A Randomized, Phase 3 Trial With Anti-PD-1 Monoclonal Antibody Pembrolizumab (MK-3475) Versus Placebo for Patients With Early Stage NSCLC After Resection and Completion of Standard Adjuvant Therapy (PEARLS)
Phase: PHASE3
Conditions: Non-small Cell Lung Cancer
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A randomized, phase 3 trial with anti-PD-1 
monoclonal antibody pembrolizumab (MK-3475) 
versus placebo for patients with early stage 
NSCLC after resection and completion of 
standard adjuvant
NCT02504372
23 September 2022

Intergroup Study (EORTC-1416-LCG)
Merck Sharp & Dohme LLC protocol MK-3475-091-05
(EudraCT number 2015-000575-27)
(NCT02504372)
A randomized, phase 3 trial with anti-PD-1 monoclonal 
antibody pembrolizumab (MK-3475) versus placebo for 
patients with early stage NSCLC after resection and 
completion of standard adjuvant therapy (PEARLS)
KEYNOTE-091
Coordinating Group: EORTC Lung Cancer Group
Collaborative Groups: ETOP
EORTC Study Coordinator:
ETOP Study Coordinator:
Protocol
version
Date of PRC
approval/notification
Amendment reference
N°
Classification
Outline
Amended
December 02, 2014
April 10, 2015
----
----
1.0
April 23, 2015
----
----
2.0
December 2, 2016
3
Scientific
3.0
August 14, 2018
8
Scientific
4.0
June 15, 2020
13
Scientific
4.1
June 20, 2022
15
Administrative
5.0
September 23, 2022
16
Scientific
EORTC v5.0/ MK-3475-091-05
©Copyright EORTC 2022
EORTC
Avenue E. Mounierlaan 83/11
Brussel 1200 Bruxelles
België – Belgique
www.eortc.org
PPD
PPD
PPD
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Study Coordinators: 
EORTC 
(Coordinating 
Group):  
ETOP: 
Steering Committee: 
Study Coordinators from each participating group and 
representative person from the coordinating group (see 
Section 9.2)  
Writing Committee: 
PPD
PPD
PPD
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Contact addresses for EORTC 
Study Coordinator: 
Clinical Research Physician: 
Clinical Operations Manager: 
Clinical Data Manager: 
Statistician: 
Pharmacovigilance Unit: 
PPD
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Contact addresses for ETOP 
 
Study Coordinator: 
ETOP Scientific Coordinator: 
ETOP President: 
ETOP Statistician: 
ETOP Director: 
Contact addresses for TR: 
 
PPD
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Sponsor signatory page 
Protocol 1416-LCG 
Sponsor: 
___________________________________________________ 
__________________ 
 
 
 
 
(Date) 
Director, Oncology Clinical Research 
Merck Sharp & Dohme LLC 
126 East Lincoln Avenue 
P.O. Box 2000 
Rahway, NJ 07065 USA 
___________________________________________________ 
__________________ 
 
(Date) 
Merck Sharp & Dohme LLC 
126 East Lincoln Avenue 
P.O. Box 2000 
Rahway, NJ 07065 USA 
Study Coordinator: 
___________________________________________________ 
__________________ 
(Date) 
Royal Marsden Hospital 
Downs Road 
GB Sutton (Surrey) SM2 5PT 
United Kingdom 

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______________________
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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Investigator 
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol). I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice. I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events as 
defined in Chapter 16. I also agree to handle all clinical supplies provided by the Sponsor and 
collect and handle all clinical specimens in accordance with the protocol. I understand that 
information that identifies me will be used and disclosed as described in the protocol, and 
that such information may be transferred to countries that do not have laws protecting such 
information. Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited. I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties 
__________________________________ _________________ __________________ 
Investigator’s full name (in capitals)  
(Signature) 
 
(Date) 
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Table of contents
Protocol summary ................................................................................................................... 15
Trial organization.................................................................................................................... 27
1
Background and introduction.......................................................................................... 28
1.1
Early stage Non Small Cell Lung Cancer............................................................... 28
1.2
Adjuvant chemotherapy for early stage NSCLC .................................................... 29
1.3
Background data for Anti- PD1 and PDL1............................................................. 31
1.4
Checkpoint inhibitors.............................................................................................. 32
1.5
Pembrolizumab characteristics and clinical data overview .................................... 33
1.5.1
Preclinical studies ........................................................................................... 33
1.5.2
Clinical studies................................................................................................ 34
Phase I studies............................................................................................. 34
Phase II and III studies................................................................................ 36
1.6
Rationale ................................................................................................................. 38
2
Objectives of the trial...................................................................................................... 39
2.1
Primary/dual-primary objectives ............................................................................ 39
2.2
Secondary objectives .............................................................................................. 39
2.3
Exploratory Objectives ........................................................................................... 39
2.4
End-points............................................................................................................... 40
2.4.1
Primary/dual-primary endpoints ..................................................................... 40
2.4.2
Secondary endpoints ....................................................................................... 40
2.4.3
Exploratory endpoints..................................................................................... 40
3
Patient selection criteria.................................................................................................. 40
3.1
Registration - step 1 (ORTA step 1) ....................................................................... 41
3.1.1
Disease status.................................................................................................. 41
3.1.2
Patient status ................................................................................................... 42
3.2
Central confirmation of PD-L1 status - step 2........................................................ 42
3.3
Randomization - step 3 (ORTA step 2) .................................................................. 42
3.3.1
Disease status.................................................................................................. 42
3.3.2
Patient status ................................................................................................... 42
4
Trial Design .................................................................................................................... 45
4.1
Multi step process for enrollment ........................................................................... 46
4.1.1
Registration - step 1 (ORTA step 1) ............................................................... 46
4.1.2
Central confirmation of PD-L1 status - step 2................................................ 46
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4.1.3
Randomization - step 3 (ORTA step 2) .......................................................... 46
4.2
Unblinding data....................................................................................................... 48
5
Therapeutic regimens, expected toxicity, dose modifications........................................ 48
5.1
Placebo.................................................................................................................... 48
5.2
Pembrolizumab (MK-3475).................................................................................... 48
5.2.1
Selected dose................................................................................................... 48
5.3
Drug supply............................................................................................................. 49
5.3.1
Placebo............................................................................................................ 49
5.3.2
Pembrolizumab ............................................................................................... 49
Initial drug supply....................................................................................... 49
Drug resupply by IVRS .............................................................................. 49
5.3.3
Packaging, labeling, handling and storage...................................................... 50
Packaging.................................................................................................... 50
Labeling ...................................................................................................... 50
Dosage and Administration......................................................................... 50
Storage ........................................................................................................ 50
5.3.4
Drug accountability......................................................................................... 50
5.3.5
Return of investigational product.................................................................... 50
5.3.6
Destruction of investigational product............................................................ 51
5.3.7
Standard Policies............................................................................................. 51
5.4
Treatment schedule ................................................................................................. 51
5.5
Treatment duration.................................................................................................. 51
5.6
Subject Withdrawal/Discontinuation Criteria......................................................... 51
5.7
Management of toxicity .......................................................................................... 52
5.8
Concomitant medications........................................................................................ 52
5.8.1
Prohibited medications.................................................................................... 52
6
Clinical evaluation, laboratory tests and follow-up ........................................................ 53
6.1
General Considerations........................................................................................... 53
6.1.1
Subject Identification Card ............................................................................. 53
6.2
Before treatment start.............................................................................................. 54
6.2.1
Within 12 weeks prior to randomization ........................................................ 54
6.2.2
Within 10 days prior to treatment initiation.................................................... 55
6.2.3
Within 72 hours prior to treatment initiation .................................................. 55
6.2.4
Within 24 hours prior to treatment initiation .................................................. 55
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6.3
During treatment ..................................................................................................... 55
6.3.1
Every 3 weeks (+/- 3 days) ............................................................................. 57
6.3.2
Every 6 weeks (+/- 3 days) ............................................................................. 57
6.3.3
Every 12 weeks (+/- 3 days) ........................................................................... 57
6.3.4
Every 12 weeks (+/- 2 weeks) starting from the day of first infusion (visit 1) 
and until disease recurrence............................................................................................ 58
6.4
End of Treatment .................................................................................................... 58
6.5
Translational research ............................................................................................. 59
6.6
Pharmacokinetic and anti-pembrolizumab antibody .............................................. 59
6.7
Follow-up................................................................................................................ 59
6.7.1
In case of early discontinuation prior to first infusion.................................... 59
6.7.2
Follow-up in the absence of disease recurrence ............................................. 59
Imaging work-up......................................................................................... 60
For other tests/investigations/questionnaires .............................................. 60
6.7.3
Follow-up after disease recurrence ................................................................. 61
6.7.4
Survival Follow-up ......................................................................................... 62
Survival Sweep ........................................................................................... 62
6.8
Summary tables....................................................................................................... 63
6.8.1
Treatment schedule before and during treatment............................................ 63
6.8.2
End of Treatment Schedule and Follow up Overview.................................... 65
6.8.3
PK/ADA and Translational Research ............................................................. 67
7
Criteria of evaluation ...................................................................................................... 69
7.1
Evaluation of efficacy............................................................................................. 69
7.1.1
Assessment of tumor lesions........................................................................... 69
Methods of assessment ............................................................................... 69
Frequency of tumor re-evaluation............................................................... 70
Date of recurrence....................................................................................... 70
7.1.2
Disease free survival (DFS)............................................................................ 70
7.1.3
Overall survival (OS)...................................................................................... 70
7.1.4
Lung Cancer Specific Survival (LCSS).......................................................... 71
7.2
Evaluation of safety ................................................................................................ 71
7.2.1
Adverse events................................................................................................ 71
7.2.2
General evaluation of adverse events ............................................................. 71
7.2.3
Serious adverse events .................................................................................... 71
7.2.4
Toxic deaths.................................................................................................... 71
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7.2.5
Evaluability for safety..................................................................................... 72
8
Statistical considerations................................................................................................. 72
8.1
Statistical design ..................................................................................................... 72
8.1.1
Sample size considerations ............................................................................. 72
8.1.2
Randomization and stratifications................................................................... 77
8.2
Statistical analysis plan........................................................................................... 77
8.2.1
Primary/dual-primary and secondary endpoints ............................................. 77
8.2.2
Analysis populations....................................................................................... 77
8.2.3
Statistical methods .......................................................................................... 77
Efficacy endpoints ...................................................................................... 77
Toxicity....................................................................................................... 80
Multiplicity ................................................................................................. 80
8.2.4
Pre-planned sensitivity or exploratory analyses ............................................. 81
8.2.5
Prognostic factor analyses............................................................................... 82
8.2.6
Data recoding and display............................................................................... 82
8.3
Interim analyses ...................................................................................................... 83
8.4
End of study ............................................................................................................ 84
9
Trial Governance and Oversight..................................................................................... 84
9.1
Scientific Advisory Committee............................................................................... 84
9.2
Trial Steering Committee........................................................................................ 84
9.3
Executive Oversight Committee............................................................................. 85
9.4
Data Monitoring Committee................................................................................... 85
10
Quality of life assessment ............................................................................................... 86
10.1
Rationale ................................................................................................................. 86
10.2
Objective................................................................................................................. 86
10.3
HRQoL instruments................................................................................................ 86
10.4
Study design............................................................................................................ 87
10.4.1
HRQoL schedule............................................................................................. 88
10.5
Statistical considerations......................................................................................... 88
10.5.1
Missing data.................................................................................................... 89
10.5.2
Other exploratory analyses ............................................................................. 89
10.6
EQ-5D instrument................................................................................................... 90
11
Translational research ..................................................................................................... 90
11.1
Objectives ............................................................................................................... 91
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11.1.1 
Immune landscape .......................................................................................... 91 
11.1.2 
TCR sequencing .............................................................................................. 92 
11.1.3 
Antitumoral cellular immune responses ......................................................... 92 
11.1.4 
Antitumoral humoral immune responses ........................................................ 93 
11.1.5 
Serum biomarkers measurements ................................................................... 93 
11.2 
Summary of sample collection ................................................................................ 94 
11.3 
Statistical considerations ......................................................................................... 96 
11.4 
Data storage, transfer and development of technical appendices ........................... 97 
11.5 
General principles for human biological material (HBM) collection ..................... 97 
12 Pharmacokinetic/Pharmacodynamic Evaluations ........................................................... 99 
12.1 
Timepoints .............................................................................................................. 99 
12.2 
PK Blood Collection for Serum MK-3475 ............................................................. 99 
12.3 
Blood Collection for Anti-Pembrolizumab Antibodies .......................................... 99 
13 Investigator authorization procedure .............................................................................. 99 
14 Patient registration & randomization procedures ......................................................... 100 
14.1 
General procedure ................................................................................................. 100 
14.2 
Registration (step 1) (ORTA step 1) ..................................................................... 101 
14.3 
Central confirmation of PD-L1 status testing (step 2) .......................................... 102 
14.4 
Randomization (step 3) (ORTA step 2) ................................................................ 102 
14.5 
Stock management process ................................................................................... 103 
14.6 
Unblinding procedure ........................................................................................... 103 
14.6.1 
Emergency Unblinding ................................................................................. 103 
14.6.2 
Unblinding by Investigator Request After First Disease Recurrence ........... 104 
14.6.3 
Unblinding at final analysis .......................................................................... 104 
14.6.4 
Other unblinding during the course of the study .......................................... 104 
15 Forms and procedures for collecting data ..................................................................... 105 
15.1 
Case report forms and schedule for completion ................................................... 105 
15.2 
Data flow ............................................................................................................... 106 
16 Reporting of Adverse Events, Serious Adverse Events and Other Reportable Safety 
Events .................................................................................................................................... 107 
16.1 
Definitions ............................................................................................................. 107 
16.2 
Exceptions ............................................................................................................. 109 
16.3 
Severity assessment .............................................................................................. 110 
16.4 
Causality assessment ............................................................................................. 110 
16.5 
Expectedness assessment ...................................................................................... 110 
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16.6 
Reporting procedure for investigators .................................................................. 110 
16.7 
Reporting responsibilities of the Sponsor ............................................................. 112 
16.8 
Pregnancy reporting .............................................................................................. 113 
17 Quality assurance .......................................................................................................... 113 
17.1 
Control of data consistency ................................................................................... 113 
17.2 
Central review of Surgery/Pathology .................................................................... 113 
17.3 
Clinical site monitoring ......................................................................................... 114 
17.4 
Audits .................................................................................................................... 114 
18 Ethical considerations ................................................................................................... 114 
18.1 
Patient protection .................................................................................................. 114 
18.2 
Subject identification ............................................................................................ 115 
18.3 
Informed consent .................................................................................................. 115 
19 Administrative responsibilities ..................................................................................... 116 
19.1 
The study coordinator ........................................................................................... 116 
19.2 
The EORTC Headquarters .................................................................................... 116 
19.3 
The EORTC group ................................................................................................ 117 
20 Trial sponsorship and financing .................................................................................... 117 
21 Administrative and regulatory details ........................................................................... 117 
21.1 
Confidentiality ...................................................................................................... 117 
21.1.1 
Confidentiality of Data ................................................................................. 117 
21.1.2 
Confidentiality of Subject Records ............................................................... 118 
21.1.3 
Confidentiality of Investigator Information .................................................. 118 
21.1.4 
Confidentiality of IRB/IEC Information ....................................................... 118 
21.2 
Compliance with Financial Disclosure Requirements .......................................... 118 
21.3 
Compliance with Law, Audit and Debarment ...................................................... 119 
21.4 
Compliance with Trial Registration and Results Posting Requirements .............. 121 
21.5 
Quality Management System ................................................................................ 121 
21.6 
Data Management ................................................................................................. 121 
21.7 
Calibration of Critical Equipment ......................................................................... 121 
22 Publication policy ......................................................................................................... 122 
 
 
 
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List of tables 
Table 1. Randomized trials of adjuvant platinum-based chemotherapy ................................. 30
Table 2. Clinical development of Immune Checkpoint Inhibitors - Efficacy Data on NSCLC
 ......................................................................................................................................... 33
Table 3. Adequate Organ Function Laboratory Values .......................................................... 42
Table 4. Treatment schedule before and during treatment ..................................................... 63
Table 5. Overview end of treatment and follow up ................................................................ 65
Table 6. PK/ADA and Translational Research ....................................................................... 67
Table 7. Enrollment Pattern .................................................................................................... 72
Table 8. Interim and Final Analyses for DFS: Number of events, p-values boundaries and 
power ............................................................................................................................... 74
Table 9. Interim and Final Analyses for OS: Number of events, HR-values boundaries and 
power ............................................................................................................................... 75
Table 10. Analysis Strategy for Key Efficacy Variables ........................................................ 79
Table 11. Sample collection .................................................................................................... 94
Table 12. Maximum detectable HR with around 80% power under different scenarios for the 
immunological marker incidence. ................................................................................... 96
List of figures 
Figure 1: Trial design .............................................................................................................. 46
Figure 2: Overview schedule of test/exams ............................................................................ 57
Figure 3: Multiplicity Graph for Alpha Re-allocation Strategy .............................................. 80
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List of appendices 
Appendix A: References ....................................................................................................... 123 
Appendix B: Abbreviations .................................................................................................. 129 
Appendix C: ECOG performance status scale ...................................................................... 133 
Appendix D: Common Terminology Criteria for Adverse Events ....................................... 134 
Appendix E: EORTC Quality of Life evaluation: guidelines for administration of 
questionnaires - EORTC QLQ-C30 (version 3) - EORTC QLQ-LC13 - EQ-5D – Health 
Questionnaire ................................................................................................................ 135 
Appendix F: IASLC VII TNM staging ................................................................................. 144 
Appendix G: Guidelines for management of toxicity ........................................................... 146 
Appendix H: Supportive care ................................................................................................ 151 
Appendix I: Event Of Clinical Interest Guidance Document ............................................... 155 
Appendix J: MSD Code of Conduct for Clinical Trials ....................................................... 195 
Appendix K: Lobe-Specific Nodal Dissection ..................................................................... 199 
Appendix L: Barrier Contraception methods ........................................................................ 200 
Appendix M: Recommendation for Contraception in United Kingdom, Portugal, 
Scandinavian countries and Other Applicable Countries ............................................. 201 
Appendix N: Disease Status and primary/second endpoints derivation ............................... 203 
 
 
 
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Protocol summary 
Title of the Study 
A randomized, phase 3 trial with anti-PD-1 monoclonal antibody 
pembrolizumab (MK-3475) versus placebo for patients with early 
stage NSCLC after resection and completion of standard adjuvant 
therapy (PEARLS). 
Objective(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary/dual-primary.  
To prospectively investigate whether adjuvant treatment with 
pembrolizumab after completion of radical surgery 
(lobectomy/pneumonectomy) with or without standard adjuvant 
chemotherapy for stage IB (T ≥ 4 cm) -II-IIIA NSCLC patients 
improves Disease Free Survival (DFS), as assessed locally by the 
investigator, compared to placebo in the PD-L1 strong positive 
subgroup (TPS≥50%) or overall population.  
Note: TNM stage (according to the 7th edition of the TNM 
classification for lung cancer)  
Secondaries. 
♦ To prospectively compare DFS as assessed by the investigator in 
the PD-L1 positive population (TPS≥1%); 
♦ To prospectively determine and compare OS in the PD-L1 strong 
positive and overall population; 
♦ To prospectively determine and compare OS in the PD-L1 
positive population; 
♦ To prospectively determine and evaluate the Lung Cancer 
Specific Survival (LCSS) in the whole population irrespective of 
PD-L1 status; 
♦ To prospectively assess the safety of pembrolizumab after radical 
surgery followed by standard adjuvant chemotherapy. 
Exploratory. 
♦ To assess outcome according to stratification factors and other 
prognostic and predictive markers for NSCLC; 
♦ To evaluate these treatments in the elderly (age ≥70 years old); 
♦ To prospectively study the influence of dose and duration of 
adjuvant chemotherapy on outcome; 
♦ To prospectively assess genetic alterations and biomarkers of 
immunological pathways with outcome;  
♦ To prospectively assess DNA mutational burden and nanostring 
RNA analysis with outcome; 
♦ To prospectively assess EQ-5D health state profiles at pre-
specified time points; 
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Endpoints 
♦To prospectively assess Health-Related Quality of Life
(HRQOL);
♦To evaluate the pharmacokinetics (PK) of pembrolizumab in this
patient population to determine the pembrolizumab exposure-
response relationships for measures of effectiveness, toxicity and
pharmacodynamic biomarkers in the study population;
♦To evaluate the development of anti-drug antibodies (ADA)
against pembrolizumab (immunogenicity evaluation);
♦To assess and describe the quality assurance for surgery.
Primary/dual-primary endpoints. 
♦DFS in the PD-L1 strong positive subgroup;
♦DFS in the overall population.
Secondary endpoints.
♦DFS in the PD-L1 positive population;
♦OS in the overall population;
♦OS in the PD-L1 strong positive subgroup;
♦OS in the PD-L1 positive population;
♦LCSS in the overall population;
♦Toxicity according to CTCAE version 4.03.
Exploratory endpoints.
♦Health-Related Quality of Life (HRQOL);
♦Pharmacokinetics (PK) of pembrolizumab;
♦ADA serum titers against pembrolizumab;
♦Quality assurance for surgery;
♦Exploratory assessment of predictive biomarkers and immune
dynamics (Translational research).
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Methodology 
This is an international, triple-blinded, placebo-controlled, 
randomized phase III trial to compare pembrolizumab versus 
placebo after complete resection of stage IB (T ≥ 4 cm), II and IIIA 
NSCLC, followed by standard adjuvant chemotherapy, where 
appropriate as per relevant local guidelines, in patients who have 
signed the informed consent.  
Note: TNM stage (according to the 7th edition of the TNM 
classification for lung cancer) 
Enrollment will be a multi-step process. 
A total of 1180 eligible patients will be randomized at 1:1 ratio into 
two triple blinded, treatment arms (approximately 590 patients 
each): 
♦Patients in the experimental arm will receive pembrolizumab (see
Sections 5.2 and 5.4);
♦Patients in the control arm will receive placebo (see Sections 5.1
and 5.4).
Patients not receiving adjuvant chemotherapy must be randomized 
and dosed with pembrolizumab/placebo within 12 weeks of their 
surgery date. Participants who receive adjuvant chemotherapy must 
begin adjuvant chemotherapy within 12 weeks of the surgery date. 
Patients receiving adjuvant chemotherapy must be randomized and 
dosed with pembrolizumab/placebo at least 3 weeks but no more 
than 12 weeks from the last dose of chemotherapy (Day 1 of last 
cycle). Randomization will be performed centrally (see Chapter 15) 
and will be stratified for the following factors: 
♦Stage (IB vs II vs IIIA);
♦Adjuvant chemotherapy (no adjuvant chemotherapy versus
adjuvant chemotherapy);
♦PD-L1 (3 groups: negative (TPS=0%) versus weak positive
(TPS=1-49%) versus strong positive (TPS≥50%);
♦Region (Western Europe versus Eastern Europe versus Rest of
the world versus Asia).
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Number of 
patients 
Number planned 
(Statistical design) 
Number analyzed 
A sample size of 1180 randomized patients is planned and the 
primary analysis is based on intent to treat (all 1180 patients). 
The study is designed with 
primary/dual-primary endpoints: DFS in the whole population and 
DFS in the PD-L1 strong positive sub-populations. Assumptions 
and testing strategy are given below. 
♦Overall, an improvement of 14 months in median DFS (from
42 months to 56 months) or equivalent to HR = 0.75 is aimed
for the whole population. 
♦The HRs for OS between the experimental and control arms
are 0.6, 0.7 and 0.765, for PD-L1 strong positive, PD-L1
positve and the whole population, respectively.
♦
he enrollment duration is 52 months with the 
accrual rates provided in Table 7 below. 
♦The yearly drop-out rate is 2.5% and 1% for DFS and OS,
respectively.
Table 7 – Enrollment Pattern 
Period 
Starting at time 
Calendar Time 
Accrual Rate 
1 
0 
January 2016 
8.375 
2 
8 
September 2016 
18 
3 
26 
March 2018 
34.24 
4 
47 
December 2019 
13.992 
♦The family-wise error rate (Type I error) for DFS and OS
hypotheses is strongly controlled at 2.5%, one-sided. The
study uses the graphical method of Maurer and Bretz
[Ref. 75] to provide strong multiplicity control for multiple
hypotheses as well as interim efficacy analyses. See Figure 3
for an overview of the multiplicity strategy.
♦
analysis, OS analysis will be performed as well. There are 
three additional analyses for OS alone after DFS FA. The 
schedule and characteristics of analyses are given in Table 8 
and Table 9 in Section 8.1.1.  
CCI
CCI
CCI
CCI
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♦ A Hwang-Shih-DeCani (HSD) spending function with gamma 
= -4 is used to establish the boundary (nominal alpha) in 
interim and final analysis of DFS and OS for the test of each 
population. The threshold alphas and HRs for each analysis 
can be found in Table 8 and Table 9 in Section 8.1.1. 
♦ The timing of interim analysis 1 and 2 will be determined by 
the number of DFS events in the PD-L1 strong positive 
population, and the final analysis for DFS will be conducted 
when target DFS event numbers are reached in the whole 
population as well as the PD-L1 strong positive subgroup.  
Approximately 1180 participants will be randomized in a 1:1 ratio 
into the experimental arm and the control arm. For DFS, based on a 
target number of 551 events at FA, the study has ~86% power at 
alpha=1.25% (one-sided) and ~92% power at alpha=2.5% (one-
sided) for the whole population. It is expected that there will be 
approximately 334 participants of PD-L1 strong positive in the 
study to achieve ~90% power at final analysis of DFS at 
alpha=1.25% (one-sided) and ~94% power at alpha=2.5% (one-
sided). If either of the tests for the primary endpoints is significant, 
then the study can be declared successful in the respective 
population.  
Diagnosis and 
main criteria for 
inclusion 
Patient enrollment will follow a three-step procedure as illustrated 
in Chapter 4 (step 1 registration, step 2 central confirmation of PD-
L1 status, step 3 randomization). Patients must meet all of the 
criteria described in Sections 3.1, 3.2 and 3.3 to be eligible for 
randomization in step 3. 
1) Registration - step 1 (ORTA step 1) 
♦ Before patient registration, written informed consent for 
tumor testing must be given according to ICH/GCP and 
national/local regulations. For patients that accept to 
participate in the translational research, we recommend the 
informed consent for translational research be signed before 
registration step 1;  
♦ Pathological diagnosis of NSCLC confirmed at surgery, any 
histology is eligible; 
♦ Confirmed UICC v7 stage IB with T ≥ 4 cm, II-IIIA NSCLC 
after complete surgical resection (lobectomy, sleeve lobectomy, 
bi-lobectomy or pneumonectomy) as documented in the 
pathology report; 
(Note: TNM stage according to the 7th edition of the TNM 
classification for lung cancer) 
♦ Resection margins proved microscopically free (R0); 
Resection margins are evaluated at the bronchial, venous and 
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arterial stumps, peribronchial soft tissue, any peripheral 
margin near the tumor or of additionally resected tissue; 
♦ A systematic complete mediastinal lymph node dissection or a 
lobe-specific mediastinal lymph node dissection (Appendix K) 
is recommended. At a minimum, the pathology and/or 
operative report must include the examination of at least two 
different mediastinal lymph node (N2) levels, one of which is 
the subcarinal (level 7) and the second of which is lobe-
specific;  
♦ In the uncommon clinical situation where the surgeon 
thoroughly examines a particular mediastinal lymph node 
level and does not find any lymph nodes, that mediasintal 
lymph node level may be counted among the minimum two 
required levels. However, the surgeon must clearly document 
in the operative report or in a separate written statement that 
the lymph node level was explored and no lymph nodes were 
present. Normal appearing lymph nodes, if present, must be 
biopsied or/removed;No extracapsular extension of tumor in 
resected mediastinal (N2) lymph nodes. Extracapsular tumor 
extension is permitted in resected N1 lymph nodes; 
♦ The highest mediastinal node removed can be positive for 
malignancy; 
♦ Carcinoma in situ can be present at bronchial margin;  
♦ Patients with two synchronous primary non-small cell lung 
cancers are excluded from the study;  
♦ Availability of tumor sample obtained at surgical resection for 
PD-L1 Immunohistochemistry (IHC) expression assessment. 
Patients must submit the tumor sample during screening for PD-
L1 IHC expression testing at a central pathology laboratory. 
Patients will be eligible to participate regardless of the level of 
PD-L1 status, however tissue must be considered satisfactory for 
characterization of PD-L1 status. Patients whose samples are 
inadequate for PD-L1 determination will not be randomized;  
♦ Submission of formalin-fixed paraffin embedded tumor tissue 
sample blocks are preferred; if submitting unstained slides, the 
slides must be freshly cut and submitted to the central testing 
laboratory; 
♦ At least 18 years; 
♦  
2) Central confirmation of PD-L1 status - step 2  
This central confirmation through EORTC is required for enrolling 
the patient in step 3.  
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3) Randomization - step 3 (ORTA step 2) 
♦ Before patient randomization, written informed consent 
(‘Main Study’) for participation in the study must be given 
according to ICH/GCP, and national/local regulations; 
♦ No evidence of disease (NED) at clinical examination and 
baseline radiological assessment as documented by contrast 
enhanced chest/upper abdomen CT scan, brain CT/MRI and 
clinical examination within 12 weeks prior to the randomization 
date; 
♦ Adjuvant chemotherapy is not mandatory but considered for 
patients with stage IB (T ≥ 4 cm) and strongly recommended for 
stage II and IIIA, and will be administered according to national 
and local guidelines. Patients who received more than 4 cycles of 
adjuvant therapy are not eligible; 
♦ Patients not receiving adjuvant chemotherapy must be 
randomized and dosed with pembrolizumab/placebo within 12 
weeks of their surgery date. 
♦ Participants who receive adjuvant chemotherapy must begin 
adjuvant chemotherapy within 12 weeks of the surgery date. 
Patients receiving adjuvant chemotherapy must be randomized 
and dosed with pembrolizumab/placebo at least 3 weeks but 
no more than 12 weeks from the last dose of chemotherapy 
(Day 1 of last cycle). 
♦ ECOG Performance status 0-1;  
♦ Adequate organ function performed within 10 days of treatment 
initiation; 
♦ No prior or planned neoadjuvant or adjuvant radiotherapy and/or 
neoadjuvant chemotherapy for the current malignancy is allowed; 
♦ No prior treatment with an anti-PD-1, anti-PD-L1/2, anti-CD137, 
CTLA-4 modulators or any other immune-modulating agents ; 
patients receiving live vaccine within 30 days prior to the first 
infusion of study treatment are not eligible;  
♦ No current participation in a interventional clinical trial or 
treatment with an investigational agent or use of an 
investigational device within 4 weeks of the first infusion of 
study treatment; 
♦ No known history of Human Immunodeficiency Virus (HIV) 
(known HIV 1/2 antibodies positive). No known active Hepatitis 
B or C. Active Hepatitis B is defined as a known positive HBsAg 
result. Active Hepatitis C is defined by a known positive Hep C 
Ab result and known quantitative HCV RNA results greater than 
the lower limits of detection of the assay; 
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♦ No chronic use of immunosuppressive agents and/or systemic 
corticosteroids or any use in the last 3 days prior to the first 
infusion of trial treatment: 
♦ Corticosteroid use on study for management of ECIs 
(pembrolizumab Event of Clinical Interest), as premedication for 
the administration of chemotherapies, and/or a premedication for 
IV contrast allergies/reactions is allowed;  
♦ Daily prednisone at doses of 5-7.5 mg is allowed as an example 
of replacement therapy. Equivalent hydrocortisone doses are also 
permitted if administered as a replacement therapy; 
♦ No history of interstitial lung disease (ILD) OR a history of (non-
infectious) pneumonitis that required oral or IV steroids (other 
than COPD exacerbation) or current pneumonitis;  
♦ No active autoimmune disease that has required systemic 
treatment in the past 2 years (i.e. with use of disease modifying 
agents, corticosteroids or immunosuppressive drugs). Any 
replacement therapy (i.e., thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment 
and is allowed. Patients with hyperthyroidism or hypothyroidism 
but that are stable on hormone replacement are also allowed; 
♦ No history of a hematologic or primary solid tumor malignancy, 
unless in remission for at least 5 years. A pT1-2 prostatic cancer 
Gleason score < 6, superficial bladder cancer, non melanomatous 
skin cancer or carcinoma in situ of the cervix is eligible; 
Note: prior radiotherapy for another malignancy (breast 
cancer/lymphoma/germ cell tumors, etc.) is not an exclusion 
criterion, the same applies for prior anti-cancer systemic 
chemotherapy.  
♦ No previous allogeneic tissue/solid organ transplant; 
♦ No active infection requiring therapy;  
♦ No surgery or chemotherapy related toxicity (non-hematological, 
toxicity resolved to grade 1 (see Appendix D), with the exception 
of alopecia, fatigue, neuropathy and lack of appetite /nausea); 
♦ Female patients with childbearing potential must have a negative 
urine or serum pregnancy test at screening (within 72 hours of 
first infusion of study medication). If the urine test cannot be 
confirmed as negative, a serum pregnancy test will be required. 
The serum pregnancy test must be negative for the subject to be 
eligible. Non-childbearing potential is defined as (by other than 
medical reasons); 
♦ ≥45 years of age and has not had menses for greater than 1 year; 
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♦ Amenorrheic for > 2 years without a hysterectomy and 
oophorectomy and an FSH value in the postmenopausal range 
upon pretrial (screening) evaluation; 
♦ Whose status is post hysterectomy, oophorectomy or tubal 
ligation. Documented hysterectomy or oophorectomy must be 
confirmed with medical records of the actual procedure or 
confirmed by an ultrasound. Tubal ligation must be confirmed 
with medical records of the actual procedure otherwise the 
subject must be willing to use two adequate barrier methods 
throughout the study, starting with the screening visit through 
120 days after the last infusion of study treatment (see Appendix 
L). Information must be captured appropriately within the site's 
source documents; 
♦ If of childbearing potential, female patients must be willing to 
use two adequate barrier methods throughout the study, starting 
with the screening visit up to 120 days after last infusion of 
chemotherapeutic and investigational agents as specified in the 
protocol;  
Note: Abstinence is acceptable if this is the usual lifestyle and 
preferred contraception for the subject. Please refer to Appendix 
M for recommendation based on Clinical Trial Facilitation Group 
guidelines for sites and countries where applicable (e.g. United 
Kingdom, Norway, Sweden, Portugal, etc.); 
♦ Male patients with a female partner(s) of child-bearing potential 
must agree to use two adequate barrier methods throughout the 
trial starting with the screening visit through 120 days after the 
last infusion of study treatment is received (see Appendix L). 
Males with pregnant partners must agree to use a condom; no 
additional method of contraception is required for the pregnant 
partner; 
Note: Abstinence is acceptable if this is the usual lifestyle and 
preferred contraception for the subject. Please refer to Appendix 
M for recommendation based on Clinical Trial Facilitation Group 
guidelines for sites and countries where applicable (e.g. United 
Kingdom, Norway, Sweden, Portugal, etc.); 
♦ Female patients who are breast feeding must discontinue nursing 
prior to the first infusion of study treatment and until 120 days 
after the last study treatment; 
♦ Absence of severe comorbidities that in the opinion of the 
Investigator might hamper the participation to the study and/or 
the treatment administration;  
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After the enrollment step in ORTA, patients will be 
automatically randomized in the Interactive Voice Response 
System (IVRS).  
Important note: An additional +2 day window is allowed for 
randomization. All eligibility criteria must be adhered to.  
Treatment 
Test product, dose, 
duration and mode 
of administration 
Pembrolizumab at a dose of 200 mg, administered by IV infusion, 
every 3 weeks, for a total of 18 infusions, approximately one year. 
Placebo administered by IV infusion, every 3 weeks, for a total of 
18 infusions, approximately one year. 
Criteria for 
evaluation  
Efficacy 
Disease free survival (DFS) Definition of date of disease 
recurrence is given in Section 7.1.1.3. Recurrence of disease can be 
a loco-regional recurrence, a distant (metastatic) recurrence or a 
second primary. NSCLC and second malignancies will be 
considered to be events. 
DFS is calculated as the time from randomization to either the date 
of disease progression or the date of death (whatever the cause). The 
date of first documented disease recurrence (if applicable) will be 
used as the date of event. Patients alive with no evidence of disease 
recurrence at the time of their last visit are censored at the time of 
the last examination. 
Overall survival (OS) is defined as the time from the date of 
randomization to the date of death, whatever the cause. The follow-
up of patients still alive will be censored at the moment of last 
visit/contact. 
Lung Cancer Specific Survival (LCSS) is calculated as the time 
from randomization to the date of death (due to lung cancer 
specifically). The follow-up of patients still alive will be censored at 
the moment of last visit/contact. Patients who die but not due to 
lung cancer are censored at the time of death. 
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Safety 
All patients who have started the treatment will be included in 
overall safety analyses. 
Patients who have discontinued treatment because of toxicity will 
always be included in the safety analyses. 
Statistical 
methods 
Efficacy endpoints 
The analyses of the primary and secondary endpoints (DFS, OS and 
LCSS ) will be performed on all randomized patients according to 
the intention to treat principle.  
Estimates and confidence intervals 
Estimates of the median DFS, OS and LCSS will be obtained by the 
Kaplan Meier technique. The 95% confidence interval (CI) for the 
median will be calculated using the reflected CI method.  
Estimates of the event-free rate at a fixed time point will be 
obtained using the Kaplan Meier technique and 95% CI will be 
calculated by the Greenwood’s formula for standard deviation. 
Estimates of hazard ratios and their 95% CI will be obtained by Cox 
regression. Kaplan Meier Curves will be drawn for both the 
experimental and control arms on the same plot.  
Inference 
The DFS and OS will be analyzed by a Cox Proportional Hazard 
Regression with treatment adjusted by the following covariates: 
stratification factors including stage, PD-L1 IHC expression, 
adjuvant chemo and regions, and additional factors including 
histology and smoking status. Permutation test [Ref. 74] will be 
used as a primary test for DFS to compare the experimental versus 
the control arm. The Wald test without permutation of allocation 
sequence will be used as a supportive analysis for DFS, but as a 
primary test for OS. The hazard ratios and corresponding 95% CIs 
will be estimated using the multivariate Cox regression model stated 
above (using Efron’s tie-handling method). A sensitivity analysis 
will include sex and age as additional adjustment factors in the Cox 
regression model. A logrank test with no adjustment factors to 
compare the two arms will also be performed as a sensitivity 
analysis.  
Analysis of LCSS will be based on log-rank test, Cox regression 
and competing risks approaches.  
Toxicity 
Analysis for toxicity is based on the safety population. The worst 
grade of toxicity/adverse events observed over the whole treatment 
period according to CTCAE version 4.03 will be displayed. In the 
primary analysis, no formal statistical analysis will be performed to 
compare toxicity in both arms.  
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Health-Related Quality of Life 
The analyses for Quality of life are defined in Section 10.5. 
Proportion of PD-L1 + status  
Proportion of PD-L1 status: negative (no staining), weak positive 
(tumor proportion score (TPS) 1-49%) and strong positive (TPS ≥ 
50%) will be checked and reported when approximately 100 
patients accrued. In case there is any large departure from current 
assumption of PD-L1 status, appropriate statistical adjustment will 
be considered. 
Pharmaco-kinetic 
and pharmaco-
dynamic 
evaluations  
To further evaluate pembrolizumab immunogenicity and 
pembrolizumab exposure in this indication, and also to evaluate 
exposure of the proposed dosing regimen, sample collections for 
analysis of anti-drug antibodies (ADA) and PK are currently 
planned. 
For sampling refer to Sections 6.2.4, 6.6, 6.8.2. 
If ongoing ADA and/or PK results continue to be consistent with 
existing ADA and/or PK data from other pembrolizumab 
clinical trials, it may be decided to discontinue further sample 
collection or analysis in this study. 
Translational 
research 
The exploratory parameters in this study will be refined 
according to the current knowledge in the field during trial 
advancement and at the time of trial completion. 
A preliminary proposal of the main objectives of the TR project 
could be at least (i.e. not limited to) to define: 
♦ Biomarker assessment including but not limited to PD-L1, PD-
L2 and other immune biomarkers (immune platform) performed 
on tumor tissue and blood samples respectively; 
♦ Intratumoral heterogeneity of PD-L1 status; 
♦ Comparison of PD-L1 status between the primary tumor and at 
relapse (optional rebiopsy); 
♦ Exploration of other markers of T cell activation in the PDL1 
positive and negative patients; 
♦ DNA mutational burden and nanostring RNA analysis. 
Health Related 
Quality of Life 
Health Related Quality of life will be assessed with the EORTC 
Quality of Life Questionnaire (QLQ-C30) version 3, EORTC QLQ-
LC13 and EQ-5D. 
 
