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

1 (220)
Clinical Study Protocol 
Drug Substance
Durvalumab (MEDI4736) and 
tremelimumab
Study Code
D419AC00001
Version
08
Date
09 January 2018
A Phase III Randomized, Open-Label, Multi-Center, Global Study of 
MEDI4736 in Combination with Tremelimumab Therapy or MEDI4736 
Monotherapy Versus Standard of Care Platinum-Based Chemotherapy in 
First-Line Treatment of Patients with Advanced or Metastatic Non-Small-
Cell Lung Cancer (NSCLC) (MYSTIC)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
EudraCT Number: 2015-001279-39

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00001
Version 08
Date 09 January 2018
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VERSION HISTORY
Version 8.0, 9 January 2018
Changes to the protocol are summarised below.
Synopsis, Sections 6.1.9, 7.2.2
Updated to include further clarification on post final Data Cut Off (DCO) procedures.
Section 1.3.2, Potential Risks
Since the MYSTIC study was started, the durvalumab programme has developed and the emerging 
safety profile has become more established.  As such, the “Potential Risks” section of this clinical 
study protocol has updated to align and be consistent with the broader durvalumab programme, 
including the Investigator Brochure and the clinical study protocol format of more recent studies.
Section 3.10.3, Survival Status for Withdrawn Consent and Lost to Follow Up Patients
Updated to clarify which analysis sets require survival status data and how and when to obtain this 
data.
Sections 6.3.1, Time period for collection of adverse events, 6.3.2, Follow-up of unresolved 
adverse events
Updated to clarify time period for collection of adverse events, and to clarify the follow-up of adverse 
events unresolved at the patient’s last visit in the study or at study completion.
6.7, Management of Investigational Product-related Toxicities
Updated to include the web link to the most current Toxicity Management Guidelines.
6.7.1, MEDI4736 + tremelimumab and MEDI4736 monotherapy adverse events of special 
interest (AESI)
Updated to align with the most current Investigator Brochure
 
Various
Updated terminology from immune related Adverse Event (irAE) to immune mediated Adverse Event 
(imAE).
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Study Code D419AC00001
Version 08
Date 19 December 2017 
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Version 7.0, 20 December 2016
Changes to the protocol are summarised below.
Synopsis, Section 1.4
Clarification of the expected proportion of patients with ≥25% PD-L1 membrane-expression in 
tumoral tissue.  With the study fully recruited there is no change in the overall patient number.
Synopsis, Glossary, Figure 1, Section 1.4
The definitions for the PD-L1 tumor membrane-expression sub-groups are provided.
Synopsis, Sections 1.1.5, 1.2.6, 1.3.1.1, 1.3.1.3, 2.1, 2.2, 2.3
For MEDI4733 in combination with tremelimumab the assessment of progression-free survival (PFS) 
and overall survival (OS) were nominated as co-primary objectives in NSCLC patients with ≥25% 
PD-L1 membrane-expression in tumoral tissue.  
For MEDI4733 monotherapy the assessment of overall survival (OS) is nominated as a co-primary 
objective in NSCLC patients with ≥25% PD-L1 membrane-expression in tumoral tissue .  
Primary and secondary objectives, endpoints and rational for endpoints were modified accordingly.
Synopsis, Section 8, Table 9, Table 12, Figure 5
The statistical considerations and analyses have been updated to accommodate the nominated
co-primary objectives.
Section 3.1, Inclusion Criteria #3
Correction of spelling error.
Section 4
Removed the set duration for treatment periods as they can be variable per protocol.
Table 2
Footnote O updated for clarity.
Table 4
Footnote J updated for clarity.
Sections 6.7.1, 6.7.2
Updated to align with the current IB and ICF.
Section 7.7
In the section on prohibited medications, the following changes have been made:

A temporary period of steroids will be allowed if clinically indicated and considered to be 
essential for the management of the patient (eg, for chronic obstructive pulmonary disease, 
radiation, nausea, etc).

EGFR TKIs should not be given concomitantly whilst the patient is on study treatment. In 
addition they should be used with caution in the 90 days after the last dose of durvalumab. 
(Increased incidences of pneumonitis (with third generation EGFR TKIs) and increased 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00001
Version 08
Date 19 December 2017 
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Version 7.0, 20 December 2016
Changes to the protocol are summarised below.
incidence of transaminase increases (with 1st generation EGFR TKIs) has been reported when 
durvalumab has been given concomitantly).
!
Inactivated viruses, such as those in the influenza vaccine, are permitted
Section 8.4.4 – 8.4.4.3
Statement that the clinical meaningfulness threshold of the PRO analyses will be described in the 
Statistical Analysis Plan (SAP)
 
 
Version 5.0, 31 March 2016
Version 6.0, 02 June 2016
Changes to the protocol are summarised below.
Section 3.8 Restrictions
Spermicide was removed as it is not a highly effective method of contraception.
Synopsis, Section 7.2.2 Duration of treatment and criteria for retreatment
To clarify that treatment through progression only applies to the immunotherapy groups
(monotherapy and combination therapy arms). 
Updated wording in section 7.2.2. to match synopsis, indicating patients in the immunotherapy 
groups (rather than only the MEDI4736 group) will not be permitted to continue immunotherapy if 
progression occurs in a target lesion that has previously shown a confirmed response.
Section 8.4.1.1 Progression-free survivalTo clarify that in the SoC group treatment can be 
continued, at investigator’s discretion, until disease progression in confirmed. Patients in the SoC 
are not allowed to continue treatment once disease progression in confirmed
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00001
Version 08
Date 19 December 2017 
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Changes to the protocol are summarized below
Title pages
MEDI4736 is identified as Durvalumab in Drug substance in the header box, and referred to as 
MEDI4736 thereafter.
Synopsis, Section 1.2.6 – Rationale for Endpoints, Section 2 – Study Objectives, Section 5.1 –
Efficacy Assessments, Section 8.4 – Outcome Measures for Analysis, Section 8.5 – Methods 
for Statistical Analysis
The primary and secondary objective endpoints have been updated to reflect changes to endpoint 
measures - Blinded Independent Central Review (BICR) tumor assessments rather than 
Investigator assessments as well as to assess the treatment benefit and efficacy of MEDI4736 as 
suggested by emerging immuno-oncology data.  Investigator assessments will be used for 
sensitivity analysis.
Synopsis, Section 1.4 – Study design and Section 8.2 – Sample size estimate 
 
 
Synopsis, Section 1.4 – Study design
The timing for patients to provide a tumor tissue sample was clarified as being the enrollment visit.
Synopsis, Section 1.4 – Study design and Section 2 – Study objectives
The assessment of progression-free survival (PFS) and overall survival (OS) were nominated as 
co-primary objectives.  Primary and secondary objectives, endpoints and rational for endpoints 
were modified accordingly.
Synopsis, Section 7.2.2 Duration of treatment and criteria for retreatment
Duration of treatment was modified so that patients in all groups can continue therapy until disease 
progression rather than stopping at 12 months. Emerging data from ongoing MEDI4736 studies is 
suggestive of some patients losing clinical benefit after they complete the 12 months of therapy.
In all groups, patients with PD (unconfirmed and confirmed) who, in the Investigator’s opinion, 
would continue to receive benefit from their assigned treatment, and who meet the criteria for 
treatment in the setting of PD, may continue to receive treatment.  It was also clarified that patients 
on MEDI4736 alone will not be permitted to continue immunotherapy, if the progression occurs 
after confirmed response to immunotherapy treatment within the target lesion, and if progression 
events occurred in the target lesions while the patient was receiving immunotherapy during the 
same treatment period. 
Synopsis, Section 8 – Statistical methods
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00001
Version 08
Date 19 December 2017 
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The statistical considerations and analyses have been updated to accommodate the new co-primary 
objectives and the modifications in provisions for duration of treatment and progression during 
treatment.
 
 
 
Section 1.2.5 - Rationale of retreatment option
The rationale for the retreatment option is amended to enable patients in the MEDI4736 + 
tremelimumab combination group who complete 4 dosing cycles (providing clinical benefit per 
Investigator judgement), and subsequently have PD during treatment with MEDI4736 alone, to 
restart combination treatment, if they also meet eligibility criteria.  
Section 1.3.2.1 - MEDI4736 + tremelimumab
The potential risks, based on the mechanism of action of MEDI4736 and related molecules, are 
updated to “colitis, pneumonitis, hepatitis/hepatotoxicity, neuropathy/neuromuscular toxicity, 
endocrinopathy, dermatitis, and nephritis.  In addition, pancreatitis is an important potential risk 
particularly with MEDI4736 and tremelimumab combination therapy.  Other inflammatory 
responses with potential immune-mediated etiology reported with MEDI4736 and similar 
molecules include myocarditis, pericarditis, and uveitis” in accordance with the current 
Investigator Brochure.
Section 3.2 - Exclusion criteria
!
Sarcomatoid variant of non-small-cell lung cancer (NSCLC) is added as an exclusion 
criteria.
!
The part of the exclusion criteria of brain metastases or spinal cord compression and off 
steroids and anticonvulsants for at least 1 month prior to study treatment is amended to 
and off steroids for at least 14 days prior to study treatment.  In addition, following 
radiotherapy and/or surgery, patients with brain metastases must wait 4 weeks after the 
intervention and must confirm stability with imaging before randomization.
!
Tuberculosis (clinical evaluation) has been added to hepatitis B, hepatitis C and human 
immunodeficiency virus as part of the active infection exclusion criterion.  The 
exclusion criterion Known history of clinical diagnosis of tuberculosis has been deleted.  
In addition supplementary information on the diagnoses are given: 
∀
HIV diagnosis requires positive HIV 1 or 2 antibodies. 
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00001
Version 08
Date 19 December 2017 
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
Active hepatitis B virus (HBV) is defined by a known positive HBV surface 
antigen (HBsAg) result.  Patients with a past or resolved HBV infection 
(defined as the presence of hepatitis B core antibody and absence of HBsAg) 
are eligible.  

Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV ribonucleic acid (RNA).
Section 3.8 - Restrictions

The restrictions for female patients of childbearing potential are strengthened from 
2 methods of effective contraception to at least 1 highly effective method (ie, low 
failure rate of <1% per year).  Additionally the male partners of a female patient of 
child bearing potential must use a male condom plus spermicide (except in countries 
where spermicides are not approved).

Male patients with a female partner of childbearing potential must use a male condom 
plus spermicide (except in countries where spermicides are not approved), and it is 
highly recommended for the female partner of a male patient to also use a highly 
effective method of contraception.
Section 3.9 - Discontinuation of IP
The stipulation for discontinuation of IP of any adverse event (AE) that meets the criteria for 
discontinuation was removed. 
Section 4 – Study plan and timing of procedures 
In Table 2 (Schedule of Assessments) the following amendments were: 

The window for Cycle 1 was amended from +1 to +3 days

Activated partial thromboplastin time (APTT) and international normalized ratio (INR) 
assessments, which will be performed as clinically indicated and at Screening, were 
added to the table.

For the pharmacokinetic samples, it is now specified that they will take place on the 
same day as the infusion and within 1 hour of end of infusion, as opposed to up to 
1 hour predose and with 10 minutes of the end of the infusion.
Section 5.1 - Efficacy Assessments
The timing for performing the baseline assessment was modified to no more than 28 days before 
randomization rather than no more than 28 days before the start of IP treatment.
Section 5.1.2 - Survival assessments
Patients on treatment or in survival follow-up will now be contacted following the data cut-off for 
the primary analysis of the PFS and for each interim and final analysis of OS rather than following 

Clinical Study Protocol
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Study Code D419AC00001
Version 08
Date 19 December 2017 
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the data cut-off for the primary analysis and all subsequent survival analyses to provide complete 
survival data.
Section 5.2.1 - Laboratory safety assessments
!
In Table 5, provision is made that if the amylase and lipase analyses could not be 
performed in a local laboratory, then 1 or the other would be performed in line with 
local practice.
!
In Table 6, APPT and INR are added to the table, and it is stipulated that they will be 
assessed at Screening rather than Baseline as indicated in the table footnote.
Section 5.2.4 – Vital signs
Blood pressure may now be measured in a supine or semi-supine position rather than just a supine 
position.
Section 6 – Safety reporting and medical management
In accordance with the new protocol template, the following first 3 sub-sections of Section 6 were 
reordered from:
6.1 Definition of serious adverse events
6.2 Recording of adverse events
6.3 Definition of adverse events
to
6.1 Definition of adverse events
6.2 Definition of serious adverse events
6.3 Recording of adverse events
Section 6.7.1 - MEDI4736 + tremelimumab and MEDI4736 monotherapy adverse events of 
special interest (AESI)
This section was updated to remove the detailed explanation of MEDI4736’s main AESIs and refer 
the reader to the current IB where these are explained in full, together with specific guidelines for 
their evaluation and treatment.
Section 7.1 - Identity of IP 
The section for MEDI4736 and tremelimumab is updated with the current recommendations for 
preparation and dose calculations. 
Section 7.7 – Concomitant and other treatments
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00001
Version 08
Date 19 December 2017 
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In the section on prohibited medications, the following amends are made:
!
Systematic corticosteroid will be permitted for the prevention of chemotherapy-related 
toxicities (nausea/vomiting prevention and prophylaxis)
!
Drugs with laxative properties should be used with caution rather than avoided 
!
Herbal and natural remedies in general, rather than those for constipation only, should 
be avoided for 90 days after the last dose of MEDI4736 monotherapy or combination 
treatment (MEDI4736 + tremelimumab) during the study
Section 8.3 - Definition of analysis set
The outcome variables for the efficacy data were updated in Table 9 to align with the revised 
co-primary endpoints.
Section 8.4.1 – Calculation or derivation of efficacy variables
BICR of Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1)-based 
assessments were moved above Investigator RECIST 1.1-based assessments. Text of BICR-based 
assessments was changed to reflect BICR-RECIST 1.1 analysis on all radiological scans of all 
patients rather than a random sample.
Section 8.4.1.2 – Calculation or derivation of efficacy variables and Section 8.5.2 – Objective 
response rate
Text was added to explain that objective response rate analysis of Investigator tumor data is based 
upon RECIST 1.1 as a sensitivity analysis.
Section 8.5.1.1 – Progression-free survival, and Section 11 – References
 
Version 4.0, 7 August 2015
Changes to the protocol are summarised in Amendment 3.
Version 3.0, 28 July 2015
Changes to the protocol are summarised in Amendment 2.
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Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00001
Version 08
Date 19 December 2017 
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Version 2.0, 27 May 2015
Changes to the protocol are summarised in Amendment 1.
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.
Version 1.0, 21 April 2015
Initial document.

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00001
Version 08
Date 09 January 2018
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PROTOCOL SYNOPSIS
A Phase III Randomized, Open-Label, Multi-Center, Global Study of 
MEDI4736 in Combination with Tremelimumab Therapy or MEDI4736 
Monotherapy Versus Standard of Care Platinum-Based Chemotherapy in 
First-Line Treatment of Patients with Advanced or Metastatic Non-Small-
Cell Lung Cancer (NSCLC) (MYSTIC)
International Coordinating Investigators
Naiyer Rizvi, MD, 177 Fort Washington, Suite 6GN-435, New York, NY 10032, USA
Study site(s) and number of patients planned
The study will enroll approximately 1850 patients to identify approximately 1092 patients 
who will be randomized to receive MEDI4736 + tremelimumab combination therapy, 
MEDI4736 monotherapy, or platinum-based Standard of Care (SoC) therapy (364 in each 
group, including approximately 160 patients in each treatment group with programmed cell 
death ligand 1 [PD-L1]–positive non-small-cell lung cancer [NSCLC], defined as PD-L1 
expression ≥25%).
Study period
Phase of development
Estimated date of first patient enrolled
Q3 2015
III
Estimated date of last patient completed
Q2 2018
III
Study design
This is a randomized, open-label, multi-center, global, Phase III study to determine the 
efficacy and safety of MEDI4736 + tremelimumab combination therapy and MEDI4736 
monotherapy versus platinum-based SoC chemotherapy in the first-line treatment of patients 
with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-
type advanced or metastatic NSCLC.  
Patients will provide a tumor tissue sample at enrollment to determine PD-L1 expression 
status (defined by the 
 in which:
!
≥25% PD-L1& >1% PD-L1 membrane-expression in tumoral tissue are considered as relevant 
positive sub-groups 
!
<25% PD-L1 is considered low/negative
!
<1% is considered negative; 
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Clinical Study Protocol
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Study Code D419AC00001
Version 08
Date 09 January 2018
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For clarity these sub-groups are referred to hereafter as patients with PD-L1 positive25%, PD-
L1 positive1%, PD-L1-low/negative or PD-L1-negative tumors, respectively.  
Patients will be randomized in a 1:1:1 ratio in a stratified manner according to PD-L1 tumor 
expression status (PD-L1 positive25% versus PD-L1-low/negative) and histology (squamous 
versus non-squamous) to receive treatment with MEDI4736 + tremelimumab combination 
therapy, MEDI4736 monotherapy, or SoC therapy.  
Tumor assessments will be performed every 6 weeks for the first 48 weeks and then every 
8 weeks until confirmed disease progression, with categorization of objective tumor response 
by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1).  
Objectives
All objectives will be evaluated for all patients, unless otherwise indicated, and where 
appropriate for patients with PD-L1 positive25%, PD-L1 positive1%, PD-L1-low/negative
and/or PD-L1–negative NSCLC.  The assessment of progression-free survival (PFS) and 
overall survival (OS) in patients with PD-L1 positive25% NSCLC will be considered the 
co-primary objectives. 
Primary Objective:
Outcome Measure:
To assess the efficacy of MEDI4736 +
tremelimumab combination therapy 
compared to SoC in terms of PFS in 
patients with PD-L1 positive25% NSCLC
PFS using Blinded Independent Central Review 
(BICR) assessments according to RECIST 1.1
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy 
compared to SoC terms of OS in patients 
with PD-L1 positive25% NSCLC
OS
To assess the efficacy of MEDI4736 
monotherapy compared to SoC in terms 
of OS in patients with PD-L1 positive25% 
NSCLC
OS

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Secondary Objectives:
Outcome Measures:
To further assess the efficacy of 
MEDI4736 + tremelimumab combination 
therapy compared to SoC in terms of 
PFS, OS, objective response rate (ORR), 
duration of response (DoR), proportion of 
patients alive and progression free at 12 
months from randomization (APF12), 
and time to second progression (PFS2)
OS in PD-L1 positive1% patients and all patients 
PFS in PD-L1 positive1% patients and all 
patients using BICR assessments according to 
RECIST 1.1
ORR, DoR, and APF12 in patients with PD-L1
positive25% NSCLC, and patients with PD-L1
positive1% NSCLC and all patients using BICR 
assessments according to RECIST 1.1
PFS2 in patients with PD-L1 positive25%
NSCLC, and patients with PD-L1 positive1%
NSCLC and all patients using local standard 
clinical practicea
To assess the efficacy of MEDI4736 
monotherapy compared to SoC in terms 
of PFS, ORR, DoR, APF12, and PFS2
PFS in patients with PD-L1 positive25% NSCLC 
using BICR assessments according to RECIST 
1.1
ORR, DoR, and APF12 in patients with PD-L1
positive25% NSCLC using BICR assessments 
according to RECIST 1.1
PFS2 in patients with PD-L1 positive25%
NSCLC using local standard clinical practicea
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy 
compared to MEDI4736 monotherapy in 
terms of PFS, OS, and ORR 
PFS and ORR in patients with PD-L1
positive25% and PD-L1 positive1% NSCLC and 
all patients using BICR assessments according 
to RECIST 1.1
OS in patients with PD-L1 positive25%  and PD-
L1 positive1% NSCLC and all patients 
To assess disease-related symptoms and 
health-related quality of life (HRQoL) in 
patients treated with MEDI4736 + 
tremelimumab combination therapy and 
MEDI4736 monotherapy compared to 
SoC using the 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) module
EORTC QLQ-C30
EORTC QLQ-LC13
Changes in World Health Organization 
(WHO)/Eastern Cooperative Oncology Group 
(ECOG) performance status will also be 
assessed.
To assess the pharmacokinetics (PK) of 
MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy
Concentration of MEDI4736 and 
tremelimumab in blood and non-compartmental 
PK parameters, such as peak concentration and 
trough (as data allow; sparse sampling)

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Secondary Objectives:
Outcome Measures:
To investigate the immunogenicity of 
MEDI4736 and tremelimumab
Presence of anti-drug antibodies (ADAs) for 
MEDI4736 and tremelimumab
a
PFS2 will be defined as the time from the date of randomization to the earliest of the 
progression event subsequent to that used for the PFS endpoint or death, based on 
Investigator tumor assessments.  
Safety Objective:
Outcome Measures:
To assess the safety and tolerability 
profile of MEDI4736 + tremelimumab 
combination therapy and MEDI4736 
monotherapy compared to SoC in the 
first-line setting for treatment of 
advanced or metastatic patients with 
NSCLC
Adverse events (AEs), physical examinations, 
laboratory findings, and vital signs
Target patient population
Adult patients (age ≥18 years) with advanced or metastatic (Stage IV) histologically or 
cytologically documented EGFR and ALK wild-type NSCLC who are treatment naive.
Duration of treatment
Unless specific treatment discontinuation criteria are met, patients in all groups will continue 
therapy until disease progression.
Progression during treatment
Patients in all groups may continue receiving therapy in the setting of unconfirmed 
progressive disease (PD) until PD is confirmed, at the Investigator’s discretion.  According to 
RECIST 1.1, modified for confirmation of progression, a confirmatory scan will be required 
following an overall time-point assessment of progression, preferably at the next scheduled 
visit, and no earlier than 4 weeks after the previous assessment of PD.  
Patients in all groups, excluding the SoC arm, with PD according to RECIST 1.1 
(unconfirmed and confirmed) who, in the Investigator’s opinion, would continue to receive 
benefit from their assigned treatment and who meet the criteria for treatment in the setting of 
PD, may continue to receive their assigned treatment for as long as they are still gaining 
clinical benefit.  However, patients in the immunotherapy group(s) will not be permitted to 
continue immunotherapy if progression occurs after confirmed response (CR, defined by 
RECIST 1.1) to immunotherapy treatment in the target lesions, ie, the response and 
progression events both occurred in the target lesions while the patient was receiving 
immunotherapy during the same treatment period.
Patients in the MEDI4736 + tremelimumab group may restart treatment with the combination 
therapy if they complete the 4 dosing cycles with MEDI4736 + tremelimumab (with clinical 

Clinical Study Protocol
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Version 08
Date 09 January 2018
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benefit per Investigator judgment) but subsequently have PD during treatment with 
MEDI4736 alone and if they meet eligibility criteria for retreatment.   
Post final Data Cut Off (DCO)
Patients who continue to receive benefit from their assigned treatment 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. For patients continuing to receive durvalumab 
treatment following the 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 in order to manage AEs in 
accordance with the durvalumab toxicity management guidelines (please see Section 6.1.9).  
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 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.
Investigational product, dosage, and mode of administration
MEDI4736 + tremelimumab combination therapy

MEDI4736 20 mg/kg via IV infusion every 4 weeks (q4w), starting on Week 0, for 
up to a total of 4 doses/cycles, and then continue MEDI4736 20 mg/kg via IV 
infusion q4w, starting on Week 16

Tremelimumab 1 mg/kg via IV infusion q4w, starting on Week 0, for up to 
4 doses/cycles
MEDI4736 monotherapy

MEDI4736 20 mg/kg via IV infusion q4w, starting on Week 0
Standard of Care therapy
Patients randomized to SoC therapy will receive 1 of the following:

Paclitaxel + carboplatin: Paclitaxel 200 mg/m2 and carboplatin area under the 
curve (AUC) 5 or 6 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 
cycles or until documented PD

Gemcitabine + cisplatin (squamous patients only): Gemcitabine 1000 or 1250 
mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + cisplatin 75 or 
80 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles or 
until documented PD 

Gemcitabine + carboplatin (squamous patients only): Gemcitabine 1000 or 
1250 mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + 

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carboplatin AUC 5 or 6 via IV infusion on Day 1 of each 21-day cycle, for 4 to 
6 cycles or until documented PD 

Pemetrexed + cisplatin (non-squamous patients only): Pemetrexed 500 mg/m2 
and cisplatin 75 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 
6 cycles or until documented PD.  Non-squamous patients who have not 
progressed after 4 cycles will be eligible for pemetrexed maintenance therapy.

