone scan which cannot be verified with correlative imaging 
(CT, MRI, X-ray) of the same anatomical region shall not be the only trigger for a progressive 
disease (PD) assessment at that timepoint. 
FDG-PET scan
18F-Fluoro-deoxyglucose positron emission tomography/computed tomography 
(FDG-PET/CT) scans may be used as a method for identifying new lesions, according to the 
following algorithm:  New lesions will be recorded where there is positive 
18F-Fluoro-deoxyglucose uptake3 not present on baseline or prior 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 or prior FDG-PET scan available, and no evidence of new lesions on CT/MRI scans 
                                               
3

Clinical Study Protocol Appendix E
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 09 July 2021
204(225)
then follow-up CT/MRI assessments should be continued, scheduled as per protocol or 
clinical indicated, in order to verify new lesions.
At present, low dose or attenuation correction CT portions of a combined FDG-PET/CT scan 
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 tumor 
measurements by RECIST 1.1.  In exceptional situations, if a site can document that the CT 
performed, as part of a PET/CT examination, is of identical diagnostic quality (with IV 
contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT can be used 
for RECIST 1.1 tumor assessments.  Caution that the PET portion of the PET/CT could 
introduce additional 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 the entire liver and both 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, eg, new lesions at 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 to the start of IP.  
Efficacy by RECIST 1.1 for all patients will be assessed according to the schedules described 
in Table 2 and Table 3 of the CSP.  If an unscheduled assessment is performed, and the patient 
has not progressed, every attempt should be made to perform the subsequent assessments at 
their scheduled imaging visits.  
For patients who discontinue study drug due to toxicity in the absence of clinical progression 
or unequivocal radiologic evidence of progression, tumor assessments should be continued 
according to the original imaging schedule (Table 2 and Table 3 of the CSP).
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.  TLs should be selected on the basis of their size 
(longest diameter for non-nodal lesions or short axis diameter 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 

Clinical Study Protocol Appendix E
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 09 July 2021
205(225)
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 TL has completely disappeared, the longest diameter should be recorded as 
0 mm. If a lesion appears in the same location on a subsequent scan, it will be 
recorded as a New Lesion.
∀
If a TL splits into two 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).  
∀
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 eg, 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 for that 
time-point and in all subsequent TL assessments (see ‘Not evaluable’ in Table 15). 
If a TL has been completely removed (surgery) or disappears following an 
intervention, the diameter should be recorded as 0 mm.
Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumor visit 
response for TL (see Table 15).

Clinical Study Protocol Appendix E
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 09 July 2021
206(225)
Table 15
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
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 (eg 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.
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 16).
Table 16
Evaluation of non-target lesions
Complete response 
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 one or more NTL.
Progression 
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 
Only relevant when one 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.

Clinical Study Protocol Appendix E
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 09 July 2021
207(225)
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 one or more NTLs is usually 
not sufficient to qualify for unequivocal progression status.
New lesions
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
one or more new lesions is assessed as progression.  The finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor.  If a new lesion is 
equivocal, for example because of its small size, the treatment and tumor assessments should 
be continued until the previously new lesion has been assessed as unequivocal and then the 
progression date should be declared using the date of the initial scan when the new lesion first 
appeared.
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. 
If a TL has completely disappeared and a lesion appears in the same location on a subsequent 
scan, it will be recorded as a New Lesion.
Symptomatic deterioration
Symptomatic (clinical) 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 clinically feasible on their regular imaging schedule.
Evaluation of overall visit response
The overall visit response will be derived using the algorithm shown in Table 17.
Table 17
Overall visit response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
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
NE
Non PD or NE
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.