 
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Trial organization 
♦ This trial is an Intergroup Trial, jointly conducted with ETOP in different countries of 
European Union and third countries;  
♦ Merck Sharp & Dohme LLC (hereafter referred to as the Sponsor or MSD) is the 
Sponsor in all participating countries;  
♦ The EORTC is the coordinating group in this trial and therefore will centrally manage 
trial design and activation, data collection and quality control of data, statistical 
analysis and publication;  
♦ This trial is fully supported by the industry. 
 
 
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1 Background and introduction 
1.1 
Early stage Non Small Cell Lung Cancer 
Lung Cancer is the leading cause of cancer-related death world-wide; in 2012, 313,000 new 
cases have been estimated in Europe and 1,825,000 worldwide with 268,000 and 1,590,000 
deaths respectively [Ref. 1, Ref. 2]. 
Non Small Cell Lung Cancer (NSCLC) accounts for 80-85% of all lung cancers, about 20% 
of cases being diagnosed at an early stage when the disease is still curable by surgery.  
The most common histological subtypes of NSCLC include adenocarcinoma, squamous cell 
carcinoma (SqCC), and large-cell carcinoma (LCC). Immunohistochemistry is often helpful 
in distinguishing between these subtypes; SqCCs is usually TTF-1-negative and p63-positive, 
whereas adenocarcinomas are often TTF-1-positive. This differentiation can dictate treatment 
management in the advanced stage but not for surgery or adjuvant chemotherapy [Ref. 3]. 
Age, performance status (PS) and stage are the main prognostic factors in early stage 
NSCLC. Gene sequencing studies in early-stage NSCLC have reported prognostic signatures, 
but no signatures have been prospectively validated in independent studies. The use of 
biomarkers predicting adjuvant chemotherapy efficacy has recently been evaluated in the 
LACE bio group without strong recommendations for further studies [Ref. 4].  
Surgical resection is the standard treatment for operable patients with resectable stage I to 
IIIA [Ref. 5, Ref. 6].  
The surgical procedure used depends on the extent of the disease and on the cardiopulmonary 
reserve of the patient. Lobectomy or pneumonectomy with lymphadenectomy are the main 
options according to the location and size of the tumor, age, performance status (PS), general 
comorbidities and lung function of the patient [Ref. 7]. Video-assisted thoracoscopic surgery 
(VATS) may be an alternative to thoracotomy for patients undergoing lobectomy [Ref. 8]. 
This is a minimally invasive approach that decreases surgical morbidity, including 
perioperative pain, and is particularly useful for those with significant medical comorbidities 
[Ref. 9]. Although the efficacy of VATS compared to conventional surgical techniques has 
not been definitively established, several large case series support the safety and efficacy of 
this technique for patients with stage I NSCLC [Ref. 10, Ref. 11, Ref. 12].  
In 2006, the European Society of Thoracic Surgeons guidelines recommended systematic 
lymph node dissection in all cases to ensure complete resection [Ref. 13]. The optimal extent 
of lymph node resection is uncertain: a meta-analysis concluded that systematic mediastinal 
nodal dissection (levels 4, 7, and 10 for right sided lesions, and levels 5 or 6 and 7 for left 
sided lesions) was associated with a small to moderate improvement in survival compared 
with lymph node sampling alone [Ref. 5].  
Despite the recent advances in staging, post operative support and adjuvant chemotherapy, 
40% of patients with stage I, 66% of stage II, and 75% of stage IIIA will still develop 
recurrence and die as a result of their disease within 5 years of resection [Ref. 14]. 
Residual micrometastases are believed to be the cause of disease recurrence. In an effort to 
eradicate micrometastases and improve overall survival (OS), numerous clinical trials have 
evaluated adjuvant and neoadjuvant chemotherapy.  
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1.2 
Adjuvant chemotherapy for early stage NSCLC 
Adjuvant chemotherapy is the standard treatment for patients with completely resected stage 
II or III NSCLC [Ref. 7]. 
A total of 23 randomized trials between 1992 and 2005 and five further meta-analyses have 
shown that adjuvant chemotherapy improves survival in patients with completely resected 
stage II and stage III disease. The Lung Adjuvant Cisplatin Evaluation (LACE) Collaborative 
Group published a meta-analysis of five cisplatin-based trials in 2008. It included a total of 
4,584 patients and demonstrated a 5.3% improvement in survival at 5 years with adjuvant 
chemotherapy (Hazard Ratio (HR)=0.89, 95% CI=0.82-0.96, P=0.0043). There was also an 
improvement in disease-free survival of 5.2% at 5 years (P<0.0001). The LACE meta-
analysis also demonstrated that there was no association between chemotherapy effect and 
sex, age, histology, type of surgery, planned radiotherapy or planned total dose of cisplatin 
[Ref. 15]. Such results were also confirmed by a further meta-analysis with individual patient 
data from the same trials [Ref. 16]. 
The improvement in survival in patients with stage IB disease did not reach statistical 
significance and patients with stage IA disease appeared to do worse with adjuvant 
chemotherapy. 
In the CALGB 9633 a total of 340 patients were randomly assigned to adjuvant 
chemotherapy or observation: no significant difference in survival (HR 0.83, 95% CI: 064-
1.08, P=0.12) between the two groups was shown but the exploratory analysis demonstrated 
a survival advantage in the adjuvant chemotherapy group among those patients whose tumors 
were greater than or equal to 4 cm in diameter (HR 0.69, 95% CI: 0.48-0.99, P=0.043). Thus, 
the analysis of the CALGB group suggested that patients with stage IB disease with T ≥ 4cm 
may also benefit from adjuvant chemotherapy [Ref. 16]. A separate study, the JBR10 trial, 
showed similar results for stage IB disease: patients with tumors measuring >5 cm in 
diameter had a survival advantage when treated with adjuvant chemotherapy [Ref. 18]. 
NSCLC, all stage IA and those tumors in stage IB which are less than 4 cm remain an area 
where there is no standard therapy. Vinorelbine/cisplatin is the most commonly used doublet 
chemotherapy on the basis of the phase III adjuvant studies in NSCLC; other combinations 
commonly used are cisplatin/gemcitabine and carboplatin/paclitaxel. However, poor 
compliance due to toxicity has been a major issue in clinical trials of adjuvant therapy, with 
approximately only 45-50% of patients completing all 4 planned cycles at full planned dose.  
 
 
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Table 1. Randomized trials of adjuvant platinum-based chemotherapy 
Trial 
Patients 
N 
Stage 
Regimen 
5y Survival 
Benefit (%) 
p 
ECOG 3590  
[Ref. 19] 
488 
II-IIIA 
Cisplatin 
Etoposide 
0 
0.56 
ALPI [Ref. 20] 
1209 
I-IIIA 
Cisplatin 
Mitomycin 
Vindesine 
3 
0.589 
ANITA  
[Ref. 21] 
840 
IB-IIIA 
Cisplatin 
Vinorelbine 
9 
0.017 
JBR.10  
[Ref. 18] 
482 
IB-II 
Cisplatin 
Vinorelbine 
15 
0.04 
IALT [Ref. 22] 
1867 
I-IIIA 
Cisplatin 
Vindesine OR 
Vinblastine OR 
Vinorelbine OR 
Etoposide 
4 
0.1 
BLT [Ref. 23] 
381 
I-IIIA 
Cisplatin 
Vindesine OR 
Vinorelbine 
Cisplatin 
Mitomycin OR 
Ifosfamide OR 
Vinblastine 
2 
0.9 
CALGB 9633  
[Ref. 17] 
344 
IB 
Carboplatin 
Paclitaxel 
4 
0.125 
 
Recently, the RADIANT trial was presented at the ASCO meeting 2014. This was a trial with 
a 2:1 randomization of erlotinib versus placebo after radical surgery followed by adjuvant 
chemotherapy for stage IB, II, IIIA NSCLC patients: erlotinib did not significantly improve 
the median disease free survival (DFS) compared to placebo in the overall population (50.5 
versus 48.2 months; HR=0.90, 95%CI=0.74-1.1) and did not show any OS benefit, even for 
the censored analysis (HR=1.09, 95%CI=0.54-2.16). However, an early improvement in DFS 
of the order of 18 months was seen in the Epidermal Growth Factor Receptor (EGFR) 
mutated subpopulation (HR=0.61, 95%CI=0.38-0.98). 
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As this was not the primary endpoint and in the context of the hierarchical statistical testing, 
this was not statistically significant [Ref. 24].  
The MAGRIT study was a double-blind, placebo-controlled trial in patients with completely 
resected MAGE-A3-positive NSCLC Stages IB, II, and IIIA. Patients were randomized (2:1) 
to intramuscular injections of MAGE-A3 vaccine versus placebo. This study was presented at 
the 2014 ESMO Conference and was negative for its primary and secondary endpoints [Ref. 
25].  
Therefore, for stage II - IIIA operable patients with resectable disease at diagnosis, the 
standard treatment is still radical surgery (lobectomy/pneumonectomy) followed by up to 4 
cycles of adjuvant chemotherapy with a platinum-based doublet, most commonly cisplatin 
plus vinorelbine. 
For stage IB, the treatment is decided on the basis of the tumor size, greater than or equal to 4 
cm tumors are treated as stage II and IIIA above and T less than 4 cm are offered no adjuvant 
chemotherapy after surgery. 
The role of postoperative radiotherapy (PORT) is so far limited to patients with pathologic 
N2 disease or to those that have residual disease at the surgical resection [Ref. 26]. There is 
no added benefit of radiotherapy in the neoadjuvant setting [Ref. 27] and there seems to be a 
detrimental role for radiotherapy in stages I and II in the adjuvant setting [Ref. 28].  
In the SEER database (population-based cohort) PORT use was associated with an increase 
in survival in patients with N2 nodal disease but not in patients with N1 and N0 nodal disease 
[Ref. 29]. 
Prospective data are awaited from the ongoing EORTC LUNGART study [Ref. 30]. 
1.3 
Background data for Anti- PD1 and PDL1 
The programmed death receptor 1 (PD-1) is a key immune checkpoint receptor expressed by 
activated T cells that modulates a late stage of the immune response by negatively regulating 
the activation of T cells in peripheral tissues. The PD-1 receptor-ligand interaction is a major 
pathway hijacked by tumors to suppress immune control. PD-1 (encoded by the gene Pdcd1) 
is an immunoglobulin (Ig) superfamily member related to CD28 and CTLA-4 which has been 
shown to negatively regulate antigen receptor signaling upon engagement of its ligands PD-
L1 and/or PD-L2 [Ref. 31, Ref. 32].  
PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-
type (V-type) domain responsible for ligand binding and a cytoplasmic tail responsible for 
the binding of signaling molecules. The cytoplasmic tail of PD-1 contains two tyrosine-based 
signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an 
immunoreceptor tyrosine-based switch motif (ITSM). Following T cell stimulation, PD-1 
recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3, PKCθ, 
and ZAP70, which are involved in the CD3 T cell signaling cascade [Ref. 32, Ref. 33, Ref. 
34, Ref. 35]. 
The mechanism by which PD-1 down modulates T cell responses is similar to, but distinct 
from, that of CTLA-4, as both molecules regulate an overlapping set of signaling proteins 
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[Ref. 36]. PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T cells, B cells, T regs, and natural killer cells [Ref. 37, Ref. 38]. 
Expression has also been shown during thymic development on CD4-CD8- (double negative) 
T cells, as well as subsets of macrophages and dendritic cells [Ref. 39]. 
The ligands for PD-1 (PD-L1 (B7-H1) and PD-L2 (B7-DC)) are constitutively expressed or 
can be induced in a variety of cell types including non-hematopoietic tissues and in various 
tumors [Ref. 36, Ref. 40, Ref. 41, Ref. 42]. Both ligands are type 1 transmembrane receptors 
containing both IgV- and IgC-like domains in the extracellular region and contain short 
cytoplasmic regions with no known signaling motifs. Binding of either PD-L1 or PD-L2 to 
PD-1 inhibits T cell activation triggered through the T cell receptor. PD-L1 is expressed at 
low levels on various non-hematopoietic tissues, most notably on vascular endothelium; 
whereas PD-L2 is only detectably-expressed on antigen-presenting cells found in lymphoid 
tissue or chronic inflammatory environments. 
PD-L2 is thought to control immune T cell activation in lymphoid organs, whereas PDL1 
serves to dampen unwarranted T cell function in peripheral tissues [Ref. 36]. Although 
healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to 
express abundant levels of this T cell inhibitor. High expression of PD-L1 on tumor cells 
(and to a lesser extent of PD-L2) has been found to correlate with poor prognosis and 
survival in various cancer types, including renal cell carcinoma [Ref. 43], pancreatic 
carcinoma [Ref. 44], hepatocellular carcinoma [Ref. 45], and ovarian carcinoma [Ref. 46].  
PD-L1 status was described in many cancer types and in particular in lung cancer where up 
to 50% of NSCLCs are reported to express PD-L1 [Ref. 47, Ref. 48]. High expressers of PD-
L1 on immunohistochemistry of tumor samples appear to get the best benefit from PD-1 or 
PD-L1 inhibitors although the benefit is not exclusive to this group [Ref. 49].  
Recent data presented at ESMO Conference [Ref. 49] in the advanced setting showed 37% 
strong positivity (defined as ≥50% membranous staining), 17% weak positivity (defined as 1-
49% membranous staining) and 10% negativity. Median PFS and OS were longer for the 
strong positive cases versus the weak/negatives (HR=0.52 and 0.59, respectively). This is a 
dynamic field and the next few years will see development of the role of PD-L1 and other 
biomarkers. 
1.4 
Checkpoint inhibitors 
Among the checkpoint inhibitors anti PD-1 and anti-PD-L1 mAbs have shown promising 
results in advanced NSCLC where they are currently being developed in phase I, II and phase 
III trials in first and subsequent lines of therapy [Ref. 50]. 
Two anti-PD-1 (nivolumab and pembrolizumab) and four anti-PD-L1 (BMS-936559, Medi-
4736, MPDL3280A, MSB0010718C) antibodies have been investigated in phase I studies 
and are under further development in NSCLC [Ref. 50]. In all phase I trials, the maximum-
tolerated dose was not reached, and all doses were found to be safe.  
The frequency of immune-related toxicities from anti–PD-1/anti–PD-L1 treatments appears 
less than that from anti-CTLA4 treatment. The common drug-related AEs were decreased 
appetite, anemia, diarrhea, nausea, pruritus, fatigue, pneumonitis, and elevated transaminase 
[Ref. 51, Ref. 52, Ref. 53, Ref. 54, Ref. 55, Ref. 56]. 
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Table 2. Clinical development of Immune Checkpoint Inhibitors - Efficacy Data on NSCLC 
Target 
Antibody 
Molecule 
Development 
stage 
ORR  
All 
comers 
Ref 
PD-1 
Nivolumab 
Fully human IgG4 
Phase III 
24% 
[Ref. 
57] 
Pembrolizumab 
Humanized IgG4 
Phase III 
21% 
[Ref. 
49] 
PD-
L1 
BMS-936559 
Fully human IgG4 
Phase I - halted 
- 
[Ref. 
58] 
MEDI-4736 
Engineered human 
IgG1 
Phase III 
16% 
[Ref. 
59] 
Mpdl-3280A 
Engineered human 
IgG1 
Phase III 
23% 
[Ref. 
60] 
MSB0010718C 
Human IgG1 
Phase I 
NA 
[Ref. 
61] 
1.5 
Pembrolizumab characteristics and clinical data 
overview 
Pembrolizumab is a highly selective humanized monoclonal antibody (mAb) that binds to the 
PD-1 receptor and directly blocks the interaction between PD-1 and its ligands, thereby 
enhancing tumor regression and ultimately immune rejection (see the IB). Pembrolizumab is 
being investigated in various oncology indications including melanoma, NSCLC, renal cell 
carcinoma (RCC), breast cancer, multiple myeloma (MM), microsatellite unstable tumors, 
and head and neck cancer. Pembrolizumab [Keytruda (US)], is approved for treatment of 
advanced (unresectable or metastatic) melanoma for adults in the US, EU and several 
countries. Pembrolizumab has also been granted approval in the US, EU and several 
countries for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 
as determined by an FDA-approved test and who have disease progression on or after 
platinum-containing chemotherapy. 
1.5.1 
Preclinical studies 
In cultured blood cells from healthy human donors, cancer subjects, and nonhuman primates 
pembrolizumab strongly enhanced T-lymphocyte immune responses. It potentiates existing 
immune responses only in the presence of antigen and does not nonspecifically activate T-
cells. 
In addition to interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), interferon gamma 
(IFNγ) and levels of other cytokines were found to be modulated by pembrolizumab.  
Using an anti-murine PD-1 surrogate antibody, PD-1 blockade has been shown to 
significantly inhibit tumor growth in a variety of syngeneic murine tumor models. In these 
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experiments in mice, anti-PD-1 therapy was synergistic with chemotherapeutic agents such 
as gemcitabine and 5-fluorouracil (5-FU), and combination therapy resulted in increased 
complete tumor regression rates in vivo.
In animal studies (cynomolgus monkeys), it was demonstrated that the systemic exposure to 
pembrolizumab, independently of sex, increased with increasing dose. Systemic exposure for 
the 7-day dosing interval increased after repeated dosing from 40 to 200 mg/kg. Area under 
the concentration-time curve (AUC) for the 7-day dosing interval after one dose appeared to 
be dose-proportional from 0.3 to 200 mg/kg, suggesting dose-independent pharmacokinetics 
(PK). Terminal half-life (t½) values from individual animals after repeated IV dosing ranged 
from 11.8 to 23.7 days (mean values ranged from 15.7 to 22.3 days) across the doses tested.
In cynomolgus monkeys pembrolizumab was well tolerated with systemic exposure over the 
course of the study and no significant in vivo toxicity was observed. In a 1-month and 6-
month toxicology study, with IV pembrolizumab (up to 200 mg/kg) administered once a 
week and once every other week respectively, up to 200 mg/kg resulted in no adverse 
treatment related effects. 
Additionally, in the tissue cross-reactivity study of pembrolizumab with human and monkey 
tissues the expected on-target staining of the membranes of mononuclear leukocytes in both 
species was demonstrated. Off-target cross-reactivity staining was also noted in both species 
but was limited to be considered related to the experimental method artifacts, i.e. tissue 
processing for IHC has well recognized limitations of tissue cross-reactivity studies and, thus 
not considered toxicologically relevant.
No reproductive or developmental toxicity studies are planned with pembrolizumab. 
Therefore, inclusion of women of childbearing potential in clinical trials should be in 
accordance with the study protocol and applicable regulatory guidance (e.g., ICH M3 (R2): 
Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing 
Authorization for Pharmaceuticals).
1.5.2
Clinical studies
Phase I studies
An open-label Phase I trial (KEYNOTE-001) was conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab. The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W), in participants with advanced solid tumors. All 3 dose levels were well tolerated and 
no dose-limiting toxicities were observed. Based on pharmacokinetic (PK) data showing a 
half-life of 21 days, the protocol was amended to change the dosing frequency in the 
expansion cohort to every 3 weeks (Q3W). All cohorts have completed enrollment.
In KEYNOTE-001, a total of 550 NSCLC participants were treated in several dose expansion 
cohorts with at least 1 dose of pembrolizumab. The initial data from 495 NSCLC participants 
have been published and reported. The ORR was 19.4% (18.0% in the 394 previously treated 
participants and 24.8% in the 101 previously untreated participants). The response rate (RR) 
was similar regardless of dose, schedule, and histologic analysis. Current or former smokers 
had a RR of 22.5%, as compared with 10.3% among participants who had never smoked 
cigarettes.
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Participants were required to submit a newly obtained tumor biopsy prior to initiating therapy 
with pembrolizumab to evaluate the tumors for expression of PD-L1. After evaluation of 
several methods for pathological assessment, in a training set, membranous PD-L1 
expression in at least 50% of tumor cells (TPS ≥ 50%) was selected as the cut-off point for 
defining PD-L1 as high. In a validation set of 313 participants, the RR was 45.2% in the 73 
participants with a TPS ≥ 50%, including 43.9% in previously treated participants and 50% 
in previously untreated participants, values that numerically exceeded the RR in the training 
group.[Ref. 62]. 
Pembrolizumab has been generally well tolerated. The most common treatment-related AEs 
were fatigue (19.4%), pruritus (10.7%), and decreased appetite (10.5%). Adverse events of 
Grade 3 or higher were reported in 47 of 495 patients (9.5%). The only treatment-related AEs 
of an inflammatory or immune-mediated nature that occurred in more than 2% of patients 
were infusion-related reactions (in 15 patients [3.0%]), hypothyroidism (in 34 patients 
[6.9%]), and pneumonitis (in 18 patients [3.6%]). One infusion reaction led to treatment 
discontinuation. All the patients with hypothyroidism were successfully treated with medical 
therapy [Ref. 62]. 
KEYNOTE-011 is a study currently ongoing in Japan, with a two stage design: in the first 
stage pembrolizumab as single agent will be tested for dose finding; in the second stage 
pembrolizumab in combination with either cisplatin/pemetrexed or carboplatin/paclitaxel in 
advanced NSCLC to assess safety and tolerability of the combination therapy [Ref. 63].  
KEYNOTE-021 Pembrolizumab has been studied in combination with other agents in 
NSCLC patients in KEYNOTE-021. This Phase I/II trial assessed the safety and efficacy of 
pembrolizumab in combination with multiple therapeutic agents including chemotherapy 
(carboplatin and pemetrexed; and carboplatin, paclitaxel, and bevacizumab); EGFR inhibitors 
including erlotinib and gefitinib; and the CTLA-4 inhibitor, ipilimumab. Cohort G of the 
study evaluated the efficacy and safety of pembrolizumab plus carboplatin and pemetrexed 
(CP) vs. CP alone as first-line therapy for advanced non-squamous NSCLC. 
KEYNOTE-021 Cohort G contained 123 participants of whom 60 were accrued to the 
pembrolizumab plus CP arm and 63 to the CP arm. Demographics were generally balanced 
between treatment arms. As of Aug 8, 2016, median follow-up was 10.6 months (range, 0.8-
19.3); median exposure was 8.0 months for pembrolizumab plus CP and 4.9 months for CP. 
In the CP arm, 43 participants discontinued therapy; 32 received subsequent anti-PD-1 
therapy as part of crossover (n = 20) or off study (n = 12). Pembrolizumab plus CP 
significantly improved ORR (55% vs. 29%; P = 0.0016) and PFS (HR 0.53, 95% CI 0.31-
0.91, P = 0.0102; median 13.0 vs. 8.9 months). Overall survival was similar; 6-month 
survival rates were 92% in each arm. Without adjusting for exposure, for pembrolizumab 
plus CP vs. CP, treatment-related AEs led to discontinuation in 10% vs. 13%, were of grade 
≥ 3 severity in 39% vs. 26%, and led to death in 2% (sepsis, n = 1) vs. 3% (sepsis and 
pancytopenia, n = 1 each). The most common any-grade treatment-related AEs were fatigue 
(64% vs. 40%), nausea (58% vs. 44%), and anemia (32% vs. 53%). [Ref. 64]. 
Finally KEYNOTE-025 is an ongoing open-label, non-randomized, multi-center phase Ib 
study of pembrolizumab 10 mg/kg IV Q3 weeks in pretreated patients with PD-L1 positive 
advanced NSCLC in Japan [Ref. 65]. 
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The observed pharmacokinetic profile of pembrolizumab was typical of other IgG mAbs with
a half-life (t½) of approximately 2 to 3 weeks. There was no indication of dose dependency 
of half-life in the 3 dose groups and a dose related increase in exposure was observed from 1 
to 10 mg/kg. The long half-life supports a dosing interval of every 2 or 3 weeks. 
Pembrolizumab has been generally well-tolerated. The most common treatment related 
adverse events were fatigue (19.4%), pruritus (10.7%), and decreased appetite (10.5%). 
Adverse events of grade 3 or higher were reported in 47 of 495 patients (9.5%). The only 
treatment-related adverse events of an inflammatory or immune-mediated nature that 
occurred in more than 2% of patients were infusion-related reactions (in 15 patients [3.0%]), 
hypothyroidism (in 34 patients [6.9%]), and pneumonitis (in 18 patients [3.6%]). One 
infusion reaction led to treatment discontinuation. All the patients with hypothyroidism were 
successfully treated with medical therapy [Ref. 62].
Phase II and III studies
Pembrolizumab has been studied for various oncology indications, the most relevant in 
melanoma. In lung cancer specifically, several studies are ongoing, among them:
KEYNOTE-010 was a randomized, adaptively designed Phase II/III trial of pembrolizumab 
at 2 dose levels versus docetaxel in participants with NSCLC with PD-L1 positive tumors 
who had experienced disease progression after platinum containing systemic therapy.
Participants were randomized according to their TPS (extent of PD-L1 expression) defined as 
follows: a TPS ≥ 50% was considered strongly positive and a TPS = 1% to 49% was 
considered weakly positive. Approximately 920 participants were planned to be enrolled in 
this trial to examine the efficacy of pembrolizumab compared to docetaxel in an enriched 
population.
Overall, the results from KEYNOTE-001 and KEYNOTE-010 demonstrated that 
pembrolizumab provided substantial, clinically meaningful benefits in OS, PFS, and ORR in 
participants with NSCLC who progressed after platinum-containing chemotherapy and 
whose tumor cells expressed PD-L1. The PD-L1 selection employed in KEYNOTE-010
identified patients more likely to benefit from pembrolizumab and resulted in favorable 
hazard ratios (HR) in OS compared to docetaxel.
In previously treated participants with NSCLC with PD-L1, TPS ≥1%, and disease 
progression following platinum-containing chemotherapy, pembrolizumab provides a 
statistically significant and clinically meaningful OS benefit compared to standard docetaxel 
chemotherapy.
In KEYNOTE-010, pembrolizumab was superior to docetaxel in the strongly positive TPS ≥ 
50% stratum with regard to OS, with an HR of 0.54 (p = 0.00024) and 0.50 (p = 0.00002) for 
pembrolizumab 2 mg/kg Q3W versus docetaxel and 10 mg/kg Q3W versus docetaxel, 
respectively. Pembrolizumab was superior to docetaxel in the overall positive TPS ≥ 1% 
population with regard to OS, with an HR of 0.71 (p = 0.00076) and 0.61 (p<0.00001) for 
pembrolizumab 2 mg/kg Q3W and 10 mg/kg Q3W, respectively. Pembrolizumab was
superior to docetaxel in the strongly positive TPS ≥ 50% stratum with regard to PFS by 
independent review committee based on RECIST 1.1, with an HR of 0.58 (p = 0.00009) and 
0.59 (p = 0.00007) for pembrolizumab 2 mg/kg Q3W and 10 mg/kg Q3W, respectively,
compared to docetaxel. Pembrolizumab provided numerically superior benefit in PFS by 
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independent review committee based on RECIST 1.1 compared to docetaxel in the overall 
positive TPS ≥ 1% population, with an HR of 0.88 and 0.79 for pembrolizumab 2 mg/kg 
Q3W and 10 mg/kg Q3W, respectively; however, the differences were not statistically 
significant at the 0.001 level required per protocol. [Ref. 84]. 
Adverse events were as expected for pembrolizumab and docetaxel. Adverse events of 
special interest based on their likely immune aetiology, irrespective of attribution to study 
treatment, occurred in 69 (20%) of 339 patients in the pembrolizumab 2 mg/kg group and 64 
(19%) of 343 patients in the pembrolizumab10 mg/kg group. The most common of these 
events were hypothyroidism, hyperthyroidism, and pneumonitis . The only adverse events of 
special interest of grade 3–5 severity that occurred in 1% or more of patients were 
pneumonitis and severe skin reactions [Ref. 84]. 
Overall, pembrolizumab prolongs overall survival and has a favorable benefit-to-risk profile 
in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. 
KEYNOTE-010 has been submitted as the confirmatory study for the accelerated approval in 
NSCLC granted based upon results observed in KEYNOTE-001. [Ref. 66]. 
KEYNOTE-024 was a multicenter, international, randomized, open-label, controlled trial of 
intravenous (IV) pembrolizumab monotherapy versus the choice of multiple standard of care 
(SOC) platinum based chemotherapies in participants previously untreated for their Stage IV 
NSCLC and whose tumors expressed PD-L1 at ≥ 50%. 
First-line treatment with pembrolizumab significantly prolonged PFS (HR 0.50; 95% CI: 
0.37, 0.68; p<0.001) and OS (HR 0.60; 95% CI: 0.41, 0.89; p = 0.005) compared with SOC 
chemotherapy, inclusive of pemetrexed maintenance for participants with non-squamous 
tumors. 
In addition, pembrolizumab was associated with a higher ORR, including a higher CR rate, 
as well as a longer DOR as compared to SOC. 
Pembrolizumab was better tolerated than chemotherapy and AEs were easily managed. The 
observed safety profile of the pembrolizumab arm was consistent with the safety profile for 
pembrolizumab established to date. Based on the mechanism of action of pembrolizumab, 
immune-mediated AEs including pneumonitis occurred at a greater frequency with 
pembrolizumab compared to chemotherapy. Most immune-mediated events were of Grade 1 
or 2 severity, and none led to death. 
These data underscore the substantial benefit of pembrolizumab as initial therapy for 
participants with previously untreated, advanced NSCLC whose tumors express high levels 
of PD-L1 (TPS ≥ 50%) [Ref. 67].  
KEYNOTE-042 is a multicenter, international, randomized, open-label, controlled trial of 
IV pembrolizumab versus SOC platinum-based chemotherapy in participants previously 
untreated for their advanced or metastatic NSCLC and whose tumors express PD-L1 ≥ 
1%.Approximately 1240 participants will be enrolled [Ref. 68]. 
 
 
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1.6 
Rationale 
Survival of completely resected NSCLC remains poor [Ref. 69]. 
The benefit of adjuvant chemotherapy in NSCLC is 5.4% in OS at 5 years with the regimens 
most commonly used, which also induce toxicities that have a major impact on the treatment 
tolerability.  
Recent clinical trials assessing the use of the MAGE A3 vaccines have failed to demonstrate 
any improvement in efficacy. The RADIANT trial of erlotinib in the EGFR mutated 
subgroup, suggests that this treatment may improve DFS in EGFR mutated tumors, but not 
affect OS. Therefore there is a need to identify new treatment strategies that can increase the 
efficacy of adjuvant treatment.  
Although first-generation immunotherapies in advanced disease were of limited efficacy, 
they provided proof-of-concept that, in some patients, the immune balance could be shifted in 
favor of tumor elimination. Expanding knowledge and understanding of the immune 
system’s role in cancer have revealed multiple mechanisms by which tumors evade immune 
destruction. In particular, negative regulatory pathways involved in the T-cell-mediated 
response, including interaction of PD-1 and PD-L1, appear to have a role in tumor 
progression. 
Checkpoint inhibitors have demonstrated benefits with a reasonable safety profile/tolerability 
in lung cancer in the advanced setting.  
Theoretically, immunotherapy should work best in the situation of minimal residual disease. 
The adjuvant setting is therefore the ideal clinical scenario to test the true place of 
immunotherapy with these new agents and potentially improve the cure rate after surgery.  
This study will be a randomized trial in NSCLC patients after surgery and completed 
adjuvant treatment comparing adjuvant pembrolizumab versus placebo.  
The planned dose of pembrolizumab for this trial is 200 mg every 3 weeks (Q3W). The initial 
dose approved by the Food and Drug Administration (FDA) for treatment of melanoma 
subjects was 2 mg/kg Q3W. Currently, clinical trials evaluating pembrolizumab are using a 
fixed dose of 200 mg Q3W. The use of a fixed dose is based on PK findings summarized 
below. 
The PK profile of pembrolizumab is consistent with that of other humanized monoclonal 
antibodies, which typically have a low clearance and a limited volume of distribution. A 
population PK model, which characterized the influence of body weight and other subject 
covariates on exposure using available data from 1139 subjects (from Keynote-001 and 
Keynote-002) has been performed. The majority of these subjects (1077; 94.6%) had 
advanced melanoma. The distribution of exposures from the 200 mg fixed dose were 
predicted to considerably overlap those obtained with the 2 mg/kg dose, and importantly, 
maintained individual subject exposures within the exposure range established in melanoma 
as associated with maximal clinical response. This comparison also demonstrated that the 
200 mg Q3W regimen provided no substantive differences in PK variability (range of the 
distribution of individual exposures) as seen with weight-based dosing. 
In translating to other solid tumor indications, similarly flat exposure-response relationships 
for efficacy and safety as observed in subjects with melanoma can be expected, as the 
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antitumor effect of pembrolizumab is driven through immune system activation rather than 
through a direct interaction with tumor cells, rendering it independent of the specific tumor 
type. In addition, available PK results in subjects with melanoma, NSCLC, and other solid 
tumor types support a lack of meaningful difference in PK exposures obtained at tested doses 
among tumor types. 
2 Objectives of the trial 
2.1 
Primary/dual-primary objectives 
To prospectively investigate whether adjuvant treatment with pembrolizumab after 
completion of radical surgery (lobectomy/pneumonectomy) with or without standard 
adjuvant chemotherapy for stage IB (T ≥ 4 cm) -II-IIIA NSCLC patients improves Disease 
Free Survival (DFS), as assessed locally by the investigator, compared to placebo in the PD-
L1 strong positive subgroup or overall population.  
Note: TNM stage (according to the 7th edition of the TNM classification for lung 
cancer) 
2.2 
Secondary objectives 
♦ To prospectively compare DFS as assessed by the investigator in the PD-L1 positive 
population (TPS≥1%); 
♦ To prospectively determine and compare OS in the PD-L1 strong positive and overall 
population; 
♦ To prospectively determine and compare OS in the PD-L1 positive population; 
♦ To prospectively determine and evaluate the Lung Cancer Specific Survival (LCSS) 
in the whole population irrespective of PD-L1 status; 
♦ To prospectively assess the safety of pembrolizumab after radical surgery followed by 
standard adjuvant chemotherapy. 
2.3 
Exploratory Objectives 
CCI
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2.4 
End-points 
2.4.1 
Primary/dual-primary endpoints 
♦ DFS in the PD-L1 strong positive subgroup;  
♦ DFS in the overall population. 
With the use of primary and dual-primary endpoints, if either of the tests in the primary or 
dual-primary endpoint is significant, then the study can be declared successful in their 
respective population or sub-population.  
2.4.2 
Secondary endpoints 
♦ DFS in the PD-L1 positive population; 
♦ OS in the overall population;  
♦ OS in the PD-L1 strong positive subgroup; 
♦ OS in the PD-L1 positive population; 
♦ LCSS in the overall population; 
♦ Toxicity according to CTCAE version 4.03. 
2.4.3 
Exploratory endpoints 
♦ Health-Related Quality of Life (HRQOL); 
♦ Pharmacokinetics (PK) of pembrolizumab in this patient population; 
♦ Anti-drug antibiodies (ADA) against pembrolizumab (immunogenicity evaluation); 
♦ Quality assurance for surgery; 
♦ Exploratory assessment of predictive biomarkers and immune dynamics 
(Translational research). 
3 Patient selection criteria 
Patient enrollment will follow a three-step procedure as illustrated in Chapter 4 (step 1 
registration, step 2 central confirmation of PD-L1 status, step 3 randomization). Patients must 
meet all of the criteria described in Sections 3.1, 3.2 and 3.3 to be eligible for randomization 
in step 3. 
CCI
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3.1 
Registration - step 1 (ORTA step 1) 
Before patients registration, written informed consent for tumor testing must be given 
according to ICH/GCP and national/local regulations. For patients that accept to 
participate in the translational research, we recommend the informed consent for 
translational research to be signed before registration step 1.  
3.1.1 
Disease status 
♦ Pathological diagnosis of NSCLC confirmed at surgery, any histology is eligible;  
♦ Confirmed UICC v7 stage IB with T ≥ 4 cm, II-IIIA NSCLC after complete surgical 
resection (lobectomy, sleeve lobectomy, bi-lobectomy or pneumonectomy) as 
documented in the pathology report;  
Note: TNM stage according to the 7th edition of the TNM classification for lung cancer 
♦ Resection margins proved microscopically free (R0); Resection margins are 
evaluated at the bronchial, venous and arterial stumps, peribronchial soft tissue, 
any peripheral margin near the tumor or of additionally resected tissue; 
♦  
 A systematic complete mediastinal lymph node dissection or a lobe-specific 
mediastinal lymph node dissection (Appendix K) is recommended. At a 
minimum, the pathology and/or operative report must include the examination of 
at least two different mediastinal lymph node (N2) levels, one of which is the 
subcarinal (level 7) and the second of which is lobe-specific.  
♦ In the uncommon clinical situation where the surgeon thoroughly examines a 
particular mediastinal lymph node level and does not find any lymph nodes, that 
mediasintal lymph node level may be counted among the minimum two required 
levels. However, the surgeon must clearly document in the operative report or in 
a separate written statement that the lymph node level was explored and no lymph 
nodes were present. Normal appearing lymph nodes, if present, must be biopsied 
or/removed. 
♦ No extracapsular extension of tumor in resected mediastinal (N2) lymph nodes. 
Extracapsular tumor extension is permitted in resected N1 lymph nodes; 
♦ The highest mediastinal node removed can be positive for malignancy;  
♦ Carcinoma in situ can be present at bronchial margin. 
♦ Patients with two synchronous primary non-small cell lung cancers are excluded 
from the study.  
♦ Availability of tumor sample obtained at surgical resection for PD-L1 
Immunohistochemistry (IHC) expression assessment. The tumor sample must be 
shipped for PD-L1 IHC expression testing at a central pathology laboratory. Please 
refer to the laboratory manual for further details. Patients will be eligible to 
participate regardless of the level of PD-L1 status, however tissue must be considered 
satisfactory for characterization of PD-L1 status.  
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♦ Submission of formalin-fixed paraffin embedded tumor tissue sample blocks are 
preferred; if submitting unstained slides, the slides must be freshly cut and 
submitted to the central testing laboratory; 
♦ Patients whose samples are inadequate for PD-L1 determination will not be 
enrolled.  
3.1.2 
Patient status 
♦ At least 18 years; 
3.2 
Central confirmation of PD-L1 status - step 2 
This central confirmation through EORTC is required for enrolling the patient in step 3. 
3.3 
Randomization - step 3 (ORTA step 2) 
Before patient randomization, written informed consent (‘Main Study’) for 
participation in the study must be given according to ICH/GCP, and national/local 
regulations. 
3.3.1 
Disease status 
♦ No evidence of disease (NED) at clinical examination and baseline radiological 
assessment as documented by contrast enhanced chest/upper abdomen CT scan, brain 
CT/MRI and clinical examination within 12 weeks prior to the randomization date.  
3.3.2 
Patient status 
♦ ECOG Performance status 0-1; 
♦ Adequate organ function performed within 10 days of treatment initiation and defined 
as follows: 
Table 3. Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,5 x 10^9/L  
Platelets 
≥100 x 10^9/L 
Hemoglobin 
≥ 9 g/dL or ≥5.6 mmol/L  
Renal 
Creatinine OR 
Measured or calculated creatinine clearance 
(GFR can also be used in place of creatinine or CrCl) 
≤ 1.5xULN OR 
≥ 30 mL/min for subject with  
creatinine levels >1.5x institutional 
ULN 
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System 
Laboratory Value 
Hepatic 
Total bilirubin 
≤ 1.5xULN OR 
Direct bilirubin ≤ ULN for subjects 
with total bilirubin levels >1.5xULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5xULN  
a Creatinine clearance should be calculated per institutional standard. 
b. For patients with Gilbert's disease total bilirubin may be > 1.5 x ULN, however direct bilirubin must be normal 
 
♦ Adjuvant chemotherapy is not mandatory but considered for patients with stage IB (T 
≥ 4 cm) and strongly recommended for stage II and IIIA, and will be administered 
according to national and local guidelines. Patients who received more than 4 cycles 
of adjuvant therapy are not eligible; 
♦ Patients not receiving adjuvant chemotherapy must be randomized and dosed with 
pembrolizumab/placebo within 12 weeks of their surgery date. 
♦ Participants who receive adjuvant chemotherapy must begin adjuvant 
chemotherapy within 12 weeks of their surgery date. Patients receiving adjuvant 
chemotherapy must be randomized and dosed with pembrolizumab/placebo at 
least 3 weeks but no more than 12 weeks from the last dose of chemotherapy (Day 
1 of last cycle). 
♦ No prior or planned neoadjuvant or adjuvant radiotherapy and/or neoadjuvant 
chemotherapy for the current malignancy is allowed;No prior treatment with anti-PD-
1, anti-PD-L1/2, anti-CD137, CTLA-4 modulators or any other immune-modulating 
agents; patients receiving live vaccine within 30 days prior to the first infusion of 
study treatment are not eligible; 
♦ No current participation in an interventional clinical trial or treatment with an 
investigational agent or use of an investigational device within 4 weeks of the first 
infusion of study treatment; 
♦ No known history of Human Immunodeficiency Virus (HIV) (known HIV 1/2 
antibodies positive). No known active Hepatitis B or C. Active Hepatitis B is defined 
as a known positive HBsAg result. Active Hepatitis C is defined by a known positive 
Hep C Ab result and known quantitative HCV RNA result greater than the lower 
limits of detection of the assay; 
♦ No chronic use of immunosuppressive agents and/or systemic corticosteroids or any 
use in the last 3 days prior to the first infusion of study treatment: 
♦ Corticosteroid use on study for management of ECIs (Pembrolizumab Event of 
Clinical Interest), as pre-medication for the administration of chemotherapies, 
and/or a premedication for IV contrast allergies/reactions is allowed;  
♦ Daily prednisone at doses of 5-7.5 mg is allowed as an example of replacement 
therapy. Equivalent hydrocortisone doses are also permitted if administered as a 
replacement therapy; 
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♦ No history of interstitial lung disease (ILD) OR a history of (non-infectious) 
pneumonitis that required oral or IV steroids (other than COPD exacerbation) or 
current pneumonitis. 
♦ No active autoimmune disease that has required systemic treatment in past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Any replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment and is allowed. Patients with hyperthyroidism or 
hypothyroidism but that are stable on hormone replacement are also allowed. 
♦ No history of a hematologic or primary solid tumor malignancy, unless in remission 
for at least 5 years. A pT1-2 prostatic cancer Gleason score < 6, superficial bladder 
cancer, non melanomatous skin cancer or carcinoma in situ of the cervix is eligible; 
Note: prior radiotherapy for another malignancy (breast cancer, lymphoma, germ cell tumor, 
etc.) is not an exclusion criterion, the same applies for prior anti-cancer systemic 
chemotherapy 
♦ No previous allogeneic tissue/solid organ transplant; 
♦ No active infection requiring therapy;  
♦ No surgery or chemotherapy related toxicity (non-hematological toxicity resolved to 
grade 1 (see Appendix D), with the exception of alopecia, fatigue, neuropathy and 
lack of appetite /nausea); 
♦ Female patients with childbearing potential must have a negative urine or serum 
pregnancy test at screening (within 72 hours of first infusion of study medication). If 
the urine test cannot be confirmed as negative, a serum pregnancy test will be 
required. The serum pregnancy test must be negative for the subject to be eligible. 
Non-childbearing potential is defined as (by other than medical reasons): 
♦ ≥45 years of age and has not had menses for greater than 1 year, 
♦ Amenorrheic for > 2 years without a hysterectomy and oophorectomy and an FSH 
value in the postmenopausal range upon pretrial (screening) evaluation, 
♦ Whose status is post hysterectomy, oophorectomy or tubal ligation. Documented 
hysterectomy or oophorectomy must be confirmed with medical records of the 
actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed 
with medical records of the actual procedure otherwise the subject must be willing 
to use two adequate barrier methods throughout the study, starting with the 
screening visit through 120 days after the last infusion of study treatment. 
Information must be captured appropriately within the site's source documents. 
♦ If of childbearing potential, female patients must be willing to use two adequate 
barrier methods throughout the study, starting with the screening visit through 120 
days after the last infusion of study treatment (see Appendix L). 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. Please refer to Appendix M for recommendation based on Clinical Trial 
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Facilitation Group guidelines for sites and countries where applicable (e.g. United 
Kingdom, Norway, Sweden, Portugal, etc.). 
♦ Male patients with a female partner(s) of child-bearing potential must agree to use 
two adequate barrier methods throughout the trial starting with the screening visit 
through 120 days after the last infusion of study treatment is received (see Appendix 
L). Males with pregnant partners must agree to use a condom; no additional method 
of contraception is required for the pregnant partner. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. Please refer to Appendix M for recommendation based on Clinical Trial 
Facilitation Group guidelines for sites and countries where applicable (e.g. United 
Kingdom, Norway, Sweden, Portugal, etc.). 
♦ Female patients who are breast feeding must discontinue nursing prior to the first 
infusion of study medication and until 120 days after the last study treatment; 
♦ Absence of severe comorbidities that in the opinion of the Investigator might hamper 
the participation to the study and/or the treatment administration;  
♦ Patients not receiving adjuvant chemotherapy must be randomized and dosed with 
pembrolizumab/placebo within 12 weeks of their surgery date. Participants who 
receive adjuvant chemotherapy must begin adjuvant chemotherapy within 12 weeks 
of the surgery date. Patients receiving adjuvant chemotherapy must be randomized 
and dosed with pembrolizumab/placebo at least 3 weeks but no more than 12 weeks 
from the last dose of chemotherapy (Day 1 of last cycle). 
After the enrollment step in ORTA, patients will be automatically randomized in the 
Interactive Voice Response System (IVRS). 
Important note: An additional +2 day window is allowed for randomization. All 
eligibility criteria must be adhered to.  
4 Trial Design 
This is an international, triple-blinded, placebo-controlled randomized phase III trial. 
 
 
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4.1
Multi step process for enrollment
Enrollment of patients will follow a three-step informed consent process.
Figure 1: Trial design
4.1.1
Registration - step 1 (ORTA step 1)
Upon signing the informed consent, patients will be registered and a sample of the resected 
tumor will be shipped and evaluated for PD-L1 status at a central pathology laboratory.
All patients will be required to submit a sample of their resected tumor for PD-L1 IHC 
expression for evaluation by a vendor designated by the Sponsor. Tumor material will be 
evaluated by the central laboratory following procedures outlined in the Procedures manual. 
If the sample is inadequate for analysis, another sample could be provided or the patient will 
be considered ineligible for further randomization in the trial. 
4.1.2
Central confirmation of PD-L1 status - step 2
Confirmation of PD-L1 status by the central laboratory through EORTC.
4.1.3
Randomization - step 3 (ORTA step 2)
The confirmation of PD-L1 status must be available before proceeding with the enrollment in 
the study. The patient's written informed consent to undergo screening for the clinical trial 
must be given prior to the performance of any protocol laboratory/imaging tests that are not 
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part of local routine guidelines. Patients who are not receiving adjuvant chemotherapy can 
sign the main consent concurrently with the PD-L1 informed consent or after the results of 
the PD-L1 status are known. Patients receiving adjuvant chemotherapy may sign the main 
informed consent after completing chemotherapy.  
Once patients are confirmed to be eligible through ORTA they will be automatically 
randomized in the Interactive Voice Response System (IVRS). For all patients, dosing must 
occur within 7 days of randomization. 
A total of 1180 eligible patients will be randomized at 1:1 ratio into two triple 
blinded,treatment arms (approximately 590 patients each): 
♦ Patients in one arm will receive pembrolizumab (see Sections 5.2 and 5.4); 
♦ Patients in the other arm will receive placebo (see Sections 5.1 and 5.4).  
Patients not receiving adjuvant chemotherapy must be randomized and dosed with 
pembrolizumab/placebo within 12 weeks of their surgery date. Participants who receive 
adjuvant chemotherapy must begin adjuvant chemotherapy within 12 weeks of their 
surgery date. Patients receiving adjuvant chemotherapy must be randomized and dosed 
with pembrolizumab/placebo at least 3 but no more than 12 weeks from the last dose of 
chemotherapy (Day 1 of last cycle). Randomization will be performed centrally (see 
Chapter 14) and will be stratified for the following factors: 
♦ Stage (IB vs II vs IIIA); 
♦ Adjuvant chemotherapy (no adjuvant chemotherapy versus adjuvant chemotherapy); 
♦ PD-L1 status: negative (TPS=0%) versus weak positive (TPS=1-49%) versus strong 
positive (TPS≥50%);  
♦ Region (Western Europe versus Eastern Europe versus the Rest of the world versus 
Asia)  
The proportion of patients with stage IB will be closely monitored by the study steering 
committee to ensure that this proportion does not exceed 35% of the study population. 
This is a triple blind study according to the CDISC Clinical Research Glossary Version 8.0. 
The patient, the investigator and study team at site (an on-site pharmacist will remain 
unblinded to treatment assignment), and the EORTC Headquarters study team will remain 
blinded to treatment allocation up to the database lock for the final analysis of the 
primary/dual-primary endpoints. 
However, at any time during the trial, in case of a safety concern affecting an individual 
patient, the site investigator can request the unblinding of that patient.  
Please see Section 14.6 for Unblinding Procedures 
The exploratory parameters in this study will be refined according to the current 
knowledge in the field during trial advancement and at the time of trial completion. 
 
 
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4.2 
Unblinding data 
The authorized unblinding of treatment arm will take place under the following conditions:  
♦ Emergency Unblinding 
♦ Unblinding by Investigator Request After Disease Recurrence 
♦ Unblinding at Final Analysis 
♦ Other Unblinding During the Course of the Study  
Please see Section 14.6 for Unblinding Procedures 
5 Therapeutic regimens, expected toxicity, 
dose modifications 
5.1 
Placebo 
Placebo will be normal saline solution prepared by the local pharmacist, dosed and 
administered in the same manner as the investigational product. 
(Note specific to Japan): normal saline solution used as a placebo is not considered an 
investigational product defined by the Japan's Pharmaceutical and Medical Devices Act. 
5.2 
Pembrolizumab (MK-3475) 
The nomenclature of pembrolizumab drug substance  
Code name: MK 3475 (Anti-PD-1) 
Chemical name: Humanized X PD-1_mAb (H409A11) IgG4 
5.2.1 
Selected dose 
The planned dose of pembrolizumab for this trial is 200 mg every 3 weeks (Q3W). Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab across all indications and regardless of tumor type. As 
outlined below, this dose is justified by:  
Clinical data from eight randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every two weeks (Q2W); 
Clinical data showing meaningful improvement in benefit-risk including overall survival at 
200 mg Q3W across multiple indications; and 
Pharmacology data showing full target saturation in both systemic circulation (inferred from 
pharmacokinetic [PK] data) and tumor (inferred from physiologically based pharmacokinetic 
[PBPK] analysis) at 200 mg Q3W.Among the eight randomized dose-comparison studies, a 
total of 2262 subjects were enrolled with melanoma and non-small cell lung cancer 
(NSCLC), covering different disease settings (treatment naïve, previously treated, PD-L1 
enriched and all-comers) and different treatment settings (monotherapy and in combination 
with chemotherapy). Five studies compared 2 mg/kg Q3W vs 10 mg/kg Q3W (KN001 B2, 
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KN001 D, KN002, KN010 and KN021), and three studies compared 10 mg/kg Q3W vs 10 
mg/kg Q2W (KN001 B3, KN001 F2 and KN006). All of these studies demonstrated flat 
dose- and exposure-response relationships across the doses studied representing an 
approximate 5 to 7.5 fold difference in exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W 
provided similar responses to the highest doses studied. Subsequently, flat dose/exposure-
response relationships were also observed in other tumor types including head and neck 
cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg 
Q3W as the appropriate dose independent of the tumor type. These findings are consistent 
with the mechanism of action of pembrolizumab, which acts by interaction with immune 
cells, and not via direct binding to cancer cells.Additionally, pharmacology data clearly show 
target saturation at 200 mg Q3W. First, PK data in KN001 evaluating target-mediated drug 
disposition (TMDD) conclusively demonstrated saturation of PD-1 in systemic circulation at 
doses much lower than 200 mg Q3W. Secondly, a PBPK analysis was conducted to predict 
tumor PD-1 saturation over a wide range of tumor penetration and PD-1 expression. This 
evaluation concluded that pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in 
both blood and tumor.Finally, population PK analysis of pembrolizumab, which 
characterized the influence of body weight and other subject covariates on exposure, has 
shown that the fixed-dosing provides similar control of PK variability as weight based 
dosing, with considerable overlap in the distribution of exposures from the 200 mg Q3W 
fixed dose and 2 mg/kg Q3W dose. Supported by these PK characteristics, and given that 
fixed-dose has advantages of reduced dosing complexity and reduced potential of dosing 
errors, the 200 mg Q3W fixed-dose was selected for evaluation across all pembrolizumab 
protocols.
5.3
Drug supply
The pharmacist shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
5.3.1
Placebo
Placebo for this trial will not be provided by MSD but will be provided by the Investigational 
sites and prepared by the local unblinded pharmacist.
5.3.2
Pembrolizumab
Pembrolizumab will be provided by MSD.
Initial drug supply
Refer to Pharmacy Manual.
Drug resupply by IVRS
Refer to the IVRS Manual.
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5.3.3
Packaging, labeling, handling and storage
Packaging
Packaging and labeling of Pembrolizumab and placebo will be in accordance with Good 
Manufacturing Practice (GMP) for clinical trials. 
Labeling
Pembrolizumab will be affixed with a clinical label in accordance with regulatory 
requirements. 
Dosage and Administration
Pembrolizumab will be provided by MSD in vials of 50 mg lyophilized powder or in 100 mg 
liquid vials. 
Details on the infusion preparation and administration are provided in the Pharmacy Manual.
Storage
Investigational product must be stored in a secure area according to local regulations. It is the 
responsibility of the Investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites
by authorized personnel according to local regulations.
The pharmacist must ensure that the investigational product is stored in accordance with the 
environmental conditions (temperature, light and humidity) as determined by the Sponsor 
and defined in the Investigator Brochure.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
5.3.4
Drug accountability
The pharmacist is responsible for investigational product accountability, reconciliation, and 
record maintenance. In accordance with all applicable regulatory requirements, the 
investigator or designated site staff must maintain investigational product accountability 
records throughout the course of the study. This person(s) will document the amount of 
investigational product dispensed and/or administered to study patients, the amount returned, 
and the amount received from and returned to MSD, when applicable.
5.3.5
Return of investigational product
The pharmacist is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed and returned and the amount remaining 
at the conclusion of the trial. 
For all trial sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return.
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5.3.6 
Destruction of investigational product 
The pharmacist is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the patients and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate. Where local 
discard and destruction is appropriate, the pharmacist is responsible for ensuring that a local 
discard/destruction procedure is documented. Unused clinical supplies can only be destroyed 
after being inspected and reconciled by the responsible study monitor. 
5.3.7 
Standard Policies 
Trial site personnel will have access to a central electronic randomization system (IVRS) to 
allocate patients, to assign treatment to patients and to manage the distribution of clinical 
supplies. Each person accessing the IVRS must be assigned an individual unique PIN. They 
must use only their assigned PIN to access the system, and they must not share their assigned 
PIN with anyone. 
5.4 
Treatment schedule 
Pembrolizumab/Placebo at a dose of 200 mg, administered intravenously (IV), every 3 
weeks, for a total of 18 infusions, approximately one year. 
Note: if visits are missed and/or delayed treatment will continue beyond 1 year in order to 
complete 18 infusions.  
5.5 
Treatment duration 
In both arms, treatment will be administered for a maximum of 18 infusions for 
approximately one year, unless one of the withdrawal criteria applies (see Section 5.6). In 
case of delay in scheduled administration, the treatment can continue beyond 1 year in order 
to complete the 18 infusions. 
5.6 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or discontinue treatment.  
In this trial, a subject may discontinue from study treatment for the reason outlined below but 
will remain in the trial for follow up as outlined in Section 6.7, as long as the subject does not 
withdraw consent. Discontinuation from study treatment is permanent. Once a subject has 
discontinued study treatment for the reason outlined below, he/she shall not be allowed to 
begin study treatment again (This is distinct and different from infusion / treatment delays 
required due to adverse events. For guidelines for management of toxicity and schedule 
modification and supportive care guidelines please refer to Appendix G and Appendix H). A 
subject should stop the study treatment (but should be encouraged to continue to be 
monitored/followed-up in the trial) for any of the following reasons: 
♦ The subject or legal representative (such as legal guardian) withdraws consent; 
♦ Disease recurrence by RECIST version 1.1; 
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♦ Unacceptable adverse events; 
♦ The subject’s treatment assignment has been unblinded by the investigator, MSD 
subsidiary, or through the emergency unblinding call center. 
♦ Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that require active treatment; 
♦ Inter-current illness (including second malignancy) that, in the opinion of the 
investigator, warrants the patient’s withdrawal from study treatment; 
♦ Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AE in 
Appendix G and Appendix H. 
♦ Investigator’s decision to withdraw the subject; 
♦ The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or Sponsor, placed the participant at unnecessary risk 
from continued administration of study intervention. 
♦ The subject has a positive pregnancy test or is pregnant; 
♦ Noncompliance with trial study treatment or procedure requirements; 
♦ Administrative reasons. 
After the end of treatment, each subject will be followed for a minimum of 30 days for 
adverse event monitoring (serious adverse events). Events of Clinical Interests (ECIs) will be 
collected for up to 90 days following cessation of treatment or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy. Subjects will have post-treatment 
follow-up specified in Section 6.7. 
5.7 
Management of toxicity 
For management of toxicity and supportive care guidelines please refer to Appendix G and 
Appendix H. 
5.8 
Concomitant medications 
All treatments that the Investigator considers necessary for a patient's welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids. If changes occur during the study period, documentation of drug dosage, 
frequency, route, and date will also be included on the CRF. 
All concomitant medications received within 30 days before the first infusion of study 
treatment and 30 days after the last infusion of study treatment must be recorded. 
5.8.1 
Prohibited medications 
♦ Any concurrent anti-cancer treatment (surgery, radiotherapy, systemic therapy); 
♦ Any investigational agents; 
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♦ Immunosuppressive agents (except for patients treated for irAE); 
♦ Immune-modulating agents  
♦ Chronic systemic corticosteroids, with equivalents of more than 7.5mg of prednisone 
(except for patients which during the study developed endocrinopathies requiring 
stable doses of hormone replacement therapy such as hydrocortisone); 
♦ Steroid premedications for contrast CTs are permissible; 
♦ Live vaccines within 30 days prior to the first infusion of study therapy and while 
participating in study. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid vaccine. 
6 Clinical evaluation, laboratory tests and 
follow-up 
6.1 
General Considerations 
The patient's written informed consent to undergo screening for the clinical trial must be 
given prior to the performance of any protocol laboratory/imaging tests that are not part of 
local routine guidelines. Therefore, if a patient had laboratory/imaging tests as part of local 
routine guidelines (standard of care) prior to signing informed consent, the procedures will be 
acceptable for screening purposes if they are within the window required by the protocol. 
The Trial Flow Charts - Section 6.8 summarize the trial procedures to be performed at each 
visit. Chest and upper abdomen CT scan to assess disease status are mandatory. PET alone 
will not be used for the disease assessment.  
Cytology and/or histology are mandatory to confirm relapse in solitary or in doubtful lesions. 
Histological or cytological evidence of recurrence should be attempted in all cases except for 
brain metastases. 
Individual trial procedures are described in detail below. It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.  
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to patient safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature and thus local regulations may require that additional informed 
consent be obtained from the patient. In these cases, such evaluations/testing will be 
performed in accordance with those regulations.  
6.1.1 
Subject Identification Card 
All patients will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the patient with a Subject Identification Card immediately after the patient 
provides written informed consent. 
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The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available. 
6.2 
Before treatment start 
♦ Eligibility criteria (see Section 3.1); 
A specific informed consent ('Registration') has been prepared to send the tumor sample for 
thePD-L1 status and must be signed by the patient before shipment of the tumor. This is 
mandatory. At the same time the consent for the optional Translational Research (TR) 
('Biomedical Research') will be presented to the patient (see Section 6.5).This consent must 
be signed before any additional TR samples are collected. It is recommended patients sign 
the TR ICF along with Registration to collect Step 1 samples. However, the patient can 
reconsider taking part in the optional TR at a later stage during the trial. The Main informed 
consent will be signed during the referral period after the surgery if no adjuvant 
chemotherapy is foreseen or at the end of standard adjuvant chemotherapy. This consent 
must be signed before any additional TR samples are collected. 
♦ Whole blood for germline (20 mL) and serum (20 mL) (during Step1) 
♦ Whole blood for correlative DNA, whole blood for correlative RNA, PBMC (for 
selected sites in Spain, France and Switzerland only, during Step 3) 
6.2.1 
Within 12 weeks prior to randomization 
The patient's written informed consent ('Main Study') to undergo screening for the clinical 
trial must be given prior to the performance of any protocol laboratory/imaging tests (that are 
not part of local routine guidelines) and collection of HQRoL,.  
Upon confirmation of the PD-L1 status and (‘Main Study’) written informed consent, the 
following exams will be performed during the screening phase (maximum of 12 weeks from 
ICF signature until the randomization) and results must be known before randomization: 
♦ Eligibility criteria (see Section 3.3); 
♦ Demographics, medical history, height and smoking status; 
♦ HIV, HBV, HCV serology (Active Hepatitis B is defined as a known positive HBsAg 
result. Active; active Hepatitis C is defined by a known positive Hep C Ab result and 
known quantitative HCV RNA results greater than the lower limits of detection of the 
assay) if clinically indicated according to the local investigator; 
♦ Physical examination (including heart rate, blood pressure, weight and temperature); 
♦ ECOG performance status (see Appendix C); 
♦ Urinalysis (specific gravity, pH, proteins, glucose, blood using a dipstick; elements 
and microscopic examination if needed); 
♦ Thyroid function: TSH; in case of elevated TSH to add free T3 and T4; 
♦ Cardiac function: 12-lead ECG;  
♦ Disease evaluation : the following imaging work up must be performed:  
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♦ Contrast-enhanced chest and upper abdomen CT scan; 
♦ Contrast-enhanced brain CT scan or MRI; 
♦ Concomitant medications assessment; 
♦ Adverse event assessment; 
♦ HRQoL evaluations : EORTC QLQ-C30 version 3, EORTC QLQ-LC13 and EQ-5D; 
Please refer to Table 4 in Section 6.8.1. 
6.2.2 
Within 10 days prior to treatment initiation 
♦ Hematology: white blood cell count (WBC), absolute neutrophils count (ANC), 
lymphocytes, eosinophils, basophils, monocytes, red blood cell count (RBC), 
hemoglobin (Hgb), haematocrit (Hct), platelets; 
♦ Serum chemistry: creatinine, urea or blood urea nitrogen (BUN), total bilirubin*, 
AST, ALT, alkaline phosphatase, LDH, tot proteins, potassium (K), sodium (Na), 
calcium (Ca), bicarbonate (HCO3) (HCO3 testing could be optional in countries where 
testing is not standard of care), albumin and glucose. 
* If total bilirubin levels >1.5xULN, direct bilirubin must be collected. 
Please refer to Table 4 in Section 6.8.1. 
Note: hematology and serum chemistry are to be repeated if performed more than 10 days 
prior to the first infusion of study treatment. 
6.2.3 
Within 72 hours prior to treatment initiation 
♦ Pregnancy test: serum (or urine) beta HCG in fertile female study participants. This 
pregnancy test is to be renewed/repeated during protocol treatment at least monthly or 
more frequently if required by national regulations/institution guidelines  
Note: the pregnancy test is to be repeated if performed more than 72 hours prior to the 
first infusion of study treatment. 
6.2.4 
Within 24 hours prior to treatment initiation 
♦ Pharmacokinetics: one blood sample of 3.5 mL;  
♦ Anti-pembrolizumab antibody (ADA): one blood sample of 6 mL; 
♦ Additional PK and ADA samples will be collected at subsequent infusions outlined in 
study;  
Please refer to in Section 6.8.3. 
6.3 
During treatment 
Pregnancy test: serum (or urine) beta HCG in fertile female study participants. This 
pregnancy test is to be renewed/repeated during protocol treatment at least monthly or more 
frequently if required by national regulations/institution guidelines.  
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Infusion schedule 
1) Normal schedule  
Window of administration is up to 3 days before or after the scheduled day of each infusion, 
due to administrative reasons, except for infusion 1 where the window is + 7 days from 
randomization.  
2) Delayed infusions 
Definition of delayed infusion: an infusion is considered as delayed if administration occurs 
at least 3 days after the theoretical date, but less than 10 days after the theoretical date. Future 
infusion dates should follow every 3 weeks, calculated from the actual date of administration 
of the delayed infusion. If infusion is delayed (e.g. patient on holiday, adverse events, 
hospitalized, etc) the site must: 
♦ Complete all protocol required laboratory tests, physical exam, adverse events 
assessments, concomitant medication assessments and HRQoL assessments within 
the required window prior to the new date of infusion.  
♦ Follow calendar days for imaging assessment and not adjust for delays. The reference 
date for imaging scans must be the date of the first infusion (infusion 1). 
3) Missed infusions 
Definition of missed infusions: an infusion is considered as missed if administration would 
occur more than 10 days after the theoretical date. In this case, no infusion is given. The next 
ainfusion should occur as soon as the cause of the missed infusion is resolved and not 
delayed until the next scheduled infusion. Future infusion dates should follow every 3 weeks, 
calculated from the actual date of administration of the delayed infusion. 
If infusion administration is missed (e.g. toxicity, delay greater than 10 days, etc), the site 
must: 
♦ Complete all protocol required laboratory tests, physical exam, adverse events 
assessments, concomitant medication assessments and HRQoL assessments within 
the required window prior to the missed date of infusion administration. If a visit did 
not occur, documentation is required (see CRF completion guidelines). 
♦ Follow calendar days for imaging assessment and do not adjust for delays. The 
reference date for imaging scans must be the date of the first infusion (infusion 1). 
Due to missed infusions, completion of 18 infusions will extend beyond 1 year and 
must be assessed as per protocol Section 6.3.  
The visits for evaluations described below refer to study drug administrations.  
It is therefore expected that results of laboratory (hematology, serum chemistry, 
thyroid, urinalysis) and imaging results are available prior to study drug 
administrations and within required timelines every 3 weeks (+/- 3 days), every 6 
weeks (+/- 3 days) and every 12 weeks (+/- 3 days or +/- 2 weeks) depending on the 
type of evaluation. 
 
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Figure 2: Overview schedule of test/exams 
 
6.3.1 
Every 3 weeks (+/- 3 days) 
Before each infusion, the following exams will be performed every 3 weeks and laboratory 
results must be available prior to study drug administration:  
♦ Physical examination / ECOG performance status see Section 6.2.1; 
♦ Assessments of adverse events;  
♦ Hematology and serum chemistry see Section 6.2.2; 
♦ Concomitant medication assessment 
Please refer to Table 4 in Section 6.8.1. 
6.3.2 
Every 6 weeks (+/- 3 days) 
The following test will be performed every 6 weeks and results must be available prior to 
study drug administration:  
♦ Thyroid function: TSH; in case of elevated TSH to add free T3 (or total T3) and free 
T4; 
Please refer to Table 4 in Section 6.8.1. 
6.3.3 
Every 12 weeks (+/- 3 days) 
In addition to the above, an urinalysis will be performed as per Section 6.2.1 and results must 
be available prior to study drug administration. 
 
HRQoL questionnaires will be collected: EORTC QLQ-C30 version 3, EORTC QLQ-LC13 
and EQ-5D  
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♦ Questionnaires are filled in every 12 weeks (+/- 3 weeks) during the first year 
(starting on day 1 infusion 1). HRQoL data must be collected regardless of the 
patient’s progression status. 
In addition to above recommendations, if patients experience any adverse event or laboratory 
event during the treatment period, additional tests and/or visits will be performed as per 
recommendations in Section 5.7. 
Please refer to Table 4 in Section 6.8.1. 
6.3.4 
Every 12 weeks (+/- 2 weeks) starting from the day of first 
infusion (visit 1) and until disease recurrence 
Imaging work up (to be based on calendar and not adjusted for delays or missed treatment):  
♦ Contrast-enhanced chest and upper abdomen CT scan; 
♦ Contrast-enhanced brain CT scan or MRI only if clinically indicated (new 
evidence of headache or neurologic symptoms); 
Note: Patients who receive treatment beyond 1 year from randomization, (to compensate for 
missed or delayed doses), should have imaging performed every 12 weeks (+/- 2 weeks) until 
discontinuation of treatment and then will follow Section 6.7 (Follow-up).  
Please refer to Table 4 in Section 6.8.1. 
6.4 
End of Treatment 
At the time of early study withdrawal or withdrawal of consent, the reason for early 
withdrawal and any new or ongoing AEs must be documented in the applicable e-CRFs. 
End of treatment visit will occur at the treatment discontinuation due to 1) completion of 
planned therapy in the protocol 2) disease recurrence or 3) treatment discontinuation due to 
reasons outlined in Section 5.6. 
In case of discontinuation prior to the first treatment infusion, the baseline visit can take 
place as end of treatment visit. Therefore only an end of treatment form must be additionally 
completed to record reason for discontinuation. 
The following exams will be performed at 4 weeks (± 2 weeks) after the last infusion 
administration: 
♦ Physical examination/ECOG performance status; 
♦ Assessment of AEs; if at the time of treatment discontinuation, the patient suffers 
from a severe Grade 3 or 4 AE, the event must be followed until resolution or 
determination by the investigator that the event has become stable or irreversible; 
♦ Concomitant medication assessment; 
♦ Hematology and serum chemistry see Section 6.2.2; 
♦ Urinalysis see Section 6.2.1; 
♦ Thyroid function: TSH; in case of elevated TSH to add free T3 (or total T3) and free 
T4; 
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♦ Disease evaluation (see imaging work-up Section 6.3.4): only in case of 
discontinuation in absence ofdisease recurrence; 
♦ HRQoL evaluations : EORTC QLQ-C30 version 3, EORTC QLQ-LC13 and EQ-5D.  
Please refer to Table 5 in Section 6.8.2. Note: Patients discontinuing treatment who had 
the last scan performed in the preceding 4 weeks (+/- 7 days) of planned EOT visit, may 
have the EOT scan omitted at the discretion of the investigator.  
6.5 
Translational research 
In the frame of a proposal for Translational research the following samples will be collected 
for patient who consented. Please refer to Table 6, Chapter 11 and Laboratory manual for 
additional information on amount of material required, collection timepoints and potential 
research purposes. 
6.6 
Pharmacokinetic and anti-pembrolizumab antibody 
Pre-infusion trough PK (3.5 mL each) and ADA (6 mL each) samples will be collected 
before administration of pembrolizumab/placebo at the following timepoints: 
♦ Before infusion 1, infusion 2, infusion 4, infusion 8, and infusion 16. 
Note: if infusions 1, 2, 4, 8 or 16 held, the PK and ADA samples should be collected at time 
of the next PK/ADA timepoint collection. 
♦ Upon treatment completion or discontinuation: end of therapy visit or until the start of 
a new anti-cancer therapy.  
All pre-infusion blood samples should be drawn within 24 hours before infusion of 
pembrolizumab/placebo as described in the Table 6. 
Please refer to Table 6 in Section 6.8.3 
6.7 
Follow-up 
6.7.1 
In case of early discontinuation prior to first infusion 
The following information will be collected: 
♦ Survival status (Refer to Section 6.7.4); 
♦ Disease recurrence assessment: every 12 weeks (± 2 weeks) during the 1st year after 
randomization starting from the date of enrolment, every 6 months (± 4 weeks 
window) for the 2nd and 3rd year, and yearly (± 4 week window) for year 4 and 5 . 
Thereafter the imaging work-up should be performed at least yearly up to year 10. 
The imaging schedule is based on C1D1 and is not adjusted for delays in treatment. 
Please refer to Section 7.1.2 for definition of disease recurrence. 
6.7.2 
Follow-up in the absence of disease recurrence 
The reference date for scheduling follow up visits is day 1 of infusion 1 
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Imaging work-up
In the two arms follow up assessment will be performed following the imaging work up
schedule.
♦
every 12 weeks (± 2 weeks) during the 1st year after randomization (starting on day 1 
of visit 1),
♦
every 6 months (± 4 weeks window) during the 2nd and 3rd year
Note: for patients who receive treatment beyond 1 year from randomization, if the last 
imaging (i.e. during treatment or EoT) is within 4 weeks from the expected first 6
monthly imaging in 2nd year, then the expected first 6 monthly imaging in 2nd year can 
be omitted.
♦
yearly (± 4 week window) for year 4 and 5. Thereafter, the imaging work-up should 
be performed at least yearly up to year 10. The imaging schedule is based on C1D1 
and is not adjusted for delays in treatment. The disease recurrence (see Section 7.1.2)
will still be collected beyond the 5th year.
Disease status through contrast enhanced chest and upper abdomen CT scan and contrast-
enhanced brain CT scan or MRI only if clinically indicated (new evidence of headache or 
neurologic symptoms);
For other tests/investigations/questionnaires
For each follow up visit, the following information/tests will be collected/performed:
♦
HRQoL evaluation : EORTC QLQ-C30 version 3, EORTC QLQ-LC13 and EQ5D.
Note: questionnaires are filled in every 12 weeks (+/- 3 weeks), during the 1st year after 
randomization (starting on day 1 of visit 1); every 6 months (+/- 4 weeks) during the 2nd
year and then yearly (+/- 4 weeks) until year 5. HRQoL data must be collected regardless of 
the patient’s progression status; no further collection is required beyond the fifth year.
♦
Thyroid function: tests are performed every 12 weeks (+/- 2 weeks) for the first year 
of follow-up. In case of elevated TSH, free T3 (or total T3) and free T4 are 
additionally measured. After the first year of follow-up, thyroid function is evaluated 
only if clinically indicated.
Note: reference point for TSH collection is determined from the last scheduled protocol 
imaging. The first Follow-up TSH sample must be collected 12 weeks ± two weeks from 
the last protocol imaging performed during treatment. If the EOT imaging does not occur 
in the scheduled imaging interval (every 12 weeks ± two weeks starting from C1 D1), it
should not be utilized to calculate the start of the Follow-up visit and TSH collection. 
Instead, as a reference, it should be taken into consideration the previous image 
conducted during the treatment period. In addition, TSH collected at the EOT visit is not 
considered as the first Follow-up TSH.
♦
Record of further anti-cancer therapies on e-CRF
Note: further anti-cancer therapies should continue to be recorded until withdrawal of 
consent, death or end of study, which ever occurs first.
♦
Survival status (Refer to Section 6.7.4)
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♦ Assessment of AEs: if a patient is discontinued from study treatment because of an 
AE considered to be related to study treatment and the event is ongoing 30 days after 
the last infusion of study treatment, the event must be followed until resolution or 
determination by the investigator that the event has become stable or irreversible. 
Serious adverse events will be collected for up to 90 days following discontinuation 
of treatment or 30 days if the subject initiates new anticancer therapy. Any treatment-
related death occurring beyond this time frame must be reported to EORTC.  
♦ If clinically indicated, the following tests/investigations: 
♦ Physical examination/ECOG performance status see Section 6.2.1; 
♦ Assessment of any other AEs; 
♦ Concomitant medication assessment; 
♦ Hematology and serum chemistry see Section 6.2.2; 
♦ Urinalysis see Section 6.1.1; 
6.7.3 
Follow-up after disease recurrence 
The reference date for scheduling follow up visits is day 1 of infusion 1 
For each follow-up visit, the following tests/exams/questionnaires will be 
collected/performed: 
♦ HRQoL evaluation : EORTC QLQ-C30 version 3, EORTC QLQ-LC13 and EQ5D.  
Note: questionnaires are filled in every 12 weeks (+/- 3 weeks), during the 1st year after 
randomization; every 6 months (+/- 4 weeks) during the 2nd year and then yearly (+/- 4 
weeks) until year 5. HRQoL data must be collected regardless of the patient’s 
progression status; no further collection is required beyond the fifth year. 
♦ Thyroid function: tests are performed every 12 weeks (+/- 2 weeks) for the first year 
of follow-up. In case of elevated TSH, free T3 (or total T3) and free T4 are measured. 
After the first year of follow-up, thyroid function is evaluated only if clinically 
indicated to continue follow up. 
Note: reference point for TSH collection is determined from the last scheduled protocol 
imaging. The first Follow-up TSH sample must be collected 12 weeks ± two weeks from 
the last protocol imaging performed during treatment. If the EOT imaging does not occur 
in the scheduled imaging interval (every 12 weeks ± two weeks starting from C1 D1), it 
should not be utilized to calculate the start of the Follow-up visit and TSH collection. 
Instead, as a reference, it should be taken into consideration the previous image 
conducted during the treatment period. In addition, TSH collected at the EOT visit is not 
considered as the first Follow-up TSH. 
♦ Record of further anti-cancer treatments; 
Note: further anti-cancer therapies should continue to be recorded until withdrawal of 
consent, death or end of study, which ever occurs first. 
♦ Survival status (Refer to Section 6.7.4) 
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♦
Assessment of AEs: if a patient is discontinued from study treatment because of an 
AE considered to be related to study treatment and the event is ongoing 30 days after 
the last infusion of study treatment, the event must be followed until resolution or 
determination by the investigator that the event has become stable or irreversible. 
Serious adverse events will be collected for up to 90 days following discontinuation 
of treatment or 30 days if the subject initiates new anticancer therapy. Any treatment-
related death occurring beyond this time frame must be reported to EORTC. 
♦
If clinically indicated, the following tests/investigations:
♦
Physical examination/ECOG performance status see Section 6.2.1;
♦
Assessment of any other AEs;
♦
Concomitant medication assessment;
♦
Hematology and serum chemistry see Section 6.2.2;
♦
Urinalysis see Section 6.1.1;
6.7.4
Survival Follow-up
All patients who discontinued study intervention, regardless the reason of discontinuation, 
will move into the Survival Follow-up Phase and should be contacted by telephone every 12
weeks (+/- 2 weeks) to assess for survival status until death, withdrawal of consent, or the 
end of the study, whichever occurs first.
Participants should continue the follow-up visits according to the protocol. If the survival 
follow-up call is scheduled to occur simultaneously with a Follow-up visit, then the call can 
be omitted.
After year 5, survival follow-up will be conducted every 6 months by telephone.
The reference date for contacting patients for survival follow-up will follow the same 
schedule as the imaging schedule (Day 1 of infusion 1 (visit 1)).
Survival Sweep
To ensure current and complete survival data is available at the time of database locks,
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (eDMC) review, interim and/or final analysis. Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact,
during the Sponsor defined time period, will be contacted for their survival status (excluding 
participants that have a previously recorded death event in the collection tool).
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6.8 
Summary tables 
6.8.1 
Treatment schedule before and during treatment 
Table 4. Treatment schedule before and during treatment 
 
Prior to randomization 
Prior to treatment initiation 
Treatment Period 
 
Any time after 
surgery or during 
adjuvant 
chemotherapy 
 Within 12 weeks 
prior to 
randomization  
Within 10 days 
prior to 
treatment 
initiation 
Within 72 
hours prior to 
treatment 
initiation 
Every 3 Weeks (± 
3 days) 
Every 6 
Weeks 
(±3 days) 
Every 12 
Weeks (±3 
days) 
Every 12 
Weeks (± 2 
Weeks)  
Reference Sections 
6.2 
6.2.1 
6.2.2 
6.2.3 
6.3.1 
6.3.2 
6.3.3 
6.3.4 
Registration consent 
⧫ 
 
 
 
 
 
 
 
Biomedical Research 
consent 
⧫ 
 
 
 
 
 
 
 
Main study consent 
 
⧫ 
 
 
 
 
 
 
Medical history, height, 
smoking status and 
demographics  
 
⧫ 
 
 
 
 
 
 
PD-L1 testing 
⧫ 
 
 
 
 
 
 
 
Serology HIV, HBV, 
HCV 
 
⧫ 
 
 
 
 
 
 
Pregnancy test (b-HCG 
test)1 
 
 
 
⧫ 
# 
 
# 
# 
Physical examination 
(weight, heart rate, BP, T) 
ECOG PS 2  
 
⧫ 
 
 
⧫ 
 
 
 
Adverse events 
 
⧫ 
 
 
⧫ 
 
 
 
Conc. Medications 
 
⧫ 
 
 
⧫ 
 
 
 
Hematology 3  
 
 
⧫ 
 
⧫ 
 
 
 
Serum chemistry 3 
 
 
⧫ 
 
⧫ 
 
 
 
Urinalysis5 
 
⧫ 
 
 
 
 
⧫ 
 
Thyroid function 
 
⧫ 
 
 
 
⧫ 
 
 
12-lead ECG 
 
⧫ 
 
 
 
 
 
 
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Prior to randomization 
Prior to treatment initiation 
Treatment Period 
 
Any time after 
surgery or during 
adjuvant 
chemotherapy 
 Within 12 weeks 
prior to 
randomization  
Within 10 days 
prior to 
treatment 
initiation 
Within 72 
hours prior to 
treatment 
initiation 
Every 3 Weeks (± 
3 days) 
Every 6 
Weeks 
(±3 days) 
Every 12 
Weeks (±3 
days) 
Every 12 
Weeks (± 2 
Weeks)  
Disease evaluation6 
 
⧫ 
 
 
 
 
 
⧫ 
HRQoL7 
 
⧫ 
 
 
 
 
⧫ 
 
⧫ in all cases 
 if clinically indicated according to the local investigator  # as per national regulations/institutions guidelines up to 30/90 days for the related AEs/SAEs 
(see Section 16.6) or if clinically indicated 
1. Pregnancy test: serum or urine beta HCG in fertile female study participants. The pregnancy test is to be renewed/repeated during protocol treatment at least monthly or more 
frequently if required by national regulations/institution guidelines. 
2. Physical examination includes ECOG performance status, blood pressure, weight, heart rate, temperature. 
3. Complete blood count: WBC, lymphocytes, ANC, monocytes, eosinophils, basophils, RBC, Hgb, Hct, Platelets and serum or plasma chemistry: creatinine, urea or BUN, 
bilirubin, AST, ALT, alkaline phosphatase, LDH, tot prot, K, Na and Ca, bicarbonate (HCO3) (HCO3 testing could be optional in countries where testing is not standard of 
care), albumin, glucose. 
5. Urinalysis: specific gravity, pH, proteins, glucose, blood using a dipstick; elements and microscopic examination if needed 
6. Disease evaluation: chest/upper abdomen CT scan; brain CT and/or MRI if clinically indicated, for example in case of headache or neurologic symptoms. Imaging needs to 
be based on calendar and not adjusted for delays in treatment. A brain CT scan or MRI must be performed within 12 weeks prior to randomization and only to be done if 
clinically needed at subsequent imaging visits. 
7. HRQoL evaluation : EORTC QLQ-C30 version 3, EORTC QLQ-LC13 and EQ-5D. Questionnaires are filled in every 12 weeks (+/- 3 weeks), during the 1st year after 
randomization (starting on day 1 cycle 1) and every 6 months (+/- 4 weeks) during the 2nd year. HRQoL data must be collected regardless of the patient’s progression status. 
After year 2 HRQoL will be collected annually (+/- 4 weeks) until the fifth year. See Chapter 10 for more details. 
 
 
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6.8.2 
End of Treatment Schedule and Follow up Overview 
Table 5. Overview end of treatment and follow up 
 
End of Treatment 
Follow-up 
 
4 weeks (± 2 
weeks) after last 
infusion 
Discontinuation prior to first 
infusion 
In the absence of disease 
recurrence  
After disease recurrence 
Reference Sections 
6.4 
6.7.1 
6.7.2 # 
6.7.3 # 
Physical examination (weight, heart rate, BP, 
T) ECOG PS 1  
⧫ 
 
 
 
Adverse events 2 
⧫ 
 
  
  
Conc. Medications 
⧫ 
 
 
 
Hematology 3  
⧫ 
 
 
 
Serum chemistry 
⧫ 
 
 
 
Urinanalysis4 
⧫ 
 
 
 
Thyroid function 
⧫ 
 
⧫8 
⧫8 
Disease evaluation 
⧫ 6 
 
⧫7 
 
HRQoL 
⧫ 
 
⧫ 
⧫ 
Survival follow-up5 
 
⧫ 
⧫ 
⧫ 
Further anti-cancer therapies 
 
 
⧫ 
⧫ 
Survival Sweep9 
⧫ 
⧫ 
⧫ 
⧫ 
⧫ in all cases 
 if clinically indicated according to the local investigator  if the discontinuation was due to an AE 
#Follow up assessment will be performed every 12 weeks (± 2 weeks) during the 1st year after randomization , every 6 months (± 4 weeks window) for the 2nd and 3rd year, 
and yearly (± 4 week window) for year 4 and 5. Thereafter, the imaging work-up should be performed at least yearly up to year 10. The imaging schedule is based on C1D1 and 
is not adjusted for delays in treatment. Disease recurrence, survival status and further anticancer therapy will continue to be collected beyond the 5th year. 
1. Physical examination includes ECOG performance status, blood pressure, weight, heart rate, temperature. 
2. Assessment of AEs; if at the time of treatment discontinuation, the patient suffers from a severe Grade 3 or 4 AE, the event must be followed until resolution or determination 
by the investigator that the event has become stable or irreversible; 
3. Complete blood count: WBC, lymphocytes, ANC, monocytes, eosinophils, basophils, RBC, Hgb, Hct, Platelets and serum or plasma chemistry: creatinine, urea or BUN, 
bilirubin, AST, ALT, alkaline phosphatase, LDH, tot prot, K, Na and Ca, bicarbonate (HCO3) (HCO3 testing could be optional in countries where testing is not standard of 
care), albumin, glucose. 
4. Urinanalysis: specific gravity, pH, proteins, glucose, blood using a dipstick; elements and microscopic examination if needed 
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End of Treatment 
Follow-up 
 
4 weeks (± 2 
weeks) after last 
infusion 
Discontinuation prior to first 
infusion 
In the absence of disease 
recurrence  
After disease recurrence 
5. Survival status: patients to be contacted by telephone approximately every 12 weeks (+/- 2 weeks) If the survival follow-up call is scheduled to occur simultaneously with a 
Follow-up visit, then the call can be omitted. After year 5, survival follow-up will be conducted every 6 months by telephone (see Section 6.7.4). Upon Sponsor request, 
participants may be contacted for survival status at any time points during the course of the study. 
6 Disease evaluation (see imaging work-up Section 6.3.4): only in case of discontinuation in absence of disease recurrence;  
7. Disease status through contrast enhanced chest and upper abdomen CT scan and contrast-enhanced brain CT scan or MRI only if clinically indicated (new evidence of 
headache or neurologic symptoms) 
8 Thyroid function: tests are performed every 12 weeks (+/- 2 weeks) for the first year of follow-up. In case of elevated TSH free T3 (or total T3) and free T4. After the first 
year of follow-up, if clinically indicated to continue follow up. 
9 Can be collected at any time. 
 
 
 
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6.8.3 
PK/ADA and Translational Research 
Table 6. PK/ADA and Translational Research 
Samples 
Prior to 
randomization 
 
During treatment 
At treatment 
completion or 
discontinuation 
At 
tumor 
relapse 
 
Step 1 
Step 3 
Infusion1 
Infusion 
2 
Infusion 4 
At week 
12  
Infusion 8 
Infusion 16 
 
 
 
FFPE 
blocks/slides* 
⧫ 
 
 
 
 
 
 
 
 
 
⧫3 
Fresh frozen 
tissue 
blocks/slides‡ 
⧫3 
 
 
 
 
 
 
 
 
 
 
Whole blood 
samples 
(germline 
source) (20 
mL)† 
⧫ 
 
 
 
 
 
 
 
 
 
 
Serum samples 
(10 mL)† 
 
 
 
 
 
⧫2 
 
 
 
⧫2 
 
Serum samples 
(20 mL)† 
⧫ 
⧫1 
 
 
 
 
 
 
 
 
⧫2 
PBMC‡ 
 
⧫ 
 
 
 
⧫2 
 
 
 
 
⧫2 
Whole Blood 
for correlative 
study (DNA)†  
 
⧫ 
 
 
 
 
 
 
 
 
 
Whole Blood 
for correlative 
study (RNA)† 
 
⧫ 
 
 
 
⧫ 
 
 
 
⧫ 
 
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Samples 
Prior to 
randomization 
 
During treatment 
At treatment 
completion or 
discontinuation 
At 
tumor 
relapse 
 
Step 1 
Step 3 
Infusion1 
Infusion 
2 
Infusion 4 
At week 
12  
Infusion 8 
Infusion 16 
 
 
 
PK samples4 
(3.5 mL 
each)** 
 
 
⧫ 
⧫ 
⧫ 
 
⧫ 
⧫ 
 
⧫ 
 
ADA samples4 
(6 mL each)** 
 
 
⧫ 
⧫ 
⧫ 
 
⧫ 
⧫ 
 
⧫ 
 
1. only if adjuvant chemotherapy was delivered 
2. Samples at wk 12, at completion or discontinuation of treatment as well at progression can be collected in a +/- 7 days interval. 
3. only if available 
4. Pre- infusion trough PK and ADA samples should be drawn before infusion of pembrolizumab/placebo at infusions 1, 2, 4, 8, and 16; at treatment 
completion/ discontinuation (end of therapy visit(or until the start of a new anti-cancer therapy). All pre- infusion blood samples should be drawn within 24 
hours before infusion of pembrolizumab/placebo 
*Sample(s) is (are) collected for PD-L1 status analysis following the registration consent, and will be transferred to central biobanks if patient's consent for 
biomedical research 
**Samples are collected following patient's consent for the main study 
†Samples are collected following patient's consent for biomedical research 
‡Samples are collected following patient's consent for biomedical research and in selected sites 
 
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7
Criteria of evaluation
7.1
Evaluation of efficacy
The following paragraphs are a reference to the RECIST version 1.1. The complete criteria 
are included in the published RECIST version 1.1 document [Ref. 71] also available at 
http://www.eortc.be/RECIST. 
7.1.1
Assessment of tumor lesions
Methods of assessment
The determination of patient’s eligibility and the determination of tumor progression will be 
done by local principal investigator based on the schedule outlined for disease evaluation in 
Table 4. Imaging needs to be based on calendar and not adjusted for delays in treatment. The 
images will be collected by the central vendor for quality assurance and future central 
review. The process for image collection and transmission to the central vendor can be found 
in the Site Imaging Manual. The same method of assessment and the same technique should 
be used to identify and report lesion during follow-up. Assessments should be identified on a
calendar schedule and should not be affected by delays in therapy, which may be treatment 
arm dependent. At the time of occurrence of a lesion, their actual measurements should be
recorded on the CRF even when very small (e.g. 2 mm). For lesions which fragment/split add 
together the longest diameters of the fragmented portions; for lesions which coalesce, 
measure the maximal longest diameter for the “merged lesion”.
♦
CT or MRI are mandatory to establish recurrence. Conventional CT with i.v. 
contrast with contiguous cuts of 10 mm or less slice thickness is the best currently 
available and reproducible method to assess and measure lesions. If CT IV contrast is 
contraindicated, a non-contrast CT is recommended over MRI for radiographic 
evaluation of the chest. MRI is also acceptable in certain situations (e.g. for body 
scans). If a patient cannot have a CT scan or MRI with contrast during the screening
phase, the patient is not eligible. A CT scan or MRI without contrast is acceptable
during the treatment and follow-up phases if the patient develops a medical problem 
that precludes the use of contrast agents. Performance of a non-contrast CT scan or 
MRI will be reported as a deviation to the protocol during medical review.
♦
PET alone will not be considered for the disease assessment. Complementary 
CT/MRI or biopsy must be performed in such cases.
♦
Cytology or Histology are mandatory to confirm recurrence in solitary or in doubtful 
lesions. Histological or cytological evidence of recurrence should be attempted in all 
cases except for brain metastases.
♦
Chest X-ray. Chest CT is preferred over chest X-ray, particularly when progression 
is an important endpoint, since CT is more sensitive than X-ray, particularly in 
identifying new lesions. 
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Frequency of tumor re-evaluation
The baseline disease evaluation by tumor imaging as outlined in Table 4 should be performed 
within 12 weeks prior to randomization date. Scans performed as part of routine clinical 
management are acceptable for use as the screening scan if they are of diagnostic quality and 
performed within 12 weeks prior to the randomization date.
Evaluation for tumor recurrence will be performed through contrast-enhanced chest and 
upper abdomen CT scan to be performed every 12 weeks (+/- 2 weeks) during the 1st year
after randomization, every 6 months (+/- 4 weeks) for the 2nd and 3rd year, yearly (+/- 4
weeks) for year 4 and 5. Thereafter, the imaging work-up should be performed at least yearly 
up to year 10. The imaging schedule takes as reference the start date of treatment (C1D1) and 
is not adjusted for delays in treatment. Imaging needs to be based on calendar and not
adjusted for delays in treatment.
Date of recurrence
This is defined as the first day when the RECIST version 1.1 criteria for disease recurrence
are met. 
The first date when recurrence was observed is taken into account regardless of the method 
of assessment. Therefore recurrence will be declared for any lesion when:
♦
Only imaging was performed and progression confirmed;
♦
Only pathology was done and malignancy confirmed (in solitary or in doubtful 
lesions, cutaneous, subcutaneous or lymph node lesions);
♦
Both pathology and imaging were done and progression/malignancy confirmed. In 
this case, whatever examination came first its date is considered the date of 
recurrence.
7.1.2
Disease free survival (DFS)
Definition of date of disease recurrence is given above (see Section 7.1.1.3). Recurrence of 
disease can be a loco-regional recurrence, a distant (metastatic) recurrence or a second 
primary. NSCLC and second malignancies will be considered to be events. 
Disease Free Survival (DFS) is calculated as the time from randomization to either the date 
of disease recurrence or the date of death (whatever the cause). The date of first documented 
disease recurrence (if applicable) will be used as the date of event. Patients alive with no 
evidence of disease recurrence at the time of their last visit are censored at the time of the last 
examination.
7.1.3
Overall survival (OS)
Overall survival (OS) is defined as the time from the date of randomization to the date of 
death, whatever the cause. The follow-up of patients still alive will be censored at the 
moment of last visit/contact.
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7.1.4 
Lung Cancer Specific Survival (LCSS) 
Lung Cancer Specific Survival (LCSS) is calculated as the time from randomization to the 
date of death (due to lung cancer specifically). The follow-up of patients still alive will be 
censored at the moment of last visit/contact. Patients who die from causes other than lung 
cancer are censored at the time of death.  
7.2 
Evaluation of safety 
7.2.1 
Adverse events 
All adverse events will be recorded as specified below in the protocol; the investigator will 
assess whether those events are drug related (reasonable possibility, no reasonable 
possibility) and this assessment will be recorded in the database for all adverse events. 
All adverse events must be followed until resolution or stabilization. 
7.2.2 
General evaluation of adverse events 
This study will use the International Common Terminology Criteria for Adverse Events 
(CTCAE), version 4.03, for adverse event reporting. A copy of the CTCAE can be accessed 
from the EORTC home page https://www.eortc.be/services/doc/ctc/. 
Hematological toxicity will be assessed on the basis of regular blood tests. The nadir count 
will be computed at each study medication administration and graded according to the 
CTCAE version 4.03.  
Non hematological acute side effects will be assessed and reported separately for each study 
medication administration, and graded according to the CTCAE version 4.03. 
Planned safety analysis and tabulations are described in the statistics Chapter 8. 
7.2.3 
Serious adverse events 
Serious adverse events are defined by the Good Clinical Practice Guideline. 
SERIOUS ADVERSE EVENTS SHOULD BE IMMEDIATELY REPORTED 
ACCORDING TO THE PROCEDURE DETAILED IN THIS PROTOCOL (see 
Chapter on Reporting Serious Adverse Events) 
For guidance regarding Events of Clinical Interest (ECI) for pembrolizumab please 
refer to Appendix I. 
7.2.4 
Toxic deaths 
Toxic death is defined as death due to toxicity (defined as a serious adverse events at least 
with reasonable possibility to be related to study treatment). The cause of death must be 
reported as "toxicity" and as a serious adverse event. The evaluation of toxic deaths is 
independent of the evaluation of response (patients can die from toxicity after a complete 
assessment of the response to therapy). 
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7.2.5 
Evaluability for safety 
All patients who have started the treatment will be included in overall safety analyses. 
Patients who have discontinued treatment because of toxicity will always be included in the 
safety analyses. 
8 Statistical considerations 
8.1 
Statistical design 
8.1.1 
Sample size considerations 
The primary endpoints are disease free survival (DFS) in all patients and in a subgroup of 
patients with PD-L1 strong positive (tumor proportion score (TPS) ≥ 50%). 
 
 
  
Assumptions for the sample size calculation: 
 
The 
study is designed with primary/dual-primary endpoints: DFS in the whole population and 
DFS in the PD-L1 strong positive sub-population. Assumptions and the testing strategy are 
given below. 
♦ Overall, an improvement of 14 months in median DFS (from 42 months to 56 
months) or equivalent to HR = 0.75 is aimed for the whole population. 
 
 
 
 
 
 
  
 
 
 The enrollment duration is 52 months with 
the accrual rates provided in Table 7 below. 
♦ The yearly drop-out rate is 2.5% and 1% for DFS and OS, respectively.  
Table 7. Enrollment Pattern 
Period Starting at time Calendar Time Accrual Rate 
1 
0  
January 2016 
8.375 
2 
8 
September 2016 
18 
3 
26 
March 2018 
34.24 
4 
47 
December 2019 
13.992 
 
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♦ The family-wise error rate (Type I error) for DFS and OS hypotheses is strongly 
controlled at 2.5%, one-sided. The study uses the graphical method of Maurer and 
Bretz [Ref. 75] to provide strong multiplicity control for multiple hypotheses as 
well as interim efficacy analyses. See Figure 3 for an overview of the multiplicity 
strategy. 
♦ 
 
The schedule and 
type of analyses for DFS and OS are given in Table 8 and Table 9, respectively.  
♦ A Hwang-Shih-DeCani (HSD) spending function with gamma = -4 is used to 
establish the boundary (nominal alpha) in interim and final analysis of DFS and OS 
for the test of each population. The threshold alphas and HRs for each analysis can be 
found in Table 8 and Table 9. 
♦ All DFS analyses are DFS event-driven. The timing for interim analysis 1 and 2 will 
be determined by the number of DFS events in the PD-L1 strong positive population, 
♦ 
Approximately 1180 participants will be randomized in a 1:1 ratio into the experimental arm 
and the control arm. 
 
 
 If either of the tests for the 
primary endpoints is significant, then the study can be declared successful in the respective 
population.Table 8 and Table 9 summarize the power to reject the null hypotheses for DFS 
and OS and their corresponding individual hypotheses at the different times of analyses. 
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8.1.2
Randomization and stratifications
All patients entered will be centrally registered at the EORTC Headquarters (for practical 
details, see Chapter on randomization procedure). The Pocock and Simon Minimization with 
Biased-coin Assignment methodology [Ref. 73] will be utilized to perform subject 
randomization for this study. Per suggestion of the ICH E9 statistical guidelines, the 
algorithm has been modified to incorporate a random allocation component in order to ensure 
15% of completely random assignments. Stratification factors are: stage (IB vs II vs IIIA), 
adjuvant chemotherapy (no adjuvant chemotherapy versus adjuvant chemotherapy), PD-L1
status: negative (TPS=0%) versus weak positive (TPS = 1-49%) - versus strong positive 
(TPS≥50%) and regions (Western Europe versus Eastern Europe versus Rest of the world 
versus Asia). Minimization algorithm separately applied for each PD-L1 status, to ensure an 
optimal balance of treatment arms within each PD-L1 level.
Treatment allocation will be blinded (see Chapter 14).
Note: Tumor staging is based on TNM stage (according to the 7th edition of the TNM 
classification for lung cancer).
8.2
Statistical analysis plan
8.2.1
Primary/dual-primary and secondary endpoints
The primary/dual-primary endpoints and all secondary endpoints are defined in Chapter 7.
Technical derivation of these endpoints using the case report forms(CRFs) is included in
Appendix N.
8.2.2
Analysis populations
♦
Intention-to-treat population: All randomized patients will be analyzed in the arm 
they were allocated by randomization.
♦
Safety population: All patients who have started their allocated treatment (at least one 
infusion of the study drug(s))
These populations are also applicable to the predefined PD-L1 subgroups.
8.2.3
Statistical methods
Efficacy endpoints
The primary analyses of the primary and secondary efficacy endpoints (DFS, OS and LCSS)
will be performed on all randomized patients according to the intention to treat (ITT) 
principle.
Estimates and confidence intervals
Estimates of the median DFS,OS and LCSS will be obtained by the Kaplan Meier technique.
The 95% confidence interval (CI) for the median will be calculated using the reflected CI 
method.
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Estimates of the event-free rate at a fixed time point will be obtained using the Kaplan Meier 
technique and 95% CI will be calculated by the Greenwood’s formula for standard deviation. 
Estimates of hazard ratios and their 95% CI will be obtained by Cox regression. Kaplan 
Meier curves will be drawn for both the experimental and control arms on the same plot.  
Inference 
The DFS and OS will be analyzed by a Cox Proportional Hazard Regression with treatment 
adjusted by the following covariates: stratification factors including stage, PD-L1 IHC 
expression, adjuvant chemo, regions, and additional factors including histology and smoking 
status. Permutation test [Ref. 74] will be used as a primary test for DFS to compare the 
experimental versus the control arm . The Wald test without permutation of allocation 
sequence will be used as a supportive analysis for DFS, but as a primary test for OS. The 
hazard ratios and corresponding 95% CIs will be estimated using the multivariate Cox 
regression model stated above (using Efron’s tie-handling method). A sensitivity analysis 
will include sex (male vs. female) and age (<65 vs. ≥ 65 years) as additional adjustment 
factors in the Cox regression model. A logrank test with no adjustment factors to compare the 
two arms will also be performed as a sensitivity analysis.  
If a randomized patient is not disease free at baseline, the date of randomization will be used 
as the date of event for the primary DFS analysis in the PD-L1 strong positive, PD-L1 
positive and the whole population. 
Analysis of LCSS will be based on the log-rank test and Cox regression model. Competing 
risks approaches such as cumulative incidence function (CIF), Gray’s test, Fine-Gray 
subdistribution hazard model, etc., will also be performed, where deaths from other causes 
are considered as competing risks. As no Type I error control is applied to LCSS, the p-
values for LCSS analyses, if provided, are nominal only and for descriptive purpose. 
 
 
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Table 10. Analysis Strategy for Key Efficacy Variables 
Endpoint/Variable 
(Description, 
Time Point) 
Primary vs. 
Supportive 
Approach† 
Statistical 
Method‡ 
Analysis 
Population 
Missing Data 
Approach 
Primary/dual-primary Endpoints 
DFS  
P 
Permutation test 
with multivariate 
Cox regression 
model§  
ITT  
♦ all 
patients,  
♦ PD-L1 
strong 
positive 
♦ PD-L1 
positive 
Model-based 
S 
Wald test in 
multivariate Cox 
regression model 
Non-adjusted 
logrank test 
 
ITT  
♦ all 
patients,  
♦ PD-L1 
strong 
positive 
♦ PD-L1 
positive 
Model-based 
Secondary Endpoints 
OS 
P 
Wald test in 
Multivariate Cox 
regression model 
ITT  
♦ all 
patients,  
♦ PD-L1 
strong 
positive 
♦ PD-L1 
positive 
Model-based 
LCSS 
P 
Non-adjusted 
logrank test 
ITT  
♦ all 
patients,  
Model-based 
 † P=Primary approach; S=Secondary approach. 
 ‡ Statistical models are described in further detail below: 
 § Adjusted by Stage (IB versus II versus IIIA), PD-L1 IHC expression (0 versus 1-49% versus ≥ 50%), 
Adjuvant Chemo (No chemotherapy vs. adjuvant platinum-based chemotherapy), Histology (squamous vs. 
non-squamous), smoking status (smokers vs. non-smokers), and regions (Western Europe versus Eastern 
Europe versus Rest of the world versus Asia). 
 
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The strategy to address multiplicity issues with regard to multiple endpoints and interim 
analyses is described in Section 8.3, Interim Analyses and in the below subsection on
Multiplicity.
Toxicity
Analysis for toxicity is based on the safety population. The worst grade of toxicity/adverse 
events observed over the whole treatment period according to CTCAE version 4.03 will be 
displayed. In the primary analysis, no formal statistical analysis will be performed to 
compare toxicity between arms. 
Multiplicity
The family-wise error rate (Type I error) for DFS and OS hypotheses is strongly controlled at 
2.5%, one-sided. The study uses the graphical method of Maurer and Bretz [Ref. 75] to
provide strong multiplicity control for multiple hypotheses as well as interim efficacy 
analyses. See Figure 3 for an overview of the multiplicity strategy.
Figure 3: Multiplicity Graph for Alpha Re-allocation Strategy
Bonferroni adjustment is adopted, by initially splitting alpha equally to test DFS, i.e. 1-sided
alpha = 1.25% is allocated to the whole population and 1-sided alpha = 1.25% is allocated to 
the PD-L1 strong positive. The graphical method is then applied to determine the multiple 
testing procedures. If the null hypothesis of DFS is rejected in PD-L1 strong positive
subgroup, its alpha is fully reallocated to DFS hypothesis testing in PD-L1 positive subgroup. 
DFS in the whole population can be tested at alpha = 2.5% when DFS hypotheses in PD-L1
strong positive and PD-L1 positive subgroups are both rejected. OS hypothesis testing in the 
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whole population and PD-L1 strong positive will not occur until DFS hypothesis is rejected 
in the whole population. Below is an illustration of possible overall alpha levels for each DFS 
hypothesis may be tested at.  
♦ DFS in PD-L1++: alpha=1.25% (initial alpha assigned), or alpha=2.5% (once all 
three OS hypotheses are rejected). 
♦ DFS in PD-L1+: alpha=1.25% (once DFS in PD-L1++ is rejected and OS in PD-
L1++ is not rejected), or alpha=2.5% (once all other hypotheses are rejected) 
♦ DFS in the whole population: alpha=1.25% (initial alpha assigned), or 
alpha=2.5% (if all other two DFS hypotheses are rejected). 
Note that a Hwang-Shih-DeCani (HSD) spending function with gamma = -4, determines the 
boundary of alpha threshold at each IAs for DFS and OS.  
The threshold alphas with the expected number of events are illustrated in Table 8 and Table 
9.  
In case only one of the primary DFS hypotheses is significant at the time of IAs, then the 
significant result will be declared in the corresponding population or subgroup. The other 
primary DFS hypothesis will continuously be tested according to the maturity of the next 
test, by using the available nominal alpha.  
In case all primary DFS hypotheses are significant at the time of IAs, then the significant 
results will be declared in all the respective populations. In such situation, the study will 
declare success in all primary hypotheses, yet the analyses for secondary endpoint will be 
continued as scheduled. 
The above multiplicity control strategy is based on current understanding on the PD-L1 
biomarker, and is subject to modification based on emerging external data on the prevalence 
of PD-L1 biomarkers, or the correlation between PD-L1 statuses and the treatment effect. 
8.2.4 
Pre-planned sensitivity or exploratory analyses 
In addition to the analyses mentioned in the previous section, the following sensitivity 
analyses may also be performed:  
♦ using the ITT population, but considering the stratification factor - Stage (AJCC 
V7) information as indicated on the CRFs based on pathology report(s). Stage 
information based on AJCC V8 converted from AJCC V7 and additional 
information collected in the database may also be considered.  
♦ For the randomized patient not disease-free at baseline, the date of randomization 
is used as the censoring date for DFS analysis. 
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♦ Proportional hazard assumption will be checked. If the data clearly do not follow 
proportional hazards, medical explanations should be identified and alternative 
statistical methods will be explored.  
♦ Sensitivity analyses for DFS may also be conducted, adjusted by complete 
resection status (complete resection vs. uncertain) as assessed and described by 
the quality assurance for surgery [Ref. 86]. 
Subgroup analyses are planned to compare DFS by treatment arm in the stratification factors. 
In addition, subgroup analyses by histology, smoking status, sex and age are also planned. 
Two cut-off values for age (70 years and 75 years) to define elderly population will be 
explored to assess the impact of geriatric domains on study primary/dual-primary endpoints 
and PD-L1 status. Subgroup analyses by complete resection status (complete resection vs. 
uncertain) as assessed and described by the quality assurance for surgery [Ref. 86] may also 
be conducted. 
The above analyses will be repeated for the secondary endpoint OS.  
Exploratory analysis: factors related to the cure rate 
Cure rate, defined as proportion of patients who are still alive when the OS curve reaches 
plateau- will be explored. Any conclusion on cure rate should incorporate all subgroups 
(mature and less mature observations with respect to the terminal plateau) and consistency 
check will be performed to examine subgroups with less mature observations if the same 
conclusion can be drawn for those subgroups.  
Proportion of PD-L1 status  
Proportion of PD-L1 status: negative (TPS=0%), weak positive (TPS 1-49%), strong 
positive (TPS≥ 50%) will be checked when approximately 100 patients accrued. In case 
there is any large departure from current assumption of PD-L1 status, necessary statistical 
adjustment will be considered. If the prevalence of PD-L1 strong positive is lower than 
expected ,the study design/ sample size may be adjusted based on the observed proportion of 
PD-L1 strong positive patients to ensure that sufficient number of PD-L1 strong positive 
patients will be in the study. 
Quality of Life 
The analyses for Quality of life are defined in Section 10.5. 
8.2.5 
Prognostic factor analyses 
Except for the analyses described in the previous sub-section, there are no other prognostic 
factor analyses foreseen in the current protocol.  
8.2.6 
Data recoding and display 
Frequency tables will be tabulated (by treatment group or otherwise) for all categorical 
variables by the levels of the variables as they appear on the CRF (with %). Categories with a 
text field specification will be tabulated as categories and then supplemented by a listing with 
the following information for the patients fulfilling the condition for the specification (patient 
id, institution, treatment group, value of the item and text field contents). 
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Dates relating to events prior to entry will be presented as the delay in days (or weeks, 
months, or years) between the past event and the date of entry (date of randomization – date 
of past event + 1) and presented using the median and range. For example, on the 
randomization checklist, the date of last administration of prior treatment (or the date of first 
diagnosis of the cancer) will be presented as the time elapsed (in days, weeks, months or 
years, as appropriate) since the day of the last administration and the date of entry on study 
(date of randomization – last administration/diagnosis +1). 
Other delays (e.g. re-treatment delays) are presented as continuous variables using the 
median and range. 
Continuous variables for which a coding system exists (such as for laboratory data) will be 
recoded into categories (for adverse events, the grading scale specified in the protocol will be 
used). Whenever no specific scale exists, lab data will be categorized based on the normal 
range: for example, below the lower normal limit (when appropriate), within the normal 
range, above the upper normal limit (ULN) and the degree to which it is above the ULN (for 
example > 2.5 x ULN, > 5 x ULN, > 10 x ULN). For laboratory data, the nadir is generally 
displayed. The nadir in a given visit is the lowest laboratory value in that cycle; the overall 
nadir for a patient is the lowest laboratory value among all cycles. 
Other continuous variables (for example age, dose …) are presented using the median and 
range (minimum, maximum).  
DI observed 
 = 
 
The relative dose intensity is calculated as the ratio of the dose intensity as calculated above 
to the dose intensity indicated in the protocol. The dose intensity indicated in the protocol is 
obtained as the dose specified per visit (in mg/m²). 
The dose intensity and the relative dose intensity are presented using median and ranges. The 
relative dose intensity can also be presented in categories (≤70%, >70-90%, >90-110%, 
>110-120%, >120. 
If appropriate, continuous data may also be presented in categories (for example, age may 
also be grouped in decades). 
8.3 
Interim analyses 



weeks
duration
total
dose
total
m
mg
2
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8.4 
End of study 
End of study occurs when all of the following criteria have been satisfied: 
1. The overall study ends when the last patient completes the last study-related phone-call or 
visit, withdraws from the study or is lost to follow-up. 
2. The trial is mature for the analysis of the primary/dual-primary endpoints as defined in the 
protocol 
3. The database has been fully cleaned and frozen for this analysis  
9 Trial Governance and Oversight 
9.1 
Scientific Advisory Committee 
This trial was developed in collaboration with a Scientific Advisory Committee (SAC). The 
SAC comprises the scientific experts from EORTC/ETOP as well as the sponsor (MSD) who 
provide input with respect to trial design, interpretation of trial results and subsequent peer -
reviewed scientific publications. 
9.2 
Trial Steering Committee 
This trial will be conducted in consultation with a Trial Steering Committee. The Trial 
Steering Committee will be chaired by study coordinators from EORTC and ETOP and 
comprises: 
♦ Study Coordinators from each participating group  
♦ Representative persons from the coordinating group  
♦ Sponsor personnels 
♦ Representative of investigators participating in the trial 
♦ Consulting therapeutic-area experts and clinical trialists 
The Trial Steering Committee will provide guidance on the operational aspects of the trial, 
evaluate recommendations from the Data Monitoring Committee (DMC) and make 
recommendations to the Executive Oversight Committee (EOC). 
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Specific details regarding responsibilities and governance of the Trial Steering Committee 
will be described in a separate charter. 
9.3 
Executive Oversight Committee 
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management. The EOC will receive any recommendations made by the Data Monitoring 
Committee (DMC) and decide upon consultation with the EORTC/ETOP leadership team 
and the trial steering Committee regarding the trial. 
9.4 
Data Monitoring Committee 
An independent data monitoring committee will be established following EORTC POL-004 
“Independent Data Monitoring Committees for EORTC studies” (EORTC IDMC) to provide 
independent review and assessment of the efficacy and safety data in a systematic manner 
and to safeguard the interest and safety of the participating patients in the study. Besides its 
Chair, the EORTC IDMC has a minimum of four (4) permanent members representing each 
of the following disciplines: medical oncology, radiation oncology, surgical oncology and 
clinical biostatistics. For interim reviews involving the review of efficacy trial data, the 
EORTC IDMC will be comprised of all permanent IDMC members and a minimum of three 
(3) trial specific external members to review the Interim Analysis Report. For interim 
reviews of safety data only, the EORTC IDMC Chair and at least one of the permanent 
IDMC members along with a minimum of two (2) trial specific external members will be 
part of the IDMC. 
The IDMC is tasked with making a recommendation to the Sponsor based on their 
assessment of efficacy and safety information to continue or stop the trial.  
No efficacy results will be presented at EORTC Group meetings or elsewhere before the trial 
is closed to recruitment and the data are mature for the analysis of the primary endpoint, 
unless recommended otherwise by the EORTC IDMC (Independent Data Monitoring 
Committee) and approved by EOC. 
The membership, key responsibilities of the IDMC, and the corresponding procedures will be 
defined in an IDMC charter in light of EORTC POL-004. 
Safety data are reviewed within the EORTC Headquarters on a regular basis as part of the 
Medical Review process. Problems which are identified will be discussed with the Study 
Coordinators and the Sponsor who will take appropriate measures.  
Safety information will be reported to the IDMC, approximately every 6 months unless 
otherwise agreed upon with the IDMC.Unblinding for global safety reasons and unblinding 
at interim analysis will be performed according to EORTC SOP CM-011-SOP “Blind 
Studies”. The unblinded Statistician, an independent Statistician at the EORTC Headquarters 
not involved in the conduct of the trial and the Pharmacovigilance Physician will write the 
unblinded interim/safety report and will present it to the IDMC.  
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10 Quality of life assessment 
10.1 Rationale 
Health related quality of life (HRQoL) is a multidimensional construct, which can be defined 
as a state of general well being reflecting physical, psychological, and social well being and 
the impact of the disease and/or treatment related symptoms on daily-life functioning. The 
patient’s subjective perspective is an inherent component of HRQoL and is therefore best 
assessed via self-administration. 
Reducing mortality and morbidity is still the most important factor in cancer clinical 
research. Nevertheless, issues such as reducing side effects, symptom relief and improving 
patients’ satisfaction have also become relevant parameters in the evaluation of medical 
strategies. Cancer treatments may produce adverse effects and diminish a patient’s quality of 
life even when survival is extended. Progress in the acceptance of new cancer therapies is 
sometimes critically dependent on their HRQoL consequences. 
10.2 Objective 
In the present study, HRQoL is a pre-specified exploratory endpoint. The working hypothesis 
is that pembrolizumab will result in improved DFS compared to placebo with no significant 
decrement in HRQoL. It is expected that overall self-reported quality of life should be 
improved due to the improved tumor control but may be affected by immunotherapy related 
side-effects (fatigue, nausea, pruritus, diarrhea and rash). In addition, the impact of self-
reported common symptoms are of interest.  
Therefore, overall HRQoL rating and selected symptoms (pain, fatigue, appetite loss, cough, 
chest pain and dyspnea) will be of interest for the duration of the treatment and for a limited 
follow-up period afterwards. 
10.3 HRQoL instruments 
Health related quality of life will be assessed with the EORTC Quality of Life Questionnaire 
(QLQ-C30) version 3. This instrument is composed of multi-item and single-item scales. 
These include five functional scales (physical, role, emotional, social, and cognitive), three 
symptom (fatigue, nausea and vomiting and pain) and a global health status/QoL scale and 
six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial 
difficulties). All scales and single items meet the standards for reliability. The reliability and 
validity of the questionnaire is highly consistent across different language-cultural groups 
[Ref. 76]. The average time to complete the questionnaire is approximately 10 minutes. 
Additionally, the QLQ-LC13 lung cancer module to the QLQ-C30, which measures HRQoL 
relevant to specific symptoms (chest pain, cough and dyspnea) common in lung cancer will 
be included [Ref. 77]. The lung cancer module is meant for use among a wide range of lung 
cancer patients varying in disease stage and treatment modality. The module comprises 13 
questions assessing lung cancer-associated symptoms (cough, haemoptysis, dyspnoea and 
site specific pain), treatment-related side effects (sore mouth, dysphagia, peripheral 
neuropathy and alopecia) and pain medication. The EORTC QLQ-C30 version 3 has been 
translated in over 50 languages according to a standardized translation procedure.  
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The domains of interest as specified in the previous paragraph are covered by the global 
health/QoL scale and the pain, fatigue appetite loss, shortness of breath, symptom scales of 
the QLQ-C30; and the cough, chest pain and dyspnea symptom scales of the QLQ-LC13.  
EuroQol (EQ)-5D was developed to assess health outcomes from a wide variety of 
interventions on a common scale, for purposes of evaluation, allocation and monitoring  
[Ref. 78]. Index-based values (‘utilities’) facilitate the calculation of quality-adjusted life 
years (QALYs) that are used to inform economic evaluations of health care interventions. 
The EQ-5D-3L descriptive system comprises 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression; each dimension has 3 levels: no problems, 
some problems, extreme problems. There are more than 100 official language versions of 
EQ-5D-3L. 
English version of these HRQoL Instruments are included as protocol Appendix E, with the 
list of validated versions available in other languages. 
10.4 Study design 
HRQoL questionnaires must be filled out at the hospital when patients come for a scheduled 
visit according to the EORTC “Guidelines for administration of questionnaires” (see 
Appendix E). The pre-treatment questionnaires must be filled in within 12 weeks before 
randomization. Subsequent questionnaires are filled in every 12 weeks, during the 1st year 
after randomization; every 6 months during the 2nd year and then yearly until year 5. 
HRQoL data must be collected regardless of the patient’s progression status; no further 
collection is required beyond the fifth year.  
The assessment schedule is chosen to coincide as much as possible with the disease 
assessment schedule in order to maximize compliance. The week 74 assessment therefore 
corresponds to the last scheduled on-treatment disease assessment visit at week 48 plus 26 
weeks (= 6 months). Subsequent assessments occur at 26 weeks (= 6 months) intervals. 
Collection beyond year 5 is not deemed necessary as most symptoms will have stabilized by 
then and the available patient population will have decreased due to attrition. 
Master copies of the HRQoL questionnaires will be sent to the institutions. Additional copies 
or translations can be provided upon request via the EORTC contact person. The clinical 
report forms will include a question whether the HRQoL forms have been filled in, and if 
not, the reason why. The questionnaire will be handed out to the patients by the investigator 
or a study nurse prior to seeing the doctor for clinical evaluations. The patient should 
complete the questionnaires by her/himself in her/his own language during the visit to the 
outpatient clinic as completely and accurately as possible. In the event telephone transcript is 
utilized, the designated study staff should capture the patient’s responses on the HRQoL 
forms. It is recommended that a key person (e.g. research nurse) at each center should be 
responsible for questionnaire data collection in order to optimize the compliance of the 
patient and to ensure the completeness of the data. 
During the study, compliance with completing questionnaires will be investigated at each 
time point and reviewed twice a year. 
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10.4.1 
HRQoL schedule 
The time windows for eligible HRQoL including EQ-5D assessments will be as follows: 
Assessment 
Time window  
Baseline 
Can be completed before or on the day of randomization 
itself but no earlier than 12 weeks before. 
Week 12 
Can be completed at week 12 (+/-3 weeks) after 
randomization. 
Week 24 
Can be completed at week 24 (+/-3 weeks) after 
randomization. 
Week 36 
Can be completed at week 36 (+/-3 weeks) after 
randomization. 
Week 48 
Can be completed at week 48 (+/-3 weeks) after 
randomization. 
Week 74 
Can be completed at week 74 (+/-4 weeks) after 
randomization. 
Week 100 
Can be completed at week 100 (+/-4 weeks) after 
randomization. 
Week 152 
Can be completed at week 152 (+/-4 weeks) after 
randomization. 
Week 204 
Can be completed at week 204 (+/-4 weeks) after 
randomization. 
Week 256 
Can be completed at week 256 (+/-4 weeks) after 
randomization. 
 HRQoL data must be collected regardless of the patient’s progression status. 
10.5 Statistical considerations 
The key exploratory HRQoL endpoint relevant for this study is the global health/QoL scale. 
The following sub-scales and single items will be considered as supportive exploratory 
HRQoL endpoints: pain, fatigue, appetite loss, shortness of breath, cough, chest pain and 
dyspnea symptom scales. The other available scales will be classified as "other" exploratory 
analyses; the financial difficulties scale will not be presented. 
The global health/QoL scale will be used as primary outcome of interest for this study. A 
difference of 10 points on the 100-point QLQ-C30 scale either within a patient or between 
the two arms will be considered as clinically relevant [Ref. 78]. The standard deviation of 
this scale is approximately 20 points. With the 2-sided alpha set at 5% and a power of 80% to 
detect a difference of 10 points (effect size of 0.5), a minimum of 128 patients (64 per 
treatment arm) is required. For an effect size of 0.75 (difference of 15 points), 56 patients (28 
per treatment arm) are required. Therefore, this study is sufficiently powered to detect 
differences in HRQoL. 
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Data will be scored according to the algorithm described in the EORTC scoring manual. All 
scales and single items are scored on categorical scales and linearly converted to 0-100 
scales. 
Changes in HRQoL scores from baseline per time point will be evaluated by classifying them 
according to the 10 point change threshold into 3 categories: improved/stable/deteriorated. 
Patients without a valid HRQoL outcome at a certain time will be considered as having 
deteriorated at that time. For each patient the proportion of assessments spent in a 
deteriorated state will be calculated and compared between treatment arms using a non-
parametric rank order test in the intent-to-treat population of the whole population and in the 
PD-L1 strong positive subgroup. 
In order to assess the robustness of the results, the following sensitivity analyses will be 
performed: 
♦ a clinical relevant threshold of 5 and 15 points will be used and patients without a 
valid HRQoL score will be classified according to the reported reason for non-
compliance. 
♦ If adequate compliance available, patients will be classified on valid HRQoL score 
received after treatment discontinuation only. 
♦ The area-under-the-curve (AUC) will be calculated for each patient based on the 
global health/QoL scores. Missing values will be considered as 0. 
♦ The change from baseline per time point will be displayed graphically. 
These analyses will be repeated on the secondary HRQoL scales. 
10.5.1 
Missing data 
Missing data is a potential major source of bias in HRQoL assessment. 
In order to check the potential impact in the study, the compliance mechanism will be 
investigated prior to initiating the HRQoL analysis. Characteristics of patients with and 
without valid HRQoL data will be compared and trends over time per dropout pattern will be 
investigated. Model building will be used in order to investigate whether the compliance 
mechanism is linked to selected prognostic variables. 
Once the main analysis is completed, sensitivity analyses will be undertaken to verify the 
robustness of the results vis-à-vis the missing data.  
In case overall compliance is deemed too low (<50%), only an exploratory analysis will be 
performed in lieu of the main analysis. 
10.5.2 
Other exploratory analyses 
The HRQoL scales from the QLQ-C30 and QLQ-LC13 not included as key or supportive 
exploratory endpoints will be analyzed as "other" exploratory endpoints. The financial 
difficulties scale will be excluded completely from analysis. 
An exploratory analysis of the difference in HRQoL score for progressed patients compared 
to patients with no radiographic evidence of tumor progression will be subject to compliance 
and data availability. The aim is to estimate the amount and nature of deterioration in 
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HRQoL that is associated with disease progression. The change from baseline per HRQoL 
scale to (i) the most recent HRQoL assessment before progression and (ii) the most recent 
HRQoL assessment after progression will be calculated and classified based on clinical 
relevance. A difference of ≥10 points on the 100 point linearly-transformed scale will be 
considered clinically relevant. Additionally, a longitudinal data analysis model can be 
constructed, with the HRQoL score as dependent variable, and treatment, time, selected 
clinical factors, and progression status (time-varying) as independent covariates. 
10.6 EQ-5D instrument 
The EQ-5D is a general health status and health utility measure [Ref. 64]. It measures 5 
dimensions of health state: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression each assessed by a single question on a three-point ordinal scale. It also 
includes a VAS scale to measure health state. The EQ-5D will be included in this study for 
the purpose of the computation of utilities that can be used in health economic studies. This 
instrument has been used extensively in cancer studies and published results from these 
studies support its validity and reliability [Ref. 65]. In addition, validated translations for this 
instrument are available for a number of countries and languages (Appendix E). 
The assessment schedule of the EQ-5D is identical to the schedule of the HRQoL instrument 
(QLQ-C30) as described in Section 10.4.1. 
11 Translational research 
PD-L1 IHC expression was described in many histological cancer types, particularly in 
melanoma and lung cancer. In NSCLC the expression pattern is variable among the different 
reports ranging from 36 to 50%, according to histologic subtype [Ref. 47, Ref. 48, Ref. 54]. 
PD-L1 IHC positive tumors showed higher response rates than those with no expression (36 
versus 13%) [Ref. 56], with a significant degree of variability according to the testing method 
as well as positivity definition and threshold used across the various clinical trials.  
Data available so far are mainly in the advanced setting but Azuma and colleagues have 
recently published the results of their study on the PD-L1expression in 164 surgically 
resected NSCLC. In that series, the expression of PD-L1 was significantly higher for women 
than for men, for never-smokers than for smokers, and for patients with adenocarcinoma 
rather than for those with squamous cell carcinoma. The multivariate analysis revealed that 
the presence of EGFR mutation and adenocarcinoma histology were significantly associated 
with increased PD-L1 status [Ref. 80]. These data need to be confirmed and prospectively 
evaluated; heterogeneity in early stage disease needs to be further explored. 
PD-L1 status has been correlated with EGFR and RAS mutations and to date the results show 
no clear trend, largely because of the lack of standardization of the PDL1 definition of 
positivity, and lack of comparison between antibody use and companion diagnostics. 
 
 
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11.1 Objectives 
The aim of this translational part of PEARLS is to explore the immunological 
parameters that parallel tumor recurrence over time (including new second primaries), 
in patients treated by pembrolizumab in comparison to the placebo arm. Finally data 
extracted would help identifying a potential set of prognostic or predictive markers for 
immune checkpoint inhibitors such as anti PD1 blockers.  
Exploratory parameters in this study will be refined according to the current 
knowledge in the field during trial advancement and at the time of trial completion. 
A preliminary proposal of the main objectives of the TR project could focus – based on the 
current available knowledge in the field and subject to changes accordingly - at least (i.e. not 
limited to) on analyzing: 
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P
PD
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11.2 Summary of sample collection 
This exploratory translational program would require the collection of the following material: 
Table 11. Sample collection 
Specimen 
type(s) 
Specimen 
amount 
Collection time 
point(s) 
Storage conditions 
Estimated 
sample size 
Tumor 
tissue 
FFPE Block 
(highly 
preferred) or 
slides 20-25 
 
At surgery 
 
Blocks: Room 
temperature (RT) if 
outdoor temperature 
is < 24°C/75°F, 
refrigerarted if RT > 
24°C/75°F 
Slides: refrigerated 
2°C-8°C 
1180, after 
central PD-
L1 testing for 
stratification 
Tumor 
tissue 
Fresh frozen 
upon feasibility 
results for those 
sites able to 
collect it (as 
standard 
practice) at the 
time of surgery 
At surgery 
Fresh frozen: As per 
local standard 
practice 
Selected 
centers 
50-100 
samples 
randomly 
distributed 
between the 2 
treatment 
arms 
Tumor 
tissue 
FFPE Block 
(highly 
preferred) or 
slides 20-25 
 
Biopsy at relapse 
(optional) 
Blocks: Room 
temperature (RT) if 
outdoor temperature 
is < 24°C/75°F, 
refrigerarted if RT > 
24°C/75°F 
Slides: refrigerated 
2°C-8°C 
Selected 
patients 
across all 
participating 
centers upon 
patients 
consent  
150-200 
samples 
Serum 
20 mL 
At enrollment 
step 1 
Store at -70°C/-80°C 
freezer 
1180 patients 
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Specimen 
type(s) 
Specimen 
amount 
Collection time 
point(s) 
Storage conditions 
Estimated 
sample size 
Whole 
blood 
(germline 
source) 
20mL 
At enrollment 
step 1 
Tubes MUST be in -
20°C freezer for 24 
hrs 
Transfer to -70°C/-
80°C freezer 
1180 patients 
Serum 
20 mL 
At enrollment 
step 3, if 
adjuvant 
chemotherapy 
was delivered 
only 
Store at -70°C/-80°C 
freezer 
Btw 65-80% 
of the 1180 
patients 
Serum 
10 mL 
At week 12 since 
D 1 infusion 1 – 
with first CT 
scan post 
randomization 
Store at -70°C/-80°C 
freezer 
1180 patients 
Serum 
10 mL 
At completion or 
discontinuation 
of treatment 
Store at -70°C/-80°C 
freezer 
1180 patients 
Serum 
20 mL 
At relapse  
Store at -70°C/-80°C 
freezer 
Expected 
approx. 50% 
of patients 
PBMC 
Up to 40 mL 
♦ Before 
treatment start 
♦ At week 12 
since D 1 
infusion 1 
♦ At tumor 
relapse 
Frozen at -70°C/-
80°C (max. 21 days) 
>21 days, store in 
liquid nitrogen tank. 
Shipment must be 
maintained in liquid 
nitrogen 
In selected 
centers 
(Switzerland, 
Spain, 
France) 
Whole 
Blood for 
correlative 
study 
(DNA) 
8.5 mL 
Before treatment 
start (step 3) 
Place in -20°C 
freezer for 24 hrs 
Transfer to -70°C or 
colder for at least 24 
hrs before shipping 
1180 patients 
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Specimen 
type(s) 
Specimen 
amount 
Collection time 
point(s) 
Storage conditions 
Estimated 
sample size 
Whole 
Blood for 
correlative 
study 
(RNA) 
2.5 mL 
Before treatment 
start (step 3) 
At week 12 since 
D 1 infusion 1  
At completion or 
discontinuation 
Place in -20°C 
freezer for 24 hrs 
Transfer to -70°C/-
80°C or colder until 
ready to ship 
1180 patients 
11.3 Statistical considerations 
The primary outcome is tumor recurrence over time (including new second primaries). 
Tumor and serum samples are collected according to Section 11.2. 
The sample size of 1180 patients gives adequate power to detect realistic prognostic effects 
for immunological parameters on the outcome of interest. More specifically, with 1180 
patients available, we will be able to observe 551 tumor recurrences (see also Chapter 8). 
Assuming that expression of each particular immunological marker will be present in 25-
75% of the available sample, the study will be adequately powered (over 80% power) for 
detecting a targeted HR of 0.78 or less, using a two-sided significance level of 5%. For serial 
measurements available for about 75% of the total sample of patients, a targeted HR of 0.75 
or less can be detected with over 80% power. 
Table 12. Maximum detectable HR with around 80% power under different scenarios for the 
immunological marker incidence. 
Marker incidence 
Detected HR 
alpha 
Power 
25% 
0.78 
5% 
80% 
50% 
0.78 
5% 
80% 
75% 
0.78 
5% 
80% 
25% 
0.75 
5% 
81% 
50% 
0.75 
5% 
81% 
75% 
0.75 
5% 
81% 
 
For the analyses exploring the predictive ability of immunological parameters, the critical 
values will result from procedures to control the false discovery rate (FDR) [Ref. 81, Ref. 
82]. When applied to censored failure time outcomes, this approach assumes that censoring is 
not related to the variables being analyzed. Whether censoring can be considered as random, 
will be examined during the analysis. 
In order to determine the significance of candidate prognostic / predictive markers, we will 
use Cox model score tests as an initially screening procedure and then apply LASSO as a 
selection procedure for the markers. Note that we will also evaluate the correlation structure 
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of the markers. If the correlations are large then we may switch to a procedure more 
appropriate like the OSCAR [Ref. 83]. 
A permutation approach [Ref. 82] will be used to control the false discovery rate in the set of 
variables selected. The initial modeling may only consider the most promising variables 
based on univariate analyses (all variables will be checked again relative to the final model). 
Cross-validated partial likelihood approach (10-fold or 20-fold depending on total sample 
size) will be used to test the results and the predictability of the derived Cox model. This will 
be an internal validation of the approach. 
11.4 Data storage, transfer and development of technical 
appendices 
The translational projects will be the result of the work of sponsor (MSD), collaborating 
institutions, groups (ETOP) and EORTC HQ. Bioinformatics and statistical analysis plan will 
be jointly developed for each project. These documents will be developed and approved 
before starting any analysis. They will specify the analytical and methodological details. 
Clinical and patient-reported outcome data will be stored in the EORTC clinical database and 
biological investigational data will be stored in the sponsor or respective collaborating 
institutions. Transfer of data will be performed according to applicable policies in each 
organization (e.g. EORTC POL008) or according to jointly approved data transfer charters. 
11.5 General principles for human biological material 
(HBM) collection 
Human biological material (HBM) collection involves the collection and storage of 
biological material, residual biological material or derivatives in compliance with ethical and 
technical requirements.  
Biobanking refers to the chain of procedures that encompass the life cycle of the biological 
material, e.g. from collection, shipping to long term storage and use, and may also be subject 
to local regulation and/or national/international legislation. 
In this study, the FFPE sample will be sent to a central lab for PDL1 expression analysis, the 
nanostring gene expression profiling and tumor mutational burden. The remaining FFPE 
tissue and the other biological material from centers will be sent, centralized and stored in a 
biobank in 
, where 
tissue analysis will be performed under the lead of 
. From 
here, the biological material will be used or distributed to the other research laboratories 
involved in the translational research (TR) projects specified in this protocol or defined in the 
future.  
The following principles apply to storage of HBM: 
♦ The biobank will have a designated manager responsible for collection and will act as 
a communication point with the EORTC and ETOP. 
♦ The collected HBM should be documented, i.e. the amount remaining and its 
location. 
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♦ The Study Steering Committee (SSC) will be responsible for TR project review and 
prioritization, including the consideration of newly proposed TR projects not 
specified in the protocol. This will be done in consultation with the sponsor (MSD). 
Final decisions on the use of HBM will be determined by a majority vote of the TSC. 
Additional expertise may be sought through advisory non-SSC members. 
Access to HBM (see EORTC Biobanking Policy POL020): HBM may be used for another 
purpose for which it was originally collected, subject to meeting ethical principles/and is 
covered by informed consent/ethics approval. In the case of secondary use of HBM, (i.e. for 
new TR projects that are not specified in the clinical study protocol and that were not 
foreseen at the time of protocol writing) interested parties may apply for the use of HBM and 
will follow the next steps:  
♦ A short description of the new TR projects will be written and submitted to EORTC 
HQ for coordination with the appropriate SSC. 
♦ The SSC will prioritize the TR projects. Access procedures defined by the SSC will 
build on the following key points:  
♦ Project prioritization  
♦ should be strongly based on scientific merit,  
♦ should consider the contribution of the different investigators to the trial and TR 
project,  
♦ will take into consideration if the applicant is an EORTC member or not (whilst 
maintaining the principle of access to the wider scientific community and 
commitments owed to study participants and ethical committees). 
♦ Protection of confidentiality must be respected. 
♦ An EORTC HQ feasibility check, including recommendations for regulatory and 
ethical matters and other restrictions on the use of the HBM, will take place. If in the 
event the HBM collections are still retained at individual clinical sites, the TR project 
leader and the involved EORTC Group are responsible for collecting and providing 
information on availability of HBM for the feasibility assessment. 
♦ Prioritized TR projects will then be reviewed by the Translational Research Advisory 
Committee (TRAC). 
♦ Once SSC prioritization, the EORTC HQ feasibility assessment, and TRAC review 
are complete and when all applicable competent Ethics Committees approvals are in 
place and ethical principles are met, the TR project can be activated and HBM release 
and analysis can commence. 
♦ The EORTC Board will mediate any disagreements of opinion between TRAC, the 
EORTC HQ feasibility assessment, the SSC and the TR project leader(s), as needed. 
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12 Pharmacokinetic/Pharmacodynamic 
Evaluations 
To evaluate the immunogenicity and exposure of pembrolizumab in this indication, sample 
collections for analysis of anti-pembrolizumab antibodies (ADA) and PK are currently 
planned as shown in the Trial Flowchart. Blood samples for PK and ADA collected may be 
stored only at this time. Further analysis may be performed if required. If ongoing PK and/or 
ADA sampling is deemed to be unnecessary by the Sponsor, it may be reduced or 
discontinued.  
Based on pharmacokinetic (PK) data obtained in this study as well as PK data obtained from 
other studies (if available), a population PK analysis will be performed to characterize 
pharmacokinetic parameters (Clearance (CL), Volume of distribution (V)) as endpoints and 
evaluate the effect of extrinsic and intrinsic factors to support proposed dosing regimen. 
Pharmacokinetic samples will also be used to explore the exposure-response relationships for 
pembrolizumab antitumor activity/efficacy as well as safety in the proposed patient 
population, if feasible. The results of these analyses, if performed, will be reported 
separately. 
12.1 Timepoints 
Sample collection is currently planned as shown in the Trial Flowchart Section 6.8.3. 
12.2 PK Blood Collection for Serum MK-3475 
Sample collection, storage and shipment instructions for serum PK samples will be provided 
in the Procedures Manual. 
12.3 Blood Collection for Anti-Pembrolizumab Antibodies 
Sample collection, storage and shipment instructions for anti-pembrolizumab antibody 
samples will be provided in the Procedures Manual. 
13 Investigator authorization procedure 
Investigators will be authorized to register and/or randomize patients in this trial only once 
all the following documents have been provided: 
♦ The updated signed and dated curriculum vitae of the Principal Investigator in 
English with a GCP training proof. 
♦ The (updated) list of normal ranges for the investigator’s institution signed and dated 
by the head of the laboratory. Please make sure normal ranges are provided also for 
those tests required by the protocol but not routinely done at the investigator’s 
institution. 
♦ The Confirmation of interest, confirming that the investigator will fully comply with 
the protocol. This must include an estimate of yearly accrual and a statement on any 
conflict of interest that may arise due to trial participation. 
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NB: A signed conflict of interest disclosure form will be required only if a possible 
conflict is declared 
♦ The Study Agreement with the investigator's institution. 
♦ A copy of the favorable opinion of the local or national (whichever is applicable) 
ethics committee mentioning the documents that were reviewed (including the 
version numbers and version dates of all documents). A list of all members of the 
ethics committee is also requested. 
♦ A copy of the translated and adapted (according to all national requirements) Patient 
Information / Informed Consent sheet. Version numbers and dates must be clearly 
stated on each page.  
♦ The signature log-list of the staff members with a sample of each authorized signature 
and the indication of the level of delegations. In case patients receive treatment at a 
satellite institution, i.e. outside the authorized institution, details on the satellite 
institution, including the CV of the local investigator, normal lab ranges and the 
approval of an ethics committee will have to be provided.  
♦ The full name, address, phone numbers and e-mail address of the local pharmacist 
who will be responsible for the trial medication (for any trial where the drug will be 
provided). 
♦ An accreditation, a certification, an established quality control / external quality 
assessment or another validation should be provided for the own laboratory. 
The center specific list of required documents will be included in the protocol activation 
package, with proper instructions as required by this protocol, your group and / or the 
applicable national law. 
The new investigator will be added to the “authorization list”, and will be allowed to register 
and enroll patients in the trial as soon as: 
♦ All the above mentioned documents are collected. 
♦ All applicable national legal and regulatory requirements are fulfilled. 
Patient registration/randomization from centers not (yet) included on the authorization list 
will not be accepted. 
14 Patient registration & randomization 
procedures 
14.1 General procedure 
Investigator will register and enroll patients through EORTC, following the standard EORTC 
procedure. Patient registration and randomization will only be accepted from authorized 
investigators (see Chapter 13). The randomization through Interactive Voice Response 
System (IVRS) will occur automatically after the eligibility has been successfully verified. 
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Patients should be registered directly on the EORTC online randomization system  
(ORTA = online randomized trials access), accessible 24 hours a day, 7 days a week, through 
the internet. To access the interactive randomization program, the investigator needs a 
username and a password (which can be requested at
In case of problems investigators can phone the EORTC Headquarters from 9.00 am to 5.00 
pm (Belgian local time) from Monday through Friday in order to register patients via the 
EORTC call center. Registration via the phone is not available on Belgian holidays. A list of 
these holidays is available on the EORTC web site 
and it is updated 
annually. 
Through internet: 
 
 
In case of problems registration by phone:  
 
A patient can only be registered and randomized after verification of eligibility. Both 
the eligibility check and randomization must be done before the start of the protocol 
treatment. 
14.2 Registration (step 1) (ORTA step 1) 
A patient can only be registered after signature of the Patient Informed Consent.  
A short list of questions needs to be answered during the registration (step 1).  
STANDARD INFORMATION REQUESTED: 
♦ institution number 
♦ protocol number: 1416 
♦ step number: 1 
♦ name of the responsible investigator 
♦ patient's code (maximum 4 alphanumerics, a unique code to help identify the patient 
within your institution) 
♦ patient's birth date (day/month/year) or year of birth (as allowed per applicable 
legislation) 
PROTOCOL SPECIFIC QUESTIONS: 
♦ All eligibility criteria will be checked one by one 
♦ Actual values for the eligibility parameters will be requested when applicable 
♦ date of written informed consent (day/month/year) 
A sequential patient identification number (“seqID”) will also be assigned at the end of 
the registration procedure. The seqID will allow the identification of the patients in the 
VISTA/Remote Data Capture system (VISTA/RDC) that will be used to complete the Case 
Report Forms. 
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14.3 Central confirmation of PD-L1 status testing (step 2) 
After registration (step 1), the central laboratory will confirm the results of PD-L1 status 
testing. 
14.4 Randomization (step 3) (ORTA step 2) 
Patient randomization will only be accepted after central confirmation (step 2) that a result 
for PD-L1 status test could be obtained.  
A patient can only be randomized after verification of eligibility.  
An exhaustive list of questions to be answered during the randomization procedure.  
STANDARD INFORMATION REQUESTED: 
♦ institution number 
♦ protocol number:1416 
♦ step number: 3 
♦ name of the responsible investigator 
♦ patient's code (maximum 4 alphanumerics, a unique code to help identify the patient 
within your institution) 
♦ patient's birth date (day/month/year) or year of birth (as allowed per applicable 
legislation) 
PROTOCOL SPECIFIC QUESTIONS: 
♦ result of the PD-L1 status test 
♦ all eligibility criteria will be checked one by one 
♦ actual values for the eligibility parameters will be requested when applicable 
♦ stratification factors 
♦ date of written informed consent (day/month/year) 
Patient randomization will only be accepted after patient eligibility has been verified. 
Patient randomization will be performed automatically in the Interactive Voice Response 
System (IVRS) . 
Additional information and instruction required for patient randomization will be provided in 
a separate registration & randomization manual. 
At the end of the randomization procedure, the treatment will be randomly allocated to the 
patients (minimization technique) through the IVRS. As this is a triple blind trial, neither the 
treatment arm nor its description will be provided to the investigator, the Sponsor, EORTC 
staff, CRO, patients and site staff. 
The local pharmacists and limited CRO personnel will be unblinded. Description of the blind 
procedure 
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IVRS will assign to each patient a treatment dynamically, based on the other patients 
randomized in the study and the stratification factors defined in the protocol. 
14.5 Stock management process 
The stock of pembrolizumab is maintained in each institution participating in the protocol 
with the help of IVRS for both ongoing and new patients. The institution needs to confirm to 
IVRS the reception of each shipment of pembrolizumab before it can be allocated to patients. 
14.6 Unblinding procedure 
The following are expected authorized unblinding events in the study: 
♦ Emergency Unblinding 
♦ Unblinding by Investigator Request After First Disease Recurrence 
♦ Unblinding at Final Analysis  
♦ Other Unblinding During the Course of the Study  
14.6.1 
Emergency Unblinding 
At any time during the trial, in case of a safety concern affecting an individual patient, the 
site investigator can request the unblinding of that patient.  
The unblinding requests should be made by the site investigator through the emergency 
unblinding call center. Alternatively, a health care provider can obtain information about the 
trial medication in emergency situations where the investigator is not available, as per 
Section 6.1.1. 
The emergency unblinding call center will use the randomization schedule for the trial to 
unblind patients and to unmask treatment identity. In the event that the emergency unblinding 
call center is not available for a given site in this trial, the central electronic randomization 
system (IVRS) should be used in order to unblind patients and to unmask treatment identity. 
The Sponsor will not provide random code/disclosure envelopes or lists with the clinical 
supplies. 
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the patient. Every effort should be made not to unblind the patient unless necessary. 
The system will ask the reason why the treatment needs to be unblinded. If the reason given 
justifies unblinding, an automatic email describing the unblinded treatment will be sent to the 
investigator. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible. The principal investigator or delegate and the respective patient will be 
unblinded. If other trial site personnel, EORTC HQ (except the statistician), Sponsor 
personnel or Covance study teams become unblinded to assist the case, it is acceptable and 
not considered an inadvertent unblinding incident due to the emergency unblinding.  
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14.6.2 
Unblinding by Investigator Request After First Disease 
Recurrence 
The investigator may request authorization for official unblinding of treatment arm upon 
disease recurrence. 
The emergency unblinding methods described in Section 14.6.1 should not be used in this 
process.  
During the study, all data must be entered in the eCRF within 5 days of each patient’s visit. 
Upon first recurrence, every effort will be made to have all pending data entered into the 
eCRFs within 1 business day or before the site is unblinded to the patient’s treatment 
assignment. 
The site should ensure data for disease recurrence is entered in the database prior to 
unblinding. Additionally, any AEs and/or Serious AEs should be reported and causality 
attributed in the database prior to unblinding. Please refer to the CRF guidelines and contact 
the site monitor for operational details. The site will request a unique unblinding code to the 
EORTC Unblinding Mailbox
in order to 
proceed to unblinding via IXRS.After unblinding for disease recurrence, the study subject, 
investigator, site personnel, Sponsor personnel, EORTC HQ study team (except the 
statistician) and Covance study teams associated with the conduct of the trial will become 
unblinded in order to continue monitoring each patient in the study.  
14.6.3 
Unblinding at final analysis 
The patient, the investigator and the site team and the EORTC HQ study team will be 
unblinded only after database lock for the final analysis of the primary endpoint. At 
unblinding for final analysis, the clinical operations manager will inform investigators that 
the allocated treatment of their patients is available upon request. Translational medicine 
studies will only be performed after unblinding for the primary endpoint. 
14.6.4 
Other unblinding during the course of the study 
Unblinding for the analysis planned in Section 8.3 and unblinding for global safety reasons 
are described in Chapter 9. 
Finally, unblinding may be required for the reporting of serious adverse events (SAEs) or 
pregnancies or submission of Development Safety Update Report (DSUR) to Competent 
Authorities, EudraVigilance Clinical Trial Module (EVCTM) and Ethics Committees. In this 
case, the patient, the investigator, the site team and the EORTC HQ study team remain 
blinded. The procedure is described in Section 16.7. 
 
 
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15 Forms and procedures for collecting data 
15.1 Case report forms and schedule for completion 
Data will be reported on the forms specifically designed by the EORTC Headquarters for this 
study. Forms should be electronically sent to the EORTC Headquarters through the 
VISTA/RDC (Remote Data Capture) system, with the exception of the HRQoL form, the 
EQ-5D questionnaire, the SAE form and the Pregnancy notification form which are paper 
CRFs. 
Copies of the HRQoL forms and the EQ-5D forms should be sent directly to the EORTC 
Headquarters by one of the following means: 
♦ By fax, to the attention of 
♦ By scanning and e-mailing the forms (see CRF completion guidelines) 
♦ By post to the EORTC Headquarters: 
SERIOUS ADVERSE EVENTS AND PREGNANCY NOTIFICATION FORMS 
SHOULD BE IMMEDIATELY REPORTED ACCORDING TO THE PROCEDURE 
DETAILED IN THIS PROTOCOL (see Chapter on Reporting Serious Adverse Events). 
A. Before the treatment starts: 
♦ The patient must be registered/randomized in the trial by INTERNET or in case of 
problems by phone. 
The electronic CRFs to be completed for a patient are available on the VISTA/RDC website 
one hour after the registration/randomization on http://rdc.eortc.be/ or on 
http://www.eortc.org in the section “Research Tools”. The paper CRFs will be made 
available for downloading through the same website. 
B. During/after treatment 
The list of forms to be completed for this study and their submission schedule are available 
on the VISTA/RDC website and are also described in the "guidelines for completion of case 
report forms" that are provided to each participating investigator.  
ALL Forms must be electronically approved and sent by the responsible investigator or 
one of his/her authorized staff members with the exception of the paper HRQoLform 
(no signature needed) 
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15.2 Data flow 
The forms must be completed electronically, with the exception of the paper forms (the 
Quality of Life form, SAE form, Pregnancy notification form and EQ-5D), according to the 
schedule defined in the guidelines for completion of Case Report Forms. 
The list of staff members authorized to enter data (with a sample of their signature) must be 
identified on the signature log and sent to the EORTC Headquarters by the responsible 
investigator before the start of the study. To enter the RDC system, the investigator or 
authorized staff member needs to use the same username and password that are used to 
access the interactive randomization program (ORTA). 
In all cases, it remains the responsibility of the principal investigator to check that data are 
entered in the database as soon as possible and that the electronic forms are filled out 
completely and correctly.  
The EORTC Headquarters will perform extensive consistency checks on the received data 
and will issue queries in case of inconsistent data. The queries for the electronic forms will 
appear in the VISTA/RDC system and must be answered there directly. 
A copy of the quality of life forms should be sent to EORTC Headquarters as soon as 
possible, while the original source document should be kept on site. If there are queries on 
the quality of life form, they will be raised electronically on a patient level in the 
VISTA/RDC system and they must be answered there directly. 
The EORTC data manager will subsequently apply the corrections into the database. 
When satellite institutions are involved, all contact is made exclusively with the primary 
institution, for purposes of data collection and all other study related issues. 
If an investigator (or an authorized staff member) needs to modify a CRF after the form has 
been electronically sent to the EORTC Headquarters, he/she should create a request for data 
correction in the VISTA/RDC system. 
Quality of life forms and EQ-5D: If an investigator (or an authorized staff member) needs to 
modify the paper quality of life form after the copy has been sent to the EORTC 
Headquarters, he/she should create a request for data correction on a patient level in the 
VISTA/RDC system. 
 
 
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16 Reporting of Adverse Events, Serious 
Adverse Events and Other Reportable 
Safety Events 
ICH GCP and the EU Directive 2001/20/EC require that both investigators and sponsors 
follow specific procedures when notifying and reporting adverse events/reactions in clinical 
trials. These procedures are described in this section of the protocol.  
16.1 Definitions 
These definitions reflect the minimal regulatory obligations; specific protocol requirements 
might apply in addition. 
AE: An Adverse Event is defined as “any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment”. An adverse event can 
therefore be any unfavorable and unintended signs (such as rash or enlarged liver), symptoms 
(such as nausea or chest pain), an abnormal laboratory finding (including results of blood 
tests, x-rays or scans) or a disease temporarily associated with the use of the protocol 
treatment, whether or not considered related to the investigational medicinal product. 
AR: An Adverse reaction of an investigational medicinal product is defined as “any 
noxious and unintended response to a medicinal product related to any dose administered”. 
All adverse events judged by either the reporting investigator or the sponsor as having a 
reasonable causal relationship to a medicinal product qualify as adverse reactions. The 
expression reasonable causal relationship means to convey in general that there is evidence 
or argument to suggest a causal relationship. 
UAR: An Unexpected Adverse Reaction is “any adverse reaction, the nature, or severity of 
which is not consistent with the applicable product information" (e.g. investigator's brochure 
for an unapproved investigational product or summary of product characteristics (SmPC) for 
a marketed product). 
When the outcome of the adverse reaction is not consistent with the applicable product 
information this adverse reaction should be considered as unexpected. 
Severity: The term “severe” is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate or severe, or as described in CTC grades); the event itself, 
however, may be of relative minor medical significance (such as severe headache). This is 
not the same as “serious,” which is based on patient/event outcome or action criteria usually 
associated with events that pose a threat to patient’s life or functioning. Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations.  
SAE: A Serious Adverse Event is defined as any untoward medical occurrence or effect in a 
patient, whether or not considered related to the protocol treatment, that at any dose: 
♦ results in death 
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♦ is life-threatening (i.e. an event in which the subject was at risk of death at the time of 
event; it does not refer to an event which hypothetically might have caused death if it 
was more severe) 
♦ requires inpatient hospitalization or prolongation of existing patient hospitalization 
♦ results in persistent or significant disability or incapacity 
♦ is a congenital anomaly or birth defect 
♦ is a medically important event or reaction. 
♦ Medical and scientific judgment should be exercised in deciding whether other 
situations should be considered serious such as important medical events that might 
not be immediately life-threatening or result in death or hospitalization but might 
jeopardize the patient or might require intervention to prevent one of the other 
outcomes listed in the definition above. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
ECI: Selected serious and nonserious AEs are also known as Event of Clinical Interests 
(ECIs) and must be reported to the Sponsor. Events of clinical interest for this study include: 
♦ Drug Induced Liver Injury (DILI): AST or ALT elevations ≥ 3 x ULN with 
concurrent elevation of total bilirubin ≥ 2 x ULN and, at the same time, alkaline 
phosphatase < 2 x ULN  
♦ If grade ≥ Grade 2: Nephritis, Autoimmune nephritis, Renal Failure, Acute Renal 
Failure, Acute interstitial pneumonitis, Interstitial lung disease, Pneumonitis  
♦ If grade ≥ Grade 2 or any grade resulting in dose modification (please refer to 
Appendix H) or use of systemic steroids to treat the AE: Intestinal Obstruction, 
Colitis, Colitis microscopic, Necrotizing colitis, Enterocolitis, Hemorrhagic 
enterocolitis, GI perforation, Diarrhea, Hepatitis, Autoimmune hepatitis, 
Transaminase elevations, Uveïtis, Iritis  
♦ If grade ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification (please refer to 
Appendix H) or use of systemic steroids to treat the AE: Adrenal Insufficiency, 
Hyperthyroidism, Hypothyroidism, Thyroid Disorder, Thyroiditis, Hypophysitis, 
Hypopituitarism  
♦ If grade ≥ Grade 3 or any grade resulting in dose modification (please refer to 
Appendix H) or use of systemic steroids to treat the AE: Autoimmune hemolytic 
anemia, Aplastic anemia, Thrombotic Thrombocytopenic Purpura (TTP), Idiopathic 
(or immune) Thrombocytopenia Purpura (ITP), Disseminated Intravascular 
Coagulation (DIC), Haemolytic Uraemic Syndrome (HUS), Creatinine elevations  
♦ If grade ≥ Grade 3: Pruritus, Rash, Rash generalized, Rash maculo-papular, 
Hyperglycemia (if associated with ketosis or metabolic acidosis (DKA), Any other 
Grade 3 (or higher) event which is considered immune-related by the physician  
♦ If grade ≥ Grade 4: Any Grade 4 anemia regardless of underlying mechanism  
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♦ Regardless of grade: Dermatitis Exfoliative, Erythema Multiforme, Stevens-Johnson 
Syndrome, Toxic Epidermal Necrolysis, Allergic reaction, Anaphylaxis, Cytokine 
release syndrome, Serum sickness, Infusion reactions, Infusion-like reactions, 
Autoimmune Neuropathy, Demyelinating Polyneuropathy, Guillain-Barre syndrome, 
Myasthenic syndrome, Myocarditis, Pericarditis, Pancreatitis, Type 1 diabetes 
mellitus (if new onset), Any rash considered clinically significant in the physician’s 
judgment  
SAR: A Serious Adverse Reaction is defined as any SAE which is considered related to the 
protocol treatment.  
SUSAR: Suspected Unexpected Serious Adverse Reaction.  
SUSARs occurring in clinical investigations qualify for expedited reporting to the 
appropriate Regulatory Authorities within the following timeframes: 
♦ Fatal or life-threatening SUSARs within 7 calendar days 
♦ Non-fatal or non-life-threatening SUSARs within 15 calendar days 
Inpatient hospitalization: a hospital stay equal to, or greater than, 24 hours. 
Second primary lung cancer is a lung tumor with a different histology from the primary 
lung tumor; a lung tumor with the same histology as the primary tumor, but occurring > 3 
years from removal of the primary tumor and not at the resection margins (local recurrence); 
Second primary extra-pulmonary malignancy is a cancer arising in organ other than the 
lungs; a cancer unrelated to the treatment of a previous malignancy  
Overdose: For this trial, an overdose will be defined as ≥1000 mg (5 times the dose) of 
pembrolizumab. No specific information is available on the treatment of an overdose of 
pembrolizumab. In the event of overdose, the subject should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated. 
16.2 Exceptions 
The following situations do not need to be reported as SAEs:  
♦ Elective hospitalization for pre-existing conditions that have not been exacerbated by 
trial treatment. 
♦ A hospitalization which was planned before the patient consented for study 
participation and where admission did not take longer than anticipated. 
♦ A hospitalization planned for protocol related treatment or protocol related procedure 
as per institutional standard timelines. 
♦ Social and/or convenience admission to a hospital 
♦ Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an (S)AE. 
♦ Situations where an untoward medical occurrence did not occur (palliative care, 
rehabilitation). 
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♦ Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
By EORTC convention, clinical events related to the primary cancer being studied or to the 
primary cancer progression are not to be reported as SAEs, even if they meet any of the 
seriousness criteria from the standard SAE definition, unless the event is more severe than 
expected and therefore the investigator considers that their clinical significance deserves 
reporting.  
16.3 Severity assessment 
The severity of all AEs (serious and non-serious) in this trial should be graded using CTCAE 
v4.03 www.eortc.org\investigators-area\ctc 
16.4 Causality assessment 
The investigator is obligated to assess the relationship between protocol treatment and the 
occurrence of each SAE following the definitions in this table: 
Relationship to the 
protocol treatment  
Description 
Reasonable possibility 
There is a reasonable possibility that the protocol treatment 
caused the event 
No reasonable 
possibility 
There is no reasonable possibility that the protocol treatment 
caused the event 
 
The investigator will use clinical judgment to determine the relationship. Alternative causes, 
such as natural history of the underlying diseases, medical history, concurrent conditions, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
protocol treatment will be considered and investigated. 
The decision will be recorded on the SAE form and if necessary the reason for the decision 
will also be recorded. 
16.5 Expectedness assessment 
The expectedness assessment is the responsibility of the sponsor of the study. The 
expectedness assessment will be performed against the following reference documents: 
♦ For Pembrolizumab: Investigator's Brochure 
♦ For Placebo: Safety Data Sheet 
16.6 Reporting procedure for investigators 
All adverse events that occur after the consent form is signed but before 
randomization/treatment allocation must be reported by the investigator only if they cause the 
subject to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
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treatment or a procedure. For patients that are receiving standard adjuvant chemotherapy 
during the screening phase; all SARs related to those drugs need to be reported to the 
Marketing Authorization Holder (MAH) of the administered drug(s). 
From the time of randomization/treatment allocation through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Please refer to Section 
16.2 for exceptions. 
For the time period beginning when the consent form is signed until randomization/treatment 
allocation, any serious adverse event, or follow up to a serious adverse event, including death 
due to any cause, that occurs to any subject must be reported within 24 hours to the Sponsor 
if it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure.  
All Serious Adverse Events (SAEs)/Events of Clinical Interest (ECI) occurring from the time 
a subject is randomized until 90 days after last blinded treatment administration (or 30 days 
following cessation of study treatment if the subject initiates new anticancer therapy, 
whichever is earlier), must be reported within 24 hours. 
Any SAE/ECI that occurs outside of the SAE detection period (after the 90-days 
period/initiation of new anticancer therapy) and considered to have a reasonable possibility to 
be related to the blinded treatment or study participation also needs to be reported to EORTC. 
All SAEs must be followed up for outcome. 
Signed Patient Registration Informed Consent till 
randomization: 
All SAEs* to EORTC 
Randomization till 30 days after last blinded 
treatment administration: 
All AEs 
Randomization till 90 days after last blinded 
treatment administration or 30 days after last 
blinded treatment administration if subject 
initiates new anticancer therapy, whichever is 
earlier:  
All SAEs/ECIs to EORTC 
From day 91 after last blinded treatment 
administration: 
Only SARs/ECIs considered to have 
a reasonable possible relationship to 
blinded treatment/study 
participation to EORTC 
* if it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention. SAR related to standard adjuvant chemotherapy during the 
screening phase need to be reported to MAH of the administered drug(s), NOT EORTC. 
 
Any secondary malignancy or second primary malignancy should also be reported in an 
expedited way on a SAE form with the appropriate seriousness criteria! 
All reporting must be done by the principal investigator or authorized staff member (i.e. on 
the signature list) to confirm the accuracy of the report. 
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All SAE / ECI data must be collected on the study-specific SAE form. 
All SAEs / ECIs must be reported immediately and no later than 24 hours from the time the 
investigator or staff became aware of the event. 
Reports of pembrolizumab overdose not associated with an adverse event must be reported 
immediately and no later than 24 hours from the time the investigator or staff became aware 
of the event on the study-specific SAE form as an ECI. 
All SAE-related information needs to be provided in English. 
All additional documents in local language must be accompanied by a translation in English, 
or the relevant information must be summarized in a follow-up SAE report form. 
All SAE-related information must be faxed to: 
 
EORTC Pharmacovigilance Unit: 
 
Investigators participating through non-EORTC groups should consult their group specific 
appendix for further details on the reporting of Serious Adverse Events. 
To enable the EORTC to comply with regulatory reporting requirements, all initial SAE 
reports should always include the following minimal information: an identifiable patient 
(SeqID), a suspect medicinal product if applicable, an identifiable reporting source, the 
description of the medical event and seriousness criteria, as well as the causality assessment 
by the investigator. Complete information requested on the SAE form of any reported serious 
adverse event must be returned within 7 calendar days of the initial report. If the completed 
form is not received within this deadline, the Pharmacovigilance Unit will make a written 
request to the investigator. 
Queries sent out by the EORTC Pharmacovigilance Unit need to be answered within 7 
calendar days. 
All forms need to be dated and signed by the principal investigator or any authorized staff 
member (i.e. on the signature list). 
16.7 Reporting responsibilities of the Sponsor 
The EORTC Pharmacovigilance Unit will forward all SAE reports to the appropriate persons 
within the EORTC Headquarters and to the pharmacovigilance contact at MSD as per Safety 
Data Exchange Agreement. 
After receipt of the initial report, all information will be reviewed and, if necessary, the 
Investigator will be contacted to obtain further information for assessment of the event. The 
Sponsor will evaluate the seriousness and the causal relationship of the event to study 
medication. In addition, the Sponsor will evaluate the expectedness according to the 
reference safety information (see above). Based on the Investigator and Sponsor’s assessment 
of the event, a decision will be made concerning the need for further action. 
Unblinding may be required for the reporting of serious adverse events (SAEs) or 
pregnancies or submission of Development Safety Update Report (DSUR) to Competent 
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Authorities, EudraVigilance Clinical Trial Module (EVCTM) and Ethics Committees. In this 
case, the patient, the investigator, the CRO, the site team and the EORTC HQ study team 
remain blinded. 
The EORTC Pharmacovigilance Unit and MSD have outlined the reporting of SUSARs in a 
Safety Data Exchange Agreement.  
16.8 Pregnancy reporting 
Pregnancy occurring during a patient’s participation in this trial, although not considered an 
SAE, must be notified to the EORTC Pharmacovigilance Unit within the same timelines as 
an SAE (within 24 hours) on a Pregnancy Notification Form. The outcome of a pregnancy 
should be followed up carefully and any adverse outcome to the mother or the child should 
be reported. This also applies to pregnancies in female partners of a male patient 
participating in this trial. 
♦ Any pregnancy in a female subject or in a female partner of a male subject diagnosed 
during the treatment period or within 120 days after last protocol treatment 
administration, or within 30 days after last protocol treatment administration if new 
anticancer therapy is initiated (whichever is earlier), must be reported to the EORTC 
Pharmacovigilance Unit  
♦ This must be reported within 24 hours of first becoming aware of the event by fax, to 
the Pharmacovigilance Unit on a Pregnancy Notification Form  
♦ If an SAE occurs in conjunction with the pregnancy, please also complete an SAE 
form as explained in the SAE reporting chapter 
♦ Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform 
mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be 
reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported. 
17 Quality assurance 
17.1 Control of data consistency 
Data forms will be entered in the EORTC Headquarters database by using the VISTA/RDC 
(Remote Data Capture) system. Computerized and manual consistency checks will be 
performed on newly entered forms; queries will be issued in case of inconsistencies. 
Consistent forms will be validated by the Data Manager. Inconsistent forms will be kept 
"pending" until resolution of the inconsistencies. 
17.2 Central review of Surgery/Pathology 
A retrospective central review of surgery will be organized. Therefore as per local 
regulations, the surgery and/or histology reports must be available. 
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17.3 Clinical site monitoring 
Clinical site monitoring visits will be performed by the Covance Monitor as described in the 
study monitoring plan. 
17.4 Audits 
The EORTC Compliance and Audits regularly conducts audits of EORTC institutions 
according to the annual audit schedule or based on a risk assessment. In addition, MSD, as 
the protocol Sponsor, routinely conducts audits of participating investigator sites in 
accordance with the sponsor's approved audit plan. These audits are performed to provide 
assurance that the rights, safety and wellbeing of patients are properly protected, to assess 
compliance with the protocol, processes and agreements, ICH GCP standards and applicable 
regulatory requirements, and to assess the quality of data.  
The investigator, by accepting to participate in this protocol, agrees that EORTC, the 
Sponsor, any third party (e.g. a CRO) acting on behalf of the EORTC or the Sponsor, or any 
domestic or foreign regulatory agency, may come at any time to audit or inspect their site and 
all sub sites, if applicable.  
This audit consists of interviews with the principal investigator and study team, review of 
documentation and practices, review of facilities, equipment and source data verification.  
The investigator will grant to the EORTC, the Sponsor, any third party (e.g. a CRO) acting 
on behalf of the EORTC or the Sponsor, direct access to paper and/or electronic 
documentation pertaining to the clinical study (e.g. CRFs, source documents such as hospital 
patient charts and investigator study files) to these authorized individuals. All site facilities 
related to the study conduct could be visited during an audit (e.g. pharmacy, laboratory, 
archives …). The investigator agrees to co-operate and provide assistance at reasonable times 
and places with respect to any auditing activity.  
If a regulatory authority inspection is announced, the investigator must inform the EORTC 
Headquarters Compliance and Audits immediately (contact at: 
  
In this way EORTC can provide support in preparing and/or facilitating the inspection. 
EORTC representatives/delegates may also attend the inspection. 
18 Ethical considerations 
18.1 Patient protection 
The responsible investigator will ensure that this study is conducted in agreement with either 
the Declaration of Helsinki (available on the World Medical Association web site 
(http://www.wma.net)) and/or the laws and regulations of the country, whichever provides 
the greatest protection of the patient. 
The protocol has been written, and the study will be conducted according to the ICH 
Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at 
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https://www.ema.europa.eu/documents/scientific-guideline/ich-e6-r1-guideline-good-
clinical-practice_en.pdf). 
The protocol must be approved by the competent ethics committee(s) as required by the 
applicable national legislation. 
18.2 Subject identification 
The name of the patient will neither be asked for nor recorded at the EORTC Headquarters. 
A sequential identification number will be automatically allocated to each patient registered 
in the trial. This number will identify the patient and will be included on all case report 
forms. In order to avoid identification errors, the patient’s code (maximum of 4 
alphanumerics) and date of birth or year of birth (as allowed per applicable legislation) will 
also be reported on the case report forms. 
18.3 Informed consent 
All patients will be informed about 
♦ the aims of the study 
♦ the possible adverse events 
♦ the procedures and possible hazards to which the patient will be exposed 
♦ the mechanism of treatment allocation 
♦ strict confidentiality of any patient data 
♦ medical records possibly being reviewed for trial purposes by authorized individuals 
other than their treating physician 
The template of the patient’s informed consent statement is given as a separate document 
dated and version controlled to this protocol. 
An adapted translation of the PIS/PIC will be provided by EORTC Headquarters and it is the 
responsibility of the Coordinating investigators for this trial (sometimes called National 
Coordinators) to adapt it to national/local requirements where necessary. 
The translated informed consent documents are to be submitted to ethics committees for 
approval. The competent ethics committee for each institution must approve the informed 
consent documents before the center can join the study. It is the responsibility of the 
competent ethics committee to ensure that the translated informed documents comply with 
ICH-GCP guidelines and all applicable national legislation. 
It is emphasized in the patient information sheet that participation is voluntary and that the 
patient is free to refuse further participation in the protocol whenever he/she wants to. This 
will not have any impact on the patient’s subsequent care. Documented informed consent 
must be obtained for all patients included in the study before they are registered and/or 
randomized at the EORTC Headquarters. The written informed consent form must be signed 
and personally dated by the patient or by the patient’s legally acceptable representative. 
All of the above must be done in accordance with the applicable national legislation and local 
regulatory requirements. 
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19 Administrative responsibilities 
19.1 The study coordinator 
The Study Coordinators work closely with the study team to develop the outline and full 
protocol and discusses the contents of the reports with the study team. The Study 
coordinators are responsible for publishing the study results. They will assist the CRP for 
answering some clinical questions concerning eligibility, treatment, and contributes to the 
medical review of the patients. 
Study coordinators: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19.2 The EORTC Headquarters 
The EORTC Headquarters will be responsible for writing the protocol and PIS/IC, reviewing 
the protocol, setting up the trial, collecting case report forms, controlling the quality of the 
reported data, organizing the medical review and generating reports and analyses in 
cooperation with the Study Coordinators. All methodological questions should be addressed 
to the EORTC Headquarters. 
EORTC HEADQUARTERS 
 
Avenue E. Mounierlaan 83/11 
 
Brussel 1200 Bruxelles 
 
België - Belgique 
 
 
 
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19.3 The EORTC group 
All questions concerning ongoing membership in the group should be addressed to the 
chairman and/or secretary of the group. 
For new membership contact Membership Committee at
EORTC Lung Cancer group 
Chairman: 
Secretary: 
20 Trial sponsorship and financing 
The legal Sponsor of this trial is Merck Sharp & Dohme LLC  
126 East Lincoln Avenue 
P.O. Box 2000 
Rahway, NJ 07065 USA 
21 Administrative and regulatory details 
21.1 Confidentiality 
21.1.1 
Confidentiality of Data 
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees. Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol. 
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21.1.2 
Confidentiality of Subject Records 
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data. By signing the consent form, the subject 
agrees to this process. If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor. 
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations. 
21.1.3 
Confidentiality of Investigator Information 
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all sub investigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law. This information may include: 
1. name, address, telephone number and e-mail address; 
2. hospital or clinic address and telephone number; 
3. curriculum vitae or other summary of qualifications and credentials; and 
4. other professional documentation. 
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information. 
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators. By signing this protocol, the investigator expressly consents to these uses and 
disclosures. 
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request. 
21.1.4 
Confidentiality of IRB/IEC Information 
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial. The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies. 
21.2 Compliance with Financial Disclosure Requirements 
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
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Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/sub investigator's 
responsibility to comply with any such request. 
The investigator/sub investigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/sub investigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form. The 
Investigator/sub investigator(s) also consent to the transmission of this information to the 
Sponsor in the United States for these purposes. This may involve the transmission of 
information to countries that do not have laws protecting personal data. 
21.3 Compliance with Law, Audit and Debarment 
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial. 
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in Appendix J - 
MSD Code of Conduct for Clinical Trials. 
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents. 
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor. 
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor. 
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms. 
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements. This 
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documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae. By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product. 
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed. The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained. The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files. 
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed. 
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial. 
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened. 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC. 
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational). When more than one trial site is 
open in an EU country, MSD, as the Sponsor, will designate, per country, a national principal 
coordinator (Protocol CI), responsible for coordinating the work of the principal investigators 
at the different trial sites in that Member State, according to national regulations. For a 
single-center trial, the Protocol CI is the principal investigator. In addition, the Sponsor must 
designate a principal or coordinating investigator to review the trial report that summarizes 
the trial results and confirm that, to the best of his/her knowledge, the report accurately 
describes the conduct and results of the trial [Clinical Study Report (CSR) CI]. The Sponsor 
may consider one or more factors in the selection of the individual to serve as the Protocol CI 
and or CSR CI (e.g., availability of the CI during the anticipated review process, thorough 
understanding of clinical trial methods, appropriate enrollment of subject cohort, timely 
achievement of trial milestones). The Protocol CI must be a participating trial investigator. 
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21.4 Compliance with Trial Registration and Results 
Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. MSD, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements. MSD entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information. 
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank. 
21.5 Quality Management System 
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial. 
21.6 Data Management 
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data. By signing this protocol, the investigator acknowledges that his/her electronic 
signature is the legally binding equivalent of a written signature. By entering his/her 
electronic signature, the investigator confirms that all recorded data have been verified as 
accurate. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately. 
21.7 Calibration of Critical Equipment 
The investigator or qualified designee has the responsibility to ensure that any critical device 
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible. Documentation of equipment calibration must be retained as source 
documentation at the trial site. 
Critical Equipment for this trial includes: 
Laboratory equipment – as required for inclusion labs and trial assessments 
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Imaging equipment – as required for study objectives 
Drug administration equipment – as required for storing, preparing, and administering study 
treatment 
22 Publication policy 
The publication of the main trial results will be written by the Study Coordinators on the 
basis of the final analysis performed at the EORTC Headquarters and will be sent to a major 
scientific journal. Authors of the manuscript will include at least the Study Coordinators, the 
investigators who have included more than 1.5% of the eligible patients in the trial (by order 
of inclusion), 2 representatives (statistician and clinical research physician) in charge of the 
trial at the EORTC Headquarters team and 2 representatives (statistician and clinical research 
physician) in charge of the trial at ETOP. For publication of translational research results, co-
authors will also include scientific collaborators who made substantial contribution to the 
research. 
The title of all manuscripts will include “EORTC, ETOP”, and all manuscripts will include 
an appropriate acknowledgment section, mentioning all investigators who have contributed 
to the trial, the EORTC Headquarters/ETOP staff involved in the study, as well as the trial 
Sponsor (MSD). 
It is the EORTC’s policy not to release trial results before data maturity has been reached for 
the primary endpoint(s) of the trial unless the publication is authorized by the Data 
Monitoring Committee. If the groups wish to publish or present study data before the 
publication of the primary trial endpoint, this may be authorized under the conditions 
specified in the EORTC Policy 009 “Release of Results and Authorship Policy” available 
from http:\\www.eortc.org, or authorized by the Data Monitoring Committee. 
The Group Chairmans, the Study Coordinators, the MSD responsible(s) and the EORTC 
Headquarters team/ETOP team must approve all publications, abstracts and presentations of 
data pertaining to patients included in this study. 
The data collected during this study are confidential. Any publications or abstracts arising 
from this study require approval by the Sponsor's (MSD) Executive Oversight Committee (as 
outlined in Section 9.3) prior to publication or presentation and must adhere to the Sponsor’s 
publication requirements as set forth in the approved clinical trial agreement (CTA). All draft 
publications, including abstracts or detailed summaries of any proposed presentations, must 
be submitted to the Sponsor (MSD) at the earliest practicable time for review, not less than 
30 days before submission or presentation unless otherwise set forth in the CTA. 
Sponsor (MSD) shall have the right to delete any confidential information contained in any 
proposed presentation or abstract and may delay publication for up to 60 days for purposes of 
filing a patent application. 
 
 
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Appendix A: References 
Ref. 1 
http://seer.cancer.gov/statfacts/html/lungb.html  
Ref. 2 
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx  
Ref. 3 
Kerr KM, Bubendorf L, Edelman MJ, et al. Second ESMO consensus conference 
on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer. 
Ann Oncol 2014; 25:1681–90 
Ref. 4 
Bergot E, Levallet G, Campbell K, et al. Predictive biomarkers in patients with 
resected non-small cell lung cancer treated with perioperative chemotherapy. Eur 
Resp Rev 2013; 22:565–76 
Ref. 5 
Seymour L, Prognostic and predictive biomarkers for ACT (adjuvant 
chemotherapy) in resected non-small cell lung cancer (R-NSCLC): LACE-Bio. 
ESMO Meeting 2014, abstract 1670 
Ref. 6 
Manser R, Wright G, Hart D, et al. Surgery for early stage non-small cell lung 
cancer. Cochrane Database Syst Rev 2005; (1):CD004699 
Ref. 7 
Vansteenkiste J, Crinò L, Dooms C, et al. 2nd ESMO Consensus Conference on 
Lung Cancer: early-stage non-small-cell lung cancer consensus on diagnosis, 
treatment and follow-up. Ann Oncol. 2014; 25:1462–74 
Ref. 8 
Yan TD, Black D, Bannon PG, et al. Systematic review and meta-analysis of 
randomized and nonrandomized trials on safety and efficacy of video-assisted 
thoracic surgery lobectomy for early-stage non-small-cell lung cancer. J Clin Oncol 
2009; 27: 2553-62 
Ref. 9 
Mentzer SJ, DeCamp MM, Harpole DH Jr, et al. Thoracoscopy and video-assisted 
thoracic surgery in the treatment of lung cancer. Chest 1995; 107:298S-301S 
Ref. 10 McKenna RJ Jr, Houck W, Fuller CB. Video-assisted thoracic surgery lobectomy: 
experience with 1,100 cases. Ann Thorac Surg 2006; 81(2):421-5 
Ref. 11 Swanson SJ, Herndon JE 2nd, D'Amico TA, et al. Video-assisted thoracic surgery 
lobectomy: report of CALGB 39802--a prospective, multi-institution feasibility 
study. J Clin Oncol 2007; 25:4993-7 
Ref. 12 Flores RM, Park BJ, Dycoco J, et al. Lobectomy by video-assisted thoracic surgery 
(VATS) versus thoracotomy for lung cancer. J Thorac Cardiovasc Surg 2009; 
138:11-8 
Ref. 13 Lardinois D, De Leyn P, Van Schil P, et al. ESTS guidelines for intraoperative 
lymph node staging in non-small cell lung cancer. Eur J Cardiothorac Surg 2006; 
30:787-92 
Ref. 14 Chansky K, Sculier J, Crowley J, et al. The International Association for the Study 
of Lung Cancer Staging project: prognostic factors and pathologic TNM stage in 
surgically managed non-small cell lung cancer. J Thorac Oncol. 2009;4(7):792-801 
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Ref. 15 Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a 
pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008; 
26(21):3552-9 
Ref. 16 NSCLC Meta-analyses Collaborative Group. Adjuvant chemotherapy, with or 
without postoperative radiotherapy, in operable non-small-cell lung cancer: two 
meta-analyses of individual patient data. Lancet 2010; 375(9722):1267-77 
Ref. 17 Strauss GM, Herndon JE 2nd, Maddaus MA, et al. Adjuvant paclitaxel plus 
carboplatin compared with observation in stage IB non-small-cell lung cancer: 
CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy 
Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin 
Oncol. 2008; 26(31):5043-51 
Ref. 18 Butts CA, Ding K, Seymour L, et al. Randomized phase III trial of vinorelbine plus 
cisplatin compared with observation in completely resected stage IB and II non-
small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol 2010; 
28:29 
Ref. 19 Keller SM1, Adak S, Wagner H, et al. A randomized trial of postoperative adjuvant 
therapy in patients with completely resected stage II or IIIA non-small-cell lung 
cancer. Eastern Cooperative Oncology Group. N Engl J Med. 2000; 343(17):1217-
22. 
Ref. 20 Scagliotti GV, Roldano F, Torri V, et al. Randomized study of adjuvant 
chemotherapy for completely resected stage I, II, or IIIA non-small cell lung cancer. 
J Natl Cancer Inst 2003; 95:1453-61.  
Ref. 21 Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin 
versus observation in patients with completely resected stage IB-IIIA non-small cell 
lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): A 
randomised controlled trial. Lancet Oncol 2006; 7:719-27. 
Ref. 22 The International Adjuvant Lung Cancer Trial Collaborative Group: Cisplatin-
based adjuvant chemotherapy in patients with completely resected nonsmall cell 
lung cancer. N Engl J Med 2004; 350:351-60. 
Ref. 23 Waller D, Peake MD, Stephens RJ, et al. Chemotherapy for patients with non-small 
cell lung cancer: the surgical setting of the Big Lung Trial. Eur J Cardiothorac Surg. 
2004; 26(1):173-82 
Ref. 24 Kelly K, et al. A randomized, double-blind phase 3 trial of adjuvant erlotinib (E) 
versus placebo (P) following complete tumor resection with or without adjuvant 
chemotherapy in patients (pts) with stage IB-IIIA EGFR positive (IHC/FISH) non-
small cell lung cancer (NSCLC): RADIANT results. ASCO Meeting 2014. 
Ref. 25 Vansteenkiste J, et al. MAGRIT, a double-blind, randomized, placebo-controlled 
Phase III study to assess the efficacy of the recMAGE-A3 + AS15 cancer 
immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-
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contribute to poor prognosis and tumor cells immune escape through suppressing 
tumor infiltrating dendritic cells maturation. Med Oncol 2011; 28:682–8 
Ref. 49 Garon E, et al. LBA43 - Antitumor activity of pembrolizumab (Pembro; MK-3475) 
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analysis of patients (pts) with advanced non-small cell lung carcinoma (NSCLC). 
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Ref. 50 Champiat S, Ileana E, Giaccone G, et al. Incorporating Immune-Checkpoint 
Inhibitors into Systemic Therapy of NSCLC. J Thorac Oncol 2014; 9(2):144-53 
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PD-L1 antibody in patients with locally advanced or metastatic tumors. J Clin 
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Ref. 55 Garon EB, et al. Safety and clinical activitiy of MK-3475 in previously treated 
patients with non-small cell lung cancer (NSCLC). ASCO Meeting 2014; abstract 
8020 
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patients with advanced non-small cell lung cancer (NSCLC). ASCO Meeting 2014; 
abstract 8007. 
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antibody, in patients with NSCLC. ASCO Meeting 2014 
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engineered antibody MPDL3280A (anti-PDL1). ESMO 2013 
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Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 
2015 May 21;372(21):2018-28. 
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docetaxel in previously treated subjects with non-small cell lung cancer. Presented 
at ASCO Meeting 2014 
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Jan;45(2):281–9. 
Ref. 72 Spiessens B1, Debois M. Adjusted significance levels for subgroup analyses in 
clinical trials. Contemp Clin Trials. 2010; 31(6):647-56 
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Ref. 73 Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics 1975;31:103-115.  
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Implementing a class of permutation tests: The coin package, Journal of Statistical 
Software, 28(8), 1–23. http: //www.jstatsoft.org/v28/i08/  
Ref. 75 Maurer W, Bretz F. Multiple testing in group sequential trials using graphical 
approaches. Stat Biopharm Res. 2013;5 (4): 311-320.  
Ref. 76 Aaronson NK, Ahmedzai S, Bergman B, et al., for the European Organization for 
Research and Treatment of Cancer QLQ-C30: A Quality-of-Life Instrument for Use 
in International Clinical Trials in Oncology. JNCI 85: 365-376, 1993 
Ref. 77 Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M. The EORTC QLQ-
LC13: a modular supplement to the EORTC Core Quality of Life Questionnaire 
(QLQ-C30) for use in lung cancer clinical trials. EORTC Study Group on Quality 
of Life. Eur J Cancer. 1994;30(5):635-42.). 
Ref. 78 The EuroQol Group (1990). EuroQol-a new facility for the measurement of health-
related quality of life. Health Policy 16(3):199-208 
Ref. 79 Osoba D, Rodrigues G, Myles J, et al: Interpreting the significance of changes in 
health related quality-of-life scores. J Clin Oncol 16:139-144, 1998 
Ref. 80 Azuma K, Ota K, Kawahara A, et al. Association of PD-L1 overexpression with 
activating EGFR mutations in surgically resected non–small cell lung cancer. Ann 
Oncol 2014 in press  
Ref. 81 Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and 
powerful approach to multiple testing. J R Stat Soc 1995;57:289–300. 
Ref. 82 Korn EL, Troendle JF, McShane LM, Simon R. Controlling the number of false 
discoveries: application to high-dimensional genomic data. J Statist Plan Infer 2004; 
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Ref. 83 Howard D. Bondell and Brian J. Reich (2008) Simultaneous Regression Shrinkage, 
Variable Selection, and Supervised Clustering of Predictors with OSCAR 
Biometrics 64, 115–123. 
Ref. 84 Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, et al. 
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced 
non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 
2016 Apr 9;387(10027):1540-50. 
Ref. 85 Wakelee HA et al. Adjuvant chemotherapy with or without bevacizumab in patients 
with resected non-small-cell lung cancer (E1505): an open-label, multicentre, 
randomised, phase 3 trial, Lancet Oncol. 2017 Dec;18(12):1610-1623. 
Ref. 86 Rami-Porta R1, Wittekind C, Goldstraw P; International Association for the Study 
of Lung Cancer (IASLC) Staging Committee: Complete resection in lung cancer 
surgery: proposed definition, Lung Cancer. 2005 Jul;49(1):25-33 
 
 
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Appendix B: Abbreviations 
AE 
Adverse Event  
ALT 
Alanine Aminotransferase 
ALP 
alkaline phosphatase 
ANC 
Absolute neutrophil count 
AR 
Adverse reaction 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase  
AUC 
area-under-the-curve  
BUN 
Blood urea nitrogen 
Ca 
Calcium 
CI  
Confidence interval 
CTCAE 
Common Terminology Criteria for Adverse Events 
CRO 
Contract Research Organization 
CRF 
Case Report Form 
DILI 
Drug Induced Liver Injury 
DIC 
Disseminated Intravascular Coagulation 
DFS 
Disease Free Survival  
DKA 
diabetic ketoacidosis 
DNA 
Deoxyribonucleic acid 
DMC  
DMC Data Monitoring Committee  
DSUR 
Development Safety Update Report  
ECI 
Event of Clinical Interest 
ECI 
Epidural Corticosteroid Injection 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic Case Report Form 
EGFR 
EGFR: Epidermal Growth Factor Receptor 
EOC  
Executive Oversight Committee 
EORTC 
European Organization for Research and Treatment of Cancer 
ETOP 
European Thoracic Oncology Platform 
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ESMO 
European Society for Medical Oncology  
EVCTM  
EudraVigilance Clinical Trial Module 
FDAAA 
Food and Drug Administration Amendments Act  
FDAMA 
Food and Drug Administration Modernization Act  
FFPE 
FFPE: Formalin Fixed Paraffin Embedded 
FSH 
Follicle-stimulating Hormone 
FWER 
Family wise error rate 
GMP 
Good Manufacturing Practice 
HBM 
Human biological material 
HCO3 
Bicarbonate 
HIV 
Human Immunodeficiency Virus  
HLA  
Human Lymphocyte Antigen 
HR 
Hazard Ratio 
HRQOL 
Health-Related Quality of Life 
HUS 
Haemolytic Uraemic Syndrome 
IA  
Interim Analysis  
IASLC 
International Association for the Study of Lung Cancer 
ICH/GCP 
The International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use / 
Good Clinical Practice 
IDMC 
Independent Data Monitoring Committee 
IFN 
interferon 
IHC 
Immunohistochemistry 
IL-2 
interleukin-2 
ILD 
interstitial lung disease 
irAE 
Immune-related Adverse Event 
IVRS 
Interactive Voice Response System 
ITIM  
immunoreceptor tyrosine-based inhibition motif 
ITP 
Idiopathic (or immune) Thrombocytopenia Purpura 
ITSM  
immunoreceptor tyrosine-based switch motif  
ITT 
intention to treat 
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IV 
Intravenous 
K 
Potassium  
LACE 
Lung Adjuvant Cisplatin Evaluation 
LCSS 
Lung Cancer Specific Survival 
MSD 
Merck Sharp & Dohme LLC 
MTD 
Maximum Tolerated Dose 
Na 
sodium  
NED 
No evidence of disease 
NGS 
next-generation sequencing 
NSCLC 
Non Small Cell Cancer 
ORR 
Overall Response Rate 
ORTA  
Online Randomized Trials Access 
OTC  
over-the-counter  
OS 
Overall Survival 
PD-1 
Programmed Death receptor 1 
PD-L1 
Programmed Death-Ligand 1 
PK  
pharmacokinetics  
PS  
Performance status 
QA&C 
Quality Assurance and Control Unit 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks  
RDC 
Remote Data Capture 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic acid 
SAC  
Scientific Advisory Committee  
SAE 
Serious Adverse Event  
seqID 
sequential patient identification 
SmPC 
Summary of Product Characteristics  
SOP 
Standard Operating Procedure 
SSC 
Study Steering Committee 
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SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TAA  
tumor-associated antigens 
TB  
Tuberculosis Bacillus 
TILs  
tumor infiltrating lymphocytes  
TNF  
tumor necrosis factor  
TPS 
Tumor proportion score 
TR 
Translational Research 
TRAC 
Translational Research Advisory Committee  
TTP 
Thrombotic Thrombocytopenic Purpura  
UAR 
Unexpected Adverse Reaction 
ULN 
upper limit of normal 
VATS  
Video-assisted thoracoscopic surgery 
 
 
 
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Appendix C: ECOG performance status scale 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair 
5 
Dead 
 
 
 
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Appendix D: Common Terminology Criteria for 
Adverse Events 
In the present study, adverse events and/or adverse drug reactions will be recorded according 
to the  
Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. 
At the time this protocol was issued, the full CTC document was available on the NCI web 
site, at the following 
address:https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ct
c_40 . 
The EORTC Headquarters web site https://www.eortc.be/services/doc/ctc/ provides a link to 
the appropriate CTC web site. This link will be updated if the CTC address is changed. 
 
 
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Appendix E: EORTC Quality of Life evaluation: 
guidelines for administration of 
questionnaires - EORTC QLQ-C30 (version 
3) - EORTC QLQ-LC13 - EQ-5D – Health 
Questionnaire 
 
 
 
 
 
 
 
 
 
 
EORTC Quality of Life evaluation: guidelines for administration of questionnaires 
The instructions given below are intended to provide some general guidelines for collecting 
quality of life (QOL) data in EORTC studies. These instructions apply for all questionnaires 
administered via paper. 
1. Who is the responsible person (RP) for QOL data collection? 
In each institution, the principal investigator is the responsible for the local organization of 
QoL data collection. This can be delegated to a physician, data manager, (research) nurse or a 
psychologist. Such a person should have the full protocol at his/her disposal as well as the 
questionnaire(s). This person would also be the intermediate contact point in case of any 
necessary clarification asked by the EORTC Headquarters. 
2. Who should fill out the questionnaire? 
In principle it is the patient who has to complete the QOL forms and preferably without help 
from others. In the case where a patient is too sick to fill out the questionnaire by him/herself 
or if the patient is not able to complete the questionnaire for such reasons as forgetting 
his/her glasses, another person could read the questions without making any suggestions and 
report the answers on the forms. It is not allowed for another person to fill in the 
questionnaire as if (s)he was the patient (proxy assessment) unless specifically allowed by 
the protocol. 
3. What instructions should be given to the patient? 
At entry in a study, the RP should give the patient an explanation of the objective of the 
study and instructions for completing the questionnaires. 
The patient should be informed that participation in the QOL protocol is voluntary and that 
the information provided is confidential (identification is only for administrative purposes 
and includes date of birth and today’s date (completion date)). 
The following issues should be explained to the patient: 
 The schedule of assessments. 
 The questionnaire is a self administered questionnaire that should be completed by the 
patient him(her)self. The patient can ask for aid in reading or writing but should not let 
another person provide the answers. 
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 The patient should   circle  the choice that best corresponds to his/her situation. 
 There is no right or wrong answer to any of these questions. The answers will not 
influence any medical decision making. 
 All questions should be answered.  
 The patient will be given a questionnaire in the default language(s) of the hospital. If 
desired, the patient may request another language. The RP will then contact the EORTC 
Headquarters for the appropriate translation. 
The RP should make sure that the patient understands the instructions. 
At each subsequent assessment as defined by the protocol, the patient should receive the 
questionnaire from the RP or from other appropriate staff if the RP is unavailable. 
4. Where should the patient complete the questionnaire? 
The patient should complete the questionnaire at the clinic, and, ideally in a quiet, private 
room. If this is not possible, the waiting room is an acceptable alternative. In general it does 
not take long to complete the questionnaire, but patients should be given the time they need 
to answer all questions. 
5. When should they complete the questionnaire? 
The timing of the planned QoL assessments is detailed in the protocol. When a QOL 
assessment is planned, the questionnaire should be given to the patient preferably before the 
meeting with the physician, ensuring that the patient has enough time to complete the 
questionnaire. If the patient is to receive a therapy, the questionnaire should be filled out 
before administration of the treatment (unless indicated otherwise in the protocol). The 
questionnaire should not be taken home and/or mailed (unless indicated otherwise in the 
protocol). 
6. Review of the completed questionnaire 
After the patient has completed the questionnaire, the person handling the questionnaire 
should: 
 Complete the “Hospital Staff” specific data box. 
 Check that the completion date is correctly filled in by the patient. 
 Screen the questionnaire for omissions. 
If this is the case: 
 Please ask the patient the reason for omissions. It may be that patient forgot to flip a page 
or did not understand a question. The patient should not be forced to provide an answer if 
(s)he does not wish to do so. 
 Additional explanation may be provided, but the questions should not be rephrased. 
7. Missing forms 
If for some reason the patient is unable or does not wish to complete a quality of life 
questionnaire the reason and the date of visit should be documented on the corresponding 
CRF (case report form).  
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8. Mailing to EORTC Headquarters 
A copy of the questionnaires should be sent to EORTC Headquarters as soon as possible, 
while the original source document should be kept on site. As it is impossible to 
retrospectively collect missing quality of life data, please make sure the patient completes the 
questionnaire at the timepoint when he/she is supposed to complete it. 
9. Administration via telephone 
If it is deemed not in the best interest of the safety of the patient, the questionnaires may be 
collected via telephone interview. 
The interviewer must confirm he is speaking to the correct person. The interviewer must 
identify how many questions there are, what the response options are and what the recall time 
(e.g. during the past week) is. All questions should be attempted. The interviewer must allow 
enough time to answer and can can repeat the questions and/or the response options to 
patients as many times as they request. But the interviewer must not suggest any answers or 
alter the question. 
The interviewer records the answer chosen by the patient. The patient is allowed to skip a 
question, if he/she requests so. If the patient did not answer all questions, the interviewer 
must offer the patient the opportunity to read them again. 
Thank you very much for your cooperation.  
 
 
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EORTC QLQ-C30 (version 3) 
We are interested in some things about you and your health. Please answer all of the 
questions yourself by circling the number that best applies to you. There are no "right" or 
"wrong" answers. The information that you provide will remain strictly confidential. 
Today's date (Day, Month, Year): 
31
 
 
___________________________________________________________________________ 
 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1. Do you have any trouble doing strenuous activities,  
 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. Do you have any trouble taking a short walk 
outside of the house? 
1 
2 
3 
4 
4. Do you need to stay in bed or a chair during the 
 
day? 
1 
2 
3 
4 
5. Do you need help with eating, dressing, washing 
 
yourself or using the toilet? 
1 
2 
3 
4 
 
 
 
 
 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. Were you limited in doing either your work or 
other  daily activities? 
1 
2 
3 
4 
7. Were you limited in pursuing your hobbies or other 
 
leisure time activities? 
1 
2 
3 
4 
8. Were you short of breath? 
1 
2 
3 
4 
9. Have you had pain? 
1 
2 
3 
4 
10. 
Did you need to rest? 
1 
2 
3 
4 
11. 
Have you had trouble sleeping? 
1 
2 
3 
4 
12. 
Have you felt weak? 
1 
2 
3 
4 
13. 
Have you lacked appetite? 
1 
2 
3 
4 
14. 
Have you felt nauseated? 
1 
2 
3 
4 
15. 
Have you vomited? 
1 
2 
3 
4 
16. 
Have you been constipated? 
1 
2 
3 
4 
 
Please go on to the next page 
 
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During the past week: 
Not 
at All 
A 
Little 
Quite 
a Bit 
Very 
Much 
17. 
Have you had diarrhea? 
1 
2 
3 
4 
18. 
Were you tired? 
1 
2 
3 
4 
19. 
Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. 
Have you had difficulty in concentrating on 
things, 
 
like reading a newspaper or watching television?  
1 
2 
3 
4 
21. 
Did you feel tense? 
1 
2 
3 
4 
22. 
Did you worry? 
1 
2 
3 
4 
23. 
Did you feel irritable? 
1 
2 
3 
4 
24. 
Did you feel depressed? 
1 
2 
3 
4 
25. 
Have you had difficulty remembering things? 
1 
2 
3 
4 
26. 
Has your physical condition or medical 
treatment 
 
interfered with your family life? 
1 
2 
3 
4 
27. 
Has your physical condition or medical 
treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
28. 
Has your physical condition or medical 
treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
 
For the following questions please circle the number between 1 and 7 that best applies 
to you 
29. How would you rate your overall health during the past week? 
 
1  
2 
 
3 
 
4 
 
5 
 
6 
 
7 
Very poor 
 
 
 
 
 
 
 
 
 
Excellent 
 
30. How would you rate your overall quality of life during the past week? 
 
1  
2 
 
3 
 
4 
 
5 
 
6 
 
7 
Very poor 
 
 
 
 
 
 
 
 
 
Excellent 
 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 
 
 
 
 
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September 23, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ENGLISH 
 
 
EORTC QLQ-LC13 
Patients sometimes report that they have the following symptoms or problems. Please 
indicate the extent to which you have experienced these symptoms or problems during the 
past week. Please answer by circling the number that best applies to you. 
___________________________________________________________________________ 
During the past week: 
Not 
at All 
A 
Little 
Quite 
a Bit 
Very 
Much 
31. How much did you cough? 
1 
2 
3 
4 
32. Did you cough up blood? 
1 
2 
3 
4 
33. Were you short of breath when you rested? 
1 
2 
3 
4 
34. Were you short of breath when you walked? 
1 
2 
3 
4 
35. Were you short of breath when you climbed 
 
stairs? 
1 
2 
3 
4 
36. Have you had a sore mouth or tongue? 
1 
2 
3 
4 
37. Have you had trouble swallowing? 
1 
2 
3 
4 
38. Have you had tingling hands or feet? 
1 
2 
3 
4 
39. Have you had hair loss? 
1 
2 
3 
4 
40. Have you had pain in your chest? 
1 
2 
3 
4 
41. Have you had pain in your arm or shoulder? 
1 
2 
3 
4 
42. Have you had pain in other parts of your body? 
1 
2 
3 
4 
 
If yes, where  
 
 
 
 
 
1 
2 
3 
4 
43. Did you take any medicine for pain? 
1 
2 
3 
4 
 
1 
No  
 
 
 
2 
Yes 
1 
2 
3 
4 
 
If yes, how much did it help? 
1 
2 
3 
4 
 
© QLQ-C30-LC13 Copyright 1994 EORTC Quality of life Group. All rights reserved 
 
 
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Health Questionnaire 
 
 
English version for the UK 
 
(Validated for Ireland) 
 
 
 
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By placing a tick in one box in each group below, please indicate which statements best 
describe your own health state today. 
 
 
Mobility 
 
I have no problems in walking about 
❑ 
I have some problems in walking about 
❑ 
I am confined to bed 
❑ 
 
 
Self-Care 
 
I have no problems with self-care 
❑ 
I have some problems washing or dressing myself 
❑ 
I am unable to wash or dress myself 
❑ 
 
 
Usual Activities (e.g. work, study, housework, family or leisure activities) 
 
I have no problems with performing my usual activities 
❑ 
I have some problems with performing my usual activities 
❑ 
I am unable to perform my usual activities 
❑ 
 
 
Pain / Discomfort 
 
I have no pain or discomfort 
❑ 
I have moderate pain or discomfort 
❑ 
I have extreme pain or discomfort 
❑ 
 
 
Anxiety / Depression 
 
I am not anxious or depressed 
❑ 
I am moderately anxious or depressed 
❑ 
I am extremely anxious or depressed 
❑ 
 
 
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September 23, 2022
9
8
7
6
5
4
3
2
1
100
0
To help people say how good or bad a health state is, we 
have drawn a scale (rather like a thermometer) on which the 
best state you can imagine is marked 100 and the worst state 
you can imagine is marked 0.
We would like you to indicate on this scale how good or 
bad your own health is today, in your opinion. Please do 
this by drawing a line from the box below to whichever 
point on the scale indicates how good or bad your health 
state is today.
Best 
imaginable 
health state
Worst 
imaginable 
health state
Your own health state
today
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Appendix F: IASLC VII TNM staging 
Stage groupings 
Stage IA 
T1a-T1b 
N0 
M0 
Stage IB 
T2a 
N0 
M0 
Stage 
IIA 
T1a,T1b,T2a 
N1 
M0 
T2b 
N0 
M0 
Stage 
IIB 
T2b 
N1 
M0 
T3 
N0 
M0 
Stage 
IIIA 
T1a,T1b,T2a,T2b 
N2 
M0 
T3 
N1,N2 
M0 
T4 
N0,N1 
M0 
Stage 
IIIB 
T4 
N2 
M0 
Any T 
N3 
M0 
Stage IV 
Any T 
Any N M1a or M1b 
 
Primary tumor (T) 
T1 
Tumor ≤3 cm diameter, surrounded by lung or visceral pleura, without invasion 
more proximal than lobar bronchus (i.e., not the main bronchus) 
T1a 
Tumor ≤2 cm in diameter* 
T1b 
Tumor >2 cm but ≤3 cm in diameter 
T2 
Tumor >3 cm but ≤7 cm, or tumor with any of the following features**: 
Involves main bronchus, ≥2 cm distal to carina 
Invades visceral pleura 
Associated with atelectasis or obstructive pneumonitis that extends to the hilar 
region but does not involve the entire lung 
T2a 
Tumor >3 cm but ≤5 cm 
T2b 
Tumor >5 cm but ≤7 cm 
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Primary tumor (T) 
T3 
Tumor >7 cm or any of the following: 
Directly invades any of the following: chest wall, diaphragm, phrenic nerve, 
mediastinal pleura, parietal pericardium, main bronchus <2 cm from carina 
(without involvement of carina) 
Atelectasis or obstructive pneumonitis of the entire lung 
Separate tumor nodules in the same lobe 
T4 
Tumor of any size that invades the mediastinum, heart, great vessels, trachea, 
recurrent laryngeal nerve, esophagus, vertebral body, carina, or with separate 
tumor nodules in a different ipsilateral lobe 
Regional lymph nodes (N) 
N0 
No regional lymph node metastases 
N1 
Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and 
intrapulmonary nodes, including involvement by direct extension 
N2 
Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) 
N3 
Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or 
contralateral scalene, or supraclavicular lymph node(s) 
Distant metastasis (M) 
M0 
No distant metastasis 
M1 
Distant metastasis 
M1a 
Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or 
malignant pleural or pericardial effusion*** 
M1b 
Distant metastasis (in extrathoracic organs) 
*The uncommon superficial spreading tumor of any size with its invasive component 
limited to the bronchial wall, which may extend proximal to the main bronchus, is also 
classified as T1a. 
**T2 tumors with these features are classified T2a if 5 cm or less or if size cannot be 
determined, and T2b if greater than 5 cms but no larger than 7 cms. 
***Most pleural (pericardial) effusions with lung cancer are due to tumor. In a few 
patients, however, multiple microscopical examinations of pleural (pericardial) fluid are 
negative for tumor, and the fluid is non-bloody and is not an exudate. Where these 
elements and clinical judgment dictate that the effusion is not related to the tumor, the 
effusion should be excluded as a staging element and the patient should be classified as 
M0. 
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Appendix G: Guidelines for management of 
toxicity 
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation as per Table 1 below.  
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Table 1. Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.  
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the last 
pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
irAEs 
Toxicity grade (CTCAE 
v4.03) 
Action with 
pembrolizumab 
Corticosteroid and/or other 
therapies  
Monitoring and follow-up  
Pneumonitis  
Grade 2 
Withhold  
•  Administer corticosteroids 
(initial dose of 1 - 2 mg/kg 
prednisone or equivalent) 
followed by taper 
•  Add prophylactic antibiotics 
for opportunistic infections 
•  Monitor participants for signs and 
symptoms of pneumonitis 
•  Evaluate participants with suspected 
pneumonitis with radiographic 
imaging and initiate corticosteroid 
treatment 
 
Recurrent Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
•  Administer corticosteroids 
(initial dose of 1 - 2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
•  Monitor participants for signs and 
symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel perforation (ie, 
peritoneal signs and ileus) 
•  Participants with ≥Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing 
endoscopy to rule out colitis 
•  Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV infusion 
Recurrent Grade 3 or 
Grade 4 
Permanently 
discontinue 
AST or ALT elevation or 
Increased Bilirubin 
Grade 2 a 
Withhold 
•  Administer corticosteroids 
(initial dose of 0.5 - 1 mg/kg 
•  Monitor with liver function tests 
(consider weekly or more frequently 
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General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.  
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the last 
pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
prednisone or equivalent) 
followed by taper 
until liver enzyme value returned to 
baseline or is stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
•  Administer corticosteroids 
(initial dose of 1 - 2 mg/kg 
prednisone or equivalent) 
followed by taper 
Type 1 diabetes mellitus 
(T1DM) or 
Hyperglycemia 
New onset T1DM or  
Grade 3 or 4 
hyperglycemia associated 
with evidence of -cell 
failure 
Withhold d 
•  Initiate insulin replacement 
therapy for participants with 
T1DM 
•  Administer anti-
hyperglycemic in participants 
with hyperglycemia 
•  Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes 
Hypophysitis 
Grade 2 
Withhold 
•  Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated 
•  Monitor for signs and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism 
Grade 2 
Continue 
•  Treat with non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate 
•  Monitor for signs and symptoms of 
thyroid disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
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General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.  
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the last 
pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
Hypothyroidism 
Grade 2, 3, 4 
Continue 
•  Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care 
•  Monitor for signs and symptoms of 
thyroid disorders 
Nephritis: 
grading according to 
increased creatinine or 
acute kidney injury 
Grade 2 
Withhold 
•  Administer corticosteroids 
(prednisone 1 – 2 mg/kg or 
equivalent) followed by taper 
•  Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All Other immune-related 
AEs 
Persistent Grade 2 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Grade 3 
Withhold or 
discontinue based on 
the event e  
Recurrent Grade 3 or 
Grade 4  
Permanently 
discontinue 
a AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 - 3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 - 10.0 x ULN if baseline normal; >3.0 - 10.0 x baseline if 
baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, Stevens-Johnson Syndrome and toxic epidermal necrolysis. 
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Patients who have a Grade 2 endocrinopathy, requiring ongoing hormonal replacement 
therapy, may restart pembrolizumab if treatment interruption was less than 12 weeks. 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks 
of the scheduled interruption, but no more than a maximum of 12 weeks for each instance. If 
the interruption is greater than 12 weeks the PI must discuss continuation in the trial with the 
Sponsor prior to administering additional therapy. For more info, please refer to Section 6.3. 
 
 
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Appendix H: Supportive care 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail in the 
ECI guidance document. Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids. Note that several courses of 
steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care. The treatment guidelines are intended to be applied when the investigator determines 
the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document). Refer to Section 5.2.1 for infusion 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 
♦ Pneumonitis:  
♦ For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. 
♦ For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed. 
♦ Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
♦ Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). 
♦ All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
♦ For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
♦ For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids. 
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♦ When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
♦ Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
♦ For T1DM or Grade 3-4 Hyperglycemia 
♦ Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
♦ Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
♦ Hypophysitis: 
♦ For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
♦ For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
♦ Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
♦ Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
♦ In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested 
as initial therapy. 
♦ In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
♦ Grade 3-4 hyperthyroidism  
♦ Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones may 
be required as the steroid dose is tapered. 
♦ Hepatic: 
♦ For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
♦ Treat with IV or oral corticosteroids 
♦ For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
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♦ When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
♦ Renal Failure or Nephritis: 
♦ For Grade 2 events, treat with corticosteroids. 
♦ For Grade 3-4 events, treat with systemic corticosteroids. 
♦ When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
♦ Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
Table 1 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab 
Table 1 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated 
for < =24 hrs 
Stop Infusion 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr). Otherwise 
dosing will be held until symptoms resolve and 
the participant should be premedicated for the 
next scheduled dose. 
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of study 
intervention with: 
 
Diphenhydramine 50 
mg po (or equivalent 
dose of antihistamine). 
 
Acetaminophen 500-
1000 mg po (or 
equivalent equivalent 
dose of analgesic). 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; 
pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine** 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should 
be used immediately. 
Participant is permanently discontinued from 
further study drug intervention. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during 
the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.03 
(CTCAE) at http://ctep.cancer.gov  
 
 
 
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Appendix I: Event Of Clinical Interest Guidance 
Document 
 
 
 
 
PEMBROLIZUMAB PROGRAM 
(MK-3475) 
 
 
 
EVENT OF CLINICAL INTEREST  
 
GUIDANCE DOCUMENT 
 
 
Version 5.0 
 
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REVISION HISTORY LOG 
Version 
Effective 
Date* 
Revision 
Author 
Action 
1 
08-Aug-
2012 
Initial Release of guidance document for MK-
3475 
2 
07-June-
2013 
Revised title, formerly was “MK-3475 Immune-
Related Adverse Event Identification, 
Evaluation and Management Guidance 
Document for Investigators” 
 
Revised the format of irAE Guidance document, 
including layout, font, sectioning, etc. for 
consistency with Sponsor Events of Clinical 
Interest guidance documents. 
 
Modified Categories for irAEs: 
Replaced GI with Colitis category. 
Removed Neurologic category. 
Added Renal category. 
 
Removed detail in the irAE Guidance document 
that can be located in the Investigator’s 
Brochure for MK-3475. 
 
Removed details regarding non-MK-3475 
compounds. 
 
Added ECI reporting guidelines. 
 
Included a Table Events of Clinical Interest: 
Immune-Related Adverse Events that includes 
the key terms. 
Also placed a pull-out quick-review sheet in the 
Appendix. 
 
Updated background, diagnosis and course of 
treatment details for irAEs. 
PPD
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Version 
Effective 
Date* 
Revision 
Author 
Action 
3 
10-Sep-
2014 
Renamed the document: “Pembrolizumab 
Program (MK-3475) - Events of Clinical 
Interest Guidance Document”. 
 
Introduced generic name: pembrolizumab (MK-
3475) and inserted throughout the document. 
 
Updated Overview – Section 1  
Clarified the scope of the document and the 
reporting window for ECIs 
 
Updated Table 1 with medDRA Preferred 
Terms for adverse events to correspond with 
reporting of terms to clinical database, 
rearranged the order, and updated the reporting 
criteria. 
 
Updated the dose modification/discontinuation 
section to clarify discontinuation and hold 
terminology. 
 
Updated Section 2 – ECI Reporting Guidelines  
Clarified that ECIs must be reported to Merck 
within 24 hours regardless of attribution to 
study treatment or etiology. 
 
Updated Section 3  
For All Sections, removed the Course of Action 
for Grade 1 events. 
 
- Section 3.1 Pneumonitis 
Moved Pneumonitis to beginning of ECI 
Section 
Updated management guidelines for Grade 2 
and Grade 3-4 events 
- Section 3.2 Colitis: 
PPD
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Version 
Effective 
Date* 
Revision 
Author 
Action 
Updated AE terms and ECI criteria, updated 
course of action language for clarity  
 
- Section 3.3 Endocrine: 
Updated ECI criteria and updated course of 
action language for clarity. 
Added subsections for hypophysitis, 
hyperthyroidism and hypothyroidism to clarify 
management guidelines. 
 
- Section 3.4 Hematologic: 
New section added. 
 
- Section 3.5: Hepatic: 
Updated terms and added additional guidance 
for reporting of DILI ECI; updated course of 
action for clarity 
 
- Section 3.6 Neurologic:  
New section added. 
 
- Section 3.7 Ocular: 
Changed the name of this section from Eye to 
Ocular 
Added the term “iritis”, updated ECI guidance, 
and updated course of action language for 
clarity 
 
- Section 3.8 Renal:  
Updated section for clarity. 
 
- Section 3.9 Skin: 
Updated list of terms and added terms for 
reporting of other skin ECIs; added section 
3.9.1: Immediate Evaluation for Potential Skin 
ECIs 
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Effective 
Date* 
Revision 
Author 
Action 
 
- Section 3.10 Other:  
Updated list of terms for clarity; revised course 
of action for clarity. 
 
- Section 3.11 Infusion Reactions: 
New section added. 
 
- Section 3.12: Follow-up to Resolution:  
New section added. 
 
- Section 4:  
References updated. 
 
- Section 5:  
ECI table updated for consistency with Table 1.  
 
- Section 6: Appendix 2 – Past Medical History 
Related to Dermatologic Event: New section 
added. 
 
- Section 7: Appendix 3 – Presentation of the 
Dermatologic Event: New section added. 
 
- Section 8: Appendix 4 – Focused Skin 
Examination: New section added. 
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Effective 
Date* 
Revision 
Author 
Action 
4 
04-Dec-
2014  
Table 1 
Updated Endocrine (reported as ECI if ≥ Grade 
3 or ≥ Grade 2 and resulting in dose 
modification or use of systemic steroids to treat 
the AE) Section to include: 
Hyperglycemia, if ≥Grade 3 and associated with 
ketosis or metabolic acidosis (DKA) 
Created new section in Table 1 – Endocrine 
(reported as ECI) and added: 
Type 1 diabetes mellitus (if new onset) 
Hepatic: Clarified Transaminase elevations as: 
Transaminase elevations (ALT and/or AST) 
Section 3.2 Colitis 
Updated the duration of diarrhea requirments 
under the Course of Action for Grade 2 and 
Grade 3 
Section 3.3 Endocrine 
Clarified Course of Action for hyperthyroidism 
and hypothyroidism 
Added Course of Action section for Type 1 
diabetes mellitus (if new onset) and ≥ Grade 3 
hyperglycemia 
Section 5 
Updated Reference Table in Appendix 1 
5 
18-Dec-
2014 
Section 3.3 Endocrine 
Updated the Course of Action for Hypophysitis 
Merged Grades 2-4 into one course of action 
*Ensure that you are using the most current version of this document.  
 
 
PPD
PPD
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TABLE OF CONTENTS 
 
1. OVERVIEW 
 
 
 
 
 
 
 
 
162 
2. ECI REPORTING GUIDELINES  
 
 
 
 
 
165 
3. ECI CATEGORIES AND TERMS 
 
 
 
 
 
166 
3.1 Pneumonitis 
 
 
 
 
 
 
 
 
166 
3.2 Colitis 
 
 
 
 
 
 
 
 
 
167 
3.3 Endocrine  
 
 
 
 
 
 
 
 
169 
3.4 Hematologic 
 
 
 
 
 
 
 
 
172 
3.5 Hepatic 
 
 
 
 
 
 
 
 
 
173 
3.6 Neurologic 
 
 
 
 
 
 
 
 
175 
3.7 Ocular 
 
 
 
 
 
 
 
 
 
176 
3.8 Renal 
 
 
 
 
 
 
 
 
 
177 
3.9 Skin 
 
 
 
 
 
 
 
 
 
178 
3.9.1. Immediate Evaluation for Potential Skin ECIs 
 
 
 
180 
3.10 Other 
 
 
 
 
 
 
 
 
 
182 
3.11 Infusion Reactions 
 
 
 
 
 
 
 
183 
3.12 Follow-up to Resolution  
 
 
 
 
 
 
186 
4. REFERENCES 
 
 
 
 
 
 
 
 
187 
5. APPENDIX 1 –Events of Clinical Interest (ECI) – Reference Table 
 
188 
6. APPENDIX 2 – Past Medical History Related to Dermatologic Event 
 
190 
7. APPENDIX 3 – Presentation of the Dermatologic Event  
 
 
192 
8. APPENDIX 4 – Focused Skin Examination 
 
 
 
 
194 
 
 
 
 
 
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1. OVERVIEW 
The purpose of this document is to provide study sites with guidance on the identification 
and management of Events of Clinical Interest for the MK-3475 (also known as 
pembrolizumab) program. 
 
Based on the literature review [1-11], and consideration of mechanism of action of 
pembrolizumab, potential immune-related adverse events (irAEs) are the primary Event of 
Clinical Interest (ECI). Immune-related AEs are adverse events associated with the treatment 
of patients with immunotherapy treatments that appear to be associated with the immune 
therapy’s mechanism of action. Based on these potential irAEs, the sponsor has defined a list 
of specific adverse event terms (ECIs) that are selected adverse experiences that must be 
reported to MSD within 24 hours from the time the Investigator/physician is aware of such 
an occurrence, regardless of whether or not the investigator/physician considers the event to 
be related to study drug(s). In addition, these ECIs require additional detailed information to 
be collected and entered in the study database. ECIs may be identified through spontaneous 
patient report and / or upon review of subject data. Table 1 provides the list of terms and 
reporting requirements for AEs that must be reported as ECIs for MK-3475 protocols. Of 
note, the requirement for reporting of ECIs applies to all arms, including comparators, of 
MK-3475 clinical trials  
 
Given that our current list of events of clinical interest is not comprehensive for all potential 
immune-related events, it is possible that AEs other than those listed in this document may be 
observed in patients receiving pembrolizumab. Therefore any Grade 3 or higher event that 
the investigator/physician considers to be immune-related should be reported as an ECI 
regardless of whether the specific event term is in Table 1 and reported to MSD within 24 
hours from the time the Investigator/physician is aware of such an occurrence. Adverse 
events that are both an SAE and an ECI should be reported one time as an SAE only, 
however the event must be appropriately identified as an ECI as well in in the database. 
 
 
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Table 4: Events of Clinical Interest 
Pneumonitis (reported as ECI if ≥ Grade 2) 
Acute interstitial pneumonitis 
Interstitial lung disease 
Pneumonitis 
Colitis (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use 
of systemic steroids to treat the AE) 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal 
perforation 
Necrotizing colitis 
Diarrhea 
 
Endocrine (reported as ECI if ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification 
or use of systemic steroids to treat the AE) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis 
or metabolic acidosis (DKA) 
Endocrine (reported as ECI) 
Type 1 diabetes mellitus (if 
new onset) 
 
 
Hematologic (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification or 
use of systemic steroids to treat the AE) 
Autoimmune hemolytic 
anemia  
Aplastic anemia  
Thrombotic 
Thrombocytopenic 
Purpura (TTP) 
Idiopathic (or immune) 
Thrombocytopenia Purpura 
(ITP) 
Disseminated Intravascular 
Coagulation (DIC) 
Haemolytic Uraemic 
Syndrome (HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
Hepatic (reported as ECI if ≥ Grade 2, or any grade resulting in dose modification or use 
of systemic steroids to treat the AE) 
Hepatitis  
Autoimmune hepatitis  
Transaminase 
elevations (ALT and/or 
AST) 
Infusion Reactions (reported as ECI for any grade) 
Allergic reaction 
Anaphylaxis 
Cytokine release 
syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
 
 
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Neurologic (reported as ECI for any grade) 
Autoimmune neuropathy 
Guillain-Barre syndrome 
Demyelinating 
polyneuropathy 
Myasthenic syndrome 
 
 
Ocular (report as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE) 
Uveitis 
Iritis 
 
Renal (reported as ECI if ≥ Grade 2)  
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations (report as ECI if ≥Grade 3 or any 
grade resulting in dose modification or use of systemic 
steroids to treat the AE) 
Skin (reported as ECI for any grade) 
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson 
syndrome 
Toxic epidermal necrolysis 
 
 
Skin (reported as ECI if ≥ Grade 3) 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
 
 
Any rash considered clinically significant in the physician’s judgment  
Other (reported as ECI for any grade) 
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 
 
 
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Each of the events above is described within this guidance document, along with site 
requirements for reporting these events to the Sponsor. The information collected should be 
entered into the narrative field(s) of the Adverse Event module in the database (please note, if 
narrative entry into the database is not available, please use the narrative text box on the 
1727/AER Form). If additional Medical History or Concomitant Medications are reported, 
the Medical History and Concomitant Medication modules in the database must be updated. 
 
In addition, the guidelines include recommendations on the management of these ECIs. 
These guidelines are intended to be applied when the physician determines the events to be 
related to pembrolizumab. Note: if after the evaluation the event is determined not to be 
related, the physician is instructed to follow the ECI reporting guidance but does not need to 
follow the treatment guidance (below). Therefore, these recommendations should be seen as 
guidelines and the treating physician should exercise individual clinical judgment based on 
the patient. For any question of dose modification or other treatment options, the specific 
language in the protocol should be followed. Any questions pertaining to the collection of 
this information or management of ECIs should be directed to your local Sponsor contact.  
 
Dose Modification/Discontinuation 
 
The treatment guidance provides specific direction when to hold and/or discontinue 
pembrolizumab for each immune related adverse event. Of note, when the guidance states to 
“discontinue” pembrolizumab this is the permanent discontinuation of treatment with 
pembrolizumab. “Hold” means to stop treating with pembrolizumab but resumption of 
treatment may be considered assuming the patient meets the criteria for resumption of 
treatment. 
2. ECI REPORTING GUIDELINES 
ECIs are selected non-serious and serious adverse experiences that must be reported to MSD 
within 24 hours regardless of attribution to study treatment. The AEs listed in this document 
and any event that meets the ECI criteria (as noted) in Table 1 or in the respective protocol 
(event term and Grade) must be reported regardless of physician-determined causality with 
study medication and whether or not considered immune-related by the physician (unless 
otherwise specified). Physicians/study coordinators/designated site personnel are required to 
record these experiences as ECIs on the Adverse Experience electronic Case Report Forms 
(eCRFs) (or on paper) and to provide supplemental information (such as medical history, 
concomitant medications, investigations, etc.) about the event. 
 
Please refer to the Data Entry Guidelines (DEGs) for your protocol.  
Please refer to protocol for details on reporting timelines and reporting of Overdose and Drug 
Induced Liver Injury (DILI). 
 
 
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3. ECI CATEGORIES AND TERMS 
This section describes the ECI categories and outlines subject management guidelines when 
an ECI is reported. 
 
3.1 Pneumonitis 
 
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be 
reported to the Sponsor within 24 hours of the event: 
 
Pneumonitis 
Interstitial lung disease 
Acute interstitial pneumonitis  
 
If symptoms indicate possible new or worsening cardiac abnormalities additional testing 
and/or a cardiology consultation should be considered.  
 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or 
viral infection. It is important that patients with a suspected diagnosis of pneumonitis be 
managed as per the guidance below until treatment-related pneumonitis is excluded. 
Treatment of both a potential infectious etiology and pneumonitis in parallel may be 
warranted. Management of the treatment of suspected pneumonitis with steroid treatment 
should not be delayed for a therapeutic trial of antibiotics. If an alternative diagnosis is 
established, the patient does not require management as below; however the AE should be 
reported regardless of etiology. 
 
Course of Action 
 
Grade 2 events: 
Report as ECI 
Hold pembrolizumab. 
Consider pulmonary consultation with bronchoscopy and biopsy/BAL. 
Consider ID consult 
Conduct an in person evaluation approximately twice per week 
Consider frequent Chest X-ray as part of monitoring 
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Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent. 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
Second episode of pneumonitis – discontinue pembrolizumab if upon re-challenge the patient 
develops a second episode of Grade 2 or higher pneumonitis. 
 
Grade 3 and 4 events: 
Report as ECI 
Discontinue pembrolizumab. 
Hospitalize patient 
Bronchoscopy with biopsy and/or BAL is recommended. 
Immediately treat with intravenous steroids (methylprednisolone 125 mg IV). When 
symptoms improve to Grade 1 or less, a high dose oral steroid (prednisone 1 to 2 mg/kg once 
per day or dexamethasone 4 mg every 4 hours) taper should be started and continued over no 
less than 4 weeks. 
If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 48 
to 72 hours, treat with additional anti-inflammatory measures. Discontinue additional anti-
inflammatory measures upon symptom relief and initiate a prolonged steroid taper over 45 to 
60 days. If symptoms worsen during steroid reduction, initiate a retapering of steroids 
starting at a higher dose of 80 or 100 mg followed by a more prolonged taper and administer 
additional anti-inflammatory measures, as needed 
Add prophylactic antibiotics for opportunistic infections. 
 
3.2 Colitis 
 
The following AE terms, if considered ≥ Grade 2 or resulting in dose modification or use of 
systemic steroids to treat the AE, are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event:  
 
Colitis  
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic  
Gastrointestinal perforation 
Intestinal obstruction  
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Necrotizing colitis 
Diarrhea 
 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or 
parasitic infection, viral gastroenteritis, or the first manifestation of an inflammatory bowel 
disease by examination for stool leukocytes, stool cultures, a Clostridium difficile titer and 
endoscopy. However the AE should be reported regardless of etiology. 
 
Course of Action 
 
Grade 2 Diarrhea/Colitis (4-6 stools/day over baseline, dehydration requiring IV fluids < 24 
hours, abdominal pain, mucus or blood in stool): 
Report as ECI 
Hold pembrolizumab.  
Symptomatic Treatment 
For Grade 2 diarrhea that persists for greater than 3 days, and for diarrhea with blood and/or 
mucus,  
Consider GI consultation and endoscopy to confirm or rule out colitis  
Administer oral corticosteroids (prednisone 1-2 mg/kg QD or equivalent) 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
If symptoms worsen or persist > 3 days treat as Grade 3 
 
Grade 3 Diarrhea/Colitis (or Grade 2 diarrhea that persists for > 1 week): 
Report as ECI 
Hold pembrolizumab.  
Rule out bowel perforation. Imaging with plain films or CT can be useful. 
Recommend consultation with Gastroenterologist and confirmation biopsy with endoscopy. 
Treat with intravenous steroids (methylprednisolone 125 mg) followed by high dose oral 
steroids (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours) When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. Taper over 6 to 8 weeks in patients with diffuse and severe ulceration 
and/or bleeding. 
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Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 48 
to 72 hours, consider treatment with additional anti-inflammatory measures as described in 
the literature [5]. Discontinue additional anti-inflammatory measures upon symptom relief 
and initiate a prolonged steroid taper over 45 to 60 days. If symptoms worsen during steroid 
reduction, initiate a retapering of steroids starting at a higher dose of 80 or 100 mg followed 
by a more prolonged taper and administer additional anti-inflammatory measures as needed.  
 
Grade 4 events:  
Report as ECI 
Permanently discontinue pembrolizumab. 
Manage as per Grade 3. 
 
3.3 Endocrine 
 
The following AE terms, if considered ≥Grade 3 or if ≥Grade 2 and require 
holding/discontinuation/ modification of pembrolizumab dosing, are considered ECIs and 
should be reported to the Sponsor within 24 hours of the event: 
 
Adrenal insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism  
Hypothyroidism 
Thyroid disorder  
Thyroiditis  
 
All attempts should be made to rule out other causes such as brain metastases, sepsis and/or 
infection. However the AE should be reported regardless of etiology. 
 
Hypophysitis or other symptomatic endocrinopathy other than hypo- or hyperthyroidism 
 
Grade 2-4 events: 
Report as ECI if appropriate 
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Hold pembrolizumab 
Rule out infection and sepsis with appropriate cultures and imaging. 
Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
Pituitary gland imaging should be considered (MRIs with gadolinium and selective cuts of 
the pituitary can show enlargement or heterogeneity and confirm the diagnosis). 
Treat with prednisone 40 mg p.o. or equivalent per day. When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered.  
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.  
Hypophysitis with clinically significant adrenal insufficiency and hypotension, dehydration, 
and electrolyte abnormalities (such as hyponatremia and hyperkalemia) constitutes adrenal 
crisis. 
Consultation with an endocrinologist may be considered. 
 
 
Hyperthyroidism and Hypothyroidism 
 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
Grade 2 hyperthyroidism, Grade 2-4 hypothyroidism events: 
Report as ECI if appropriate (see Table 1) 
Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
Thyroid hormone and/or steroid replacement therapy to manage adrenal insufficiency. 
Therapy with pembrolizumab can be continued while treatment for the thyroid disorder is 
instituted.  
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as initial 
therapy.  
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care.  
Consultation with an endocrinologist may be considered. 
 
 
 
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Grade 3 hyperthyroidism events: 
Report as ECI 
Hold pembrolizumab.  
Rule out infection and sepsis with appropriate cultures and imaging. 
Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed by oral 
prednisone 1 to 2 mg/kg per day. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered.  
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 hyperthyroidism events: 
Report as ECI 
Discontinue pembrolizumab.  
Manage as per Grade 3 
 
Type 1 diabetes mellitus (if new onset) and ≥ Grade 3 Hyperglycemia 
 
The following AE terms are considered ECIs and should be reported to the Sponsor within 
24 hours of the event: 
 
Type I diabetes mellitus (T1DM), if new onset, including diabetic ketoacidosis (DKA)  
Grade 3 or higher hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA). 
 
Immune-mediated diabetes may present as new onset of Type 1 diabetes or an abrupt 
worsening of pre-existing diabetes associated with laboratorial evidence of beta cell failure. 
All attempts should be made to rule out other causes such as type 2 diabetes mellitus 
(T2DM), T2DM decompensation, steroid-induced diabetes, physiologic stress-induced 
diabetes, or poorly controlled pre-existing diabetes (either T1DM or T2DM), but events 
meeting the above criteria should be reported as ECIs regardless of etiology. The patients 
may present with hyperglycemia (abrupt onset or abrupt decompensation) with clinical 
evidence of diabetic ketoacidosis or laboratory evidence of insulin deficiency, such as 
ketonuria, laboratory evidence of metabolic acidosis, or low or undetected c-peptide. 
 