Pemetrexed + carboplatin (non-squamous patients only): Pemetrexed 500 
mg/m2 and carboplatin AUC 5 or 6 via IV infusion on Day 1 of each 21-day 
cycle, for 4 to 6 cycles or until documented PD.  Non-squamous patients who 
have not progressed after 4 cycles will be eligible for pemetrexed maintenance 
therapy.
Statistical methods
The primary objectives of this study are to assess the efficacy of MEDI4736 + tremelimumab 
treatment compared with SoC in terms of PFS and OS and of MEDI4736 monotherapy 
compared with SoC in terms of OS in patients with EGFR and ALK wild-type advanced or 
metastatic NSCLC with PD-L1 positive25% tumors.  PFS (per RECIST 1.1, using BICR tumor 
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.  OS will be defined as the time from the date of randomization 
until death due to any cause.  Thus, primary endpoints in this study are PFS and OS, in 
patients with PD-L1 positive25% NSCLC.  To control for type I error, an alpha of 0.03 will be 
used for the OS comparison of MEDI4736 monotherapy versus SoC, an alpha of 0.015 will be 
used for the OS comparison of MEDI4736 + tremelimumab versus SoC and an alpha of 0.005 
will be used for the PFS comparison of MEDI4736 + tremelimumab versus SoC.  The study 
will be considered positive (a success) if any of the OS or PFS analysis results are statistically 
significant.
Secondary efficacy variables include PFS and OS for MEDI4736 + tremelimumab versus SoC 
in patients with PD-L1 positive1% ,and all randomized patients, PFS for MEDI4736 
monotherapy versus SoC in patients with PD-L1 positive25% tumours, and PFS and OS for 
MEDI4736+tremelimumab versus MEDI4736 monotherapy in patients with PD-L1 
positive25% and PD-L1 positive1% tumors and all randomized patients, as well as ORR, DoR, 
APF12, and PFS2.  All tumor-assessment-related endpoints are as assessed by BICR
Efficacy data will be summarized and analyzed on an intent-to-treat (ITT) basis and the 
treatment groups will be compared on the basis of randomized treatment, regardless of the 
treatment actually received.  Patients who were randomized but did not subsequently go on to 
receive study treatment are included in the ITT population.
Approximately 1092 patients (including approximately 160 patients per arm with PD-L1 
positive25% NSCLC) will be randomized 1:1:1 to MEDI4736 + tremelimumab, MEDI4736 
monotherapy, or SoC.  The randomization will be stratified based on PD-L1 tumor expression 
status (≥25% versus <25%) and histology (squamous versus non-squamous). The primary PFS 

Clinical Study Protocol
Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00001
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Date 09 January 2018
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analysis for superiority will be performed when both of the following conditions have been 
met: 
!
Approximately 231 BICR PFS events have occurred across the MEDI4736 + 
tremelimumab and SoC treatment groups in patients with PD-L1 positive25%  
tumors (72% maturity) AND
!
 to the study
The final (primary) OS analysis for superiority will be performed when the following 
conditions have been met: 
!
Approximately 225 OS events have occurred across the MEDI4736 + 
tremelimumab and SoC treatment groups in patients with PD-L1 positive25%  
tumors (70% maturity) AND
!
Approximately 225 OS events have occurred across the MEDI4736 monotherapy
and SoC treatment groups in patients with PD-L1 positive25% tumors (70% 
maturity)
Two interim analyses to assess the superiority of the MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy group (compared to the SoC group) in terms of OS will 
be performed at the time of the primary PFS analysis, and when approximately 80% of the 
target OS events have been reached, respectively.
MEDI4736 + tremelimumab versus SoC (PFS in PD-L1 positive25% population))
 
 
 
 
 
MEDI4736 + tremelimumab versus SoC (OS in PD-L1 positive25% population))
 
 
 
 
 
 
MEDI4736 monotherapy versus SoC (OS in PD-L1 positive25% population)
 
 
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Date 09 January 2018
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PFS, based on the programmatically derived PFS from BICR, and OS will be analyzed using a 
stratified log-rank test The stratification will be by histology alone (squamous, non-squamous)
for the primary comparisons using the PD-L1 positive25% population, and will be by PD-L1
tumor expression status (≥25%, <25%) and histology for the secondary analyses using the PD-
L1 positive1% population and full ITT population. The effect of treatment will be estimated by 
the HR together with corresponding two-sided appropriately sized CI, (adjusted for interim 
analyses) and p-value.
Safety data will be summarized descriptively and formal statistical comparisons will not be 
made.
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Drug Substance Durvalumab (MEDI4736) and tremelimumab
Study Code D419AC00001
Version 08
Date 09 January 2018
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TABLE OF CONTENTS
PAGE
VERSION HISTORY...............................................................................................2
PROTOCOL SYNOPSIS........................................................................11
TABLE OF CONTENTS........................................................................19
1.
INTRODUCTION ..................................................................................31
1.1
Background and rationale for conducting this study ................................31
1.1.1
Immunotherapies ....................................................................................31
1.1.2
MEDI4736..............................................................................................32
1.1.3
Tremelimumab........................................................................................32
1.1.4
MEDI4736 in combination with tremelimumab.......................................33
1.1.5
Rationale for conducting this study .........................................................34
1.2
Rationale for study design, doses, and control groups..............................35
1.2.1
MEDI4736 + tremelimumab combination therapy dose rationale ............35
1.2.2
Rationale for 4 cycles of combination therapy followed by MEDI4736 
monotherapy...........................................................................................37
1.2.3
MEDI4736 monotherapy dose rationale ..................................................37
1.2.4
Rationale for Standard of Care as a comparator.......................................39
1.2.5
Rationale for retreatment option..............................................................39
1.2.6
Rationale for endpoints ...........................................................................40
1.3
Benefit/risk and ethical assessment .........................................................41
1.3.1
Potential benefits.....................................................................................41
1.3.1.1
MEDI4736..............................................................................................41
1.3.1.2
Tremelimumab........................................................................................41
1.3.1.3
MEDI4736 + tremelimumab ...................................................................42
1.3.2
Potential risks .........................................................................................43
1.3.2.1
MEDI4736..............................................................................................43
1.3.2.2
Tremelimumab........................................................................................44
1.3.2.3
MEDI4736 + tremelimumab ...................................................................44
1.3.3
Overall benefit-risk and ethical assessment .............................................45
1.4
Study design ...........................................................................................45
2.
STUDY OBJECTIVES...........................................................................49
2.1
Primary objective....................................................................................49
2.2
Secondary objectives...............................................................................50
2.3
Safety objective.......................................................................................52
2.4
Exploratory objectives ............................................................................52

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3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL.........53
3.1
Inclusion criteria .....................................................................................53
3.2
Exclusion criteria ....................................................................................55
3.3
Patient enrollment and randomization .....................................................58
3.4
Procedures for handling incorrectly enrolled patients ..............................59
3.5
Methods for assigning treatment groups..................................................59
3.6
Methods for ensuring blinding ................................................................60
3.7
Methods for unblinding...........................................................................60
3.8
Restrictions.............................................................................................60
3.9
Discontinuation of investigational product ..............................................62
3.9.1
Procedures for discontinuation of a patient from investigational product .63
3.10
Criteria for withdrawal of the patient from the study ...............................63
3.10.1
Screen failures ........................................................................................63
3.10.2
Withdrawal of the informed consent........................................................63
3.10.3
Survival status for withdrawn consent and lost to follow up patients .......64
3.11
Discontinuation of the study....................................................................64
4.
STUDY PLAN AND TIMING OF PROCEDURES................................65
4.1
Enrollment/screening period ...................................................................79
4.2
Treatment period.....................................................................................79
4.3
Follow-up period.....................................................................................79
5.
STUDY ASSESSMENTS.......................................................................80
5.1
Efficacy assessments...............................................................................80
5.1.1
Central reading of scans ..........................................................................81
5.1.2
Survival assessments...............................................................................81
5.2
Safety assessments..................................................................................82
5.2.1
Laboratory safety assessments.................................................................82
5.2.2
Physical examination ..............................................................................84
5.2.3
Electrocardiograms .................................................................................84
5.2.4
Vital signs...............................................................................................84
5.3
Other assessments...................................................................................85
5.3.1
Patient-reported outcomes.......................................................................85
5.3.1.1
EORTC QLQ-C30 ..................................................................................86
5.3.1.2
EORTC QLQ-LC13................................................................................86
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5.3.2
Administration of the patient-reported outcome questionnaires ...............87
5.3.3
WHO/ECOG performance status.............................................................88
5.4
Pharmacokinetics ....................................................................................89
5.4.1
Collection of samples and determination of drug concentration...............89
5.4.2
Collection of samples to measure for the presence of ADAs....................89
5.4.3
Storage and destruction of pharmacokinetic/ADA samples......................89
5.5
Biomarker analysis..................................................................................89
5.5.1
Collection of patient samples for stratification by PD-L1 ........................90
5.5.3
Storage, re-use, and destruction of biological samples.............................94
5.5.4
Labeling and shipment of biological samples ..........................................94
5.5.5
Chain of custody of biological samples ...................................................95
5.5.6
Withdrawal of informed consent for donated biological samples.............95
5.6
Pharmacogenetics ...................................................................................95
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT..................96
6.1
Definition of adverse events....................................................................96
6.1.1
Causality collection.................................................................................96
6.1.2
Relationship to protocol procedures ........................................................96
6.1.3
Adverse events based on signs and symptoms.........................................97
6.1.4
Adverse events based on examinations and tests .....................................97
6.1.5
Hy’s law .................................................................................................97
6.1.6
Disease progression.................................................................................97
6.1.7
New cancers............................................................................................98
6.1.8
Deaths.....................................................................................................98
6.2
Definitions of serious adverse event ........................................................99
6.3
Recording of adverse events....................................................................99
6.3.1
Time period for collection of adverse events ...........................................99
6.3.2
Follow-up of unresolved adverse events..................................................99
6.3.3
Variables...............................................................................................100
6.4
Reporting of serious adverse events ......................................................101
6.5
Overdose...............................................................................................102
6.6
Pregnancy .............................................................................................102
6.6.1
Maternal exposure.................................................................................102
6.6.2
Paternal exposure..................................................................................103
6.7
Management of investigational product-related toxicities......................103
6.7.1
MEDI4736 + tremelimumab and MEDI4736 monotherapy adverse events 
of special interest ..................................................................................104
6.7.2
Immune-related adverse events .............................................................105
6.7.3
Standard of Care agents.........................................................................106
6.8
Study governance and oversight............................................................106
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7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ......106
7.1
Identity of investigational product(s).....................................................106
7.1.1
MEDI4736............................................................................................107
7.1.2
Tremelimumab......................................................................................108
7.1.3
Standard of Care treatment....................................................................109
7.2
Dose and treatment regimens ................................................................109
7.2.1
Treatment regimens...............................................................................110
7.2.2
Duration of treatment and criteria for retreatment..................................112
7.3
Labeling................................................................................................113
7.4
Storage..................................................................................................113
7.5
Compliance...........................................................................................114
7.6
Accountability.......................................................................................114
7.7
Concomitant and other treatments.........................................................114
7.7.1
Other concomitant treatment .................................................................116
7.8
Post study access to study treatment......................................................116
8.
STATISTICAL ANALYSES BY ASTRAZENECA.............................117
8.1
Statistical considerations.......................................................................117
8.2
Sample size estimate .............................................................................117
8.3
Definitions of analysis sets....................................................................120
8.3.1
Full analysis set.....................................................................................121
8.3.2
PD-L1 positive25% analysis set ..............................................................121
8.3.3
PD-L1 positive1% analysis set................................................................121
8.3.4
PD-L1- low/negative analysis set ..........................................................121
8.3.5
Safety analysis set.................................................................................121
8.3.6
Pharmacokinetic analysis set.................................................................122
8.4
Outcome measures for analyses.............................................................122
8.4.1
Calculation or derivation of efficacy variables.......................................122
8.4.2
RECIST 1.1-based endpoints ................................................................122
8.4.2.1
Co-Primary endpoints ...........................................................................123
8.4.2.2
Secondary endpoints .............................................................................124
8.4.3
Calculation or derivation of safety variables..........................................126
8.4.3.1
Adverse events......................................................................................126
8.4.3.2
Other significant adverse events............................................................126
8.4.3.3
Safety assessments................................................................................126
8.4.4
Calculation or derivation of patient-reported outcome variables ............127
8.4.4.1
EORTC QLQ-C30 ................................................................................127
8.4.4.2
Lung cancer module (EORTC QLQ-LC13)...........................................129
8.4.5
Calculation or derivation of pharmacokinetic variables .........................130
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Date 09 January 2018
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8.4.5.1
Population pharmacokinetics and exposure-response/safety analysis.....130
8.4.5.2
Pharmacokinetic non-compartmental analysis .......................................130
8.4.5.3
Immunogenicity analysis.......................................................................130
8.4.6
Calculation or derivation of biomarker variables ...................................131
8.5
Methods for statistical analyses.............................................................131
8.5.1
Analysis of the co-primary endpoints....................................................135
8.5.1.1
Progression-free survival.......................................................................135
8.5.1.2
Overall survival.....................................................................................137
8.5.2
Objective response rate .........................................................................138
8.5.3
Duration of response .............................................................................139
8.5.4
Proportion of patients alive and progression free at 12 months ..............139
8.5.5
Time from randomization to second progression ...................................140
8.5.6
Patient reported outcomes .....................................................................140
8.5.6.1
EORTC QLQ-C30 ................................................................................140
8.5.6.2
EORTC QLQ-LC13..............................................................................141
8.5.8
Safety data ............................................................................................142
8.5.9
Pharmacokinetic data ............................................................................142
8.5.10
Immunogenicity analysis.......................................................................142
8.5.11
Pharmacokinetic/Pharmacodynamic relationships .................................143
8.5.12
Biomarker data......................................................................................143
8.5.13
Interim analysis.....................................................................................143
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA............145
9.1
Training of study site personnel ............................................................145
9.2
Monitoring of the study.........................................................................145
9.2.1
Source data ...........................................................................................145
9.2.2
Direct access to source data in Japan.....................................................146
9.2.3
Study agreements..................................................................................146
9.2.4
Archiving of study documents...............................................................146
9.3
Study timetable and end of study...........................................................146
9.4
Data management by AstraZeneca or delegate ......................................146
10.
ETHICAL AND REGULATORY REQUIREMENTS..........................148
10.1
Ethical conduct of the study ..................................................................148
10.2
Patient data protection...........................................................................148
10.3
Ethics and regulatory review .................................................................148
10.4
Informed consent ..................................................................................149
10.5
Changes to the protocol and informed consent form..............................150
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Study Code D419AC00001
Version 08
Date 09 January 2018
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10.6
Audits and inspections ..........................................................................150
11.
LIST OF REFERENCES ......................................................................151
LIST OF TABLES
Table 1
Highly effectivea methods of contraception (<1% failure rate).................. 62
Table 2
Schedule of assessments for MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy treatment and retreatment periods .66
Table 3
Schedule of assessments for Standard of Care therapy treatment period ... 71
Table 4
Schedule of assessments for patients who have completed/discontinued 
treatment with MEDI4736 + tremelimumab, MEDI4736 monotherapy, or 
Standard of Care therapy ......................................................................... 76
Table 5
Clinical chemistry (serum or plasma) ....................................................... 83
Table 6
Hematology ............................................................................................. 83
Table 7
Urinalysis................................................................................................. 83
Table 8
List of investigational products for this study......................................... 107
Table 9
Summary of outcome variables and analysis populations ....................... 120
Table 12 Pre-planned statistical and sensitivity analyses to be conducted.............. 132
Table 13 Summary of methods of assessment ....................................................... 177
Table 14 Evaluation of target lesions .................................................................... 181
Table 15 Evaluation of non-target lesions ............................................................. 182
Table 16 Overall visit response............................................................................. 183
LIST OF FIGURES
Figure 1 Overall study design................................................................................. 47
Figure 2 Study flow chart....................................................................................... 48
Figure 3 MEDI4736 + tremelimumab combination therapy dosing scheme.......... 110
Figure 4 MEDI4736 monotherapy dosing scheme................................................ 111
Figure 5 Multiple testing procedures for controlling the type 1 error rate.............. 135

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Study Code D419AC00001
Version 08
Date 09 January 2018
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Study Code D419AC00001
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Date 09 January 2018
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse events of special interest
ALK
Anaplastic lymphoma kinase
ALT
Alanine aminotransferase
APTT
Activated partial thromboplastin time;
APF12
Proportion of patients alive and progression free at 12 months from 
randomization
AST
Aspartate aminotransferase
AUC
Area under the plasma drug concentration-time curve
AUCss
Area under the curve at steady state
BICR
Blinded Independent Central Review
BoR
Best objective response
BP
Blood pressure
CD
Cluster of differentiation
CI
Confidence interval
Cmax
Maximum plasma concentration
Cmax,ss
Maximum plasma concentration at steady state
CR
Complete response
CSA
Clinical study agreement
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
CTLA-4
Cytotoxic T–lymphocyte-associated antigen 4
Ctrough,ss
Trough plasma concentration at steady state
CXCL
Chemokine (C-X-C motif) ligand
DCR
Disease control rate
DLT
Dose-limiting toxicity
DoR
Duration of response

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Abbreviation or 
special term
Explanation
EC
Ethics Committee, synonymous to Institutional Review Board 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
ESMO
European Society for Medical Oncology
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
Gastrointestinal
GMP
Good Manufacturing Practice
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Hazard ratio
HRQoL
Health-related quality of life
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IFN
Interferon
IgG
Immunoglobulin G
IHC
Immunohistochemistry
IL
Interleukin
IMT
Immunomodulatory therapy
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Abbreviation or 
special term
Explanation
INR
International normalized ratio
IP
Investigational product 
imAE
Immune-mediated adverse event
IRB
Internal Review Board
irRECIST 1.1
Immune-related response criteria, Version 1.1
ITT
Intent-to-Treat
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
mAb
Monoclonal antibody
MDSC
Myeloid-derived suppressor cell
MedDRA
Medical Dictionary for Regulatory Activities
MHLW
Minister of Health, Labor, and Welfare
miRNA
Micro-ribonucleic acid
MRI
Magnetic resonance imaging
NCI
National Cancer Institute
NE
Not evaluable
NSCLC
Non–small-cell lung cancer
OAE
Other significant adverse event
ORR
Objective response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PD-L1 positive25%
≥25% of tumor cells with membrane staining for PD-L1 at any intensity
PD-L1-positive1%
≥1% of tumor cells with membrane staining for PD-L1 at any intensity
PD-L1-low/negative
<25% of tumor cells with membrane staining for PD-L1 at any intensity
PD-L1-negative
<1% of tumor cells with membrane staining for PD-L1 at any intensity
PD-L2
Programmed cell death ligand 2
PFS
Progression-free survival

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Abbreviation or 
special term
Explanation
PFS2
Time to second progression
PGx
Pharmacogenetic research
PK
Pharmacokinetic(s)
PR
Partial response
PRO
Patient-reported outcome
q2w
Every 2 weeks
q3w
Every 3 weeks
q4w
Every 4 weeks
q8w
Every 8 weeks
q12w
Every 12 weeks
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
RNA
Ribonucleic acid
RR
Response rate
RT-QPCR
Reverse transcription quantitative polymerase chain reaction
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Safety analysis set
SD
Stable disease
SNP
Single nucleotide polymorphism
SoC
Standard of Care
sPD-L1
Soluble programmed cell death ligand 1
T3
Triiodothyronine
T4
Thyroxine
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
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Study Code D419AC00001
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Date 09 January 2018
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Abbreviation or 
special term
Explanation
US
United States
WBDC
Web-Based Data Capture
WHO
World Health Organization

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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Lung cancer has been the most common cancer in the world for several decades, with an 
estimated 1.8 million new cases in 2012 (12.9% of all new cancers), and was also the most 
common cause of death from cancer in 2012, with 1.59 million deaths (19.4% of the total
cancer deaths; GLOBOCAN 2012).  Non-small-cell lung cancer (NSCLC) represents 
approximately 80% to 85% of all lung cancers.  Unfortunately, at the time of diagnosis, 
approximately 70% of patients with NSCLC already have advanced or metastatic disease not 
amenable to surgical resection.  Furthermore, a significant percentage of patients with early 
stage NSCLC who have undergone surgery subsequently develop distant recurrence and die as 
a result of their lung cancer (Pisters and LeChevalier 2005). 
Despite advances in the diagnosis, imaging, staging, and treatment of NSCLC, the estimated 
overall 5-year survival for patients in Europe and the United States (US) continues to be low 
(11% and 17%, respectively; D’Addario et al 2010, Howlander et al 2014).  Patients 
presenting with advanced NSCLC have a median overall survival (OS) of 10 to 12 months 
(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 
(Scagliotti et al 2008, Schiller et al 2002).  The durations of responses (DoRs) are also limited, 
and toxicities can be a major limiting factor.  The 1-year survival rate is 30% to 40% for 
patients with a good performance status.  Maintenance therapy, with either continuation or 
switch, has also been recommended for certain histologic subtypes of NSCLC; for example, 
maintenance with pemetrexed has been shown to improve OS and PFS, particularly in 
non-squamous histologies (Ciuleanu et al 2009, Paz-Ares et al 2013).
Common first-line treatment regimens for advanced NSCLC in major global markets are 
typically platinum-based doublets and include carboplatin and paclitaxel, carboplatin and 
gemcitabine (squamous only), carboplatin and pemetrexed (non-squamous only), cisplatin and 
gemcitabine (squamous only), and cisplatin and pemetrexed (non-squamous only).  
Platinum-based doublet chemotherapy regimens vary to some extent with regard to 
convenience, associated toxicities, and cost, with the selection of a specific regimen often 
dictated by local practice and individualized on a case-by-case basis.
1.1.1
Immunotherapies
It is increasingly understood that cancers are recognized by the immune system, and, under 
some circumstances, the immune system may control or even eliminate tumors (Dunn 
et al 2004).  Studies in mouse models of transplantable tumors have demonstrated that 
manipulation of co-stimulatory or co-inhibitory signals can amplify T-cell responses against 
tumors (Peggs et al 2009).  This amplification may be accomplished by blocking co-inhibitory 
molecules, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed 
cell death 1(PD-1) , from binding with their ligands, B7 or B7-H1 programmed cell death 
ligand 1 [PD-L1]).  

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1.1.2
MEDI4736
MEDI4736 is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa 
subclass that inhibits binding of PD-L1 and 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.)  As MEDI4736 is an engineered mAb, it does not induce antibody-dependent 
cellular cytotoxicity or complement-dependent cytotoxicity.  The proposed mechanism of 
action for MEDI4736 is interference of the interaction of PD-L1.
PD-L1 is expressed in a broad range of cancers with a high frequency, up to 88% in some 
types of cancers.  In a number of these cancers, including lung, the expression of PD-L1 is 
associated with reduced survival and an unfavorable prognosis.  In lung cancer, only 12% of 
patients with tumors expressing PD-L1 survived for more than 3 years, compared with 20% of 
patients with tumors lacking PD-L1 (Mu et al 2011).  Based on these findings, an anti-PD-L1 
antibody could be used therapeutically to enhance anti-tumor immune responses in patients 
with cancer.  Results of several non-clinical studies using mouse tumor models support this 
hypothesis, where antibodies directed against PD-L1 or its receptor PD-1 showed anti-tumor 
activity (Hirano et al 2005, Iwai et al 2002, Okudaira et al 2009, Zhang et al 2008).
MEDI4736 has been given to humans as part of ongoing studies as a single drug or in 
combination with other drugs.  As of 14 July 2014, 509 patients have been enrolled and 
treated in 10 ongoing clinical studies of MEDI4736 (5 employing MEDI4736 as monotherapy 
and 5 as combination therapy).  Details on the safety profile of MEDI4736 monotherapy are 
summarized in Section 1.3.2.1.  Refer to
for a complete summary of non-clinical 
and clinical information and guidance on management of MEDI4736-related toxicities.  
MEDI4736 monotherapy exhibits nonlinear (dose-dependent) pharmacokinetics (PK) 
approaching linearity with a ≥3-mg/kg dose, likely due to saturable target-mediated clearance, 
and has a half-life of approximately 21 days.  Of the 220 patients who received MEDI4736 
monotherapy for whom PK/anti-drug antibody (ADA) data were available from 
Study CD-ON-MEDI4736-1108 (referred to hereafter as Study 1108) as of 14 July 2014, 
5 patients (1 patient each in the 0.1- and 3-mg/kg cohorts and 3 patients in the 10-mg/kg
cohort) were detected ADA-positive, with an impact on PK/pharmacodynamics in 1 patient in 
the 3-mg/kg cohort.
1.1.3
Tremelimumab
Tremelimumab, a CTLA-4 mAb of the IgG 2 kappa isotype, is an immunomodulatory therapy 
(IMT) that is being developed by AstraZeneca for use in the treatment of cancer.  
Tremelimumab is a human IgG2 mAb directed against CTLA-4.  
Binding of CTLA-4 to its target ligands (B7-1 and B7-2) provides a negative regulatory 
signal, which limits T-cell activation.  Anti-CTLA-4 inhibitors antagonize the binding of 
CTLA-4 to B7 ligands and enhance human T-cell activation as demonstrated by increased 
cytokine (interleukin [IL]-2 and interferon [IFN] gamma) production in vitro in whole blood 
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or peripheral blood mononuclear cell (PBMC) cultures (Tarhini and Kirkwood 2008).  In 
addition, blockade of CTLA-4 binding to B7 by anti-CTLA-4 antibodies results in markedly 
enhanced T-cell activation and anti-tumor activity in animal models, including killing of 
established murine solid tumors and induction of protective anti-tumor immunity.  (Refer to 
the current version of the tremelimumab investigator brochure [IB] for more information.)  
Therefore, it is expected that treatment with an anti-CTLA-4 antibody, such as tremelimumab, 
will lead to increased activation of the human immune system, increasing anti-tumor activity 
in patients with solid tumors.
An extensive program of non-clinical and clinical studies has been conducted for 
tremelimumab both as monotherapy and combination therapy with conventional anticancer 
agents to support various cancer indications using different dose schedules.  As of the data 
cut-off date of 12 November 2014 (for all studies except D4190C00006, which has a cut-off 
date of 4 December 2014), 973 patients have received tremelimumab monotherapy (not 
including 497 patients who have been treated in the blinded Phase 2b study, D4880C00003) 
and 208 patients have received tremelimumab in combination with other agents.  Details on 
the safety profile of tremelimumab monotherapy are summarized in Section 1.3.2.3.  Refer to 
the current tremelimumab IB for a complete summary of non-clinical and clinical information
and see
for guidance on management of tremelimumab-related toxicities.  
Tremelimumab exhibited a biphasic PK profile with a long terminal phase half-life of 22 days.  
Overall, a low incidence of ADAs (<6%) was observed for treatment with tremelimumab.  
1.1.4
MEDI4736 in combination with tremelimumab
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity (Pardoll 
2012) because the mechanisms of action of CTLA-4 and PD-1 are non-redundant; therefore, 
AstraZeneca is also investigating the use of MEDI4736 + tremelimumab combination therapy 
for the treatment of cancer.
Study D4190C00006 is a Phase Ib dose-escalation study to establish safety, 
PK/pharmacodynamics, and preliminary anti-tumor activity of MEDI4736 + tremelimumab 
combination therapy in patients with advanced NSCLC.  The dosing schedule utilized is 
MEDI4736 every 2 or 4 weeks (q2w; q4w) up to Week 50 and 48 (12 months), combined with 
tremelimumab q4w up to Week 24 for 7 doses then every 12 weeks (q12w) for 2 additional 
doses for up to 12 months.  The study is ongoing and continues to accrue.  
As of 27 January 2015, a total of 74 patients have been treated in the study, including 
58 patients on the q4w dosing schedule and 16 patients on the q2w dosing schedule.  Patients 
have received between 1 and 13 doses of MEDI4736 and between 1 and 9 doses of 
tremelimumab.  Details on the safety profile of MEDI4736 + tremelimumab combination 
therapy are summarized in Sections 1.2.1 and 1.3.2.4.  Refer to the current versions of the 
MEDI4736 IB and the tremelimumab IB for a complete summary of non-clinical and clinical 
information and
for guidance on management of MEDI4736 + tremelimumab-
related toxicities.
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As of 27 January 2015 in Study D4190C00006, an approximately dose-proportional increase 
in PK exposure (maximum plasma concentration [Cmax] and area under the plasma drug 
concentration-time curve (AUC) from time zero to Day 28 post-dose) of both MEDI4736 and 
tremelimumab was observed over the dose range of 3 to 20 mg/kg MEDI4736 q4w or q2w 
and 1 to 10 mg/kg tremelimumab q4w.  Four of 60 patients with ADA data available were 
ADA positive for either anti-MEDI4736 or anti-tremelimumab antibodies post-treatment; 
MEDI4736 PK was impacted in only 2 of these 4 patients.  Complete soluble programmed 
cell death ligand 1 (sPD-L1) suppression (surrogate for PD-L1 targeting) was observed in 
almost all patients over the dose range of 3 to 20 mg/kg of MEDI4736 q4w or q2w.  
1.1.5
Rationale for conducting this study
Current therapies for advanced NSCLC have poor outcomes (low 5-year survival of 17% for 
the US), with responses to systemic chemotherapy in the first-line setting of approximately 
20% to 30%, and a median OS of approximately 10 to 12 months (Bonomi 2010, 
D’Addario et al 2010, Scagliotti et al 2008, Schiller et al 2002).  Responses are also limited in 
duration.  Systemic chemotherapy is associated with significant side effects, including 
neutropenia, nausea, vomiting and dehydration, and alopecia (Sandler et al 2006, 
Scagliotti et al 2008).  There is still a significant unmet medical need for additional treatment 
options for use in this patient population as the 1-year survival rate is 30% to 40%.
As an antibody that blocks the interaction between PD-L1 and its receptors, MEDI4736 may 
relieve PD-L1-dependent immunosuppressive effects and, therefore, enhance the cytotoxic 
activity of anti-tumor T-cells.  This hypothesis is supported by emerging clinical data from 
other mAbs targeting the PD-L1/PD-1 pathway, which provide early evidence of clinical 
activity and a manageable safety profile (Brahmer et al 2012, Topalian et al 2012).  Responses 
have been observed in patients with PD-L1-positive tumors and patients with PD-L1-negative 
tumors.  In addition, MEDI4736 monotherapy has shown durable responses in NSCLC in 
Study 1108 (see Section 1.3.1.1).
The rationale for combining MEDI4736 and tremelimumab is that the mechanisms of 
CTLA-4 and PD-1 are non-redundant, suggesting that targeting both pathways may have 
additive or synergistic activity (Pardoll 2012).  In fact, combining immunotherapy agents has 
been shown to result in improved response rates relative to monotherapy.  For example, the 
concurrent administration of nivolumab and ipilimumab to patients with advanced melanoma 
induced higher objective response rates (ORRs) than those obtained with single-agent therapy.  
Importantly, responses appeared to be deep and durable (Wolchok et al 2013).  Similar results 
have been observed in an ongoing study of MEDI4736 + tremelimumab in NSCLC (Antonia 
et al 2014a), with further updated details presented in this clinical study protocol.
Based on the preliminary clinical efficacy and safety data observed in patients with NSCLC in 
Study D4190C00006 (with MEDI4736 + tremelimumab) and in Study 1108 (with MEDI4736 
monotherapy), AstraZeneca plans to determine the activity of MEDI4736 in combination with 
tremelimumab and MEDI4736 monotherapy as first-line treatment in patients with NSCLC.  
The preliminary efficacy, safety, and tolerability data of the MEDI4736 + tremelimumab 
combination in Study D4190C00006 and MEDI4736 monotherapy in Study 1108 support the 

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development of these treatments in NSCLC.  The primary endpoints of this Phase III study are 
to determine the activity of MEDI4736 + tremelimumab combination therapy and MEDI4736 
monotherapy compared to Standard of Care (SoC) in patients with EGFR and ALK wild-type 
NSCLC when used as first-line treatment in patients with PD-L1 positive25% tumors and 
secondary endpoints will include the comparison of the activity in patients with PD-L1 
positive1% tumours and all randomised patients. In addition to quantifying the clinical effects 
of MEDI4736 in combination with tremelimumab, this will also allow comparison between 
the relative efficacy and tolerability of MEDI4736 + tremelimumab and MEDI4736 alone. 
1.2
Rationale for study design, doses, and control groups
This study will utilize an open-label design due to the different treatment administration 
schedules and treatment durations.
1.2.1
MEDI4736 + tremelimumab combination therapy dose rationale
The MEDI4736 + tremelimumab doses and regimen selected for this study are based on the 
goal of selecting an optimal combination dose of MEDI4736 and tremelimumab that would 
yield sustained target suppression (sPD-L1), demonstrate promising efficacy, and have an 
acceptable safety profile.  
As of 27 January 2015, a total of 74 patients with advanced NSCLC have been treated in 
Study D4190C00006.  The 74 patients have received between 1 and 9 doses of tremelimumab 
and between 1 and 13 doses of MEDI4736. Various dose combinations were explored, with 
doses of tremelimumab ranging from 1 to 10 mg/kg and doses of MEDI4736 ranging from 
3 to 20 mg/kg. Fifty-eight of these patients were in the q4w dosing schedule and 16 patients 
were in the q2w dosing 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.
In order to reduce the dosing frequency of MEDI4736 to align with the q4w dosing of 
tremelimumab, while ensuring an acceptable PK/pharmacodynamic, safety, and efficacy 
profile, cohorts were narrowed to 15 and 20 mg/kg MEDI4736 q4w.  PK simulations from the 
MEDI4736 monotherapy data indicated that a similar area under the plasma drug 
concentration-time curve at steady state (AUCss; 4 weeks) was expected following both 
10 mg/kg q2w and 20 mg/kg q4w MEDI4736. The observed MEDI4736 PK data from the 
D4190C00006 study were well in line with the predicted monotherapy PK data developed 
preclinically. This demonstrates similar exposure of MEDI4736 20 mg/kg q4w and 10 mg/kg 
q2w, with no alterations in PK when MEDI4736 and tremelimumab (doses ranging from 1 to 
3 mg/kg) are dosed together.  While the median Cmax at steady state (Cmax,ss) is expected to be 
higher with 20 mg/kg q4w (approximately 1.5 fold) and median trough concentration at steady 
state (Ctrough,ss) is expected to be higher with 10 mg/kg q2w (approximately 1.25 fold), this is 
not expected to impact the overall safety and efficacy profile, based on existing preclinical and 
clinical data.
Monotonic increases in pharmacodynamic activity were observed with increasing doses of 
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monotherapy.  There was evidence of augmented pharmacodynamic activity relative to 
MEDI4736 monotherapy with combination doses containing 1 mg/kg tremelimumab, 
inclusive of both the 15 and 20 mg/kg MEDI4736 plus 1 mg/kg tremelimumab combinations. 
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse 
events (AEs), including discontinuations due to AEs, serious AEs (SAEs), and severe AEs.  
Between the 10 mg/kg MEDI4736 + 1 mg/kg tremelimumab and 10 mg/kg MEDI4736 + 
3 mg/kg tremelimumab cohorts treated at the q2w schedule, the number of patients reporting 
any AE, Grade 3 AEs, SAEs, and treatment-related AEs was higher in the 10 mg/kg 
MEDI4736 + 3 mg/kg tremelimumab cohort than the 10 mg/kg MEDI4736 + 1 mg/kg 
tremelimumab cohort. A similar pattern was noted in the q4w regimens, suggesting that, as 
the dose of tremelimumab increased above 1 mg/kg, a higher rate of treatment-related events 
may be anticipated. Further, the SAEs frequently attributed to immunotherapy, pneumonitis 
and colitis, were more commonly seen in cohorts using either 3 mg/kg or 10 mg/kg of 
tremelimumab compared to the 1-mg/kg dose cohorts. Together, these data suggest that a 
combination using a tremelimumab dose of 1 mg/kg appeared to minimize the rate of toxicity 
when combined with MEDI4736. As a result, all combination doses utilizing either the 3 or 
10 mg/kg doses of tremelimumab were eliminated in the final dose selection.
In contrast, cohorts assessing higher doses of MEDI4736 with a constant dose of 
tremelimumab did not show an increase in the rate of AEs. The data suggested that increasing 
doses of MEDI4736 may not impact the safety of the combination as much as the 
tremelimumab dose. Further, safety data between the 10-mg/kg and 20-mg/kg cohorts were 
similar, with no change in safety events with increasing dose of MEDI4736.
In Study D4190C00006, of all treatment cohorts, the cohort of 11 patients treated in the 
20 mg/kg MEDI4736 + 1 mg/kg tremelimumab group had the fewest AEs, Grade ≥3 AEs, 
SAEs, and treatment discontinuations due to AEs, but still showed strong evidence of clinical 
activity.  This cohort had a lower number of treatment-related Grade ≥3 AEs or treatment 
related SAEs. No dose-limiting toxicities (DLTs) were reported.  
Preliminary clinical activity of the MEDI4736 and tremelimumab combination did not appear 
to change with increasing doses of tremelimumab.  The 15- and 20-mg/kg MEDI4736 q4w
cohorts demonstrated objective responses at all doses of tremelimumab, and increasing doses 
of tremelimumab did not provide deeper or more rapid responses.
Efficacy data suggested that the 20 mg/kg MEDI4736 + 1 mg/kg tremelimumab dose cohort 
may demonstrate equivalent clinical activity to other dose combinations. A total of 5 of 
11 patients in the 20 mg/kg MEDI4736 + 1 mg/kg tremelimumab cohort were evaluable for 
efficacy with at least 8 weeks of follow-up.  Of these, there were 2 patients (40%) with partial 
response (PR), 1 patient (20%) with stable disease (SD), and 1 patient (20%) with progressive 
disease (PD).  (The fifth patient had only a single scan, which was conducted outside the 
window for these evaluations.)
Additionally, of all cohorts, the 20 mg/kg MEDI4736 + 1 mg/kg tremelimumab dose cohort 
had the fewest AEs, Grade ≥3 AEs, SAEs, and treatment discontinuations due to AEs, but still 

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showed some evidence of clinical activity.  All together, the data suggested that a 20 mg/kg 
MEDI4736 + 1 mg/kg tremelimumab dose combination should be selected for further 
development.  
1.2.2
Rationale for 4 cycles of combination therapy followed by MEDI4736 
monotherapy
Long-term follow up on melanoma patients treated with ipilimumab, an anti-CTLA-4 
targeting antibody (dosed every 3 weeks for 4 doses and then discontinued), shows that 
patients responding to ipilimumab derive long-term benefit, with a 3-year OS rate of 
approximately 22%.  Furthermore, the survival curve in this population reached a plateau at 
3 years and was maintained through 10 years of follow up (Schadendorf et al 2013). 
Similar data have been presented for other anti-PD-1/PD-L1 targeting antibodies: 

Nivolumab (anti-PD-1) was dosed q2w for up to 96 weeks in a large Phase I
dose-escalation and expansion study, and showed responses were maintained for a 
median of 22.94 months for melanoma (doses 0.1 mg/kg to 10 mg/kg), 17 months 
for NSCLC (doses 1, 3, and 10 mg/kg), and 12.9 months for renal cell carcinoma 
patients (doses 1 and 10 mg/kg) at the time of data analysis (Hodi et al 2014, 
Brahmer et al 2014, Drake et al 2013).  Furthermore, responses were maintained 
beyond treatment discontinuation in the majority of patients who stopped 
nivolumab treatment (either due to protocol specified end of treatment, complete 
response [CR], or toxicity) for up to 56 weeks at the time of data analysis (Topalian 
et al 2014). 

MPDL3280a (anti-PD-L1) and the combination of nivolumab with ipilimumab, in 
which patients were dosed for a finite time period and responses maintained beyond 
treatment discontinuation have been reported (Herbst et al 2013, Wolchok 
et al 2013).
Similar long term results may be expected with use of other immune-mediated cancer 
therapeutics including anti-CTLA-4 antibodies such as tremelimumab, anti PD-L1 antibodies 
such as MEDI4736, or the combination of the two. 
The MEDI4736 + tremelimumab combination regimen will be administered for 4 doses
followed by monotherapy MEDI4736 20 mg/kg q4w.
1.2.3
MEDI4736 monotherapy dose rationale
A dose of MEDI4736 dose of 20 mg/kg q4w 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 (ongoing first-time-in-humans study).  
As of 14 July 2014, 393 patients enrolled in Study 1108 have received MEDI4736, 
predominantly at 10 mg/kg q2w (either in the dose-escalation or dose-expansion phase of the 
study).  Data presented at the European Society for Medical Oncology (ESMO) meeting 2014 

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with a later cut-off of 21 August 2014 showed that MEDI4736 was well tolerated at all doses 
in the NSCLC subset of patients enrolled into Study 1108, with drug-related Grade ≥3 AEs 
reported in 3% of patients and drug-related AEs leading to discontinuation reported in 1% of 
patients.  No drug-related colitis or hyperglycemia of any grade, no Grade ≥3 pneumonitis 
reported, and no drug-related AEs leading to death were reported (Antonia et al 2014b). No 
DLTs were observed up to a dose of 10 mg/kg q2w or 15 mg/kg every 3 weeks (q3w).
Efficacy data on the patients with NSCLC in Study 1108, presented at ESMO 2014 (cut-off 
date of 21 August 2014), showed a disease control rate (DCR) at 12 weeks of 41% and ORR 
of 16% among 162 evaluable patients, with activity observed in both squamous and non-
squamous histologies.  The ORR was higher (25%; 12 CR/PR; n=48) in patients with PD-L1 
positive tumors, defined as those with ≥25% of tumor cells with membrane staining for PD-
L1, compared to patients with PD-L1 negative tumors (10%; 7 CR/PR; n=74) (Antonia et al 
2014b).
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging 
from 0.1 to 10 mg/kg q2w or 15 mg/kg q3w, MEDI4736 exhibited non-linear 
(dose-dependent) PK consistent with target-mediated drug disposition.  The PK approached 
linearity at ≥3 mg/kg q2w, suggesting near complete target saturation (membrane-bound and 
sPD-L1), and further shows that the MEDI4736 dosing frequency can be adapted to a 
particular regimen given the linearity seen at higher doses than 3 mg/kg.   The expected 
half-life with doses ≥3 mg/kg q2w is approximately 21 days.  A dose-dependent suppression 
in peripheral sPD-L1 was observed over the dose range studied, consistent with engagement 
of MEDI4736 with PD-L1.  Dose-related changes in a variety of peripheral biomarkers have 
been observed over the dose range of 0.1 to 15 mg/kg. A low level of immunogenicity has 
been observed.  No patients have experienced immune-complex disease following exposure to 
MEDI4736.  Of the 220 patients who received MEDI4736 monotherapy and for whom 
PK/ADA data were available as of14 July 2014, 5 were ADA positive, with an impact on 
PK/pharmacodynamics reported in 1 patient at 3 mg/kg.  
Data from Study 006 (Phase I trial in patients with NSCLC using the combination of 
MEDI4736 and tremelimumab), also show an approximately dose-proportional increase in PK 
exposure for MEDI4736 over the dose range of 3 to 20 mg/kg MEDI4736 q4w or q2w.  The 
observed MEDI4736 PK data from the combination study were well in line with the predicted 
monotherapy PK data (5th median and 95th percentiles) for a q4w regimen.
A population PK model was developed using the data from Study 1108 (doses=0.1 to 
10 mg/kg q2w or 15 mg/kg q3w; Fairman et al 2014).  Multiple simulations indicate that a 
similar overall exposure is expected following both 10 mg/kg q2w and 20 mg/kg q4w 
regimens, as represented by AUCss; 4 weeks.  Median Cmax,ss is expected to be higher with 
20 mg/kg q4w (~1.5 fold) and median Ctrough,ss is expected to be higher with 10 mg/kg q2w 
(~1.25 fold).  Clinical activity with the 20 mg/kg q4w dosing regimen is anticipated to be 
consistent with 10 mg/kg q2w with the proposed similar dose of 20 mg/kg q4w expected to (a) 
achieve complete target saturation in majority of patients; (b) account for anticipated 
variability in PK, pharmacodynamic, and clinical activity in diverse cancer populations; (c) 

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maintain sufficient PK exposure in case of ADA impact; and (d) achieve PK exposure that 
yielded maximal anti-tumor activity in animal models.
As of 8 April 2015, there is initial safety data for 16 patients receiving the 20 mg/kg q4w 
dosing regimen (12 patients from Study 1108 and 4 patients from the Japan Phase I trial).  The 
toxicities observed with 20 mg/kg q4w are consistent with the 10 mg q2w regimen, and there 
were no DLTs observed.  Of the 12 patients in Study 1108, 42% of patients have experienced 
any grade AE, with 2 being Grade 3 and above (17%).  None of the Grade 3 and higher events 
was considered treatment-related.  No patients on the Japan Phase I trial have experienced a 
Grade 3 or above AE.  At present, the data do not suggest that the safety profile of MEDI4736 
will be different in the 20 mg/kg q4w dosing regimen when compared to 10 mg/kg q2w 
regimen.
Given the similar AUC and modest differences in median peak and trough levels at steady 
state, the observation that both regimens maintain complete sPD-L1 suppression at trough,
and the available clinical data, the 20 mg/kg q4w and 10 mg/kg q2w regimens are expected to 
have similar efficacy and safety profiles, supporting further development with a dose of 
20 mg/kg q4w. 
1.2.4
Rationale for Standard of Care as a comparator
The choice of SoC options provided in this study includes carboplatin and paclitaxel, 
carboplatin (or cisplatin) and gemcitabine (squamous only), carboplatin (or cisplatin) and 
pemetrexed (non-squamous only), and for eligible patients, pemetrexed maintenance 
(non-squamous only). Patients in the SoC group will receive treatment determined by the 
Investigator, from the SoC agents approved for use in NSCLC in their local market, until 
progression per standard practice.  The SoC options provided in this study include agents that 
are commonly used in advanced or metastatic NSCLC and allow sufficient flexibility for 
Investigators and patients to select the agents that reflect their normal clinical practice and 
national guidelines (NCCN 2014 and Reck et al 2014).
1.2.5
Rationale for retreatment option
In contrast to patients treated with chemotherapy, who are unlikely to respond to rechallenge 
with the same agent upon progression, responses have been observed upon retreatment with 
IMTs.  Several potential mechanisms of resistance to IMT exist, including loss of T-cell 
“memory” or recurrence of immune escape, which suggest retreatment for patients who 
initially respond or demonstrate SD is reasonable.  Preliminary data in patients previously 
treated with IMTs suggest that responses are similar to those observed following initial 
treatment (Forde et al 2014; Hodi et al 2010).
Patients in the MEDI4736 + tremelimumab group who complete 4 dosing cycles (with clinical 
benefit per Investigator judgement), and subsequently have PD during treatment with 
MEDI4736 alone may restart treatment if they meet eligibility criteria for retreatment.   

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1.2.6
Rationale for endpoints
The primary objectives of this study are to assess the efficacy of:
! MEDI4736 + tremelimumab treatment compared with SoC in terms of PFS in patients with 
EGFR and ALK wild-type advanced or metastatic NSCLC with PD-L1 positive25% tumors
! MEDI4736 + tremelimumab treatment compared with SoC in terms of OS in patients with 
EGFR and ALK wild-type advanced or metastatic NSCLC with PD-L1 positive25% tumors
! MEDI4736 treatment compared with SoC in terms of OS in patients with EGFR and ALK 
wild-type advanced or metastatic NSCLC with PD-L1 positive25% tumors 
Within the statistical hierarchy, a key secondary endpoint of the study is to assess the efficacy 
in the overall study population:
! MEDI4736 + tremelimumab treatment compared with SoC in terms of PFS and OS in 
patients with EGFR and ALK wild-type advanced or metastatic NSCLC with PD-L1 
positive1% tumors and in the overall NSCLC population
Emerging data in immuno-oncology suggest that the treatment benefit of immunotherapies
can more strongly manifest in OS compared to PFS (Borghaei et al 2015, Brahmer et al 2015,
Fehrenbacher et al 2016), and therefore, both PFS and OS are co-primary endpoints.  
Additionally, the emerging immuno-oncology data indicate an improved treatment effect in 
patients with NSCLC tumors that express PD-L1 for both combination and monotherapy
(Hellman et al 2016, Reck et al 2016).  Therefore, the study characterizes the efficacy of 
MEDI4736 + tremelimumab and MEDI4736 monotherapy in the treatment in the PD-
L1-positive NSCLC population (≥25%, ≥1%) and in the overall NSCLC population.
The secondary efficacy endpoints of ORR, DoR, proportion of patients alive and 
progression-free and time to second progression (PFS2) will be examined to further evaluate 
the anti-tumor effect and survival benefit of MEDI4736 + tremelimumab versus SoC.  The 
secondary efficacy endpoints of PFS, ORR and PFS2 will also be examined to further evaluate 
the anti-tumor effect and survival benefit of MEDI4736 monotherapy compared to SoC.  PFS 
and ORR will be examined to further evaluate the anti-tumor effect of MEDI4736 + 
tremelimumab combination therapy compared to MEDI4736 monotherapy.  ORR and DoR 
will be assessed using Blinded Independent Central Review (BICR) assessments according to 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1).
 
 
 
The secondary health-related quality of life (HRQoL) assessments (the European Organisation 
for Research and Treatment of Cancer [EORTC] 30-item core quality of life questionnaire, 
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Version 3 [QLQ-C30 v3] and 13-item lung cancer quality of life questionnaire [QLQ-LC13])
will show the overall influence of the benefits and toxicity of the treatment from a patient’s
perspective and will aid in understanding of the benefit/risk evaluation. These 
patient-reported outcome (PRO) questionnaires are well-established instruments that have 
been previously included in lung cancer clinical trials.  
 
1.3
Benefit/risk and ethical assessment
The following sections include summaries of the potential benefits and risks associated with 
MEDI4736 monotherapy, tremelimumab monotherapy, and MEDI4736 + tremelimumab 
combination therapy, respectively, prior to the overall benefit:risk assessment.
1.3.1
Potential benefits
1.3.1.1
MEDI4736
The majority of the safety and efficacy data currently available for MEDI4736 are based on 
the first time in-human, single-agent study (Study 1108) in patients with advanced solid 
tumors.  Data from Study 1108 were presented at the ESMO 2014 Congress.  As of 
21 August 2014, 162 patients with NSCLC were evaluable for response analysis.  The DCR at 
12 weeks in patients receiving 10 mg/kg MEDI4736 q2w was 39%, and the ORR was 15% 
(26% [12 out of 47 patients] with known PD-L1-positive NSCLC [ie, ≥25% PD-L1 
expression] and 10% [7 out of 74 patients] with known PD-L1 low/negative NSCLC [ie, 
<25% PD-L1 expression]).  A total of 24% of patients receiving 10 mg/kg MEDI4736 q2w 
had SD for ≥12 weeks (including 21% [10 out of 47 patients] with known PD-L1-positive 
NSCLC and 32% [24 out of 74 patients] with known PD-L1-negative NSCLC).  Responses 
were ongoing in 88% of patients with NSCLC, with an objective response duration ranging 
from 0.1 to 32.4 weeks (Antonia et al 2014b).
1.3.1.2
Tremelimumab
In a single-group, Phase II study (Study A3671008) of tremelimumab administered at 
15 mg/kg every 90 days to patients with refractory melanoma, a response rate (RR) of 7% and 
a median OS of 10 months in the second-line setting (as compared to approximately 6 months 
with best supportive care reported from a retrospective analysis, Korn et al 2008) were 
observed (Kirkwood et al 2010).  In a randomized, open-label, first-line Phase III study of 
tremelimumab (administered at 15 mg/kg every 90 days) versus chemotherapy (dacarbazine or 
temozolomide) in advanced melanoma (Study A3671009), results of the final analysis showed 
an RR of 11% and a median OS of 12.58 months in this first-line setting as compared to 
10.71 months with standard chemotherapy; however, these results were not statistically 
significant (Ribas et al 2013).  Additionally, a Phase II maintenance study (Study A3671015) 
in patients with Stage IIIB or IV NSCLC who had responded or remained stable failed to 
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achieve statistical significance.  The primary endpoint of PFS at 3 months was 22.7% in the 
tremelimumab group (15 mg/kg) compared with 11.9% in the best supportive care group
(Study A3671015).
1.3.1.3
   MEDI4736 + tremelimumab
The preclinical and clinical justification for this combination as noted in Section 1.2.1 also 
supports the synergy of this combination.  Available data, such as those presented by 
Wolchok et al, suggest that the combination of agents targeting PD-1/PD-L1 and CTLA-4 
may have profound and durable benefits in patients with melanoma (Wolchok et al 2013).  
Further, preliminary efficacy data from Study D4190C00006 has demonstrated that this 
combination is clinically active and well tolerated.  As of 27 January 2015, 53 patients were 
evaluable for response across various MEDI4736 + tremelimumab dose regiments.  Of these, 
12 patients (23%) had a best response of PR and 14 patients (26%) had a best response of SD.
In the MEDI4736 20 mg/kg plus tremelimumab 1 mg/kg q4w cohort, a total of 5 of 11 
patients were evaluable for efficacy with at least 8 weeks of follow-up. Of these, there were 
2 patients (40%) with PR, 1 patient (20%) with SD, and 1 patient (20%) with PD.  (The fifth 
patient had only a single scan, which was conducted outside the window for these 
evaluations.)
Current experience with single agent IMT studies suggests that clinical responses may be 
restricted to a subset of any given patient population and that it might be beneficial to enrich 
the patient population by selecting patients likely to respond to therapy. To date, no assay has 
been established or validated, and no single approach has proven accurate, for patient 
enrichment for IMTs. However, independent data from multiple sources using different 
assays and scoring methods suggests that PD-L1 expression on tumor cells and/or tumor 
infiltrating cells may be associated with greater clinical benefit.
Data from ongoing studies with MEDI4736 and other agents targeting the PD-1/PD-L1 
pathway suggest, as shown in a number of tumor types (eg, NSCLC, renal cell carcinoma, and 
melanoma), that monotherapy may be more efficacious (in terms of ORR) in patients who are 
PD-L1-positive. 
Given the findings, a number of ongoing studies are assessing the activity of agents in patients 
with PD-L1–positive tumors. Though biomarker development is ongoing, and the final 
boundaries of these populations are yet to be established, there is also an unmet medical need 
in patients with PD-L1–low/negative tumors that needs to be addressed. Data, as of 
27 January 2015 from Study 006 show that with the addition of tremelimumab to MEDI4736, 
the ORR can be increased to 25% in patients with PD-L1-low/negative NSCLC (as defined by 
the 
). As patients with PD-L1 
positive(≥25%) tumors can also have an increase in ORR, from 25% with MEDI4736 
monotherapy, to 36% with the combination of MEDI4736 and tremelimumab, the study will 
enroll all patients with NSCLC, with efficacy analysis performed in the overall study 
population, and pre-defined PD-L1 subgroups.
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1.3.2
Potential risks
1.3.2.1
Overall risks
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed cell 
death ligand 1 (PD-L1) as well as those directed against programmed cell death-1 (PD-1) or 
cytotoxic T-lymphocyte antigen-4 (CTLA-4), aim to boost endogenous immune responses 
directed against tumor cells.  By stimulating the immune system however, there is the 
potential for adverse effects on other tissues.
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues.  These risks are 
generally events with a potential inflammatory or immune mediated mechanism and which 
may require more frequent monitoring and/or unique interventions such as 
immunosuppressants and/or endocrine therapy.  These immune mediated effects can occur in 
nearly any organ system, and are most commonly seen as gastrointestinal AEs such as colitis 
and diarrhoea, 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.
1.3.2.2
MEDI4736 
Risks with durvalumab include, but are not limited to, diarrhea/colitis and intestinal 
perforation, pneumonitis/ILD, endocrinopathies (hypo- and hyper-thyroidism, type I diabetes 
mellitus, hypophysitis and adrenal insufficiency) hepatitis/increases in transaminases, 
nephritis/increases in creatinine, pancreatitis/increases in amylase and lipase, 
rash/pruritus/dermatitis, myocarditis, myositis/polymyositis, other rare or less frequent 
inflammatory events including neurotoxicities, infusion-related reactions, hypersensitivity 
reactions and infections/serious infections. 
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 (all grades) reported very commonly (≥ 10% of patients) 
are fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back 
pain, pyrexia, asthenia, anemia, arthralgia, peripheral edema, headache, rash, and pruritus. 
Approximately 9% of patients experienced an AE that resulted in permanent discontinuation 
of durvalumab and approximately 6% of patients experienced an SAE that was considered to 
be related to durvalumab by the study investigator.
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 6.7.2).

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A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab IB.
1.3.2.3
Tremelimumab
Risks with tremelimumab monotherapy include, but are not limited to, GI effects (colitis, 
diarrhoea, 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, other 
gastrointestinal events e.g. ulcerative colitis, dehydration, nausea and vomiting; hepatic events 
including hepatitis, and liver enzyme elevations; pneumonitis and ILD; nervous system events 
including encephalitis, peripheral motor and sensory neuropathies, Guillain-Barre and 
proximal muscle weakness; cytopenias including thrombocytopenia, anemia and neutropenia;
infusion-related reactions, anaphylaxis, and allergic reactions; renal events including renal 
failure, acute kidney injury, nephritis, nephrotic syndrome, autoimmune nephritis and 
electrolyte abnormalities such as hypokalemia; autoimmune diseases including autoimmune 
arthritis, Sjogren's syndrome and giant cell temporal arteritis; hyperglycemia and diabetes 
mellitus; and pyrexia. 
For information on all identified and potential risks with tremelimumab please always refer to 
the current version of the tremelimumab IB.
Using pooled data from monotherapy clinical studies AEs (all grades) reported very 
commonly (≥ 10% of patients)  were diarrhea, nausea, fatigue, pruritus, decreased appetite, 
rash,  vomiting, dyspnoea, constipation, cough, pyrexia, abdominal pain, decreased weight, 
headache, asthenia, and anaemia. Approximately 16% of patients experienced an AE that
resulted in permanent discontinuation of tremelimumab and approximately 45% of patients 
experienced an SAE.
A detailed summary of tremelimumab monotherapy AE data can be found in the current 
version of the tremelimumab IB. 
1.3.2.4
MEDI4736 + tremelimumab
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 trials, in a number of different indications, and 
has to date shown a manageable safety and tolerability profile.  
The types of risks with the combination of durvalumab + tremelimumab (based on an 
equivalent durvalumab dose of 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.
For information on all identified and potential risks with the durvalumab+tremelimumab 
combination please always refer to the current version of the durvalumab IB

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In durvalumab+tremelimumab combination studies at the dose of durvalumab 20mg/kg and 
tremelimumab 1mg/kg AEs (all grades) reported very commonly (≥ 10% of patients) are 
fatigue, diarrhoea,nausea, dyspnea, decreased appetite, pruritus, vomiting, anaemia, 
constipation, cough, abdominal pain, pyrexia, back pain, arthralgia, hypothyroidism, asthenia, 
oedema peripheral, weight, decreased hyponatraemia 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.
1.3.3
Overall benefit-risk and ethical assessment
There remains a significant unmet medical need for additional treatment options for patients 
with EGFR and ALK wild-type, advanced or metastatic NSCLC who have not received prior 
chemotherapy or any systemic therapy for advanced or metastatic NSCLC.  
The study design aims to minimize potential risks; intensive monitoring, including early safety 
assessment, is in place for those risks deemed to be most likely based on prior experience with 
the IPs (ie, MEDI4736 + tremelimumab, MEDI4736, and SoC).
Based upon the available non-clinical and clinical safety data, the limited survival benefit 
provided by the currently available treatment options to patients, the limited life expectancy 
due to malignant disease, the activity seen with MEDI4736 in this tumor type, and the strength 
of the scientific hypotheses under evaluation, the MEDI4736 + tremelimumab combination 
and the MEDI4736 monotherapy treatments proposed for evaluation in this study may have 
the potential to provide meaningful clinical benefit with a manageable safety and tolerability 
profile by generating durable clinical responses, thereby improving quality of life (QoL) and 
potentially extending survival. 
Therefore, the investigation of the potential therapeutic efficacy of the combination of 
MEDI4736 with tremelimumab and MEDI4736 monotherapy in patients with PD-L1-positive 
and -negative tumors is acceptable, and the overall benefit/risk assessment supports the 
proposed study design.
1.4
Study design
This is a randomized, open-label, multi-center, global Phase III study to determine the 
efficacy and safety of MEDI4736 + tremelimumab combination therapy and MEDI4736 
monotherapy versus platinum-based SoC chemotherapy in the first-line treatment of patients 
with EGFR and ALK wild-type advanced or metastatic NSCLC. A schematic diagram of the 
overall study design is shown in Figure 1, and a detailed study flow chart is shown in Figure 
2.

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This study will enroll approximately 1850 patients at sites in North America, Asia, Australia, 
and Europe to randomize approximately 1092 patients (including approximately 160 patients 
with PD-L1 positive25% NSCLC in each treatment group) to treatment.  
Patients will provide a tumor tissue sample at enrollment (newly acquired or archived sample 
<3 months old) to determine PD-L1 expression status at 25% (defined by the
 
in which:
! ≥25% PD-L1& >1% PD-L1 membrane-expression in tumoral tissue are considered as 
relevant positive sub-groups 
! <25% PD-L1 is considered low/negative 
! <1% is considered negative;
Patients will be randomized in a 1:1:1 ratio in a stratified manner according to PD-L1 tumor 
expression status (PD-L1 positive25% versus PD-L1-low/negative) and histology (squamous 
versus non-squamous) to receive treatment with MEDI4736 + tremelimumab combination 
therapy, MEDI4736 monotherapy, or SoC therapy.  
Doses and treatment regimens are described in Section 7.2.  Assessments will be conducted as 
indicated in Table 2, Table 3, and Table 4.
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Figure 1
Overall study design
a
Statification by PD-L1 membrane-expression in tumoral tissue (≥25%, <25%).  Sites will be supplied with PD-L1 status upon request at disease progression.
b
Offer of standard chemotherapy per Investigator discretion.
c
Standard of Care is an Investigator choice from the following: paclitaxel + carboplatin, gemcitabine + cisplatin (or carboplatin) (squamous only), pemetrexed + cisplatin (or carboplatin) 
(non-squamous only), and for eligible patients, pemetrexed maintenance (non-squamous only following pemetrexed/platinum induction).

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Figure 2
Study flow chart
a
Informed consent of study procedures and tumor biopsy sample may be obtained prior to the 28-day screening window, if necessary, in order to permit tumor biopsy 
sample acquisition and analysis prior to randomization.  
b
Tumor assessments were performed using RECIST 1.1
c
A confirmatory scan is always required following the initial demonstration of PD and preferably at the next scheduled visit (in the absence of clinically significant 
deterioration).  (See Section 5.1 for more information.) 

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2.
STUDY OBJECTIVES
All objectives will be evaluated for all patients, unless otherwise indicated, and where 
appropriate for patients with PD-L1-positive and/or PD-L1–negative NSCLC.  The 
assessment of PFS and OS in all patients and PFS in patients with PD-L1-positive NSCLC 
will be considered co-primary objectives. 
2.1
Primary objective
Primary Objective:
Outcome Measure:
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy 
compared to SoC in terms of PFS in 
patients with PD-L1 positive25% NSCLC
PFS using Blinded Independent Central Review 
(BICR) assessments according to RECIST 1.1
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy 
compared to SoC terms of OS in patients 
with PD-L1 positive25% NSCLC
OS
To assess the efficacy of MEDI4736
monotherapy compared to SoC in terms 
of OS in patients with PD-L1 positive25% 
NSCLC
OS

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2.2
Secondary objectives

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Secondary Objectives:
Outcome Measures:
To further assess the efficacy of 
MEDI4736 + tremelimumab combination 
therapy compared to SoC in terms of PFS, 
OS, objective response rate (ORR), 
duration of response (DoR), proportion of 
patients alive and progression free at 12
months from randomization (APF12), and 
time to second progression (PFS2)
OS in PD-L1 positive1% patients and all patients 
PFS in PD-L1 positive1% patients and all patients
using BICR assessments according to RECIST 
1.1
ORR, DoR, and APF12 in patients with PD-L1
positive25% NSCLC, and patients with PD-L1
positive1% NSCLC and all patients using BICR 
assessments according to RECIST 1.1
PFS2 in patients with PD-L1 positive25%
NSCLC, and patients with PD-L1 positive1%
NSCLC and all patients using local standard 
clinical practicea
To assess the efficacy of MEDI4736 
monotherapy compared to SoC in terms of 
PFS, ORR, DoR, APF12, and PFS2
PFS in patients with PD-L1 positive25% NSCLC 
using BICR assessments according to RECIST 
1.1
ORR, DoR, and APF12 in patients with PD-L1
positive25% NSCLC using BICR assessments 
according to RECIST 1.1
PFS2 in patients with PD-L1 positive25% NSCLC 
using local standard clinical practicea
To assess the efficacy of MEDI4736 + 
tremelimumab combination therapy 
compared to MEDI4736 monotherapy in 
terms of PFS, OS, and ORR
PFS and ORR in patients with PD-L1 positive25%
NSCLC and all patients using BICR assessments 
according to RECIST 1.1
OS in patients with PD-L1 positive25%  and PD-
L1 positive1% NSCLC and all patients 
To assess disease-related symptoms and 
health-related quality of life (HRQoL) in 
patients treated with MEDI4736 + 
tremelimumab combination therapy and 
MEDI4736 monotherapy compared to SoC 
using the 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) module
EORTC QLQ-C30
EORTC QLQ-LC13
Changes in World Health Organization 
(WHO)/Eastern Cooperative Oncology Group 
(ECOG) performance status will also be 
assessed.
To assess the pharmacokinetics (PK) of 
MEDI4736 + tremelimumab combination 
therapy and MEDI4736 monotherapy
Concentration of MEDI4736 and tremelimumab 
in blood and non-compartmental PK parameters, 
such as peak concentration and trough (as data 
allow; sparse sampling)
To investigate the immunogenicity of 
MEDI4736 and tremelimumab
Presence of anti-drug antibodies (ADAs) for 
MEDI4736 and tremelimumab

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a
PFS2 will be defined as the time from the date of randomization to the earliest of the progression event 
subsequent to that used for the PFS endpoint or death, based on Investigator tumor assessments.  
2.3
Safety objective
Safety Objective:
Outcome Measures:
To assess the safety and tolerability profile 
of MEDI4736 + tremelimumab 
combination therapy and MEDI4736 
monotherapy compared to SoC in the first-
line setting for treatment of advanced or 
metastatic patients with NSCLC
Adverse events (AEs), physical examinations, 
laboratory findings, and vital signs
2.4
Exploratory objectives
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3.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL 
Each patient must meet all of the inclusion criteria (Section 3.1) and none of the exclusion 
criteria (Section 3.2) for this study.  Under no circumstances will there be exceptions to this 
rule.
3.1
Inclusion criteria
For inclusion in the study, patients should fulfill the following criteria:
1.
Age ≥18 years at the time of screening
2.
Written informed consent and any locally required authorization (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 7 of the International 
Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology; 
IASLC Staging Manual in Thoracic Oncology). 
4.
Patients must have tumors that lack sensitizing EGFR mutation (eg, exon 19 
deletion or exon 21 L858R, exon 21 L861Q, exon 18 G719X, or exon 20 S768I
mutation) and ALK rearrangement.  (If a patient has squamous histology or is 
known to have a tumor with a KRAS mutation, then EGFR and ALK testing is not 
required).
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5.
No prior chemotherapy or any other systemic therapy for advanced or metastatic 
NSCLC.  Patients who have received prior platinum-containing adjuvant, 
neoadjuvant, or definitive chemoradiation for advanced disease are eligible, 
provided that progression has occurred >6 months from last therapy.   
6.
Tumor PD-L1 status, with the 
confirmed by a 
reference laboratory, 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 fresh biopsies should not be target lesions, unless there are no other lesions 
suitable for biopsy.  Fine needle aspirate specimens are not acceptable.  Specimens 
from metastatic bone lesions are typically unacceptable unless there is a significant 
soft tissue component.  The tumor specimen submitted to establish eligibility should 
be of sufficient quantity to allow for PD-L1 IHC and 
 
7.
WHO/ECOG performance status of 0 or 1 at enrollment.
8.
At least 1 lesion, not previously irradiated, that can be accurately measured at 
baseline as ≥10 mm in the longest diameter (except lymph nodes which must have a 
short axis ≥15 mm) with computed tomography (CT) or magnetic resonance 
imaging (MRI) and that is suitable for accurate repeated measurements as per 
RECIST 1.1 guidelines.
9.
No prior exposure to immune-mediated therapy including, but not limited to, other 
anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 anti-
(PD-L2) antibodies, excluding therapeutic anticancer vaccines.
10.
Adequate organ and marrow function as defined below:
∀
Hemoglobin ≥9.0 g/dL
∀
Absolute neutrophil count ≥1.5 × 109 /L
∀
Platelet count ≥100 × 109/L
∀
Serum bilirubin ≤1.5 × the upper limit of normal (ULN).  This will not apply to 
patients with confirmed Gilbert’s syndrome, who will be allowed in 
consultation with their physician.
∀
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 × ULN
∀
Calculated creatinine clearance ≥50 mL/min as determined by Cockcroft-Gault 
(using actual body weight) or 24 hour urine collection
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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)
11.
Evidence of post-menopausal status or negative urinary or serum pregnancy test for 
female pre-menopausal patients.  Women will be considered post-menopausal if 
they have been amenorrheic for 12 months without an alternative medical cause. 
The following age-specific requirements apply: 

Women <50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of exogenous
hormonal treatments and if they have luteinizing hormone and follicle-
stimulating hormone levels in the post-menopausal range for the institution or 
underwent surgical sterilization (bilateral oophorectomy or hysterectomy). 

Women ≥50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced oophorectomy with last menses 
>1 year ago, had chemotherapy-induced menopause with >1 year interval since 
last menses, or underwent surgical sterilization (bilateral oophorectomy or 
hysterectomy).
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site)
2.
Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional study
3.
Mixed small-cell lung cancer and NSCLC histology, sarcomatoid variant
4.
Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer 
treatment.  Concurrent use of hormonal therapy for non-cancer-related conditions 
(eg, hormone replacement therapy) is acceptable.  

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5.
Radiotherapy treatment to more than 30% of the bone marrow or with a wide field 
of radiation within 4 weeks of the first dose of study drug.  Note: Local treatment of 
isolated lesions, excluding target lesions, for palliative intent is acceptable.
6.
Major surgical procedure (as defined by the Investigator) within 28 days prior to the 
first dose of IP.  Note: Local surgery of isolated lesions for palliative intent is 
acceptable.
7.
History of allogenic organ transplantation
8.
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis with the 
exception of diverticulosis, celiac disease or other serious gastrointestinal chronic 
conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis 
syndrome, or Wegener syndrome (granulomatosis with polyangiitis), Graves’ 
disease, rheumatoid arthritis, hypophysitis, uveitis, etc within the past 3 years prior 
to the start of treatment.  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
9.
Any condition that, in the opinion of the Investigator, would interfere with the 
evaluation of IP or interpretation of patient safety or study results, including, but not 
limited to, ongoing or active infection, symptomatic congestive heart failure, 
uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial 
lung disease, or psychiatric illness/social situations that would limit compliance 
with study requirement, substantially increase risk of incurring AEs from 
MEDI4736 or tremelimumab, or compromise the ability of the patient to give
written informed consent
10.
Medical contraindication to platinum (cisplatin or carboplatin)-based doublet 
chemotherapy
11.
History of another primary malignancy except for

Malignancy treated with curative intent and with no known active disease 
≥5 years before the first dose of study drug and of low potential risk for 
recurrence

Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease

Adequately treated carcinoma in situ without evidence of disease (eg, cervical 
cancer in situ)

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12.
History of leptomeningeal carcinomatosis
13.
Brain metastases or spinal cord compression unless the patient is stable 
(asymptomatic, no evidence of new or emerging brain metastases) and off steroids 
for at least 14 days prior to start of study treatment.  Following radiotherapy and/or 
surgery, patients with brain metastases must wait 4 weeks following the 
intervention and must confirm stability with imaging before randomization.  
Patients with suspected brain metastases at screening should have a CT/MRI of the 
brain prior to study entry. 
14.
Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) 
≥470 ms
15.
History of active primary immunodeficiency 
16.
Active infection, including tuberculosis (clinical evaluation), hepatitis B, hepatitis 
C, or human immunodeficiency virus (HIV, positive HIV 1 or 2 antibodies). Active 
hepatitis B virus (HBV) is defined by a known positive HBV surface antigen 
(HBsAg) result. Patients with a past or resolved HBV infection (defined as the 
presence of hepatitis B core antibody and absence of HBsAg) are eligible. Patients 
positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain 
reaction is negative for HCV ribonucleic acid (RNA).
17.
Current or prior use of immunosuppressive medication within 14 days before the 
first dose of MEDI4736 or tremelimumab.  The following are exceptions to this 
criterion:

Intranasal, inhaled, topical steroids, or local steroid injections 
(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)
18.
Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP.  
Note: Patients, if enrolled, should not receive live vaccine during the study and up 
to 30 days after the last dose of IP.
19.
Female patients who are pregnant or breast-feeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 180 days after the last dose of MEDI4736 + tremelimumab 
combination therapy or 90 days after the last dose of MEDI4736 monotherapy.

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20.
Known allergy or hypersensitivity to IP or any excipient or to other humanized 
mAbs
Procedures for withdrawal of incorrectly enrolled patients are presented in Section 3.4.
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 suitably trained delegate will:
1.
Obtain signed informed consent before any study specific procedures are 
performed. (Informed consent of study procedures may be obtained prior to the 
28-day screening window in order to permit tumor biopsy sample acquisition which 
must be analyzed prior to randomization.)
2.
Obtain a unique 7-digit enrollment number (E-code), through the Interactive Voice 
Response System (IVRS)/(Interactive Web Response System) IWRS in the 
following format (ECCNNXXX: CC being the country code, NN being the center 
number, and XXX being the patient enrollment code at the center).  This number is 
the patient’s unique identifier and is used to identify the patient on the electronic 
case report forms (eCRFs).
3.
Obtain tumor sample and send for PD-L1 expression (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 in order to permit analysis prior to randomization.)
The sample should be sent only for the patient with known EGFR and ALK status. 
If a patient has squamous histology or is known to have a tumor with a KRAS 
mutation, then EGFR and ALK testing is not required. If EGFR and ALK 
status is unknown, then the tumor sample (archive or fresh, primary or metastatic) 
should be used firstly for (local or central) EGFR and ALK mutation testing in 
accordance to inclusion criterion 4.
4.
Determine patient eligibility (see Sections 3.1 and 3.2)
5.
Obtain signed informed consent for genetic research study (optional)
At randomization, once the patient is confirmed to be eligible, the Investigator or suitably 
trained delegate will:
1.
Define the SoC treatment (based on the most appropriate option for the patient) that 
the patient would receive if randomized to the SoC group prior to randomization of 

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the patient.  This must be completed for all patients.  The information will be 
recorded in the IVRS/IWRS system.
Note, for all patients with non-squamous tumor histology who would be 
scheduled to receive pemetrexed if randomized to the SoC group, folic acid and 
vitamin B12 should commence prior to randomization for up to 7 days, in line 
with local practice.  This is to ensure SoC treatment can begin on Day 1.  
2.
Obtain a unique randomization number via the IVRS/IWRS.  Numbers will start at 
001 and will be assigned strictly sequentially by IVRS/IWRS as patients are eligible 
for entry into the study.  The system will randomize the eligible patient to 1 of the 
3 treatment groups.  PD-L1 expression status results must be received from the 
central laboratory by the IVRS/IWRS prior to randomization.
If the patient is ineligible and not randomized, the IVRS/IWRS should be contacted to 
terminate the patient in the system. 
Patients will begin treatment on Day 1.  Patients must not be treated unless all eligibility 
criteria have been met.  
If a patient withdraws from participation in the study, then his or her 
enrollment/randomization code cannot be reused.  Withdrawn patients will not be replaced.
3.4
Procedures for handling incorrectly enrolled patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive 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.
When a patient does not meet all the eligibility criteria but is randomized in error or 
incorrectly started on treatment, the Investigator should inform the Study Physician 
immediately, and the Study Physician and the Investigator should discuss whether to continue 
or discontinue the patient from treatment.  The Study Physician must ensure that all decisions 
are appropriately documented.
3.5
Methods for assigning treatment groups
The actual treatment given to patients will be determined by the randomization scheme in the 
IVRS/IWRS.  The randomization scheme will be produced by a computer software program 
that incorporates a standard procedure for generating randomization numbers.  
One randomization list will be produced for each of the randomization strata.  A blocked 
randomization will be generated, and all centers will use the same list in order to minimize 
any imbalance in the number of patients assigned to each treatment group.
Patients will be identified to the IVRS/IWRS per country regulations.  Randomization codes 
will be assigned strictly sequentially, within each stratum, as patients become eligible for 

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

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Note - Females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-
menopausal.  
Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause.  The following age-specific requirements apply: 

Women <50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of exogenous 
hormonal treatments and if they have luteinizing hormone and follicle-
stimulating hormone levels in the post-menopausal range for the institution or 
underwent surgical sterilization (bilateral oophorectomy or hysterectomy). 

Women ≥50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses 
>1 year ago, had chemotherapy-induced menopause with last menses >1 year 
ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy).
Highly effective methods of contraception, defined as 1 that results 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 intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel, which is considered highly effective]; and triphasic combined oral 
contraceptive pills).
Patients in the SoC group: Follow the local prescribing information relating to contraception, 
the time limits for such precautions, and any additional restrictions for agents in the SoC 
group.

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Table 1
Highly effectivea methods of contraception (<1% failure rate)
Barrier/Intrauterine methods
Hormonal methods

Copper T intrauterine device

Levonorgesterel-releasing intrauterine 
system (eg, Mirena®)b


Etonogestrel implants: eg, Implanon or 
Norplan

Intravaginal device: eg, ethinylestradiol 
and etonogestrel

Medroxyprogesterone injection: eg,
Depo-Provera 

Normal and low-dose combined oral 
contraceptive pill

Norelgestromin/ethinylestradiol 
transdermal system

Cerazette (desogestrel)
a
Highly effective (i.e. failure rate of <1% per year)
b
This is also considered a hormonal method
3.
All patients: Patients should not donate blood or blood components while 
participating in this study and for 90 days following the last dose of IP.
4.
Restrictions relating to concomitant medications are described in Section 7.7
3.9
Discontinuation of investigational product
An individual patient will not receive any further IP (MEDI4736 + tremelimumab 
combination, MEDI4736 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

Pregnancy or intent to become pregnant

Non-compliance with the study protocol that, in the opinion of the Investigator or
AstraZeneca, warrants withdrawal from study treatment (eg, refusal to adhere to 
scheduled visits)

Initiation of alternative anticancer therapy including another investigational agent

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
Confirmed PD and Investigator determination that the patient is no longer
benefiting from treatment with IP
3.9.1
Procedures for discontinuation of a patient from investigational product 
At any time, patients are free to discontinue IP without prejudice to further treatment.  A 
patient who decides to discontinue IP will always be asked about the reason(s) for 
discontinuation and the presence of any AE.  If possible, they will be seen and assessed by an 
Investigator.  AEs will be followed up (see Section 6).  The Study Physician should be 
notified of any ongoing AE that may delay treatment or necessitate permanent discontinuation 
of treatment.
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment.  Patients who are 
permanently discontinued will enter follow-up (see Table 4).  All patients will be followed for 
survival until the end of the study.  Patients who decline to return to the site for evaluations 
should be contacted by telephone as an alternative.  
Any patient who discontinues study treatment for reasons other than objective disease 
progression should have tumor assessments performed as scheduled in Table 4 until objective 
disease progression is documented or death occurs, unless consent is withdrawn.
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IVRS/IWRS.
3.10
Criteria for withdrawal of the patient from the study
3.10.1
Screen failures 
Screen failures are patients who do not fulfill the eligibility criteria for the study, and therefore 
must not be randomized.  These patients should have the reason for study withdrawal recorded 
as “eligibility criteria not fulfilled” (ie, patient does not meet the required inclusion/exclusion 
criteria).  This reason for study withdrawal is only valid for screen failures (ie, not randomized 
patients).  Patients can be rescreened a single time, but they cannot be re-randomized. 
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.

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A patient who withdraws consent will always be asked about the reason(s) for withdrawal and 
the presence of any AE.  The Investigator will follow up AEs outside of the clinical study.  
The patient will return electronic PRO devices, if applicable.  
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (see Section 9.3), such that there is insufficient information to 
determine the patient’s status at that time.  Patients who refuse to continue participation in the 
study, including telephone contact, should be documented as “withdrawal of consent” rather 
than “lost to follow-up.”  Investigators should document 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.
3.10.3
Survival status for withdrawn consent and lost to follow up patients
In order to support key end points 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 SURVIVE module will be updated.)

In the event that the patient has actively withdrawn consent to the processing of 
their personal data, the survival status of the patient can be obtained by site 
personnel from publicly available death registries (if available) where it is possible 
to do so under applicable local laws to obtain a current survival status.   (The 
SURVIVE module 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 6.8).
Regardless of the reason for termination, all data available for the patients at the time of 
discontinuation of follow-up must be recorded in the eCRFs.  All reasons for discontinuation 
of treatment must be documented.

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In terminating the study, AstraZeneca will ensure that adequate consideration is given to the 
protection of the patients’ interests.  If this study is discontinued, all other studies involving 
MEDI4736 or tremelimumab will remain open to enrollment and screening, if deemed 
appropriate by AstraZeneca.
4.
STUDY PLAN AND TIMING OF PROCEDURES 
The procedures for the screening and the treatment periods in this study are presented for the 
MEDI4736 + tremelimumab combination therapy group and MEDI4736 monotherapy group 
in Table 2and for the SoC therapy group in Table 3.  The procedures for the follow-up period 
are presented in Table 4.

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Table 2
Schedule of assessments for MEDI4736 + tremelimumab combination therapy and MEDI4736 
monotherapy treatment and retreatment periods 
Screening
C1
C2
C3
C4
C5
C6
C7
C8 to C12
C13a etc
For details see 
Section
Week
-4 to -1
0
4
8
12
16
20
24
28, 32, 36, 40, 44
48 etc
Day
-28 to -1
1
29
57
85
113
141
169
197, 225, 253, 281, 
309
337 etc
Window (days)
NA
+3b
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
Informed consent: study procedures
Xc
4.1, 10.4
3.3
Study procedures
Physical exam (full)
X
5.2.2
Targeted physical exam (based on symptoms)
X
X
X
X
X
X
X
X
X
5.2.2
Vital signsd
X
X
X
X
X
X
X
X
X
X
5.2.4
ECGe
X
As clinically indicated
5.2.3
Concomitant medications
<--------------------------------------------------------------------------------------------------------------------------
--->
7.7
Demography, including baseline characteristics 
and tobacco use
X
4.1
Eligibility criteria
X
3.1, 3.2
Laboratory assessmentsf
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
Table 5
Hematology
X
X
X
X
X
X
X
X
X
X
Table 6
APTT and INR 
X
As clinically indicated
Table 6
TSH, free T3, and free T4g
X
X
X
X
X
X
X
X
X
X
5.2.1
Urinalysis
X
As clinically indicated
Table 7
Hepatitis B and C and HIV
X
5.2.1
CCI

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Table 2
Schedule of assessments for MEDI4736 + tremelimumab combination therapy and MEDI4736 
monotherapy treatment and retreatment periods 
Screening
C1
C2
C3
C4
C5
C6
C7
C8 to C12
C13a etc
For details see 
Section
Week
-4 to -1
0
4
8
12
16
20
24
28, 32, 36, 40, 44
48 etc
Day
-28 to -1
1
29
57
85
113
141
169
197, 225, 253, 281, 
309
337 etc
Window (days)
NA
+3b
±3
±3
±3
±3
±3
±3
±3
±3
Pregnancy testh
X
X
X
X
X
X
X
X
X
X
5.2.1
Pharmacokinetics
MEDI4736 PK sample (serum)
Xi
Xi
Xi
5.4.1
Tremelimumab PK sample (serum; 
combination therapy group only)
Xi
Xi
5.4.1
Monitoring
WHO/ECOG performance status
X
X
X
X
X
X
X
X
X
X
5.3.3
AE/SAE assessment
<--------------------------------------------------------------------------------------------------------------------------
--->
6.3.1
Drug accountability
X
X
X
X
X
X
X
X
X
7.6
Pre-randomization medication
Folic acidj
X
Discontinue as randomized to monotherapy or combination therapy
3.3
IM Vitamin B12j
X
Discontinue as randomized to monotherapy or combination therapy
3.3
IP administration
Combination therapy group
MEDI4736 (combination therapy)kl
X
X
X
X
X
X
X
X
X
7.2.1
Tremelimumabi,j
X
X
X
X
7.2.1
Monotherapy group
MEDI4736 (monotherapy)l
X
X
X
X
X
X
X
X
X
7.2.1
PRO assessmentsm

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Table 2
Schedule of assessments for MEDI4736 + tremelimumab combination therapy and MEDI4736 
monotherapy treatment and retreatment periods 
Screening
C1
C2
C3
C4
C5
C6
C7
C8 to C12
C13a etc
For details see 
Section
Week
-4 to -1
0
4
8
12
16
20
24
28, 32, 36, 40, 44
48 etc
Day
-28 to -1
1
29
57
85
113
141
169
197, 225, 253, 281, 
309
337 etc
Window (days)
NA
+3b
±3
±3
±3
±3
±3
±3
±3
±3
EORTC QLQ-C30, 
X
Every 4 weeks for the first 8 weeks relative to the date of randomization, then every 
8 weeks thereafter until second progression/death (whichever comes first)
5.3.1.1, 5.3.1.5
EORTC QLQ-LC13,
X
Every 2 weeks for the first 8 weeks relative to the date of randomization, then every 
4 weeks thereafter until second progression/death (whichever comes first)
5.3.1.2, 5.3.1.3
X
X
X
X
X
5.3.1.4
Other laboratory assessments and assays
Immunogenicity assessment (ADA sampling to 
identify ADA responses in patient circulation)
X
X
Xo
5.4.2
sPD-L1 (serum)
X
X
X
5.5.2
Circulating soluble factors (plasma)
X
X
X
5.5.2
Tumor biopsy (newly acquired or archived 
<3 months old)
Xc
5.5.1
Archival tumor sample ≥3 months old, if 
available
X
5.5.1
EGFR and ALK test
Xp
3.3
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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Table 2
Schedule of assessments for MEDI4736 + tremelimumab combination therapy and MEDI4736 
monotherapy treatment and retreatment periods 
Screening
C1
C2
C3
C4
C5
C6
C7
C8 to C12
C13a etc
For details see 
Section
Week
-4 to -1
0
4
8
12
16
20
24
28, 32, 36, 40, 44
48 etc
Day
-28 to -1
1
29
57
85
113
141
169
197, 225, 253, 281, 
309
337 etc
Window (days)
NA
+3b
±3
±3
±3
±3
±3
±3
±3
±3
Tumor evaluation (CT or MRI) (RECIST 1.1)q,r
X
Every 6 weeks ± 1 week for the first 48 weeks relative to the date of randomization, and 
then every 8 weeks ± 1 week thereafter
5.1
 
5.6
Health economics measurements
To be completed at each hospitalization and unscheduled visit by site staff
8.5.7
a.
Patients who continue on treatment will be assessed in the same manner 
b.
Every effort should be made to minimize the time between randomization and starting treatment. (ie. on the same day after randomization)
c.
Informed consent of study procedures and tumor biopsy sample may be obtained prior to the 28-day screening window, if necessary, in order to permit
tumor biopsy sample acquisition and analysis prior to randomization.  The collection of tumor biopsies at the time of progression prior to retreatment is 
mandated; the Investigator must consult with the Study Physician if such sampling is not feasible.  
 
d.
Body weight is recorded along with vital signs.
e.
Any clinically significant abnormalities detected require a confirmatory ECG.
f.
If screening laboratory assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need to be repeated at Day 1.
g.
Free T3 and free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
h.
For women of childbearing potential only.  A urine or serum pregnancy test is acceptable.  
i.
Pre-dose same day as infusion and within 1 hour of end of infusion.
j.
To be administered in line with local practice for patients with non-squamous tumors who will receive pemetrexed if randomized to SoC group.
k.
During the combination portion of treatment, tremelimumab will be administered first; the MEDI4736 infusion will start approximately 1 hour after the end of the 
tremelimumab infusion.  If there are no clinically significant infusion reactions with the first cycle, then for all other cycles, the MEDI4736 can be given immediately after 
the tremelimumab infusion has finished.
l.
Results for urea and electrolytes, full blood count, and liver function tests must be available before commencing an infusion (within 3 days).
m.
In instances where the PRO assessments coincide with a clinic visit, the research nurse or study coordinator should verify that the questionnaire was completed before the 
visit.  If not, the patient should complete the questionnaire prior to any other study procedures and before discussion of disease progression to avoid biasing the patient’s 
responses to the questions.
n.
o.
MEDI4736 sample only at this time point.
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Date 09 January 2018
70 (220)
p.
For patients with unknown status of ALK and/or EGFR NSCLC. (If patients have squamous histology or are known to have a tumor with a KRAS mutation, then EGFR 
and ALK testing is not required.)
q.
RECIST 1.1 assessments will be performed on CT/MRI images of the chest and abdomen (including liver and adrenal glands).  Additional anatomy should be imaged 
based on signs and symptoms of individual patients at baseline and follow-up.  Baseline assessments should be performed no more than 28 days before the date of 
randomization and, ideally, should be performed as close as possible to and prior to the start of study treatment.  The radiological progression confirmatory scans should 
be performed no less than 4 weeks after the prior assessment of PD and preferably at the next scheduled visit (in the absence of clinically significant deterioration).  If an 
unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform the subsequent assessments at their next scheduled 
visit.
r.
Patients with confirmed PD can continue to receive MEDI4736 + tremelimumab or MEDI4736 at the discretion of the Investigator 
s.
 
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated.
Note: For “retreatment”, the same assessments should be done as in the first treatment period, with the exception of the PK, ADA, , SNP genotyping, and MDSCs assessments, 
which do not need to be collected a second time.  
ADA Anti-drug antibody; AE Adverse event; ALK Anaplastic lymphoma kinase; APTT activated partial thromboplastin time; C Cycle; CT Computed tomography; 
ECG Electrocardiogram; ECOG Eastern Cooperative Oncology Group; EGFR Epidermal growth factor receptor; EORTC QLQ-C30 30-item core Eastern Cooperative 
Oncology Group Quality of Life Questionnaire; EORTC QLQ-LC13 13-item lung cancer EORTC QLQ;
 
HIV Human immunodeficiency virus; IM intramuscular; INR international normalized ratio; IP Investigational product; MDSC Myeloid-derived suppressor cell; 
MRI Magnetic resonance imaging; NSCLC Non-small-cell lung cancer; PBMC Peripheral blood mononuclear cell; PD Progressive disease; 
 
PGx Pharmacogenetic research; PK Pharmacokinetic(s); 
 
RNA Ribonucleic acid; SAE Serious adverse event; SNP Single nucleotide polymorphism; sPD-L1 Soluble programmed cell death ligand 1; TSH Thyroid-stimulating 
hormone; T3 Triiodothyronine; T4Thyroxine; WHO World Health Organization.
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Table 3
Schedule of assessments for Standard of Care therapy treatment period 
Screening
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 to C17
C18, C19, etc
For details 
see Section
Week
-4 to -1
0
3
6
9
12
15
18
21
24
27, 30, 33, 36, 39, 42, 
45, 48
51, 54, etc
Day
-28 to -1
1
22
43
64
85
106
127
148
169
190, 211, 232, 253, 274, 
295, 316, 337
358, 379, etc
Window (days)
NA
+3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
Informed consent: study 
procedures
Xb
4.1, 10.4
Consent: genetic sample and 
analysis (optional)
X
3.3
Study procedures
Physical exam (full)
X
5.2.2
Targeted physical exam 
(based on symptoms)
X
X
X
X
X
X
X
X
X
X
X
5.2.2
Vital signsc
X
X
X
X
X
X
X
X
X
X
X
X
5.2.4
ECGd
X
As clinically indicated
5.2.3
Concomitant medications
<-------------------------------------------------------------------------------------------------------------------------------------------------
------->
7.7
Demography, including 
baseline characteristics and 
tobacco use
X
4.1
Eligibility criteria
X
3.1, 3.2
Laboratory assessments
Clinical chemistrye,f
X
X
X
X
X
X
X
X
X
X
X
X
Table 5
Hematologye,f
X
X
X
X
X
X
X
X
X
X
X
X
Table 6
APTT and INR
X
As clinically indicated
Table 6

Clinical Study Protocol
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Study Code D419AC00001
Version 08
Date 09 January 2018
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Table 3
Schedule of assessments for Standard of Care therapy treatment period 
Screening
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 to C17
C18, C19, etc
For details 
see Section
Week
-4 to -1
0
3
6
9
12
15
18
21
24
27, 30, 33, 36, 39, 42, 
45, 48
51, 54, etc
Day
-28 to -1
1
22
43
64
85
106
127
148
169
190, 211, 232, 253, 274, 
295, 316, 337
358, 379, etc
Window (days)
NA
+3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
TSH, free T3, and free T4g
X
X
X
5.2.1
Urinalysis
X
As clinically indicated
Table 7
Hepatitis B and C and HIV
X
5.2.1
Pregnancy testh
X
As clinically indicated
5.2.1
Monitoring
WHO/ECOG performance 
status
X
X
X
X
X
X
X
X
X
X
X
X
5.3.3
AE/SAE assessment 
<-------------------------------------------------------------------------------------------------------------------------------------------------
------->
6.3.1
Pre-randomization medication
Folic acidi
X
Continue in line with local practice
3.3
IM Vitamin B12i
X
Continue in line with local practice
3.3
SoC administration
Platinum-based chemotherapy
X
Cycle every 3 weeks
7.2.1
PRO assessmentsj
EORTC QLQ-C30, 
X
Every 4 weeks relative for the first 8 weeks relative to the date of randomization, 
then every 8 weeks thereafter until second progression/death (whichever comes first)
5.3.1.1, 
5.3.1.5
EORTC QLQ-LC13, 
X
Every 2 weeks for the first 8 weeks relative to the date of randomization, 
then every 4 weeks thereafter until second progression/death (whichever comes first)
5.3.1.2, 
5.3.1.3
Weeks 4, 8, 12, 24, and 48
5.3.1.4
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73 (220)
Table 3
Schedule of assessments for Standard of Care therapy treatment period 
Screening
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 to C17
C18, C19, etc
For details 
see Section
Week
-4 to -1
0
3
6
9
12
15
18
21
24
27, 30, 33, 36, 39, 42, 
45, 48
51, 54, etc
Day
-28 to -1
1
22
43
64
85
106
127
148
169
190, 211, 232, 253, 274, 
295, 316, 337
358, 379, etc
Window (days)
NA
+3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Other laboratory assessments and assays
sPD-L1 (serum)
X
X
X
5.5.2
Circulating soluble factors 
X
X
X
5.5.2
Tumor biopsy (newly acquired 
or archived <3 months old)
Xb
5.5.1
Archival tumor sample 
≥3 months old, if available
X
5.5.1
EGFR and ALK test
Xl
3.3
 
 
 
Tumor evaluation (CT or 
MRI) (RECIST 1.1)m
X
Every 6 weeks ± 1 week for the first 48 weeks relative to the date of randomization, 
and then every 8 weeks ± 1 week thereafter
5.1
 
5.6
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Table 3
Schedule of assessments for Standard of Care therapy treatment period 
Screening
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10 to C17
C18, C19, etc
For details 
see Section
Week
-4 to -1
0
3
6
9
12
15
18
21
24
27, 30, 33, 36, 39, 42, 
45, 48
51, 54, etc
Day
-28 to -1
1
22
43
64
85
106
127
148
169
190, 211, 232, 253, 274, 
295, 316, 337
358, 379, etc
Window (days)
NA
+3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Health economics measurements
 
To be completed at each hospitalization and unscheduled visit by site staff
8.5.7
a.
Every effort should be made to minimize the time between randomization and starting treatment. (ie, on the same day after randomization)
b.
Informed consent of study procedures and tumor biopsy sample may be obtained prior to the 28-day screening window, if necessary, in order to permit tumor biopsy 
sample acquisition and analysis prior to randomization
c.
Before every infusion or administration and as clinically indicated.
d.
Any clinically significant abnormalities detected require a confirmatory ECG.  
e.
To be collected every 3 weeks prior to the start of infusion and as clinically indicated.
f.
If screening laboratory assessments are performed within 3 days prior to Day 1 (first infusion day), they do not need to be repeated at Day 1.
g.
Free T3 and free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
h.
For women of childbearing potential only.  A urine or serum pregnancy test is acceptable.
i.
To be administered in line with local practice for patients with non-squamous tumors who will receive pemetrexed if randomized to SoC group.
j.
In instances where the PRO assessments coincide with a clinic visit, the research nurse or study coordinator should verify that the questionnaire was completed before the 
visit.  If not, the patient should complete the questionnaire prior to any other study procedures and before discussion of disease progression to avoid biasing the patient’s 
responses to the questions.
k.
l.
For patients with unknown status of ALK and/or EGFR NSCLC. (If patients have squamous histology or is known to have a tumor with a KRAS mutation, then EGFR 
and ALK testing is not required.)
m.
RECIST 1.1 assessments will be performed on CT/MRI images of the chest and abdomen (including liver and adrenal glands).  Additional anatomy should be imaged 
based on signs and symptoms of individual patients at baseline and follow-up.  Baseline assessments should be performed no more than 28 days before the date of 
randomization and, ideally, should be performed as close as possible to and prior to the start of study treatment.  The radiological progression confirmatory scans should 
be performed no less than 4 weeks after the prior assessment of PD and preferably at the next scheduled visit (in the absence of clinically significant deterioration).  If an 
unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform the subsequent assessments at their next scheduled 
visit.
 
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Note: All assessments on treatment days are to be performed prior to infusion or administration, unless otherwise indicated.
ADA Anti-drug antibody; AE Adverse event; ALK Anaplastic lymphoma kinase; APTT activated partial thromboplastin time; C Cycle; CT Computed tomography; 
ECG Electrocardiogram; ECOG Eastern Cooperative Oncology Group; EGFR Epidermal growth factor receptor; EORTC QLQ-C30 30-item core Eastern Cooperative 
Oncology Group Quality of Life Questionnaire; EORTC QLQ-LC13 13-item lung cancer EORTC QLQ; 
 
HIV Human immunodeficiency virus; IM intramuscular; INR international normalized ratio; IP Investigational product; MDSC Myeloid-derived suppressor cell; 
MRI Magnetic resonance imaging; NSCLC Non-small-cell lung cancer; PBMC Peripheral blood mononuclear cell; PD Progressive disease; 
 
 PGx Pharmacogenetic research; PK Pharmacokinetic(s);
 
 RNA Ribonucleic acid; SAE Serious adverse event; SNP Single nucleotide polymorphism; sPD-L1 Soluble programmed cell death ligand 1; TSH Thyroid-stimulating 
hormone; T3 Triiodothyronine; T4 Thyroxine; WHO World Health Organization.
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Table 4
Schedule of assessments for patients who have completed/discontinued treatment with MEDI4736 + 
tremelimumab, MEDI4736 monotherapy, or Standard of Care therapy
Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
12 months and every 
2 months (±2 weeks)
30
2
3
4
6
8
10
Physical examination (full)a
X
Vital signs (temperature, respiratory rate, blood 
pressure, and pulse)
X
Weight
X
Pregnancy testb
X
As clinically indicated
AE/SAE assessmentc
X
X
X
Concomitant medications
X
X
X
WHO/ECOG performance status
At timepoints consistent with tumor assessments; at 30, 60, and 90 days; and then at initiation of subsequent anticancer 
therapyd
Subsequent anticancer therapye; and second 
progression assessmentf,g
<--------------------------------------------------------------------------------------------------------------------------------------------------
----->
Survival statush
X
X
X
X
X
X
X 
Hematology
X
X
X
Clinical chemistry
X
X
X
TSH, free T3, and free T4i
X
Pharmacokinetic assessmentj
X
Immunogenicity assessment (ADA sampling) to 
identify ADA responses in patient circulationj
X
X
sPD-L1 concentration (to assess target 
engagement)j
X
EORTC QLQ-C30k,
Every 4 weeks relative for the first 8 weeks relative to the date of randomization, then every 8 weeks thereafter until 
second progression/death (whichever comes first)
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Table 4
Schedule of assessments for patients who have completed/discontinued treatment with MEDI4736 + 
tremelimumab, MEDI4736 monotherapy, or Standard of Care therapy
Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
12 months and every 
2 months (±2 weeks)
30
2
3
4
6
8
10
EORTC QLQ-LC13k,
Every 2 weeks for the first 8 weeks relative to the date of randomization, then every 4 weeks thereafter until second 
progression/death (whichever comes first)
X
Tumor assessment (CT or MRI)m
Every 6 weeks  ± 1 week for the first 48 weeks (relative to the date of randomization), and then every 8 weeks  ± 1 week
thereafter until confirmed objective disease progression/death (whichever comes first).  Additional scans to be completed 
per standard practice post progression.
a.
Physical exams are described in Section 5.2.2.
b.
For women of childbearing potential only.  A urine or serum pregnancy test is acceptable.
c.
The AE/SAE follow-up for SoC is only 30 days
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) post the last dose of study treatment must be recorded in the eCRF. 
f.
PFS2 assessment will be performed by the Investigator and defined according to local standard clinical practice and may involve any of the following: objective 
radiological imaging, symptomatic progression, or death.
g.
For patients who discontinue their assigned IP following confirmed progression, available readings of CT/MRI from local practice will be collected from the patients’ 
medical charts while information on subsequent anticancer treatment and/or PFS2 is collected. 
h.
Patients may be contacted in the week following data cut-offs to confirm survival status.  Details of any treatment for NSCLC (including surgery) post the last dose of 
study treatment must be recorded in the eCRF.
i.
Free T3 and free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
j.
For patients in the MEDI4736 + tremelimumab or MEDI4736 monotherapy groups only.  The 3 month follow-up collections for MEDI4736 and Tremelimumab PK and 
ADA are relative to respective last dose and the 6-month follow-up collections for MEDI4736 and Trememlimumab ADA are relative to respective last dose.
k.
Patients will complete PROs using handheld devices at home.
l.
m.
Only for patients yet to progress, RECIST 1.1 assessments will be performed on CT/MRI images of the chest and abdomen (including liver and adrenal glands).  
Additional anatomy should be imaged based on signs and symptoms of individual patients.  The radiological progression confirmatory scans should preferably be 
performed no less than 4 weeks after the prior  assessment of PD and preferably at the next scheduled visit (in the absence of clinically significant deterioration).  If an 
unscheduled assessment was performed and the patient has not progressed, every attempt should be made to perform the subsequent assessments at their scheduled visits 
(relative to the date of randomization).  All confirmatory scans should be recorded on the database. 
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ADA Anti-drug antibody; AE Adverse event; CT Computed tomography; ECOG Eastern Cooperative Oncology Group; eCRF electronic case repot form; EORTC QLQ-
C30 Eastern Cooperative Oncology Group Quality of Life Questionnaire; EORTC QLQ-LC13 EORTC QLQ Lung Cancer 13; 
 
IP Investigational product; MRI Magnetic resonance imaging; NSCLC Non-small-cell lung cancer; PD Progressive disease; PFS2 Time to second 
progression; 
 RECIST Response Evaluation Criteria In Solid 
Tumors; SAE Serious adverse event; sPD-L1 Soluble programmed cell death ligand 1TSH Thyroid-stimulating hormone; T3 Triiodothyronine; T4 Thyroxine; WHO World 
Health Organization.
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4.1
Enrollment/screening period
All screening and enrollment procedures will be performed according to the assessment 
schedule in Table 2 and Table 3. Demographic data and other characteristics will be recorded 
including date of birth or age, gender, smoking history, and race/ethnicity, according to local 
regulations.  A standard medical and surgical history will be obtained.
Written informed consent and any locally required privacy act document authorization must 
be obtained prior to performing any protocol-specific procedures, including screening 
evaluations.  All patients will be required to provide consent to supply a sample of their tumor 
(archived or newly acquired biopsy) for entry into this study.  This consent is included in the 
main patient informed consent form (ICF).  
Screening evaluations may be performed over more than 1 visit.
The timing of vital sign assessments should be such that it allows the blood draw (eg, PK 
blood sample) to occur at the timepoints indicated in Table 2 and Table 3.
4.2
Treatment period
All procedures to be conducted during the treatment period will be performed according to the 
assessment schedule (see Table 2 and Table 3). 
Whenever vital signs and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: vital signs and then blood draws.  The timing 
of the vital signs assessments should be such that it allows the blood draw (eg, PK blood 
sample) to occur at the timepoints indicated in Table 2 and Table 3.
4.3
Follow-up period
All procedures to be conducted during the follow-up period will be performed according to 
the assessment schedule (see Table 4).
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 4.

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5.
STUDY ASSESSMENTS
A Web-Based Data Capture (WBDC) system will be used for data collection and query 
handling.  The Investigator will ensure that data are recorded on the eCRFs as specified in this
study protocol and in accordance with the instructions provided.
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
the provision of answers to data queries according to the clinical study agreement (CSA).  The 
Investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be archived 
at the study site.
5.1
Efficacy assessments
RECIST 1.1 criteria will be used to assess patient response to treatment by determining PFS, 
ORR, DoR, and APF12 using BICR assessments (primary), and using Investigator 
assessments for sensitivity analysis.  The RECIST 1.1 guidelines for measurable, 
non-measurable, target, and non-target lesions and the objective tumor response criteria (CR, 
PR, SD, or PD) are presented in 
  PFS2 defined by local standard clinical 
practice, and OS will also be evaluated.
The methods of assessment of tumor burden used at baseline are CT and MRI scans of the 
chest and abdomen (including liver and adrenal glands).  Any other areas of disease 
involvement should be additionally imaged based on the signs and symptoms of individual 
patients.
The baseline assessment should be performed no more than 28 days before randomization and 
ideally as close as possible to the start of the assigned IP.  Efficacy for all patients will be 
assessed by objective tumor assessments every 6 weeks for the first 48 weeks (relative to the 
date of randomization; Table 2, Table 3 and Table 4) then every 8 weeks (q8w) thereafter,
until confirmed objective disease progression per RECIST 1.1 (irrespective of the reason for 
stopping treatment or subsequent therapy).  If an unscheduled assessment is performed, and 
the patient has not progressed, every attempt should be made to perform the subsequent 
assessments at their scheduled visits.
For patients who discontinue IP (including SoC) due to toxicity in the absence of confirmed 
objective progression, objective tumor assessments per the scheduled assessments should be
continued every 6 weeks for 48 weeks (relative to randomization) and then every 8 weeks
until confirmed objective disease progression. 
A confirmatory scan is required for all patients following the initial demonstration of PD. The 
confirmatory scan should occur no earlier than 4 weeks after the initial assessment of PD and 
preferably at the next scheduled visit in the absence of clinically significant deterioration.  
Treatment with MEDI4736 + tremelimumab, MEDI4736 monotherapy, or SoC may continue 
between the initial assessment of progression and confirmation of progression.  Progression 
would be considered confirmed per RECIST 1.1 criteria available in 
using 
Investigator assessments.
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If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) prior to 
progression, then the patient should still continue to be followed until confirmed objective 
disease progression.
Categorization of objective tumor response assessment will be based on the RECIST 1.1 
criteria of response: CR, PR, SD, and PD.  Target lesion progression will be calculated in 
comparison to when the tumor burden was at a minimum (ie, smallest sum of diameters 
previously recorded on study).  In the absence of progression, tumor response (CR or PR) and 
SD will be calculated in comparison to the baseline tumor measurements obtained before 
starting treatment.
Following confirmed progression, patients should continue to be followed up for survival 
every 1 to 2 months as outlined in the study plan (Table 4).  Subsequent anticancer therapy 
information will be collected at the timepoints indicated in Table 4.
Patients in the MEDI4736 + tremelimumab who will receive retreatment must have a baseline 
tumor assessment within 28 days of restarting treatment and additional scans every 6 weeks 
for the first 48 weeks relative to the date of randomization, and then q8w thereafter until 
disease progression.  All assessments in Table 2will be followed for patients who receive 
retreatment.
It is important to follow the assessment schedule as closely as possible.  Please refer to the 
study plans (Table 2 and Table 3 [screening and the treatment period] and Table 4 for 
follow-up of patients who have completed or discontinued IP treatment]) and 
5.1.1
Central reading of scans
A BICR of all radiological scans in accordance with RECIST 1.1 will be performed for the 
evaluation of the co-primary PFS endpoint (and all secondary endpoints determined from the 
tumor assessments).
All images will be collected centrally.  Guidelines for imaging collection and storage will be 
provided in a separate document.  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 RECIST1.1 assessment conducted by the Investigator.  
5.1.2
Survival assessments
Assessments for survival must be made every 2 months following treatment discontinuation.  
Survival information may be obtained via telephone contact with the patient, patient’s family,
or by contact with the patient’s current physician.  The details of first and subsequent 
therapies for cancer, after discontinuation of treatment, will be collected.  
In addition, patients on treatment or in survival follow-up will be contacted following the data 
cut-off for the primary analysis of PFS and for each interim and final analysis of OS to 
provide complete survival data.  These contacts should generally occur within 7 days of the 
data cut off.
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5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood samples for determination of clinical chemistry and hematology will be taken at the 
times indicated in the assessment schedules and as clinically indicated (see Table 2, Table 3
and Table 4). Urine samples for analysis will be taken at screening.
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a 
licensed clinical laboratory according to local standard procedures.  Sample tubes and sample 
sizes may vary depending on the laboratory method used and routine practice at the site.  
Urine pregnancy tests may be performed at the site using a licensed test (urine or serum 
pregnancy test).  Abnormal clinically significant laboratory results should be repeated as soon 
as possible (preferably within 24 to 48 hours).
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  The date, time of collection, and results (values, units, and reference ranges) will 
be recorded on the appropriate eCRF.
The laboratory variables to be measured are presented in Table 5 (clinical chemistry), Table 6
(hematology), and Table 7 (urinalysis).
Pregnancy tests on either urine (human chorionic gonadotropin [hCG]) or blood (serum 
β-hCG) samples will be performed for pre-menopausal women of childbearing potential at 
screening and subsequent visits as specified in the assessment schedule (see Table 2, Table 3
and Table 4).  Tests will be performed by the hospital’s local laboratory.  If results are 
positive, the patient must not start or continue treatment.  In the event of a suspected 
pregnancy during the study, the test should be repeated.
Other safety tests to be performed at screening include assessment for HBV surface antigen, 
HCV antibodies, HIV antibodies, thyroid-stimulating hormone, free triiodothyronine (T3), and 
free thyroxine (T4).

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Table 5
Clinical chemistry (serum or plasma)
Albumin
Glucose
Alkaline phosphatase
Lactate dehydrogenase
Alanine aminotransferase
Lipasea
Amylasea
Magnesium
Aspartate aminotransferase
Potassium
Bicarbonate
Sodium
Calcium 
Total bilirubinb
Chloride
Total protein
Creatinine 
Urea or blood urea nitrogen, depending on local practice
Gamma glutamyltransferasec
Uric acid
a
In the event that amylase and lipase analyses cannot performed, 1 or the other will be performed in line with 
local practice.
b
If total bilirubin is ≥2 × ULN (and evidence of Gilbert’s syndrome) then fractionate into direct and indirect bilirubin.
c
At screening and as clinically indicated.
Table 6
Hematology
Basophils
Mean corpuscular volume
Eosinophils
Monocytes
Hematocrit
Neutrophils
Hemoglobin
Platelet count
Lymphocytes
Red blood cell count
Mean corpuscular hemoglobin
Total white cell count
Mean corpuscular hemoglobin concentration
Activated partial thromboplastin time and international 
normalized ratioa
a
Activated partial thromboplastin time and international normalized ratio are to be assessed at screening and as clinically 
indicated.
Table 7
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 
for further instructions.  These cases should be reported as SAEs if, after 
evaluation, they meet the criteria for a Hy’s law case or if any of the individual liver test 
parameters fulfill any of the SAE criteria.  All patients with an elevated AST, ALT, or 
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bilirubin value (the latter at ≥1.5 × ULN) at the time of the last dose of study treatment should 
have a further liver chemistry profile (AST, ALT, bilirubin, and alkaline phosphatase) 
performed 30 days (±3 days) after permanent discontinuation of study treatment.
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 97
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 (see Table 2, 
Table 3 and Table 4).  Full physical examinations will include assessments of the head, eyes, 
ears, nose, and throat and the respiratory, cardiovascular, GI, urogenital, musculoskeletal, 
neurological, dermatological, hematologic/lymphatic, and endocrine systems.  Height will be 
measured at screening only.  Targeted physical examinations are to be utilized by the 
Investigator on the basis of clinical observations and symptomatology.  Situations in which 
physical examination results should be reported as AEs are described in Section 6.1.4.
5.2.3
Electrocardiograms
Resting 12-lead electrocardiograms (ECGs) will be recorded at screening and as clinically 
indicated throughout the study (see Table 2 and Table 3).  ECGs should be obtained after the 
patient has been in a supine position for 5 minutes and recorded while the patient remains in 
that position.
At screening, a single ECG will be obtained on which QTcF must be <470 ms.  
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 
2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm 
the finding.  
Situations in which ECG results should be reported as AEs are described in Section 6.1.4. 
5.2.4
Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the assessment schedules (see Table 2, Table 3 and Table 4).  Body weight is also 
recorded along with vital signs.
Supine or semi-supine BP will be measured using a semi-automatic BP recording device with 
an appropriate cuff size, after the patient has rested for at least 5 minutes.  BP and pulse will 

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be collected from patients in the MEDI4736 + tremelimumab and MEDI4736 monotherapy 
treatment groups at the following times (based on a 60-minute infusion):
For the first infusion, patients in the MEDI4736 + tremelimumab and MEDI4736 
monotherapy treatment groups will be monitored as follows:
!
Prior to the beginning of the infusion (measured once from approximately 
30 minutes before up to 0 minutes [ie, the beginning of the infusion])
!
Approximately 30 minutes during the infusion (halfway through infusion) 
!
At the end of the infusion ( approximately 60 minutes)
!
A 1-hour observation period is recommended after the first infusion of MEDI4736 
and tremelimumab.  If no clinically significant infusion reactions are observed 
during or after the first cycle, subsequent infusion observation periods can be at the 
Investigator’s discretion (suggested 30 minutes after each MEDI4736 and 
tremelimumab infusion).
On subsequent infusion days, patients in the MEDI4736 + tremelimumab and MEDI4736 
monotherapy treatment groups will be monitored at the start of the infusion and then per 
institution standard and as clinically indicated.
Patients in the SoC group will be monitored before every infusion or administration and as 
clinically indicated.  
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow 
the principles as described above or be taken more frequently if clinically indicated.  The date 
and time of collection and measurement will be recorded on the appropriate eCRF.  Additional 
monitoring with assessment of vital signs is at the discretion of the Investigator per standard 
clinical practice or as clinically indicated.  
Situations in which vital signs results should be reported as AEs are described in 
Section 6.1.4.
5.3
Other assessments
5.3.1
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 trials. The following PROs will be administered in this study: EORTC 
QLQ-C30 (core questionnaire), QLQ-LC13 (lung cancer module),
 
The PRO instruments will be completed by the patients using a handheld ePRO device.  All 
assessments should be completed without assistance from anyone according to the assessment 
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schedules (see Table 2, Table 3 and Table 4). It takes approximately 30 to 45 minutes for 
patients to complete the questionnaires; therefore, the burden to the patient is 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 commonly used as an endpoint in 
cancer clinical trials.  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 QoL scale. Six single-item 
symptom measures are also included: dyspnea, insomnia, appetite loss, constipation, diarrhea, 
and financial difficulties (see 
).  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 (QLQ-LC13;
) 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 side 
effects 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 
(#43 “Did you take any medicine for pain?”) has a response option of “Yes” or “No.”  The 
scoring approach for the QLQ-LC13 is similar to the EORTC QLQ-C30.
 
 
 
 
 
 
 
 
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5.3.2
Administration of the patient-reported outcome questionnaires
Patients will complete the PRO assessments by using a handheld electronic device (ePRO).
Each center must allocate the responsibility for the administration of the PRO devices 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 
completed per the schedule of assessments (see Table 2, Table 3 and Table 4).  Patients will 
be instructed to bring their handheld devices to every clinic visit.  In instances where the PRO 
assessments coincide with a clinic visit, the research nurse or study coordinator should verify 
that the questionnaire was completed before the visit.  If not, the patient should complete the 
questionnaire prior to any other study procedures and before discussion of disease progression 
to avoid biasing the patient’s responses to the questions. 
The following best practice guidelines should be followed when collecting PRO data via an 
electronic device:
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
The research nurse or appointed site staff must explain the value and relevance of 
participation to patients and inform them that these questions are being asked in 
order to find out from them directly how they feel.  The research nurse or appointed 
site staff should also stress that the information is confidential.  Therefore, if the 
patient has any medical problems, he/she should 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 by the ePRO vendor, and 
also provide guidance on whom to call if there are problems with the 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.  

The research nurse or appointed site staff must monitor compliance; minimizing 
missing data is a key aspect of study success.  Compliance must be checked at each 
study visit and should be checked more frequently to identify problems early.  If 
compliance drops below 85%, a check-in call from the site to ask the patient if 
he/she has any difficulties is highly recommended.
5.3.3
WHO/ECOG performance status
WHO/ECOG performance status will be assessed at the times specified in the assessment 
schedules (see Table 2, Table 3 and Table 4) based on the following:
3.
Fully active; able to carry out all usual activities without restrictions
4.
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)
5.
Ambulatory and capable of self-care, but unable to carry out any work activities; up 
and about more than 50% of waking hours.
6.
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours
7.
Completely disabled; unable to carry out any self-care and totally confined to bed or 
chair
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5.4
Pharmacokinetics
5.4.1
Collection of samples and determination of drug concentration
Blood samples for determination of MEDI4736 and tremelimumab concentration in serum 
will be obtained according to the assessment schedules (see Table 2 and Table 4).  
 
5.4.2
Collection of samples to measure for the presence of ADAs
The presence of ADA will be assessed in serum samples taken according to the assessment 
schedules (see Table 2, and Table 4).
 
 
 
5.4.3
Storage and destruction of pharmacokinetic/ADA samples
PK and ADA samples will be disposed of a maximum of 10 years after the IPs are approved 
for marketing.
PK and ADA samples may be disposed of or destroyed and 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).
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Validation Report.
 
 
5.5
Biomarker analysis
 
 
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5.5.1
Collection of patient samples for stratification by PD-L1
At screening, there are 2 mandatory options for provisions of tissue to be used for 
determination of eligibility. There is 1 subsequent mandatory provision of tissue at 
progression if retreatment is planned:
!
MANDATORY: Provision of a recent tumor biopsy formalin fixed and embedded in paraffin.  A 
freshly collected tumor biopsy is strongly preferred; however, if not clinically feasible, an archival 
sample taken less than 3 months prior to screening may be submitted.  
Samples should be collected via a core needle (18 gauge or larger) or be collected as an 
excisional or incisional tumor biopsy sample.
When tissue is newly obtained for the purpose of entry into this study, 2 cores should be 
placed in formalin and processed to a single paraffin embedded block, as described in the 
Laboratory Manual.
The tumor specimen submitted to establish eligibility should be of sufficient quantity to allow 
for PD-L1 IHC analyses (see the Laboratory Manual).  Newly acquired or archived specimens 
with limited tumor content and fine needle aspirates are inadequate for defining tumor PD-L1 
status.
Tumor lesions used for fresh biopsies should not be the same lesions used as RECIST 1.1 
target lesions, unless there are no other lesions suitable for biopsy. If a RECIST 1.1 target 
lesion is used for biopsy (preferably core needle biopsy), the lesion must be imaged after 
biopsy prior to randomization.
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!
MANDATORY: The collection of additional archived tumor tissue block greater 
than 3 months old (formalin-fixed paraffin-embedded) is mandated, where such 
samples exist in a quantity sufficient to allow for analysis. Tumor tissue block is 
preferred.  If a tissue block is unavailable, unstained sections from the tissue block 
may be submitted.  Please consult the laboratory manual for specific instructions 
and guidelines regarding sections.   
!
MANDATORY: The collection of tumor biopsies at the time of progression prior to 
retreatment is mandated.  The Investigator can consult with the Study Physician if 
such sampling is not feasible, but retreatment is indicated.
!
OPTIONAL: The collection of additional biopsies upon progression of patients in 
the MEDI4736 + tremelimumab and MEDI4736 monotherapy groups is strongly 
encouraged.
!
Additional tumor biopsies collected as part of clinical care (eg, for mixed responses 
or upon PD) can be submitted for further analysis.
See the Laboratory Manual for further details of requirements including sample QC and 
shipping.
 
 
The
 will be used to determine PD-L1 IHC status in this 
study for the purposes of stratification and for the analysis of the original diagnostic sample.  
To meet the requirement of Food and Drug Administration (FDA) approval of a companion 
diagnostic, sections of the tumor will be retained at 
 
for potential additional studies, as requested by the FDA, to support potential test approval.
5.5.2
Exploratory biomarkers
 
 
  
 
 
 
 
 
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Myeloid-derived suppressor cells
 
 
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Peripheral blood mononuclear cells
 
 
 
 
 
 
Soluble factors - plasma
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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Tumor markers
 
 
 
 
Management of biomarker data
The biomarker data will have unknown clinical significance.  AstraZeneca will not provide 
biomarker research results to patients, their family members, any insurance company, an 
employer, clinical study Investigator, general physician, or any other third party, unless 
required to do so by law.  The patient’s samples will not be used for any purpose other than 
those described in the study protocol.
Individual patients will not be identified in any report or publication resulting from this work.  
The data and results of this research may be reviewed with collaborators and published, but 
neither the patient’s name nor any other personal identifiers will appear in any publication or 
report.
5.5.3
Storage, re-use, and destruction of biological samples
Samples will be stored for a maximum of 15 years from the end of study, after which they will 
be destroyed.  
 
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 
“IATA 6.2 Guidance Document.”
Any samples identified as Infectious Category A materials will not be shipped, and no further 
samples will be taken from the involved patients unless agreed upon with AstraZeneca and 
appropriate labeling, shipment, and containment provisions are approved.
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5.5.5
Chain of custody of biological samples
A full chain of custody will be maintained for all samples throughout their life cycle.
The Principal Investigator at each center will keep full traceability of collected biological 
samples from the patients while in storage at the center until shipment or disposal (where 
appropriate) and will keep documentation of receipt of arrival.
The sample receiver will keep full traceability of the samples while in storage and during use 
until used or disposed of or until further shipment and will keep documentation of receipt of 
arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, and auditing of external laboratory providers.
Samples retained for further use will be registered in the AstraZeneca-designated Biobank 
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 of or destroyed and the action documented. If samples have already been analyzed,
AstraZeneca is not obliged to destroy the results of this research.
The Principal Investigator will:
!
Ensure that AstraZeneca is immediately notified of the patients’ withdrawal of 
informed consent to the use of donated samples
!
Ensure that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of or destroyed and the action documented
!
Ensure that the laboratory(ies) holding the samples is/are immediately informed 
about the withdrawn consent and that samples are disposed of or destroyed, the 
action is documented, and the signed document is returned to the study site
!
Ensure that the patient and AstraZeneca are informed about the sample disposal
5.6
Pharmacogenetics
Refer to
for details of the genetic research (optional DNA component).
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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.
6.1
Definition of adverse events
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition during or following exposure to a pharmaceutical product, 
whether or not the condition is considered to be causally related to the product.  An 
undesirable medical condition can be a symptom (eg, nausea or chest pain), sign 
(eg, tachycardia or enlarged liver), or the abnormal result of an investigation (eg, laboratory 
findings or ECG).  In clinical studies, an AE can include an undesirable medical condition 
occurring at any time, including run-in or washout periods, even if no study treatment has 
been administered.
The term ‘AE’ is used to include both serious and non-serious AEs.
6.1.1
Causality collection
The Investigator will assess the causal relationship between the IPs and each AE and answer 
“yes” or “no” to the question “Do you consider that there is a reasonable possibility that the 
event may have been caused by the investigational product?”
For SAEs, causal relationship will also be assessed for other medications and study 
procedures.  Note that, for SAEs that could be associated with any study procedure, the causal 
relationship is implied as “yes.”
A guide to the interpretation of the causality question is found in
6.1.2
Relationship to protocol procedures
The Investigator is also required to provide an assessment of the relationship of SAEs to 
protocol procedures on the SAE report form.  This includes both non-treatment–emergent 
(ie, SAEs that occur prior to the administration of MEDI4736 +/- tremelimumab and 30 days 
after last dose of SoC) 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.
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6.1.3
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: “Have you had any health problems since the previous visit/you 
were last asked?” or revealed by observation will be collected and recorded in the eCRF.  
When collecting AEs, the recording of diagnoses is preferred, when possible, to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
6.1.4
Adverse events based on examinations and tests
The results from protocol-mandated laboratory tests and vital signs measurements will be 
summarized in the CSR.  Deterioration as compared to baseline in protocol-mandated 
laboratory values and vital signs should therefore only be reported as AEs if they fulfill any of 
the SAE criteria or are the reason for discontinuation of treatment with the IPs.
If deterioration in a laboratory value or vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory result 
or vital sign will be considered as additional information.  Whenever possible, the reporting 
Investigator should use the clinical rather than the laboratory term (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.
6.1.5
Hy’s law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need 
to be reported as SAEs.  further instruction on cases of increases in liver biochemistry and 
evaluation of Hy’s law. Further instruction on cases of increases in liver biochemistry and 
evaluation of Hy’s law are shown in 
6.1.6
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP is being studied.  It may be an increase in the severity of the 
disease under study and/or increases in the symptoms of the disease. The development of new 
or progression of existing metastasis to the primary cancer under study should be considered 
as disease progression and not an AE.  Events that are unequivocally due to disease 
progression should not be reported as an AE during the study.
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6.1.7
New cancers
The development of a new cancer should be regarded as an SAE.  New primary cancers are 
those that are not the primary reason for the administration of the study treatment and have 
been identified after the patient’s inclusion in this study.
6.1.8
Deaths
All deaths that occur during the study, or within the protocol-defined follow-up period after 
the administration of the last dose of study treatment, must be reported as follows:
!
Death clearly resulting from disease progression should be reported to the Study 
Physician at the next monitoring visit and should be documented in the eCRF.  It 
should not be reported as an SAE.
!
Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to the Study Physician as an SAE 
within 24 hours.  The report should contain a comment regarding the 
co-involvement of PD, if appropriate, and should assign main and contributory 
causes of death.
!
Deaths with an unknown cause should always be reported as an SAE.  A 
post-mortem may be helpful in the assessment of the cause of death, and if 
performed, a copy of the post-mortem results should be forwarded to AstraZeneca 
Drug Safety or its representative within the usual timeframes.
6.1.9
Safety Data to be Collected Following the Final DCO of the Study
For patients continuing to receive durvalumab treatment 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 in order to manage AEs in accordance with the durvalumab toxicity management 
guidelines 
  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 treatment (or within the 90 days 
following the last dose of durvalumab treatment) post the final DCO and database closure 
must be reported as detailed in Section 6.4.
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6.2
Definitions of serious adverse event
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, or 
follow-up) that fulfills 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 or incapacity or substantial disruption of the
ability to conduct normal life functions
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above
For further guidance on the definition of an SAE, see 
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
AEs and SAEs will be collected from the time of the patient signing the informed consent 
form until the follow-up period is completed (90 days after the last dose of MEDI4736+/-
tremelimumab and 30 days after last dose of SoC).  AEs and SAEs collected prior to 
randomization will be reported as pre-randomization AEs and SAEs.  If an event that starts 
post the defined safety follow up period noted above is considered to be due to a late onset 
toxicity to study drug then it should be reported as an AE or SAE as applicable.
6.3.2
Follow-up of unresolved adverse events
During the course of the study, all AEs and SAEs should be proactively followed up for each 
patient for as long as the event is ongoing.  Every effort should be made to obtain a resolution 
for all events, even if the events continue after the patient has discontinued on study drug or 
the study has completed.
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the eCRF.  
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
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6.3.3
Variables 
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

The maximum CTCAE grade reported

Changes in CTCAE grade

Whether the AE is serious or not

Investigator causality rating against the IPs (yes or no)

Action taken with regard to IPs

Administration of treatment for the AE

Whether the AE caused the patient’s withdrawal from the study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date the AE met criteria for SAE

Date the Investigator became aware of the SAE

Seriousness criteria fulfilled

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Whether an autopsy was performed

Causality assessment in relation to study procedure(s)

Description of the AE

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The grading scales found in the revised NCI CTCAE Version 4.03 will be utilized for all 
events with an assigned CTCAE grading.  For those events without assigned CTCAE grades, 
the recommendation in the CTCAE criteria that converts mild, moderate, and severe events 
into CTCAE grades should be used.  A copy of the CTCAE Version 4.03 can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity, whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but it is not an SAE unless it meets the criteria 
shown in Section 6.2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke, but it would be an SAE if it satisfies the criteria 
shown in Section 6.2.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not they are considered causally related to the IPs or 
to any study procedure.  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then the Investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1 day, 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 an 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 
MEDI4736 and tremelimumab.

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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
Overdose
Use of IP in doses in excess of that specified in the protocol is considered to be an overdose.  
There is currently no specific treatment in the event of overdose of IP, and possible symptoms 
of overdose are not established.

An overdose with associated AEs will be recorded as the AE diagnosis or 
symptoms in the relevant AE modules of the eCRF and in the Overdose eCRF 
module.

An overdose without associated symptoms will only be reported in the Overdose 
eCRF module.
If an overdose of an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel will inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1
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.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1 day, ie, immediately, but 
no later than 24 hours of when he or she becomes aware of it.

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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.
6.6.2
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
180 days after the last dose of MEDI4736 + tremelimumab combination therapy or 90 days 
after the last dose of MEDI4736 monotherapy. Please follow the local prescribing 
information relating to contraception and the time limit for such precautions for SoC agents.
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) occurring from the date of the first dose until 90 days after the last 
dose 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 (EC)/Internal Review Boards (IRB) prior to use.
6.7
Management of investigational product-related toxicities
For guidance on the management of IP-related toxicities, please see 
The following general guidance should be followed for management of toxicities.
!
Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity if required).
!
If the symptoms promptly resolve with supportive care, consideration should be 
given to continuing the same dose of the assigned IP along with appropriate 
continuing supportive care.  If medically appropriate, dose modifications are 
permitted (see Section 6.7.2).  In addition, guidelines on dose modifications are
provided in 
!
All dose modifications should be documented with clear reasoning and 
documentation of the approach taken.
In addition, guidelines on dose modification and toxicity management for immune-mediated 
reactions, infusion-related reactions, and non-immune-mediated reactions for MEDI4736 and 
tremelimumab will be provided to investigators
. The most current version of 
the TMGs is also available through the following link: https://tmg.azirae.com.  In addition a 
version of the current TMGs is maintained within the Site Master File.  Please contact your 
clinical trial associate for information on how to gain access to this website.  
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There are certain circumstances in which MEDI4736 and tremelimumab should be 
permanently discontinued.  Following the first dose of IP, subsequent administration of 
MEDI4736 and tremelimumab can be modified.  All toxicities will be graded according to 
CTCAE Version 4.03.  Dose reductions are not permitted.  Dose modifications of MEDI4736 
and tremelimumab may be required in the event of treatment-related toxicity.  All toxicities 
will be graded according to NCI CTCAE Version 4.03.  In case of doubt, the Investigator 
should consult with the Study Physician.
Acetaminophen and/or an antihistamine (eg, diphenhydramine) or equivalent medications per 
institutional standard may be administered prior to infusion at the discretion of the 
Investigator for primary prophylaxis against infusion-related reactions.  In the event of 
Grade ≤2 infusion-related reaction, the infusion rate of IP may be decreased by 50% or 
interrupted until resolution of the event and re-initiated at 50% of the initial rate until 
completion of the infusion.  In patients experiencing Grade ≤2 infusion-related reaction, 
subsequent infusions may be administered at 50% of the initial rate.  If a patient experiences 
an infusion-related reaction, acetaminophen and/or an antihistamine (eg, diphenhydramine) 
and/or corticosteroid or equivalent medications per institutional standard may be administered 
prior to subsequent infusions at the discretion of the Investigator for secondary prophylaxis of 
infusion-related reactions.  If the infusion-related reaction is Grade 3 or higher in severity, 
treatment with IP will be discontinued.
As with any antibody, allergic reactions to dose administration are possible.  Appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study personnel must be trained to recognize and treat anaphylaxis.  The study 
site must have immediate access to emergency resuscitation teams and equipment in addition 
to the ability to admit patients to an intensive care unit if necessary.
6.7.1
MEDI4736 + tremelimumab and MEDI4736 monotherapy adverse events of 
special interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the Investigator to the Sponsor. An AESI may be serious or non-serious. 
The rapid reporting of AESIs allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of this investigational product.
AESIs for MEDI4736 ± tremelimumab include, but are not limited to, events with a potential 
inflammatory or immune-mediated mechanism and that may require more frequent 
monitoring and/or interventions such as steroids, immunosuppressants, and/or hormone 
replacement therapy.  These AESIs are being closely monitored in clinical studies with 
MEDI4736 monotherapy and combination therapy.  An immune-mediated adverse event 
(imAE) is defined as an AE that is associated with drug exposure and is consistent with an 
immune-mediated mechanism of action and where there is no clear alternate aetiology.  
Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to 
support an imAE diagnosis.  Appropriate efforts should be made to rule out neoplastic, 
infectious, metabolic, toxin, or other etiologic causes of the imAE. 

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If the Investigator has any questions in regards to an AE being an imAE, the Investigator 
should promptly contact the Study Physician.
AESIs observed with MEDI4736 ± tremelimumab include:
!
Diarrhea / Colitis and intestinal perforation
!
Pneumonitis / ILD
!
hepatitis / transaminase increases
!
Endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypothyroidism and type I diabetes mellitus)
!
Rash / Dermatitis
!
Nephritis / Blood creatinine increases
!
Pancreatitis / serum lipase and amylase increases
!
Myocarditis
!
Myositis / Polymyositis
!
Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis)
!
Other inflammatory responses that are rare / less frequent with a potential immune-
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis 
and other events involving the eye, skin, haematological and rheumatological 
events.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological aetiology are also considered AESIs.
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the MEDI4736 IB. More specific guidelines for their evaluation and treatment are 
described in detail in 
6.7.2
Immune-mediated adverse events
Based on the mechanism of action of MEDI4736 and tremelimumab leading to T-cell 
activation and proliferation, there is a possibility of observing imAEs during the conduct of 
this study.  Potential imAEs may be similar to those seen with the use of ipilimumab, BMS-
936558 (anti-PD-1 mAb), and BMS-936559 (anti-PD-L1 mAb) and may include immune-
mediated enterocolitis, dermatitis, hepatitis (hepatotoxicity), pneumonitis, and 
endocrinopathies (Brahmer et al 2012, Hodi et al 2010, Topalian et al 2012).  These AEs are 
inflammatory in nature and can affect any organ.  With anti-PD-L1 and anti-CTLA-4 
combination therapy, the occurrence of overlapping or increasing cumulative toxicities that 
include imAEs could potentially occur at higher frequencies than with either MEDI4736 or 
tremelimumab monotherapy.  Patients should be monitored for signs and symptoms of imAEs.  
In the absence of an alternate etiology (eg, infection or PD), an immune-related etiology 
should be considered for signs or symptoms of colitis, dermatitis, pneumonitis, hepatitis, and 
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endocrinopathy.    Dose modification guidelines are provided in
and it is 
recommended that:
1.
Patients should be evaluated to identify any alternative etiology.
2.
In the absence of a clear alternative etiology, all events of an inflammatory nature 
should be considered immune related.
3.
Symptomatic and topical therapy should be considered for low-grade events.
4.
Systemic corticosteroids should be considered for a persistent low-grade event or 
for a severe event.
5.
More potent immunosuppressives should be considered for events not responding to 
systemic steroids (eg, infliximab or mycophenolate). If the Investigator has any 
questions in regards to an AE being an imAE, then the Investigator should 
immediately contact the Study Physician.  
6.7.3
Standard of Care agents
IP-related toxicity management, including dose delays, reductions, and adjustments for 
patients in the SoC group should be performed as indicated in the local prescribing 
information for the relevant agent.
6.8
Study governance and oversight
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the study protocol and letters to 
Investigators.
An IDMC comprised of independent experts will be convened and will meet approximately 
6 months after the study has started or after the first 30 patients have been randomized, 
whichever occurs first, to review safety assessments and make recommendations to continue, 
amend, or stop the study based on safety findings.  The committee will meet approximately
every 6 months thereafter.
Full details of the IDMC procedures, processes, and interim analyses can be found in the 
statistical analysis plan and the IDMC Charter.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
AstraZeneca will supply MEDI4736 and tremelimumab, while the SoC treatments (paclitaxel 
+ carboplatin, gemcitabine + cisplatin, gemcitabine + carboplatin, pemetrexed + cisplatin, 
pemetrexed + carboplatin, and pemetrexed maintenance) will be supplied locally (Table 8).  
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Table 8
List of investigational products for this study
Investigational product
Dosage form and strength
Manufacturer
MEDI4736
50 mg/mL, solution, IV
MedImmune
Tremelimumab
20 mg/mL, solution, IV
MedImmune
Standards of Care
Paclitaxela
IV (as sourced locally)
Sourced locally
Carboplatina
IV (as sourced locally)
Sourced locally
Gemcitabinea
IV (as sourced locally)
Sourced locally
Cisplatina
IV (as sourced locally)
Sourced locally
Pemetrexeda
IV (as sourced locally)
Sourced locally
a
Under certain circumstances when local sourcing is not feasible, a Standard of Care treatment may be supplied centrally 
through AstraZeneca.
IV, intravenous.
7.1.1
MEDI4736
MEDI4736 will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution. The solution contains 50 mg/mL MEDI4736, 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% (weight/volume) 
polysorbate 80; it has a pH of 6.0.  The nominal fill volume is 10 mL.  Investigational product 
vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen.
Preparation of MEDI4736 doses for administration with an IV bag
The dose of 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 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
A dose of 20 mg/kg will be administered using an IV bag containing 0.9% weight/volume 
(w/v) saline or 5% (w/v) dextrose, with a final MEDI4736 concentration ranging from 1 to 
20 mg/mL, and delivered through an IV administration set with a 0.2 μm or 0.22 μm in-line 
filter.  
Patient weight at baseline should be used for dosing calculations unless there is a 
≥10% change in weight.  Dosing day weight can be used for dosing calculations instead of 
baseline weight per institutional standard.  A volume of 0.9% (w/v) saline or 5% (w/v) 
dextrose equal to the calculated volume of MEDI4736 to be added to the IV bag must be 
removed from the bag prior to addition of MEDI4736.  The calculated volume of MEDI4736

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is then added to the IV bag such that final concentration is within 1 mg/mL to 20 mg/mL. The 
bag is mixed by gentle inversion to ensure homogeneity of the dose in the bag.
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature.  In the event that either 
preparation time or infusion time exceeds the time limit, a new dose must be prepared using 
new vials. MEDI4736 does not contain preservatives, and any unused portion must be 
discarded. 
No incompatibilities between MEDI4736 and polyvinylchloride or polyolefin have been 
observed.
Dose calculation
The volume of MEDI4736 (in mL) to add to the IV bag is calculated as follows:
20 mg/kg × patient weight (kg) ÷ MEDI4736 concentration (nominal: 50 mg/mL)
Example: For a patient weighing 80 kg, dosed at 20 mg/kg, 32 mL [20 mg/kg × 80 kg divided 
by 50 mg/mL] of MEDI4736 is to be diluted into an IV bag such that the final MEDI4736 
concentration is within 1 to 20 mg/mL (100 – 1000 mL bag sizes).  First, 32 mL of IV bag 
diluent is removed from the IV bag, and then 32 mL of MEDI4736 is added to the bag.  The 
bag is mixed by gentle inversion to ensure homogeneity of the dose in the bag and the diluted 
MEDI4736 is administered as described above.
7.1.2
Tremelimumab
Tremelimumab will be supplied by AstraZeneca as a 400 mg vial solution for infusion after 
dilution.  The solution contains 20 mg/mL tremelimumab, 20 mM histidine/histidine-
hydrochloride, 222 mM trehalose dihydrate, 0.27 mM disodium edetate dihydrate and 0.02% 
(w/v) polysorbate 80; it has a pH of 5.5. The nominal fill volume is 20 mL.  Investigational 
product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen.
Product preparation of tremelimumab 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 start of administration should not exceed

24 hours at 2°C to 8°C (36°F to 46°F) or

4 hours at room temperature
A dose of 1 mg/kg will be administered using an IV bag containing 0.9% (w/v) saline, with a 
final tremelimumab concentration ranging from 0.15 mg/mL to 10 mg/mL, and delivered 
through an IV administration set with a 0.2 μm or 0.22 μm in-line filter.  

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Patient weight at baseline should be used for dosing calculations unless there is a 
≥10% change in weight.  Dosing day weight can be used for dosing calculations instead of 
baseline weight per institutional standard.  The volume of 0.9% (w/v) saline equal to the 
volume of tremelimumab to be added to the IV bag must be removed from the bag prior to the 
addition of tremelimumab.  The volume of tremelimumab is then added to the IV bag such 
that final concentration is within 0.15 mg/mL to 10 mg/mL.  The bag is then mixed by gentle 
inversions to ensure homogeneity of the dose in the bag.
Standard infusion time is 1 hour, however if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature.  In the event that either 
preparation time or infusion time exceeds the time limit, a new dose must be prepared using
new vials. Tremelimumab does not contain preservatives, and any unused portion must be 
discarded.
No incompatibilities between tremelimumab and polyvinylchloride or polyolefin have been 
observed. However, polycarbonate syringes and administration set containing cellulose-based 
filters should not be used with tremelimumab. 
Dose calculation of tremelimumab
The volume of tremelimumab (in mL) to add to the IV bag is calculated as follows:
In combination with MEDI4736: 1 mg/kg × patient weight (kg) ÷ tremelimumab 
concentration (nominal: 20 mg/mL)
Example: For a patient weighing 80 kg, dosed at 1 mg/kg, 4 mL [1 mg/kg × 80 kg divided by 
20 mg/mL] of tremelimumab is to be diluted into 0.9% (w/v) saline bag such that the final 
tremelimumab concentration is within 0.15 to 10 mg/mL (100 – 500 mL bag sizes).  First, 
4 mL of IV bag diluent is removed from the IV bag, and then 4 mL of tremelimumab is added 
to the bag.  The bag is mixed by gentle inversion to ensure homogeneity of the dose in the bag 
and the diluted tremelimumab is administered as described above..
7.1.3
Standard of Care treatment
Each SoC agent will be sourced as commercially available material/locally sourced,
prescribed according to local regulations, and will be administered according to prescribing 
information or treatment guidance in general use by the Investigating site.  Under certain 
circumstances when local sourcing is not feasible, an SoC will be supplied centrally by 
AstraZeneca.  This will be labeled with local language translated text in accordance with 
regulatory guidelines.
7.2
Dose and treatment regimens
Patients will be randomized in a 1:1:1 ratio to receive treatment with MEDI4736 + 
tremelimumab combination therapy, MEDI4736 monotherapy, or SoC.

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7.2.1
Treatment regimens
MEDI4736 + tremelimumab combination therapy
Patients in the MEDI4736 + tremelimumab combination therapy group will receive 20 mg/kg 
MEDI4736 via IV infusion q4w for up to 4 doses/cycles and 1 mg/kg tremelimumab via IV 
infusion q4w for up to 4 doses/cycles, and then continue 20 mg/kg MEDI4736 q4w starting on 
Week 16 (see Figure 3).  Dosing outside the window should be discussed with the Study 
Physician.  Tremelimumab will be administered first.  MEDI4736 infusion will start 
approximately 1 hour after the end of tremelimumab infusion.  The duration will be 
approximately 1 hour for an infusion.  A 1-hour observation period is recommended after the 
first infusion of MEDI4736 and tremelimumab.  If no clinically significant infusion reactions 
are observed during or after the first cycle, subsequent infusion observation periods can be at 
the Investigator’s discretion (suggested 30 minutes after each MEDI4736 and tremelimumab 
infusion).
Figure 3
MEDI4736 + tremelimumab combination therapy dosing scheme
Q4W every 4 weeks.

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MEDI4736 monotherapy 
Patients in the MEDI4736 monotherapy treatment group will receive 20 mg/kg MEDI4736 via 
IV infusion q4w (see Figure 4).  
Figure 4
MEDI4736 monotherapy dosing scheme
Q4W every 4 weeks.
Standard of Care treatment
Patients in the SoC group will receive 1 of the following treatments until documented PD
(unconfirmed and confirmed) , initiation of alternative anticancer therapy, unacceptable 
toxicity, withdrawal of consent to continued treatment, or other reasons to discontinue 
treatment criterion occur:

Paclitaxel + carboplatin: Paclitaxel 200 mg/m2 and carboplatin AUC 5 or 6 via IV 
infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles or until documented PD

Gemcitabine + cisplatin (squamous patients only): Gemcitabine 1000 or 
1250 mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + cisplatin 75 or
80 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles or until 
documented PD

Gemcitabine + carboplatin (squamous patients only): Gemcitabine 1000 or 
1250 mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + carboplatin 
AUC 5 or 6 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles or until 
documented PD

Pemetrexed + cisplatin (non-squamous patients only): Pemetrexed 500 mg/m2 and 
cisplatin 75 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles 
or until documented PD. Non-squamous patients who have not progressed after 
4 cycles will be eligible for pemetrexed maintenance therapy.

Pemetrexed + carboplatin (non-squamous patients only): Pemetrexed 500 mg/m2
and carboplatin AUC 5 or 6 via IV infusion on Day 1 of each 21-day cycle, for 4 to 
6 cycles or until documented PD. Non-squamous patients who have not progressed 
after 4 cycles will be eligible for pemetrexed maintenance therapy.

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For all SoC therapies, a particular treatment (paclitaxel, gemcitabine, cisplatin, carboplatin, or 
pemetrexed) will not be used in patients who have experienced recurrence or progression of 
disease within 6 months of prior multimodal therapy using that particular treatment.  
A confirmatory scan is required for all patients in the SoC group, even if a subsequent 
treatment is started.
7.2.2
Duration of treatment and criteria for retreatment
Duration of treatment
Unless specific treatment discontinuation criteria are met, patients in all groups will continue 
therapy until disease progression. 
Progression during treatment
At the Investigator’s discretion, patients in all groups may continue receiving therapy in the 
setting of unconfirmed PD until PD is confirmed.  According to RECIST 1.1 modified for 
confirmation of progression, a confirmatory scan is required following an overall time-point 
assessment of progression (PD), preferably at the next scheduled visit and no earlier than 4 
weeks after the previous assessment of PD.  
Patients in all groups, excluding the SoC arm, with PD according to RECIST 1.1
(unconfirmed and confirmed) who, in the Investigator’s opinion, continue to receive benefit 
from their assigned treatment and who meet the criteria for treatment in the setting of PD may 
continue to receive their assigned treatment for as long as they are gaining clinical benefit.
However, patients in the immunotherapy group(s) will not be permitted to continue 
immunotherapy if progression occurs in a target lesion that has previously shown a confirmed 
response.  Confirmed response is CR or PR, as defined by RECIST 1.1.
Patients in the MEDI4736 + tremelimumab group may restart treatment with the combination 
therapy if they complete the 4 dosing cycles with MEDI4736 + tremelimumab (with clinical 
benefit per Investigator’s judgment), but subsequently have PD during treatment with 
MEDI4736 alone and if they meet eligibility criteria for retreatment.
For all groups, excluding the SoC arm, treatment through progression and retreatment in the 
MEDI4736 + tremelimumab combination therapy group are at the Investigator’s discretion, 
and the Investigator should ensure that patients do not have any significant, unacceptable, or 
irreversible toxicities that indicate that continuing treatment will not provide further benefit.  
The Investigator should ensure that patients still meet all of the inclusion criteria and none of 
the exclusion criteria for this study and that these patients meet the following specific criteria 
for treatment in the setting of PD: 

Written informed consent for retreatment in the setting of PD.  This consent 
document will specify that treatment beyond initial evidence of PD is not the SoC

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and that alternative treatment options, either locally licensed treatments or other 
clinical trials, are available for this patient population.

Absence of clinical symptoms or signs indicating clinically significant disease 
progression and no decline in WHO performance status to >1

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
Post final Data Cut Off (DCO)
Patients who continue to receive benefit from their assigned treatment 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. For patients continuing to receive durvalumab 
treatment following the 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 in order to manage AEs in 
accordance with the durvalumab toxicity management guidelines (please see Section 6.1.9).
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 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.
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.
7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions.  The IP 
label on the pack/bottle/carton specifies the appropriate storage.  Storage is also described in 
the IB.

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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 
Drug accountability should be performed until the patient stops study treatment completely.  
Study site personnel will account for all study drugs received at the site, for all unused study 
drugs, and for appropriate destruction of study drugs.  Certificates of delivery, destruction, and 
return should be signed.
7.7
Concomitant and other treatments 
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical treatment phase of the study including the 3 
month follow up period following the last dose of study drug. Any concomitant 
medication(s), including herbal preparations, taken during this time 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 the following 
tables. Refer also to the Dosing Modification and Toxicity Management Guidelines in 
For agents in the SoC arm, please refer to the local prescribing information with 
regards to warnings, precautions, and contraindications.
Prohibited medication/class of drug:
Usage:
Additional investigational anticancer therapy 
concurrent with those under investigation in 
this study
Should not be given whilst the patient is on IP 
treatment (including SoC) 
mAbs against CTLA-4, PD-1, or PD-L1
Should not be given whilst the patient is on IP 
treatment (including SoC) through 90 days after the 
last dose of IP.
Any concurrent chemotherapy, local therapy 
(except palliative radiotherapy for non-target 
lesions, eg, radiotherapy, surgery, 
radiofrequency ablation), biologic therapy, or 
hormonal therapy for cancer treatment
Should not be given whilst the patient is on IP 
treatment (including SoC).  (Concurrent use of 
hormones for non-cancer-related conditions 
[eg, insulin for diabetes and hormone replacement 
therapy] is acceptable.)
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Prohibited medication/class of drug:
Usage:
Immunosuppressive medications, including, 
but not limited to: systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or 
its equivalent, methotrexate, azathioprine, and 
tumor necrosis factor -α blockers  
Should not be given whilst the patient is on IP 
treatment (including SoC).  (Use of 
immunosuppressive medications for the management 
of IP-related AEs or in patients with contrast allergies 
is acceptable.  In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted.
Systemic corticosteroids may be used for prevention 
of chemotherapy-related toxicities (nausea/vomiting 
prevention and prophylaxis)
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential for 
the management of the patient (eg, for chronic 
obstructive pulmonary disease, radiation, nausea, 
etc).
Drugs with laxative properties
Should be used with caution for 90 days after the last 
dose of tremelimumab during the study
Herbal or natural remedies (all herbal or 
natural remedies, rather than those for 
constipation only)
Should be avoided for 90 days after the last dose of 
MEDI4736 monotherapy or combination treatment 
(MEDI4736+ tremelimumab)
Sunitinib
Should not be given within 3 months of a dose of 
tremelimumab (acute renal failure has been reported 
with combination therapy of tremelimumab and 
sunitinib)
Live attenuated vaccines
Should not be given through 30 days after the last 
dose of IP (including SoC) during the study
EGFR TKIs 
Should not be given concomitantly whilst the patient 
is on study treatment.
In addition they should be used with caution in the 90 
days after the last dose of 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).
Rescue/supportive medication/class of drug:
Usage:
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) 
deemed necessary by the Investigator to 
provide adequate prophylactic or supportive 
care, except for those medications identified as 
“prohibited” as listed above
To be administered as prescribed by the Investigator

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Rescue/supportive medication/class of drug:
Usage:
Best supportive care (including antibiotics, 
nutritional support, growth factor support,
correction of metabolic disorders, optimal 
symptom control, and pain management 
[including palliative radiotherapy, etc])
Should be used when necessary for all patients
Inactivated viruses, such as those in the 
influenza vaccine
Permitted
7.7.1
Other concomitant treatment
Medications other than those described in Section 7.7 that are considered necessary for the 
patient’s safety and well-being may be given at the discretion of the Investigator and should 
be recorded in the appropriate sections of the eCRF.
7.8
Post study access to study treatment
After the final analysis, AstraZeneca will continue to supply open-label drug to patients 
receiving MEDI4736 + tremelimumab or MEDI4736 monotherapy (see Section 7.2.2).

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8.
STATISTICAL ANALYSES BY ASTRAZENECA
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 reporting of the data.  The primary aim of the study 
is to compare the efficacy and safety of MEDI4736 in combination with tremelimumab and 
MEDI4736 monotherapy to SoC.  
8.2
Sample size estimate
The study will plan to enroll approximately 1850 patients in order to randomize 1092 eligible 
patients 1:1:1 to MEDI4736 + tremelimumab combination therapy, MEDI4736 monotherapy, 
or SoC.  The 1092 patients will comprise approximately 480 patients who have PD-L1 
positive25% tumors. 
The study is sized to characterize the OS benefit of MEDI4736 in combination with 
tremelimumab and MEDI4736 monotherapy versus SoC in patients with EGFR and ALK 
wild-type advanced or metastatic NSCLC in patients with PD-L1 positive25% tumors and PFS 
benefit of MEDI4736 in combination with tremelimumab versus SoC in patients with PD-L1 
positive25%  tumors
 
Two interim analysis of OS will be performed; the first at the time of the primary PFS analysis 
and the second when 80% of the target OS events have occurred.  The alpha will be split 
between the 3 OS 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 OS events at the time of 
analysis.
The primary PFS analysis for superiority will be performed when both of the following 
conditions have been met: 
!
Approximately 231 BICR PFS events have occurred across the MEDI4736 + 
tremelimumab and SoC treatment groups in patients with PD-L1 positive25%  
tumors (72% maturity) AND
!
 to the study
The final (primary) OS analysis for superiority will be performed when the following 
conditions have been met: 
!
Approximately 225 OS events have occurred across the MEDI4736 + 
tremelimumab and SoC treatment groups in patients with PD-L1 positive25%  
tumors (70% maturity) AND
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!
Approximately 225 OS events have occurred across the MEDI4736 monotherapy 
and SoC treatment groups in patients with PD-L1 positive25%  tumors (70% 
maturity)
MEDI4736 + tremelimumab versus SoC (PFS in PD-L1 positive25% population)
 
 
 
 
 
 
MEDI4736 + tremelimumab versus SoC (OS in PD-L1 positive25% population)
 
 
 
 
 
MEDI4736 monotherapy versus SoC (OS in PD-L1 positive25% population) 
 
  
 
 
 
MEDI4736 + tremelimumab versus SoC (OS in PD-L1 positive1% population)
 
 
 
 
 
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MEDI4736 + tremelimumab versus SoC (OS, all patients)
 
 
 
 
 
 
 
 
 
 
 
MEDI4736 monotherapy versus SoC (PFS in PD-L1 positive25% population)
 
 
 
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MEDI4736 + tremelimumab versus SoC (PFS in PD-L1 positive1% population)
 
 
 
 
 
 
 
 
 
 
MEDI4736 + tremelimumab versus SoC (PFS, all patients)
 
 
 
 
 
 
8.3
Definitions of analysis sets
Definitions of the analysis sets for each outcome variable are provided in Table 9.
Table 9
Summary of outcome variables and analysis populations
Outcome variable
Population
Efficacy data
PFS and OS
PD-L1 positive25% analysis set
PFS and OS
PD-L1 positive1% analysis set
PFS and OS
Full analysis set (ITT population)
ORR, DoR, APF12, PFS2, PROs, and symptom endpoints
PD-L1 positive25% analysis set
ORR, DoR, APF12, PFS2, PROs, and symptom endpoints
PD-L1 positive1% analysis set
PFS, OS, ORR, , DoR, APF12, PFS2
PD-L1-low/negative analysis set
ORR, DoR, APF12, PFS2, PROs, and symptom endpoints
Full analysis set (ITT population)
PK data
PK analysis Set
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Outcome variable
Population
Safety Data
Exposure
Safety analysis Set
AEs
Safety analysis Set
Laboratory measurements
Safety analysis Set
Vital signs
Safety analysis Set
ECGs
Safety analysis Set
8.3.1
Full analysis set
The full analysis set (FAS) will include all randomized patients. The full analysis set will be 
used for all efficacy analyses (including PROs).  Treatment groups will be compared on the 
basis of randomized study treatment, regardless of the treatment actually received.  Patients 
who were randomized but did not subsequently go on to receive study treatment are included 
in the analysis in the treatment group to which they were randomized.
8.3.2
PD-L1 positive25% analysis set
The PD-L1 positive25% analysis set will include the subset of patients in the FAS whose PD-
L1 status is PD-L1 positive25%  as defined by the 
 (ie, ≥25%  
PD-L1–membrane expression in tumoral tissue).
8.3.3
PD-L1 positive1% analysis set
The PD-L1 positive1% analysis set will include the subset of patients in the FAS whose PD-L1 
status is PD-L1 positive1% as defined by the 
 (ie, ≥1% PD-
L1–membrane expression in tumoral tissue).   This analysis set will be used for for supportive 
analyses of efficacy endpoints.
8.3.4
PD-L1- low/negative analysis set
The PD-L1-low/negative analysis set will include the subset of patients in the FAS whose PD-
L1 status is PD-L1 low/negative as defined by the 
 
(ie, <25% PD-L1–membrane expression in tumoral tissue). 
8.3.5
PD-L1- negative analysis set
The PD-L1-negative analysis set will include the subset of patients in the FAS whose PD-L1 
status is PD-L1 negative as defined by the
 (ie, <1% PD-L1–
membrane expression in tumoral tissue).
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8.3.6
Safety analysis set
The safety analysis set (SAS) will consist of all patients who received at least 1 dose of study 
treatment.  Safety data will not be formally analyzed but summarized using the SAS, 
according to the treatment received, that is, erroneously treated patients (e.g., those 
randomized to treatment A but actually given treatment B) will be summarized according to 
the treatment they actually received.
8.3.7
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 the co-primary endpoint, PFS, and the analyses of the secondary endpoints, 
ORR, DoR, and APF12, will be based on BICR tumor assessments according to RECIST 1.1.  
OS will be evaluated as a co-primary endpoint 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.  For each patient, the 
BICR will define the overall visit response data (CR, PR, SD, PD, or not evaluable [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 BICR Charter.
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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 
8.4.2.1
Co-Primary endpoints 
OS and PFS are the co-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 either reviewer where both select PD as a time point response and there is 
no adjudication for central review (BICR).
!
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. 
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Note: For target lesions, only the latest scan date is recorded out of all scans performed at that 
assessment for the target lesions, and similarly for non-target lesions, only the latest scan date 
is recorded out of all scans performed at that assessment for the non-target lesions.
 
 
 
 
 
 
 
 
PFS by irRECIST 1.1 criteria using BICR assessments will also be reported.
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.
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ORR by irRECIST 1.1 criteria using BICR assessments will also be reported.
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 documented response.
Time from randomization to second progression (PFS2)
PFS2 will be defined as the time from the date of randomization to the earliest of the 
progression event subsequent to that used for the PFS endpoint or death.  The date of 
second progression will be recorded by the Investigator in the eCRF and defined according to 
local standard clinical practice and may involve any of the following: objective radiological 
imaging, symptomatic progression, or death.  Second progression status will be reviewed 
(every 6 weeks for the first 48 weeks relative to the date of randomization and then every 
8 weeks thereafter) following the progression event used for the primary variable PFS (the 
first progression) and status recorded.  Patients alive and for whom a second disease 
progression has not been observed should be censored at the last time known to be alive and 
without a second disease progression, that is, censored at the latest of the PFS or PFS2 
assessment date if the patient has not had a second progression or death.
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
Best objective response (BoR) is calculated based on the overall visit responses from each 
RECIST 1.1 assessment, described in 
  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 
 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.
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For patients who die with no evaluable RECIST 1.1assessments, if the death occurs ≤90 days 
(ie, 2*(6 weeks ±3 days)) after randomization, then BoR will be assigned to the progression 
(PD) category.  For patients who die with no evaluable RECIST 1.1assessments, if the death 
occurs >90 days (ie, 2*(6 weeks ±3 days)) after the date of randomization then BoR will be 
assigned to the NE category.
Progression events that have been censored due to them being >90 days after the last 
evaluable assessment will not contribute to the BoR derivation.  
8.4.3
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 of MEDI4736 + tremelimumab combination therapy or MEDI4736 
monotherapy, or within 30 days of the last dose of SoC) may be included in the AE 
summaries, but the majority of those summaries will omit those AEs observed after a patient 
has received further therapy for cancer.  Further details will be provided in the SAP.  Any 
events in this period that occur after a patient has received further therapy for cancer 
(following discontinuation of IP) will be flagged in the data listings.
A separate data listing of AEs occurring more than 90 days after discontinuation of 
MEDI4736 + tremelimumab combination therapy or MEDI4736 monotherapy, or more than 
30 days after discontinuation of SoC 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 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.  

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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)] x 0.02)
The denominator used in laboratory summaries will only include evaluable patients, in other 
words those who had sufficient data to have the possibility of an abnormality.  
For example:
!
If a CTCAE criterion involves a change from baseline, evaluable patients would 
have both a pre-dose and at least 1 post-dose value recorded
!
If a CTCAE criterion does not consider changes from baseline, to be evaluable the 
patient need only have 1 post dose-value recorded.
The denominator in vital signs data should include only those patients with recorded data.
8.4.4
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 positive25% and PD-L1 positive1% 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.
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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? 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 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.  
 
 
 
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.  
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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 sute-specific 
pain), treatment-related side effects (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: 

Dyspnoea (multi-item scale based on three questions: “Were you short of breath when 
you rested; walked; climbed stairs”) LC13,

Cough: one item (“How much did you cough?”), LC13

Pain: three individual items (“Have you had pain in your chest; your arm or shoulder; 
other parts of your body?”). LC13

Appetite Loss (“ Have you lacked appetite?”) C30

Fatigue (“Have you felt weak?”, “Did you need to rest?” “Were you tired?”) C30
The dyspnea scale is only 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 a 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.  

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8.4.5
Calculation or derivation of pharmacokinetic variables
8.4.5.1
Population pharmacokinetics and exposure-response/safety analysis
A population PK model will be developed using a non-linear mixed-effects modeling 
approach.  The impact of physiologically-relevant patient characteristics (covariates) and 
disease on PK will be evaluated. 
 
 The results of such an analysis will be 
reported in a separate report.  The PK, pharmacodynamic, demographic, safety, and efficacy 
data collected in this study may also be combined with similar data from other studies and 
explored using population PK and/or PK-pharmacodynamic methods.
8.4.5.2
Pharmacokinetic non-compartmental 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.  PK parameters will 
be determined using standard non-compartmental methods.  
 
 
  Samples below the lower limit of quantification will be treated as missing in the 
analyses.
8.4.5.3
Immunogenicity analysis
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADAs against MEDI4736 and tremelimumab.  
The immunogenicity titer and presence of neutralizing ADAs will be reported for samples 
confirmed positive for the presence of ADAs.  
 
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8.4.6
Calculation or derivation of biomarker variables
Biomarker status, as defined in the secondary objectives, will be assessed according to 
pre-specified criteria that will be detailed in the SAP.
8.5
Methods for statistical analyses
The formal statistical analysis will be performed to test the main hypotheses: 
!
H0: No difference between MEDI4736 + tremelimumab and SoC
!
H1: Difference between MEDI4736 + tremelimumab and SoC
The co-primary endpoints are OS and PFS in patients with PD-L1 positive25% tumors (with 
PFS using BICR assessments per RECIST 1.1) .  The study has been sized to characterize the 
OS and PFS benefits of MEDI4736 + tremelimumab versus SoC in patients with PD-L1 
positive25% and OS  benefit of MEDI4736 monotherapy versus SoC in patients with PD-L1 
positive25% tumors.  
The primary PFS analysis for superiority will be performed when both of the following 
conditions have been met: 
!
Approximately 231 BICR PFS events have occurred across the MEDI4736 + 
tremelimumab and SoC treatment groups in patients with PD-L1 positive25% tumors 
(72% maturity) AND
!
 to the study
The final (primary) OS analysis for superiority will be performed when the following 
conditions have been met: 
!
Approximately 225 OS events have occurred across the MEDI4736 + 
tremelimumab and SoC treatment groups in patients with PD-L1 positive25%  
tumors (70% maturity) AND
!
Approximately 225 OS events have occurred across the MEDI4736 monotherapy 
and SoC treatment groups in patients with PD-L1 positive25%  tumors (70% 
maturity)
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment group.  Continuous variables will be summarized by the number of observations, 
mean, standard deviation, median, minimum, and maximum.  Categorical variables will be 
summarized by frequency counts and percentages for each category.  Unless otherwise stated, 
percentages will be calculated out of the population total for the corresponding treatment 
group. 
Baseline will be the last assessment of the variable under consideration prior to the intake of 
the first dose of IP, except for efficacy variables.  For efficacy variables, baseline is defined as 
the last visit prior to randomization.
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All data collected will be listed.  Efficacy and PRO data will be summarized and analyzed 
based on the FAS, the PD-L1 positive25% and PD-L1 positive1%  analysis sets.  PK data will be 
summarized and analyzed based on the PK Analysis Set.  Safety data will be summarized on 
the Safety Analysis Set.
All outputs will be summarized by treatment group for all randomized patients (ITT) and for 
all randomized patients in the PD-L1 positive25% and PD-L1 positive1%  analysis sets, and 
where required, for all randomized patients within the PD-L1-low/negative analysis set. 
Results of all statistical analysis will be presented using appropriately sized confidence 
intervals (CIs) and 2-sided p-values, unless otherwise stated.
The following table (Table 10) details which endpoints are to be subjected to formal statistical 
analysis, together with pre-planned sensitivity analyses, making it clear which analysis is 
regarded as primary for that endpoint.  
Table 10
Pre-planned statistical and sensitivity analyses to be conducted
Endpoints analyzed
Notes
Progression-free survival
Stratified log-rank tests for:
Co-Primary analyses using BICR RECIST 1.1 assessments:
-
MEDI4736 + tremelimumab versus SoC for PD-L1 
positive25% population (stratified only for histology)
Secondary analysis using BICR RECIST 1.1 assessments: 
-
MEDI4736 monotherapy versus SoC for PD-L1positive25%
population (stratified only for histology)
-
MEDI4736 + tremelimumab versus SoC for PD-L1 
positive1% population MEDI4736 + tremelimumab versus 
SoC (ITT population)
-
-
-
MEDI4736 + tremelimumab versus MEDI4736 
monotherapy (ITT population)
-
MEDI4736 + tremelimumab versus MEDI4736 
monotherapy for PD-L1 positive25%, population (stratified 
only for histology)
Sensitivity analyses using Investigator assessments (RECIST 1.1)
Sensitivity analysis based on RECIST 1.1 modified for confirmation 
of progression using BICR assessments 
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Endpoints analyzed
Notes
Overall survival
Stratified log-rank tests for:
Co-primary analysis
-
: MEDI4736 + tremelimumab versus SoC for PD-L1 
positive25% population (stratified only for histology)
-
MEDI4736 monotherapy versus SoC for PD-L1 positive25%
population (stratified only for histology)
Secondary analysis: 
-
MEDI4736 + tremelimumab versus SoC for PD-L1 
positive1%  population MEDI4736 + tremelimumab versus 
SoC ITT population)
-
MEDI4736 + tremelimumab versus MEDI4736 
monotherapy (ITT population)
-
MEDI4736 + tremelimumab versus MEDI4736 
monotherapy for PD-L1 positive25%, population (stratified 
only for histology)
Objective response rate
Logistic regression for:
Secondary analysis for the ITT, PD-L1 positive25%, PD-L1 
positive1%, populations using BICR RECIST 1.1 assessments
 
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 co-primary endpoints (PFS, OS), analysis 
populations (ITT, PD-L1 positive25% and PD-L1 positive1%, and treatment regimens 
(MEDI4736 + tremelimumab, MEDI4736 monotherapy, and SoC).  If the higher level 
hypothesis in the MTP is rejected for superiority, the following hypothesis will then be tested 
as shown in Figure 5.
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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 5. According to alpha (test mass) splitting and alpha 
recycling, the test mass that becomes available after each rejected hypothesis is recycled to 
secondary hypotheses not yet rejected.   Since OS is tested at multiple timepoints (ie, 2 interim 
analyses and final analysis), the OS tests that for the same comparison/population (ie, shown 
in 1 box in the MTP) will be considered as 1 test family. As long as one test in the family can 
be rejected, the family is rejected thus the assigned total alpha to the family can be recycled to 
next MTP level.  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 key hypotheses.  
Figure 5 shows the multiple testing framework.
The details on the alpha-exhaustive recycling procedure will be provided in the Statistical 
Analysis Plan.
The co-primary endpoint OS is tested at 2 interim and a final timepoint.  The alpha level 
allocated to OS will be controlled at the interim and primary time points by using 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.  The first OS interim analysis for superiority will occur at the primary 
PFS analysis, when it is expected that approximately 68% of the target death events may 
occur.  
The second OS interim will subsequently be performed at approximately 80% of the target 
death events, with the primary OS analysis performed when 225 deaths have accumulated.  If 
exactly 68% and 80% of the target events in the PD-L1 positive25% patients are available at the 
time of the first and second interims analyses, respectively (ie, 152/225 and 180/225 deaths 
have occurred), with overall 2-sided alpha levels of 0.015 and 0.03 respectively for the 
comparisons of MEDi4736 + tremelimumab versus SoC MEDi4736 monotherapy versus SoC 
, the 2-sided alpha level to be applied for the interim and final analyses would be 
0.0023,0.0049 and 0.0132 for the comparison of MEDi4736 + tremelimumab versus SoC and 
0.0062,0.0113 and 0.0258 for the comparison of MEDi4736 monotherapy versus SoC.
If the interim or final analyses indicate superiority in OS for either monotherapy or 
combination therapy in PD-L1 positive25%, then subsequent analyses of secondary OS 
endpoints will be performed in accordance with the hierarchical testing strategy. A separate 
Lan DeMets (O’Brien Fleming) spending function will be used to determine the alpha levels 
at the interim and final analyses for testing the PD-L1 positive1% and the all-comers 
hypotheses.
If the interim results do not meet the criterion of stopping for superiority for a given 
hypothesis, then follow-up will continue until the final target number of OS 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. The above testing 

Clinical Study Protocol
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procedure will ensure strong control of the family-wise error rate (Glimm et al, 2010). 
Additional details of the multiple testing procedure will be provided in the statsistical analysis 
plan.
Figure 5
Multiple testing procedures for controlling the type 1 error rate
Combo  MEDI4736 + tremelimumab combination therapy; Mono  MEDI4736 monotherapy; SoC  Standard of care.
8.5.1
Analysis of the co-primary endpoints
8.5.1.1
Progression-free survival
The co-primary PFS analyses will be based on the programmatically derived RECIST 1.1 
using the BICR tumor assessments.  The co-primary analysis performed in the PD-L1 
positive25%,  population uses a stratified log-rank test adjusting for histology (squamous versus 
non-squamous) only.  The effect of MEDI4736 + tremelimumab versus SoC treatment will be 
estimated by the HR together with its corresponding 99.5% 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, except in cases where the secondary analyses are 

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performed on the FAS or PD-L1 positive1% population, in which case the stratification will 
also adjust for PD-L1 status (≥25%, <25%).
Kaplan-Meier plots of PFS will be presented by treatment group, and by treatment group and 
PD-L1 tumor status subgroup, where appropriate.  Summaries of the number and percentage 
of 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.
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
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!
 
 
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.  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.
 
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 factor.  These 
will be presented on a forest plot including the HR and 95% CI.  
If there are too few events available for a meaningful analysis of a particular subgroup (it is 
not considered appropriate to present 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.
8.5.1.2
Overall survival
Co-primary OS in the PD-L1 positive25% population will be analyzed using a stratified 
log-rank tests, using the same methodology as described for the co-primary PFS endpoint.  
The effect of MEDI4736 + tremelimumab versus SoC and MEDI4736 monotherapy versus 
SoC will be estimated by the HR together with its corresponding two-sided CI (98.5% for 
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MEDI4736 + tremelimumab versus SoC and 97% for MEDI4736 monotherapy versus SoC, 
adjusted for two interim analyses) and p-value.  Kaplan-Meier plots will be presented by 
treatment group.  Summaries of the number and percentage of patients who have died, those 
still in survival follow-up, those lost to follow-up, and those who have withdrawn consent will 
be provided along with the median 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 8.28.2).
Subgroup analyses will be conducted, as deemed appropriate, in the PD-L1 positive25%
analysis set comparing OS between MEDI4736 + tremelimumab versus SoC and MEDI4736 
monotherapy versus SoC and in the  PD-L1 positive1% analysis set comparing OS between 
MEDI4736 + tremelimumab versus SoC using the same subgroups as specified for PFS.  
Similar subgroup analyses will be performed in the FAS for the comparison between 
MEDI4736 + tremelimumab versus SoC as deemed appropriate.
Impact of switching (crossover outside of this study) to immunotherapies (or other potentially 
active investigational agents) on OS analyses
 
 
 
  The decision to adjust and the final choice of methods will be based on a blinded 
review of the data and the plausibility of the underlying assumptions.  
 
 
8.5.2
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 MEDI4736 + tremelimumab versus SoC using 
logistic regression models adjusting for the same factors as the primary endpoint (PD-L1 
tumor expression and histology, as appropriate).  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 PD-L1 positive25%, PD-L1 positive1% and ITT
populations..  The analysis of the PD-L1 subgroup patients will be performed using a logistic 
regression model adjusting for only histology.
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.
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ORR by irRECIST 1.1 criteria using BICR assessments will also be reported in the ITT 
population.  
Summaries will be produced that present the number and percentage of patients with a tumor 
response (CR/PR).  Overall visit response data will be listed for all patients.  For each 
treatment group, 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.
8.5.3
Duration of response
In order to analyze the DoR between MEDI4736 + tremelimumab and SoC, the expected 
duration of response (EDoR) will be derived for each treatment group (Ellis et al 2008) using 
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. 
 
 Additionally, descriptive data will be provided for the DoR in responding patients, 
including the associated Kaplan-Meier curves (without any formal comparison of treatment 
groups or p-value attached).  This analysis will be performed in the PD-L1 positive25%, PD-L1 
positive1% and ITT populations.
8.5.4
Proportion of patients alive and progression free at 12 months
The APF12 will be summarized (using the Kaplan-Meier curve) and presented by treatment 
group.  APF12 will be compared between MEDI4736 + tremelimumab and SoC by using the 
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This analysis will be performed in the PD-L1 positive25%, PD-L1 positive1% and ITT
populations.
8.5.5
Time from randomization to second progression
PFS2 is 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.  PFS2 in the ITT population will 
be analyzed using a stratified log-rank tests, using the same methodology as described for the 
primary PFS endpoint.  The effect of MEDI4736 + tremelimumab versus SoC will be 
estimated by the HR together with its corresponding CI and p-value.  Kaplan-Meier plots will 
be presented by treatment group.  Summaries of the number and percentage of patients who 
have an event as well as who were censored will be provided along with the medians for each 
treatment.
 
 
 
 
 
A summary table of first subsequent therapies by treatment group will be provided, as well as 
response to first subsequent therapy by treatment group.
This analysis will be performed in the PD-L1 positive25%, PD-L1 positive1% and ITT 
populations.
8.5.6
Patient reported outcomes
8.5.6.1
EORTC QLQ-C30
Time to deterioration in the PD-L1 positive25%, PD-L1 positive1% and ITT populations will be 
analyzed using a stratified log-rank test, using the same methodology as described for the 
primary PFS endpoint.
The effect of MEDI4736 + tremelimumab versus SoC will be estimated by the HR together 
with its corresponding CI and p-value.  Kaplan-Meier plots will be presented by treatment 
group.  Summaries of the number and percentage of patients who have an event as well as 
who were censored will be provided along with the medians for each treatment.
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.  
Summaries of original and 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 
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group.  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 (in terms of the proportion of patients in the categories of improvement, no change, and 
deterioration as defined in Section 8.4.4.1 will also be produced for each treatment group. 
8.5.6.2
EORTC QLQ-LC13
Time to deterioration in the PD-L1 positive25%, PD-L1 positive1% and ITT populations will be 
analyzed using a stratified log-rank test, using the same methodology as described for the 
primary PFS endpoint.
The effect of MEDI4736 + tremelimumab versus SoC will be estimated by the HR together 
with its corresponding CI and p-value.  Kaplan-Meier plots will be presented by treatment 
group.  Summaries of the number and percentage of patients who have an event as well as 
who were censored will be provided along with the medians for each treatment.
A summary of the symptom improvement rate for each of the 6 individual symptom items will 
be produced.  
Summaries of original and change from baseline values of each symptom (dyspnea, cough, 
hemoptysis, chest pain, arm/shoulder pain, other pain) and each treatment-related side effect 
(sore mouth, dysphagia, peripheral neuropathy and alopecia) will be reported by visit for each 
treatment group.  Graphical presentations may also be produced as appropriate.  Summaries of 
the number and percentage of patients in each response category at each visit for each ordinal 
symptom item (in terms of the proportion of patients in the categories of improvement, no 
change, and deterioration as defined in Section 8.4.4.2) will also be produced for each 
treatment group.  
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.
 
 
 
 
 
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8.5.8
Safety data
Safety and tolerability data will be presented by treatment group using the safety population.
Data from all cycles of treatment will be combined in the presentation of safety data.  AEs 
(both in terms of MedDRA preferred terms and CTCAE grade) will be listed individually by 
patient.  The number of patients experiencing each AE will be summarized by treatment group 
and CTCAE grade.  Additionally, data presentations of the rate of AEs per person-years at risk 
may be produced.  Any safety summaries examining retreatment with MEDI4736 + 
tremelimumab 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 MEDI4736 + tremelimumab, MEDI4736 
monotherapy, and SoC will be summarized.  Time on study, MEDI4736 + tremelimumab, 
MEDI4736 monotherapy, and SoC, dose delays/interruptions and dose reductions will also be 
summarized.  At the end of the study, appropriate summaries of all safety data will be 
produced, as defined in the SAP. 
8.5.9
Pharmacokinetic data
PK concentration data will be listed for each patient and each dosing day, and a summary 
provided for all evaluable patients in the PK analysis population.
8.5.10
Immunogenicity analysis
Immunogenicity results will be listed by patient and a summary will be provided of the 
number and percentage of patients who develop detectable anti-MEDI4736 and 
anti-tremelimumab antibodies.  The immunogenicity titer and neutralizing ADA data will be 
listed for samples confirmed positive for the presence of anti-MEDI4736 and anti-
tremelimumab antibodies.  
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The effect of immunogenicity on PK, pharmacodynamics, efficacy and safety will be 
evaluated if data allow.
8.5.11
Pharmacokinetic/Pharmacodynamic relationships
 
8.5.12
Biomarker data
 
 
8.5.13
Interim analysis
Interim monitoring for safety will be conducted by the IDMC.  Details of the plan and 
communication process will be provided in the statistical analysis plan and the IDMC charter.  
In addition, two OS interim analyses will be performed for superiority; the first one at the time 
of the primary PFS analysis and the second one when approximately 80% of the final number 
of deaths has been reached.  These analyses will be performed by an IDMC.
The Lan DeMets spending function that approximates an O’Brien Fleming approach will be 
used to account for multiplicity introduced by including the 2 interim analyses for superiority 
(Lan and DeMets 1983). 
 
 
 
 
 
 
 
 
 
 
 
If the interim analyses indicate superiority in the PD-L1 positive25% population, then 
subsequent analyses of the further secondary endpoints will be performed in accordance with 
the hierarchical multiple testing strategy.
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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 electronic PRO 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 the location of source data.

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9.2.2
Direct access to source data in Japan
The Head of the study site and the Principal Investigator/Investigator will cooperate for 
monitoring and audit by AstraZeneca and accept inspection by the IRB or regulatory 
authorities. All study documents such as raw data will be open for direct access to source data 
at the request of the monitor and the auditor of AstraZeneca, the IRB, or regulatory 
authorities.
The monitor will verify data from the eCRFs against source data before the Principal 
Investigator signs the eCRFs to ensure accuracy and completeness of documentation and 
ensure that the Principal Investigator has submitted the eCRFs to AstraZeneca.
9.2.3
Study agreements
The Principal Investigator at each center should comply with all the terms, conditions, and 
obligations of the CSA for this study.  In the event of any inconsistency between this clinical 
study protocol and the CSA, the terms of clinical study protocol shall prevail with respect to 
the conduct of the study and the treatment of patients.  In all other respects not relating to 
study conduct or treatment of patients, the terms of the CSA shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place or before any patients are enrolled.
9.2.4
Archiving of study documents
The Investigator will follow the principles outlined in the CSA.
9.3
Study timetable and end of study
The end of the study is defined as the “last visit of the last patient undergoing the study.”  The 
Investigator will be notified by AstraZeneca when recruitment is complete.
The study is expected to start in Q3 2015 and end by Q2 2018.  
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP) or if recruitment is slow.  AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study involving MEDI4736.
9.4
Data management by AstraZeneca or delegate
Data management will be performed by a chosen vendor according to the Data Management 
Plan.  AEs and medical/surgical history will be classified according to the terminology of the 
latest version of MedDRA.  Medications will be classified according to the AstraZeneca Drug 
Dictionary.  Classification coding will be performed by the chosen vendor.
The data collected through third party sources will be obtained and reconciled against study 
data.

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Data queries will be raised for inconsistent, impossible, or missing data.  All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.
When all data have been coded, validated, signed, and locked, a clean file will be declared.  
Any treatment-revealing data may be added thereafter, and the final database will be locked.
Serious adverse event reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
Data management of genotype data
Any genotype data generated in this study will be stored in the AstraZeneca genotyping 
database or other appropriate secure system within AstraZeneca and/or a third party 
contracted to work with AstraZeneca to analyze samples.  The results from this genetic 
research may be reported in the CSR for the main study or in a separate report, as appropriate.
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Data associated with human biological samples
Data associated with human biological samples will be transferred from laboratories internal 
or external to AstraZeneca.

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10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation
(ICH)/GCP, applicable regulatory requirements, and the AstraZeneca policy on Bioethics and 
Human Biological Samples.  The applicable regulatory requirements in Japan are “Good 
Clinical Practice for Trials on Drugs” (Ministry of Health, Labor, and Welfare [MHLW] 
Ordinance No. 28, 27 March 1997, partially revised by MHLW Ordinance and their related 
notifications).
10.2
Patient data protection
The ICF will incorporate wording that complies with relevant data protection and privacy 
legislation.  In some cases, such wording will be in a separate accompanying document.
AstraZeneca will not provide individual genotype results to patients, their family members, 
their general physician, any insurance company, any employer, or any other third party, unless 
required to do so by law.
Precautions are taken to preserve confidentiality and prevent genetic data from being linked to 
the identity of the patient.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient.  For example, in the case of 
a medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and might also have access to his or her genetic data.  Also, regulatory authorities 
may require access to the relevant files.  Even so, the patient’s medical information and the 
genetic files would remain physically separate.
10.3
Ethics and regulatory review
An EC/IRB should approve the final study protocol, including the final version of the ICF and 
any other written information and/or materials to be provided to the patients.  The Investigator 
will ensure the distribution of these documents to the applicable EC/IRB and to the study site 
staff.
The opinion of the EC/IRB should be given in writing.  The Investigator should submit the 
written approval to AstraZeneca before enrollment of any patient into the study. 
The EC/IRB should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the EC/IRB annually.

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Before enrollment of any patient into the study, the final study protocol, including the final 
version of the ICF, should be approved by the national regulatory authority or a notification to 
the national regulatory authority should be approved, according to local regulations.
AstraZeneca will handle the distribution of these documents to the national regulatory 
authorities.
AstraZeneca will provide regulatory authorities, ECs/IRBs, and Principal Investigators safety 
updates or reports according to local requirements.
Each Principal Investigator is responsible for providing the EC/IRB with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the IP.  
AstraZeneca will provide this information to the Principal Investigator so that he/she can meet 
these reporting requirements.
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

Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided

Ensure that each patient provides a signed and dated informed consent before 
conducting any procedure specifically for the study

Ensure that the original, signed ICF(s) is/are stored in the Investigator’s Study File

Ensure that a copy of the signed ICF is given to the patient

Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the ICF that is approved by an EC/IRB.
For sites in Japan only
If any new information on the study medication becomes available that may influence the 
decision of the patient to continue the study, the Investigator should inform the patient of such 
information immediately, record this in a written form, and confirm with the patient if he or 
she wishes to continue the participation in the study.  In addition, if the Investigator deems it 
necessary to revise the ICF, he or she should revise it immediately (refer to Section 10.5).  

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The Investigator should re-explain to the patients using the updated ICF even if the patients
have already been informed of the new information verbally.  Written informed consent to 
continue participation in the study should be provided separately.
10.5
Changes to the protocol and informed consent form
For sites outside Japan
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and, where required, in a new version of the study 
protocol (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.
10.6
Audits and inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an EC/IRB may perform 
audits or inspections at the center, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and to determine if data 
were recorded, analyzed, and accurately reported according to the protocol, GCPs, ICH 
guidelines, and any applicable regulatory requirements.  The Investigator will contact 
AstraZeneca immediately if contacted by a regulatory agency about an inspection at the 
center.

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11.
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D419AC00001 Clinical Study Protocol Version 8
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