Clinical Study Protocol Appendix E
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 09 July 2021
208(225)
Confirmation of Radiological Progression
Patients who are clinically stable at an initial RECIST 1.1-defined PD can continue to receive 
study treatment at the discretion of the Investigator and patient. A subsequent follow-up scan 
is collected after the initial RECIST 1.1-defined PD, preferably at the next (and no later than   
the next) scheduled imaging visit, and no less than 4 weeks after the prior assessment of PD, 
and the Confirmation of Radiological Progression criteria described below are applied for 
tumor assessments of this follow-up scan. Patients with confirmed radiological PD who 
continue to receive study treatment at the discretion of the Investigator (following consultation 
with AstraZeneca) and patient can receive treatment until no longer having clinical benefit and 
should continue on their regular imaging schedule.
Confirmation of Radiological Progression Criteria:
Confirmation of radiological progression guidelines are used to evaluate scans subsequent to a 
prior radiological PD. An immediate prior RECIST 1.1-defined radiologic PD would be 
considered confirmed if any of the following criteria are met in the subsequent follow-up scan 
(acquired preferably at the next regularly scheduled imaging visit but no sooner than 4 weeks 
after the RECIST 1.1-defined PD 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 to nadir
∀
and/or significant progression (worsening) of NTLs at the follow-up scan timepoint 
compared with the immediate prior timepoint 
∀
and/or additional (brand) new unequivocal lesions at the follow-up scan timepoint
∀
and/or significant progression (worsening) of pre-existing new lesions at the 
follow-up scan timepoint compared with the immediate prior timepoint
Note: In order to have confirmed radiological progression, there should be 2 consecutive PDs, 
the first PD by RECIST 1.1 and the second PD using the confirmation of radiological 
progression criteria (above).  If radiologic progression is not confirmed, in the absence of 
significant clinical deterioration, then the patient may continue with assessments until the next 
RECIST 1.1-defined PD, which will also require a follow-up scan evaluated using the 
confirmation of radiological progression criteria.  If the first PD (by RECIST 1.1) is not 
confirmed by the immediate next scan, then the Investigator should not change the PD 
assessment of the first scan.
Central Review
All images will be collected, quality checked, and stored centrally by an Imaging CRO 
appointed by AstraZeneca.  Guidelines for image acquisition, storage at the investigative site 
as source data, and transfer to the imaging CRO will be provided in a separate document.  A 
blinded independent central review (BICR) of images will be performed at the discretion of 
AstraZeneca. Results of these independent reviews will not be communicated to Investigators, 
and results of Investigator RECIST 1.1 assessments will not be shared with the central 

Clinical Study Protocol Appendix E
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 09 July 2021
209(225)
reviewers. The management of patients will be based in part upon the results of the 
RECIST 1.1 assessment conducted by the Investigator.
Further details of the BICR will be documented in the Independent Review Charter, (also 
referred to as ‘Imaging Charter’).
Specifications for radiological anatomical 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/deidentification, 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 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 should be contiguous throughout all the anatomic region 
of interest.
The most critical CT image acquisition parameters for optimal tumor evaluation using 
RECIST 1.1 are anatomic coverage, contrast administration, slice thickness, and 
reconstruction interval.
a.  Anatomic coverage: Optimal anatomic coverage for most solid tumors is the chest and 
abdomen.  Coverage should encompass all areas of known predilection for metastases in the 
disease under evaluation and should additionally investigate areas that may be involved based 
on signs and symptoms of individual patients.  Because a lesion later identified in a body part 
not scanned at baseline would be considered as a new lesion representing disease progression, 
careful consideration should be given to the extent of imaging coverage at baseline and at 
subsequent follow-up time points.  This will enable better consistency not only of tumor 
measurements but also identification of new disease.
b. IV contrast administration: Optimal visualization and measurement of metastases in 
solid tumors 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 

Clinical Study Protocol Appendix E
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 09 July 2021
210(225)
non-enhanced) should be performed should also be based on the tumor type, anatomic 
location of the disease and should be optimized 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 TLs 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 visualize 
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 pelvic) 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.
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 other anatomies eg pelvis, 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 
optimized for the specific body part being imaged as well as the scanner utilized.  CT of the 
chest is typically recommended over MRI due to significant motion artefacts (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.

Clinical Study Protocol Appendix E
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 3
Date 09 July 2021
211(225)
References
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al.  New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1).  
Eur J Cancer 2009;45(2):228-47.

Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 10 March 2017
212(225)
Appendix F
Patient Reported Outcomes

Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 10 March 2017
213(225)

Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 10 March 2017
214(225)

Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 10 March 2017
215(225)
CCI

Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 10 March 2017
216(225)
CCI

Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 10 March 2017
217(225)
CCI

Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 10 March 2017
218(225)
CCI

Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 10 March 2017
219(225)
CCI

Clinical Study Protocol Appendix F
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 10 March 2017
220(225)
CCI

Clinical Study Protocol Appendix G
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 09 July 2021
221(225)
Appendix G
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis, including COVID-19 Outbreak
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
agreement from the sponsor.
G 1
Reconsent of Study Participants During Study Interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Sections 0 to 0. Local and regional regulations and/or guidelines regarding 
reconsent of study participants should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should 
be signed at the participant’s next contact with the study site). Visiting the study sites for the 
sole purpose of obtaining reconsent should be avoided. 
G 2
Rescreening of Participants to Reconfirm Study Eligibility 
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened participants. The investigator should confirm this with the designated 
study clinical lead.
In addition, during study disruption there may be a delay between confirming eligibility of a 
participants and either enrolment into the study or commencing of dosing with study 
intervention. If this delay is outside the screening window specified in Section 4.1 the 
participant will need to be rescreened to reconfirm eligibility before commencing study 
procedures. This will provide another opportunity to re-screen a participant in addition to that 
detailed in Section 3.10.1. The procedures detailed in Section 4.1 must be undertaken to 
confirm eligibility using the same randomisation number as for the participant.

Clinical Study Protocol Appendix G
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 09 July 2021
222(225)
G 3
Home or Remote Visit to Replace On-site Visit (Where Applicable)
A qualified HCP from the study site or TPV service may visit the participants home/or other 
remote location as per local SOPs, as applicable. Supplies will be provided for a safe and 
efficient visit. The qualified HCP will be expected to collect information per the CSP.
G 4
Telemedicine Visit to Replace On-site Visit (Where Applicable)
In this appendix the term telemedicine visit refers to remote contact with the participants using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow AEs, concomitant medication to be reported and documented.
G 5
Data Capture During Telemedicine or Home/Remote Visits
Data collected during telemedicine or home/remote visits will be captured by the qualified 
HCP from the study site or TPV service in the source documents, or by the participant 
themselves.
G 6
COVID-19 Risk Assessment 
The safety of participants is of primary importance. Any potential risks of participating in the 
study, particularly with the added challenges due to COVID-19 outbreak, should be weighed 
against the anticipated benefit (see also principle 2.2 of ICH GCP). Investigators are advised 
to use clinical judgment in determining infection prevention precautions for study participants.
The emergence of SARS-CoV-2 presents a potential safety risk for cancer patients. 
Participants enrolling in this study may require more frequent visits to the site for study 
treatment administration and for study assessments compared to participants receiving 
standard of care. Therefore, several risk mitigation factors have been implemented related to 
study conduct during the COVID-19 outbreak, for patient management in an event of 
COVID-19, and actions to be taken on study treatment (see Section 0). With these measures in 
place, it is considered that the anticipated potential benefits for the participants enrolled in this 
study outweigh the potential risks. All implemented measures prioritise trial participant safety 
and data validity; in case these two conflict with each other, trial participant safety should 
always prevail (see also European Medicines Agency Guidance on the management of clinical 
trials during the COVID-19 [coronavirus] pandemic [EMA 2020]). 

Clinical Study Protocol Appendix G
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 09 July 2021
223(225)
Notably, participants with active COVID-19 infection confirmed by local laboratory testing
will not be eligible for study enrolment (see CSP Section 3.2, Exclusion Criterion 1). 
G 7
Potential Risks during COVID-19
Every effort should be made to follow the CSP. Section 0 provides a dose modification and 
management plan for participants with confirmed or suspected COVID-19 who are being 
treated with study intervention durvalumab and tremelimumab. The risk-benefit assessment 
should be carefully considered for each participant enrolling in the study based on the known 
safety risks related to COVID-19, individual needs, and local guidelines and restrictions. 
Investigators must continue to use their best clinical judgment in determining the most optimal 
care for participants and utmost diligence in determining their eligibility for study 
participation, continued study treatment, and overall assessment of benefit/risk of study 
treatment or participation.
The sponsor must be promptly notified of a site’s inability to perform study activities due to 
COVID-19 outbreak in order to minimise any potential risks.
G 8
New Participant Enrolment (Only applicable for China tail)
Study sites may continue to recruit new participants into the study provided the following 
activities to preserve study integrity can be met:
Upon discussion with the site monitor, the study site has confirmed the ability to enrol and 
manage new participants effectively and in compliance with the protocol.
Data will continue to be entered into the eCRF and queries resolved in a timely manner. 
Per CSP Exclusion Criterion 1 (see CSP Section 3.2), participants with uncontrolled 
intercurrent illness, including but not limited to, ongoing or active infection are not eligible for 
the study participation and hence such participants (including those who have confirmed 
COVID 19) should not be included for study participation.
G 9
Study Treatment Administration
If an AE or SAE is associated with COVID-19, the investigator should determine whether the 
participants’ treatment with investigational product should continue, be interrupted, or be 
discontinued in accordance with the CSP.
AEs, SAEs, cycle delays and/or treatment suspensions associated with COVID-19 along with 
logistical issues should be reported according to the eCRF Completion Guidelines. 