 
 
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Course of Action 
 
T1DM should be immediately treated with insulin. 
 
T1DM or Grade 3-4 Hyperglycemia events: 
Report as ECI if appropriate (see Table 1) 
Hold pembrolizumab for new onset Type 1 diabetes mellitus or Grade 3-4 hyperglycemia 
associated with evidence of beta cell failure, and resume pembrolizumab when patients are 
clinically and metabolically stable.  
Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-4 
hyperglycemia associated with metabolic acidosis or ketonuria.  
Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide.  
Consultation with an Endocrinologist is recommended. 
Consider local testing for islet cell antibodies and antibodies to GAD, IA-2, ZnT8, and 
insulin may be obtained.  
 
3.4 Hematologic 
 
The following AE term, if considered Grade ≥3 or requiring dose modification or use of 
systemic steroids to treat the AE, are considered an ECI and should be reported to the 
Sponsor within 24 hours of the event: 
 
Autoimmune hemolytic anemia 
Aplastic anemia 
Disseminated Intravascular Coagulation (DIC) 
Haemolytic Uraemic Syndrome (HUS) 
Idiopathic (or immune) Thrombocytopenia Purpura (ITP) 
Thrombotic Thrombocytopenic Purpura (TTP) 
Any Grade 4 anemia regardless of underlying mechanism 
 
All attempts should be made to rule out other causes such as metastases, sepsis and/or 
infection. Relevant diagnostic studies such as peripheral blood smear, reticulocyte count, 
LDH, haptoglobin, bone marrow biopsy or Coomb’s test, etc., should be considered to 
confirm the diagnosis. However the AE should be reported regardless of etiology. 
 
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Course of Action 
 
Grade 2 events: 
Report as ECI 
Hold pembrolizumab 
Prednisone 1-2 mg/kg daily may be indicated 
Consider Hematology consultation. 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3 events: 
Report as ECI 
Hematology consultation.  
Hold pembrolizumab Discontinuation should be considered as per specific protocol 
guidance. 
Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as 
appropriate 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
Report as ECI 
Hematology consultation 
Discontinue pembrolizumab for all solid tumor indications; refer to protocol for hematologic 
malignancies. 
Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as 
appropriate 
 
3.5 Hepatic 
 
The following AE terms, if considered ≥ Grade 2 or greater (or any grade with dose 
modification or use of systemic steroids to treat the AE), are considered ECIs and should be 
reported to the Sponsor within 24 hours of the event: 
 
Autoimmune hepatitis  
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Hepatitis  
Transaminase elevations 
 
All attempts should be made to rule out other causes such as metastatic disease, infection or 
other hepatic diseases. However the AE should be reported regardless of etiology. 
 
Drug Induced Liver Injury (DILI) 
 
In addition, the event must be reported as a Drug Induced Liver Injury (DILI) ECI, if the 
patient meets the laboratory criteria for potential DILI defined as:  
An elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value that is 
greater than or equal to three times (3X) the upper limit of normal (ULN) and  
An elevated total bilirubin lab value that is greater than or equal to two times (2X) ULN and 
At the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN,  
As a result of within-protocol-specific testing or unscheduled testing. 
 
Note that any hepatic immune ECI meeting DILI criteria should only be reported once as a 
DILI event. 
 
Course of Action 
 
Grade 2 events: 
Report as ECI 
Hold pembrolizumab when AST or ALT >3.0 to 5.0 times ULN and/or total bilirubin >1.5 to 
3.0 times ULN. 
Monitor liver function tests more frequently until returned to baseline values (consider 
weekly). 
Treat with 0.5-1 mg/kg/day methylprednisolone or oral equivalent and when LFT returns to 
grade 1 or baseline, taper steroids over at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume pembrolizumab per protocol  
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
Permanently discontinue pembrolizumab for patients with liver metastasis who begin 
treatment with Grade 2 elevation of AST or ALT, and AST or ALT increases ≥50% relative 
to baseline and lasts ≥1 week. 
 
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Grade 3 events: 
Report as ECI 
Discontinue pembrolizumab when AST or ALT >5.0 times ULN and/or total bilirubin >3.0 
times ULN. 
Consider appropriate consultation and liver biopsy to establish etiology of hepatic injury, if 
necessary 
Treat with high-dose intravenous glucocorticosteroids for 24 to 48 hours. When symptoms 
improve to Grade 1 or less, a steroid taper with dexamethasone 4 mg every 4 hours or 
prednisone at 1 to 2 mg/kg should be started and continued over no less than 4 weeks.  
If serum transaminase levels do not decrease 48 hours after initiation of systemic steroids, 
oral mycophenolate mofetil 500 mg every 12 hours may be given. Infliximab is not 
recommended due to its potential for hepatotoxicity. 
Several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events:  
Report as ECI 
Permanently discontinue pembrolizumab 
Manage patient as per Grade 3 above 
 
3.6 Neurologic 
 
The following AE terms, regardless of grade, are considered ECIs and should be reported to 
the Sponsor within 24 hours of the event: 
 
Autoimmune neuropathy 
Demyelinating polyneuropathy 
Guillain-Barre syndrome 
Myasthenic syndrome 
 
All attempts should be made to rule out other causes such as metastatic disease, other 
medications or infectious causes. However the AE should be reported regardless of etiology. 
 
 
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Course of Action 
 
Grade 2 events: 
Report as ECI 
Moderate (Grade 2) – consider withholding pembrolizumab.  
Consider treatment with prednisone 1-2 mg/kg p.o. daily as appropriate 
Consider Neurology consultation. Consider biopsy for confirmation of diagnosis. 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3 and 4 events: 
Report as ECI 
Discontinue pembrolizumab 
Obtain neurology consultation. Consider biopsy for confirmation of diagnosis 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once 
per day. If condition worsens consider IVIG or other immunosuppressive therapies as per 
local guidelines 
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
 
3.7 Ocular 
 
The following AE terms, if considered Grade ≥2 or requiring dose modification or use of 
systemic steroids to treat the AE, is considered an ECI and should be reported to the Sponsor 
within 24 hours of the event: 
 
Uveitis 
Iritis  
 
All attempts should be made to rule out other causes such as metastatic disease, infection or 
other ocular disease (e.g. glaucoma or cataracts). However the AE should be reported 
regardless of etiology. 
 
 
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Course of Action 
 
Grade 2 events:  
Evaluation by an ophthalmologist is strongly recommended. 
Treat with topical steroids such as 1% prednisolone acetate suspension and iridocyclitics. 
Discontinue pembrolizumab as per protocol if symptoms persist despite treatment with 
topical immunosuppressive therapy. 
 
Grade 3 events: 
Evaluation by an ophthalmologist is strongly recommended  
Hold pembrolizumab and consider permanent discontinuation as per specific protocol 
guidance. 
Treat with systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per day. 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
 
Grade 4 events:  
Evaluation by an ophthalmologist is strongly recommended  
Permanently discontinue pembrolizumab. 
Treat with corticosteroids as per Grade 3 above 
 
3.8 Renal 
 
The following AEs if ≥ Grade 2 are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event: 
 
Nephritis 
Nephritis autoimmune 
Renal failure 
Renal failure acute 
 
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Creatinine elevations ≥ Grade 3 or any grade with dose modification or use of systemic 
steroids to treat the AE. 
 
 
All attempts should be made to rule out other causes such as obstructive uropathy, 
progression of disease, or injury due to other chemotherapy agents. A renal consultation is 
recommended. However the AE should be reported regardless of etiology. 
 
 
Course of Action 
 
 
Grade 2 events: 
Hold pembrolizumab 
Treatment with prednisone 1-2 mg/kg p.o. daily. 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3-4 events:  
Discontinue pembrolizumab 
Renal consultation with consideration of ultrasound and/or biopsy as appropriate 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone IV or equivalent 
once per day. 
 
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
 
3.9 Skin 
 
Rash and Pruritus 
 
The following AEs should be considered as ECIs, if ≥ Grade 3 and should be reported to the 
Sponsor within 24 hours of the event:  
 
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Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
In addition to CTCAE Grade 3 rash, any rash that is considered clinically significant, in the 
physician's judgment, should be treated as an ECI. Clinical significance is left to the 
physician to determine, and could possibly include rashes such as the following:  
rash with a duration >2 weeks; OR  
rash that is >10% body surface area; OR  
rash that causes significant discomfort not relieved by topical medication or temporary 
cessation of study drug. 
 
Other Skin ECIs 
 
The following AEs should always be reported as ECIs, regardless of grade, and should be 
reported to the Sponsor within 24 hours of the event:  
 
Dermatitis exfoliative 
Erythema multiforme 
Steven’s Johnson syndrome 
Toxic epidermal necrolysis 
 
Please note, the AE should be reported regardless of etiology. 
 
Course of Action 
 
Grade 2 events: 
Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., 
betamethasone 0.1% cream or hydrocortisone 1%) or urea-containing creams in combination 
with oral anti-pruritics (e.g., diphenhydramine HCl or hydroxyzine HCl).  
Treatment with oral steroids is at physician’s discretion for Grade 2 events. 
 
 
 
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Grade 3 events: 
Hold pembrolizumab. 
Consider Dermatology Consultation and biopsy for confirmation of diagnosis. 
Treatment with oral steroids is recommended, starting with 1 mg/kg prednisone or equivalent 
once per day or dexamethasone 4 mg four times orally daily. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
Permanently discontinue pembrolizumab. 
Dermatology consultation and consideration of biopsy and clinical dermatology photograph. 
Initiate steroids at 1 to 2 mg/kg prednisone or equivalent. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
 
3.9.1. Immediate Evaluation for Potential Skin ECIs 
 
A. Photographs:  
Every attempt should be made to get a photograph of the actual ECI skin lesion or rash as 
soon as possible. Obtain appropriate consent for subject photographs if a consent form 
addendum is required by your IRB/ERC.  
Take digital photographs of:  
the head (to assess mucosal or eye involvement),  
the trunk and extremities, and  
a close-up of the skin lesion/rash.  
 
If possible, a ruler should be placed alongside the site of a skin occurrence as a fixed marker 
of distance.  
The time/date stamp should be set in the 'ON' position for documentation purposes.  
Photographs should be stored with the subject’s study records.  
The Sponsor may request copies of photographs. The local study contact (e.g., CRA) will 
provide guidance to the site, if needed.  
 
 
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B. Past Medical History:  
Collect past medical history relevant to the event, using the questions in Appendix 2 (Past 
Medical History Related to Dermatologic Event) as a guide. Any preexisting conditions not 
previously reported (e.g., drug allergy) should be entered into the Medical History eCRF.  
 
C. Presentation of the Event:  
Collect information on clinical presentation and potential contributing factors using the 
questions in Appendix 3 (Presentation of the Dermatologic Event) as a guide. This 
information should be summarized and entered in narrative format in the AE eCRF. Please 
use the available free-text fields, such as Signs and Symptoms. Note pertinent negatives 
where applicable to reflect that the information was collected. Any treatments administered 
should be entered on the Concomitant Medication eCRF.  
 
D. Vitals Signs and Standard Laboratory Tests:  
Measure vital signs (pulse, sitting BP, oral temperature, and respiratory rate) and record on 
the Vital Signs eCRF. Perform standard laboratory tests (CBC with manual differential and 
serum chemistry panel, including LFTs).  
 
E. Focused Skin Examination:  
Perform a focused skin examination using the questions in Appendix 4 (Focused Skin 
Examination) as a guide. Information should be summarized and entered on the Adverse 
Experience eCRF as part of the narrative.  
 
F. Dermatology Consult  
Refer the subject to a dermatologist as soon as possible.  
For a “severe rash”, the subject must be seen within 1-2 days of reporting the event.  
For clinically significant rash, the subject should be seen within 3-5 days.  
 
The dermatologist should submit a biopsy sample to a certified dermatopathology laboratory 
or to a pathologist experienced in reviewing skin specimens.  
 
The site should provide the dermatologist with all relevant case history, including copies of 
clinical photographs and laboratory test results.  
 
 
 
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3.10 Other 
 
The following AEs, regardless of grade, are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event: 
 
Myocarditis 
Pericarditis 
Pancreatitis 
Any additional Grade 3 or higher event which the physician considers to be immune related 
 
All attempts should be made to rule out other causes. Therapeutic specialists should be 
consulted as appropriate. However the AE should be reported regardless of etiology. 
 
 
Course of Action 
 
Grade 2 events or Grade 1 events that do not improve with symptomatic treatment: 
Withhold pembrolizumab. 
Systemic corticosteroids may be indicated.  
Consider biopsy for confirmation of diagnosis. 
If pembrolizumab held and corticosteroid required, manage as per grade 3 below. 
 
Grade 3 events: 
Hold pembrolizumab 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once 
per day. 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. Otherwise, pembrolizumab treatment may 
be restarted and the dose modified as specified in the protocol 
 
Grade 4 events: 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once 
per day. 
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Discontinue pembrolizumab  
 
3.11 Infusion Reactions 
 
The following AE terms, regardless of grade, are considered ECIs and should be reported to 
the Sponsor within 24 hours of the event: 
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
 
Please note, the AE should be reported regardless of etiology. 
 
 
Course of Action 
 
Refer to infusion reaction table in the protocol and below. 
 
 
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Infusion Reactions  
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator. 
If symptoms resolve within one 
hour of stopping drug infusion, 
the infusion may be restarted at 
50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 
mL/hr). Otherwise dosing will be 
held until symptoms resolve and 
the subject should be 
premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to 
infusion of 
pembrolizumab with: 
 
Diphenhydramine 50 mg 
p.o. (or equivalent dose 
of antihistamine). 
 
Acetaminophen 500-
1000 mg p.o. (or 
equivalent dose of 
antipyretic). 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently 
discontinued from further trial 
treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse 
Events v4.03 (CTCAE) at http://ctep.cancer.gov 
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3.12 Follow-up to Resolution  
 
Subjects should be followed to resolution. The Adverse Experience eCRF should be updated 
with information regarding duration and clinical course of the event. Information obtained 
from the consulting specialist, including diagnosis, should be recorded in the appropriate AE 
fields. Free-text fields should be used to record narrative information:  
 
Clinical course of the event  
Course of treatment  
Evidence supporting recovery  
Follow-up to the clinical course  
 
Any treatments administered for the event should also be entered in the Concomitant 
Medication eCRF.  
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4. REFERENCES 
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature 
Reviews Cancer 2012; 12:252-264. 
Weber JS Practical Management of Immune-Related Adverse Events from Immune 
Checkpoint Protein Antibodies for the Oncologist. American Society of Clinical Oncology 
2012; 1092-9118/10/1-10. 
Weber JS, Ka¨hler KC, and Hauschild A. Management of Immune-Related Adverse Events 
and Kinetics of Response With Ipilimumab. J Clin Oncol 30. 2012. 
http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.41.6750. 
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, et al. Improved Survival with 
Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med 363:711-723, 2010. 
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med 2012; 
366:2443-2454. 
Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, et al. Safety and Activity of Anti–PD-L1 
Antibody in Patients with Advanced Cancer. N Engl J Med 2012; 366:2455-2465. 
Weber J, Thompson JA, Hamid O, et al: A randomized, double-blind, placebo-controlled, 
phase II study comparing the tolerability and efficacy of ipilimumab administered with or 
without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin 
Cancer Res 15:5591-5598, 2009. 
Lemech C and Arkenau HT. Novel Treatments for Metastatic Cutaneous Melanoma and the 
Management of Emergent Toxicities. Clinical Medicine Insights: Oncology 2012:6 53–66. 
Phan GQ, Weber JS, and Sondak VK. CTLA-4 Blockade with Monoclonal Antibodies in 
Patients with Metastatic Cancer: Surgical Issues. Annals of Surgical Oncology 15(11):3014–
3021. 
Bristol-Myers Squibb: YERVOY (ipilimumab): Serious and fatal immune-mediated adverse 
reactions—YERVOY Risk Evaluation and Mitigation Strategy (REMS). 
http://www.yervoy.com/hcp/rems.aspx 
Bristol-Myers Squibb: YERVOY (ipilimumab) prescribing information revised March 2011. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf 
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5. APPENDIX 1 –Events of Clinical Interest (ECI) – Reference Table 
Pneumonitis (reported as ECI if ≥ Grade 2) 
Acute interstitial pneumonitis 
Interstitial lung disease 
Pneumonitis 
Colitis (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE) 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal 
perforation 
Necrotizing colitis 
Diarrhea 
 
Endocrine (reported as ECI if ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or 
use of systemic steroids to treat the AE) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis 
or metabolic acidosis (DKA) 
Endocrine (reported as ECI) 
Type 1 diabetes mellitus (if 
new onset) 
 
 
Hematologic (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification or 
use of systemic steroids to treat the AE) 
Autoimmune hemolytic 
anemia  
Aplastic anemia  
Thrombotic 
Thrombocytopenic 
Purpura (TTP) 
Idiopathic (or immune) 
Thrombocytopenia Purpura 
(ITP) 
Disseminated Intravascular 
Coagulation (DIC) 
Haemolytic Uraemic 
Syndrome (HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
Hepatic (reported as ECI if ≥ Grade 2, or any grade resulting in dose modification or use 
of systemic steroids to treat the AE) 
Hepatitis  
Autoimmune hepatitis  
Transaminase 
elevations (ALT and/or 
AST) 
Infusion Reactions (reported as ECI for any grade) 
Allergic reaction 
Anaphylaxis 
Cytokine release 
syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
 
 
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Neurologic (reported as ECI for any grade) 
Autoimmune neuropathy 
Guillain-Barre syndrome 
Demyelinating 
polyneuropathy 
Myasthenic syndrome 
 
 
Ocular (report as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE) 
Uveitis 
Iritis 
 
Renal (reported as ECI if ≥ Grade 2)  
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations (report as ECI if ≥Grade 3 or any 
grade resulting in dose modification or use of systemic 
steroids to treat the AE) 
Skin (reported as ECI for any grade) 
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson 
syndrome 
Toxic epidermal necrolysis 
 
 
Skin (reported as ECI if ≥ Grade 3) 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
 
 
Any rash considered clinically significant in the physician’s judgment  
Other (reported as ECI for any grade) 
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 
 
 
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6. APPENDIX 2 – Past Medical History Related to Dermatologic Event 
 
Past Medical History:  
Any preexisting conditions not previously reported (e.g., drug allergy) should be entered into 
the Medical History eCRF.  
 
1. Does the subject have any allergies? □ Yes □ No  
 
If yes, please obtain the following information:  
 
a. Any allergy to drugs (including topical or ophthalmic drugs)? □ Yes □ No  
 
List the drug name(s) and describe the type of allergic response (e.g. rash, anaphylaxis, etc): 
______________________________________________  
_____________________________________________________________  
 
b. Any allergy to external agents, such as laundry detergents, soaps, poison ivy, nickel, etc.? 
□ Yes □ No  
 
Describe the agent and type of allergic response: _____________________  
_____________________________________________________________  
 
c. Any allergy to food? □ Yes □ No  
 
Describe the food and type of allergic response: _____________________  
____________________________________________________________  
 
d. Any allergy to animals, insects? □ Yes □ No  
 
Describe the allergen and type of allergic response: ___________________  
____________________________________________________________  
 
 
 
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e. Any other allergy? □ Yes □ No  
 
Describe the allergen and type of allergic response: _________________  
___________________________________________________________  
 
2. Does the subject have any other history of skin reactions, skin eruptions, or rashes? □ Yes 
□ No  
 
If so what kind? ______________________________________________  
 
3. Has the subject ever been treated for a skin condition? □ Yes □ No  
 
If so what kind? ______________________________________________  
 
4. Is the current finding similar to a past experience? □ Yes □ No  
 
 
 
 
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7. APPENDIX 3 – Presentation of the Dermatologic Event 
 
Presentation of the event:  
Collect information on clinical presentation and potential contributing factors. Key 
information should be summarized and entered on the Adverse Experience eCRF. Any 
treatments administered should be entered on the Concomitant Medication eCRF.  
 
1. What is the onset time of the skin reaction, skin eruption, or rash relative to dose of study 
drug? ___________________________________________  
2. Has the subject contacted any known allergens? □ Yes □ No  
 
If so what kind? ______________________________________________  
 
3. Has the subject contacted new, special, or unusual substances (e.g., new laundry 
detergents, soap, personal care product, poison ivy, etc.)? □ Yes □ No  
 
If so what kind? _________________________________________________  
 
4. Has the subject taken any other medication (over the counter, prescription, vitamins, and 
supplement)? □ Yes □ No  
 
If so what kind? _________________________________________________  
 
5. Has the subject consumed unaccustomed, special or unusual foods? □ Yes □ No  
 
If so what kind? _________________________________________________  
 
6. Does the subject have or had in the last few days any illness? □ Yes □ No  
 
If so what kind? __________________________________________________  
 
7. Has the subject come into contact with any family or house members who are ill? □ Yes □ 
No  
 
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If so who and what? _____________________________________________  
 
8. Has the subject recently been near children who have a skin reaction, skin eruption, or rash 
(e.g. Molluscum Contagiosum)? □ Yes □ No  
 
 
9. Has the subject had recent sun exposure? □ Yes □ No  
10. For the current rash, have there been any systemic clinical signs? □ Yes □ No  
 
If so what kind? ________________________________________________  
 
i. Anaphylaxis? □ Yes □ No  
ii. Signs of hypotension? □ Yes □ No  
iii. Signs of dyspnea? □ Yes □ No  
iv. Fever, night sweats, chills? □ Yes □ No  
 
11. For the current rash, has the subject needed subcutaneous epinephrine or other systemic 
catecholamine therapy? □ Yes □ No  
 
If so what kind? ________________________________________________  
 
12. For the current rash, has the subject used any other medication, such as inhaled 
bronchodilators, antihistaminic medication, topical corticosteroid, and/or systemic 
corticosteroid? □ Yes □ No  
 
List medication(s) and dose(s): _________________________________________  
___________________________________________________________________ 
 
13. Is the rash pruritic (itchy)? □ Yes □ No  
 
 
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8. APPENDIX 4 – Focused Skin Examination 
 
Focused Skin Examination:  
Key information should be summarized and entered on the Adverse Experience eCRF.  
 
Primary Skin Lesions Description  
Color: _______________________________________________________  
 
General description:  
______________________________________________________________  
______________________________________________________________  
 
Describe the distribution of skin reaction, skin eruption, or rash on the body:  
______________________________________________________________  
______________________________________________________________  
 
Is skin reaction, skin eruption, or rash resolving or continuing to spread? 
______________________________________________________________  
______________________________________________________________  
 
Any associated signs on physical examination? 
 
 
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Appendix J: MSD Code of Conduct for Clinical 
Trials 
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)  
Code of Conduct for Interventional Clinical Trials 
 
I. Introduction 
A. Purpose 
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and 
effectiveness of our products. As such, we are committed to designing, implementing, 
conducting, analyzing and reporting these trials in compliance with the highest ethical and 
scientific standards. Protection of participants in clinical trials is the overriding concern in the 
design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted in 
compliance with local and/or national regulations (including all applicable data protection 
laws and regulations), and International Council for Harmonisation Good Clinical Practice 
(ICH-GCP), and also in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki. B. Scope 
Highest ethical and scientific standards shall be endorsed for all clinical interventional 
investigations sponsored by MSD irrespective of the party (parties) employed for their 
execution (e.g., contract research organizations, collaborative research efforts). This Code is 
not intended to apply to trials that are observational in nature, or which are retrospective. 
Further, this Code does not apply to investigator-initiated trials which are not under the full 
control of MSD. 
II. Scientific Issues 
A. Trial Conduct 
1. Trial Design 
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess 
safety, efficacy and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator 
products. Alternatively, MSD may conduct outcomes research trials, trials to assess or 
validate various endpoint measures, or trials to determine patient preferences, etc. 
The design (i.e., participant population, duration, statistical power) must be adequate to 
address the specific purpose of the trial and shall respect the data protection rights of all 
participants, trial site staff and, where applicable, third parties. All trial protocols are and will 
be assessed for the need and capability to enroll underrepresented groups. Participants must 
meet protocol entry criteria to be enrolled in the trial. 2. Site Selection 
MSD’s clinical trials are conducted globally in many different countries and in diverse 
populations, including people of varying age, race, ethnicity, gender, and accounting for 
other potential disease related factors. MSD selects investigative sites based on medical 
expertise, access to appropriate subjects, adequacy of facilities and staff, previous 
performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
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sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the 
ability to successfully conduct the trial. 
Where appropriate, and in accordance with regulatory authority guidance, MSD will make 
concerted efforts to raise awareness of clinical trial opportunities in various communities. 
MSD will seek to engage underrepresented groups and those disproportionately impacted by 
the disease under study. MSD will support clinical trial investigators to enroll 
underrepresented groups and expand access to those who will ultimately use the products 
under investigation.3. Site Monitoring/Scientific Integrity 
Investigative trial sites are monitored to assess compliance with the trial protocol and Good 
Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness and 
consistency. Data are verified versus source documentation according to standard operating 
procedures. Per MSD policies and procedures, if potential fraud, scientific/research 
misconduct, privacy incidents/breaches or Clinical Trial-related Significant Quality Issues 
are reported, such matters are investigated. When necessary, appropriate corrective and/or 
preventative actions are defined and regulatory authorities and/or ethics review committees 
are notified.B. Publication and Authorship 
Regardless of trial outcome, MSD commits to publish the primary and secondary results of 
its registered trials of marketed products in which treatment is assigned, according to the pre-
specified plans for data analysis. To the extent scientifically appropriate, MSD seeks to 
publish the results of other analyses it conducts thar are important to patients, physicians, and 
payers. Some early phase or pilot trials are intended to be hypothesis-generating rather than 
hypothesis testing; in such cases, publication of results may not be appropriate since the trial 
may be underpowered and the analyses complicated by statistical issues such as multiplicity. 
MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, authorship should 
reflect significant contribution to the design and conduct of the trial, performance or 
interpretation of the analysis, and/or writing of the manuscript. All named authors must be 
able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged 
in publications. 
III. Subject Protection 
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC]) 
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance 
with local and/or national regulations. 
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and 
other relevant documents must be reviewed and approved by an IRB/ERC before being 
implemented at each site, in compliance with local and/or national regulations. Changes to 
the protocol that are required urgently to eliminate an immediate hazard and to protect 
participants safety may be enacted in anticipation of ethics committee approval. MSD will 
inform regulatory authorities of such new measures to protect participant safety, in 
compliance with local and/or national regulations.  
 
 
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B. Safety 
The guiding principle in decision-making in clinical trials is that participants welfare is of 
primary importance. Potential participants will be informed of the risks and benefits of, as 
well as alternatives to, trial participation. At a minimum, trial designs will take into account 
the local standard of care.  
All participation in MSD clinical trials is voluntary. Participants enter the trial only after 
informed consent is obtained. Participants may withdraw from a MSD trial at any time, 
without any influence on their access to, or receipt of, medical care that may otherwise be 
available to them.C. Confidentiality 
MSD is committed to safeguarding subject confidentiality, to the greatest extent possible as 
well as applicable data protection rights. Unless required by law, only the investigator, 
sponsor (or individuals acting on behalf of MSD), ethics committee, and/or regulatory 
authorities will have access to confidential medical records that might identify the participant 
by name.D. Genomic Research 
Genomic Research will only be conducted in accordance with a protocol and informed 
consent authorized by an Ethics Committee.IV. Financial Considerations 
A. Payments to Investigators 
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators 
(or the sponsoring institution) in a fair manner for the work performed in support of MSD 
trials. MSD does not pay incentives to enroll participants in its trials. However, when 
enrollment is particularly challenging, additional payments may be made to compensate for 
the time spent in extra recruiting efforts. 
MSD does not pay for participants referrals. However, MSD may compensate referring 
physicians for time spent on chart review and medical evaluation to identify potentially 
eligible participants.B. Clinical Research Funding  
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing the 
trial. However, the local ethics committee may wish to alter the wording of the disclosure 
statement to be consistent with financial practices at that institution. As noted above, all 
publications resulting from MSD trials will indicate MSD as a source of funding.C. Funding 
for Travel and Other Requests 
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator 
meetings, etc.) will be consistent with local guidelines and practices. V. Investigator 
Commitment 
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial 
protocol, and in signing the protocol, agree to support these ethical and scientific 
standards.VI. Letters to Patients 
At the close of the trial after unblinding, a letter is to be sent by the investigator to those 
participants who received placebos in the image of the competitor’s product to provide the 
following advice:  
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“You have participated in a trial conducted by the Sponsor. This is to advise you that you 
were among those who received a look-alike [insert tablet/capsule/device/vaccine] created by 
the Sponsor to resemble the drug/vaccine [insert competitor drug trade name followed by its 
generic name in parentheses] as much as possible. You may also have received the active 
drug/vaccine [insert competitor drug trade name followed by its generic name in parentheses] 
as manufactured by [insert competitor drug manufacturer’s name].” 
 
 
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Appendix K: Lobe-Specific Nodal Dissection 
Right-sided resection 
Left-sided resection 
Right Upper Lobe (RUL) 
Levels 2R, 3a, 4R, 7 
Left Upper Lobe (LUL) 
Levels 3, 5, 6, 7 
Right Middle Lobe (RML) 
Levels 2R, 3a, 4R, 7 
Left Lower Lobe (LLL) 
Levels 7, 8, 9 
Right Lower Lobe (RLL) 
Levels 4, 7, 8, 9 
LUL & LLL (Pneumonectomy) 
Levels 3, 5, 6, 7, 8, 9 
RUL & RML 
Levels 2R, 3a, 4R, 7 
 
RML & RLL 
Levels 2R, 3a, 4R, 7, 8, 9 
 
RUL & RML & RLL (pneumonectomy) 
Levels 2R, 3a, 4R, 7, 8, 9 
 
Important Note: Minimum acceptable nodal dissection is level 7 + another lobe specific mediastinal nodal 
level, which is dependent on the location of the primary lung tumor. 
 
 
 
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Appendix L: Barrier Contraception methods 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide, as per local regulations 
and guidelines. Appropriate hormonal contraceptives will include any registered and 
marketed contraceptive agent that contains an estrogen and/or a progestation al agent 
(including oral, subcutaneous, intrauterine, or intramuscular agents). Subjects should be 
informed that taking the study medication may involve unknown risks to the fetus (unborn 
baby) if pregnancy were to occur during the study. In order to parti cipate in the study they 
must adhere to the contraception requirement (described above) for the duration of the study 
and during the follow-up period. If there is any question that a subject will not reliably 
comply with the requirements for contraception, that subject should not be entered into the 
study. 
 
 
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Appendix M: Recommendation for 
Contraception in United Kingdom, 
Portugal, Scandinavian countries and 
Other Applicable Countries 
It is unknown whether pembrolizumab has adverse effects on a fetus in utero or on the 
composition of sperm. Therefore, non-pregnant, non-breast-feeding women may only be 
enrolled if they are willing to follow the Clinical Trial Facilitation Group (CTFG) guidance 
(Final Version 2014-09-15, Sections 4.1 and 4.2) for highly effective birth control as outlined 
below, or are considered to be highly unlikely to conceive. Highly unlikely to conceive is 
defined as 1) surgically sterilized, or 2) postmenopausal1 (a woman who is ≥45 years of age 
and has not had menses for greater than 1 year will be considered postmenopausal), or 3) not 
heterosexually active2 for the duration of the study. 
(1) and (2) Refer to Portugal section below 
Subjects should use birth control methods that can achieve a failure rate of less than 1% per 
year when used consistently and correctly and are considered as highly effective birth control 
methods. Such methods include:  
♦ Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
♦ Oral 
♦ Intravaginal 
♦ Transdermal 
♦ Progestogen-only hormonal contraception associated with inhibition of ovulation: 
♦ Oral 
♦ Injectable 
♦ Implantable 
♦ Intrauterine device (IUD) 
♦ Intrauterine hormone-releasing system (IUS) 
♦ Bilateral tubal occlusion 
♦ Vasectomised partner 
♦ Sexual abstinence3 
(3) Refer to Portugal section below 
Subjects should start using birth control from study Visit 1 throughout the study period up to 
180 days after the last dose of study therapy. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study they must adhere to the contraception requirement (described above) for the 
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duration of the study and during the follow-up period defined in Section 7.2.2-Reporting of 
Pregnancy and Lactation to the Sponsor. If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered 
into the study. 
Monthly4 pregnancy testing is recommended or more frequently if required by national 
regulations/institution guidelines. 
(4) Refer to Portugal section below 
 
Specific guidelines for Portugal 
 
1. For Portugal postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy. However in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient. 
2. For Portugal the absence of heterosexual activity refers to sexual abstinence. 
3. For Portugal, sexual abstinence (relative to heterosexual activity) can be used as the sole 
method of contraception only when it is consistently employed as the subject’s preferred and 
usual lifestyle, and if considered acceptable by local regulatory agencies and ethical 
committees. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
4. For Portugal, pregnancy testing should be performed at monthly intervals. 
 
 
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Appendix N: Disease Status and 
primary/second endpoints derivation 
Disease free Survival (DFS), overall survival (OS) and Lung Cancer Specific Survival 
(LCSS) are the primary and secondary endpoints of this study which is defined in Chapter 7. 
Below, disease status definition and derivation of endpoints from the case report forms 
(CRFs) is outlined. 
 
1. Disease status 
 
Disease status will be reported in the full ITT population, and entails the tabulation of the 
following event frequency. The reporting will be repeated in the PD-L1++, PD-L1+ sub-
populations.  
Events or censoring will be categorized as follows: 
1. Recurrence (PD);  
2. New secondary malignancy  
3. Death 
4. Alive with no recurrence nor secondary malignancy.  
In addition, for those with recurrence, type of recurrence will be tabulated as follows: 
1. Local and or regional  
2. Distant metastasis 
3. Both Recurrence (PD); 
 
2. Date of recurrence, secondary malignancy or death 
 
The event could be in the following form: 
a. First date of recurrence (for DFS) 
b. Date of secondary malignancy (for DFS) 
c. The date of death (for DFS, OS and LCSS) 
 
2.1  
Date of recurrence is recorded in the recurrence form (formrec), from variable 
dtassrec. Type of recurrence (1=Local and\or regional/2=Distant metastasis/3=Both) is 
taken from variable typrec.  
2.2  
Date of secondary malignancy is recorded in follow up form (formfu) and end of 
treatment form (eotform). In the follow up form formfu (var = DTNEWFU,where 
NYNEWFU = 1) and in the end of treatment form eotform (var= DTNEW, where NYNEW 
=1) 
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Apart from the above dates, the following dates need be checked to ensure that the recurrence 
dates are consistent and captured in the recurrence form in (2.1). 
♦ From the Imaging Assessment form (IMASS), the first date of assessment for which 
the reported result was abnormal, lung tumor related and either 
♦ a) pathology was done and positive for lung tumor or  
♦ b) the method of assessment was CT or MRI 
 
In addition, the following information will be used to check for the recurrence: 
♦ From the Clinical Assessment form (CASS): the first date of visit at which a 
recurrence since the previous examination was reported.  
♦ The first reported date of recurrence from the Follow-up (FU) form. 
2.3  
Date of death is taken from end of treatment form, eotform (dtssof, ssof=2) or 
follow up form, fuform (dtssfu, ssfu= 2) or survival sweep form sweepform (dtsssweep, 
sssweep = 2) 
2.4  
Date of last disease evaluation is taken from the following:  
♦ - 
Date of randomization 
♦ - 
IMASS form, imassform(dtmethod1,dtmethod2,dtmethod3, maximum). 
In each patient without DFS event, the max of those dates will be used as date of censoring. 
2.5 Date of last known to be alive is taken from the last dates of the following forms 
(dates): 
♦ Date of last disease evaluation as in (2.4) 
♦ formFAT (dtsurfat, dtrtfat, dtst1fat, dtst2fat, dtst3fat, dtst4fat, dtst5fat, dtst6fat, 
dtst7fat, dtsp1fat, dtsp2fat, dtsp3fat, dtsp4fat, dtsp5fat, dtsp6fat, dtsp7fat) 
♦ formEOT (dtssof, dtnew) 
♦ formLBBIO (dtbio and nybio = 1) 
♦ formLBHEM (dthem and nyhem = 1) 
♦ formLBTHY (dtthy and nythy = 1) 
♦ formLBURI (dtLBURI and nyLBURI = 1) 
♦ formTRT (dttrt and nytrtadm=1) 
♦ formSWEEP (dtsssweep and sssweep in (1,2)) 
♦ formFU (dtssfu)  
♦ formAE (aestdtc, aeendtc) 
In each patient without OS event, the max of the above dates will be used as date of 
censoring. 
 
 
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2.6 Date of death due to NSCLC is taken from end of treatment form, eotform (dtssof, 
ssof=2 and rdeadof =1) or follow up form, fuform (dtssfu, ssfu= 2 and rdeadfu =1 ) or 
survival sweep form sweepform (dtsssweep, sssweep = 2 and ) when cause of death is PD 
(eotform [dtssof, ssof=2] or fuform [dtssfu, ssfu= 2]). If cause of death is missing, not 
defined or not available then such case will be treated as censoring at the date of death.  
3. Disease free survival endpoint 
 
Disease free survival considering the following event or censoring: 
♦ Date of recurrence (2.1) 
♦ Date of secondary malignancy (2.2) 
♦ Date of death (2.3)  
♦ Censoring: In the absence of event, date of last disease evaluation (2.4). 
Disease Free Survival (DFS) is calculated as the time from randomization to either the date 
of disease recurrence or the date of death (whatever the cause). Patients alive with no 
evidence of disease recurrence at the time of their last visit are censored at the time of the last 
examination. 
Therefore, DFS is the time between the date of randomization and the earliest date among of 
events or censoring as described in 2.1, 2.2, 2.3 and 2.4. 
Note that in some rare occasions, patients are randomized but are found to be not disease 
free later on. Such cases are detected in the CRF by checking the recurrence dates prior to 
randomization. Such cases are handled as follows: the date of randomization is used as the 
recurrence time or censoring in the analysis (see Section 8.2.3).  
 
4. Overall survival endpoint 
This endpoint considers the following as events: 
♦ Death (2.3) 
The endpoint is calculated as the time duration from randomization until the date of death 
(2.3), if the patient died. If the patient does not experience an event, he/she will be censored 
at the last follow-up date (2.5). 
 
5. Lung Cancer Specific Survival endpoint 
This endpoint considers the following as events: 
♦ Death due to NSCLC (2.6) 
This endpoint is calculated as the time duration from randomization until the date of death 
due to NSCLC (2.6), if the patient died. If the patient died from other causes than NSCLC 
(event in 2.3 but not in 2.6) then the patients will recorded as censoring (for the primary 
analysis) or competing event (for the supporting analysis, competing risk). If the patient does 
not experience either event or competing event, he/she will be censored at the last follow-up 
date (2.5). This latter will be analysed with competing risk method. 
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