Clinical Study Protocol Appendix G
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 09 July 2021
224(225)
For dosing discontinuations, where applicable, the dosing discontinuation guidelines should 
be followed, and the End of Treatment Form(s) completed
G 10
Ongoing Participants
Participants receiving study intervention should continue to undergo safety assessments prior 
to dosing in accordance with the CSP. In case it is not feasible to perform safety assessments, 
study intervention should be interrupted until such assessments can be completed.
G 10.1 If a Participant has an Event Suspected to be COVID-19
Delay or omit study intervention as appropriate and test for COVID-19 per local health 
authority or institutional guidance. 
-
Signs and symptoms of COVID-19 include but are not limited to new onset of fever, new or 
worsening cough, shortness of breath, difficulty breathing and sometimes abnormal chest 
imaging and may be similar to those of an imAE. 
-
In accordance with the CSP and the TMGs for imAEs, thorough evaluation should be 
performed to accurately identify the underlying pathology in case an AE is encountered for a 
participant. 
-
If COVID-19 is ruled out, study intervention may be resumed per the CSP.
-
If COVID-19 is confirmed or diagnosis still suspected after evaluation, manage COVID-
19 per local guidance until full recovery. 
G 10.2 Participants with Confirmed COVID-19
Participants with confirmed COVID-19 (by local laboratory testing and/or combination of 
key symptoms) should have study intervention withheld and COVID-19 managed per local 
guidance.
In case of confirmed COVID-19 and a simultaneous imAE requiring treatment, investigators 
are advised to apply clinical judgement regarding the use of corticosteroids as per the 
durvalumab/tremelimumab TMGs. This includes also the consideration of alternate 
immunosuppressive agents other than corticosteroids for imAE management, depending on 
the individual participant’s presentation (Curigliano et al 2020).
G 10.3 Restarting Study Intervention
Study intervention must not be resumed until recovery from COVID-19 (eg, confirmed by 
imaging, lab testing and/or absence of symptoms) and COVID-19-specific treatment has been 
completed per local guidance.

Clinical Study Protocol Appendix G
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419MC00004
Version 1
Date 09 July 2021
225(225)
The study clinical lead should be contacted if any additional guidance or clarification is 
needed.
G 10.4 Vaccination Against COVID-19
Protocol restrictions applying to live attenuated vaccines are relevant for live attenuated 
COVID-19 vaccines as well. Investigators should apply their discretion assessing the 
risk-benefit of other types of COVID-19 vaccines for participants in clinical trials. Ideally, 
administration of the vaccine should be done on a different day other than the day of study 
drug administration to differentiate any potential AEs seen from the vaccine and study drug. 
The administration of the vaccine and any potential AEs associated with the vaccine are to be 
documented on the concomitant medication and AE eCRFs, respectively.
G 11
References
Curigliano et al 2020 
Curigliano G, Banerjee S, Cervantes A, Garassino M, Garrido P, Girard N. Managing cancer 
patients during the COVID-19 pandemic: an ESMO multidisciplinary expert consensus. Ann 
Oncol 2020;31(10):1320-35.
EMA 2020
EMA, Clinical Trials Facilitation and Coordination Group, European Commission. Guidance 
on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, 
Version 2, 27 March 2020. Available from: URL: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf. Accessed: 17 December 2020.

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d419mc00004-csp-v6
Document Title:
D419MC00004 Clinical Study Protocol version 6
Document ID:
Doc ID-003513330
Version Label:
8.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
14-Jul-2021 09:44 UTC
Content Approval
12-Jul-2021 18:54 UTC
Content Approval
13-Jul-2021 13:42 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD