A Phase 3 Study of Pembrolizumab in Combination With Pemetrexed/Platinum (Carboplatin or Cisplatin) Followed by Pembrolizumab and Maintenance Olaparib vs Maintenance Pemetrexed in the First-Line Treatment of Participants With Metastatic Nonsquamous Non-Small-Cell Lung Cancer (NSCLC)
Phase: PHASE3
Conditions: Carcinoma, Nonsquamous Non-small-cell Lung
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase 3 Study of Pembrolizumab in Combination with 
Pemetrexed/Platinum (Carboplatin or Cisplatin) Followed by 
Pembrolizumab and Maintenance Olaparib vs Maintenance 
Pemetrexed in the First-Line Treatment of Participants with 
Metastatic Non-squamous Non-Small-Cell Lung Cancer 
(NSCLC)
NCT03976323
17-OCT-2024

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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3 Study of Pembrolizumab in Combination with 
Pemetrexed/Platinum (Carboplatin or Cisplatin) Followed by Pembrolizumab and 
Maintenance Olaparib vs Maintenance Pemetrexed in the First-Line Treatment of 
Participants with Metastatic Nonsquamous Non-Small-Cell Lung Cancer (NSCLC)
Protocol Number: 006-08
Compound Number: MK-7339
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
3976323
EU CT
2023-509774-40
EudraCT
2018-004720-11
JRCT
Not Applicable
WHO/UTN
U1111-1300-7107
IND
140819
Approval Date: 17 October 2024
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Protocol 
Amendment 08
17-OCT-2024
To rectify the incorrect standard text mistakenly 
added in last amendment.
Protocol 
Amendment 07
27-MAY-2024
At the final analysis, the pembrolizumab plus 
olaparib arm did not meet the primary endpoint 
of OS. In addition, at the protocol prespecified 
final PFS analysis at Interim Analysis 2 that 
occurred on PFS was not statistically significant 
compared with the control arm. The study will
remain open so ongoing participants will have 
continued access to olaparib, pemetrexed and 
pembrolizumab if they qualify per protocol or 
until transferred to an extension study, if 
applicable.
Protocol 
Amendment 06
07-OCT-2022
Merck Sharp & Dohme Corp. underwent an 
entity name and address change to Merck Sharp 
& Dohme LLC, Rahway, NJ, USA. This 
conversion resulted only in an entity name 
change and update to the address.
Protocol 
Amendment 05
23-DEC-2021
The protocol was amended to update the 
assumptions and timing of the analyses in the 
SAP to allow reasonable intervals between IAs 
and FA, and sufficient duration of follow-up 
based on updated enrollment period and the long-
term survival data from the reference study 
KEYNOTE-189.
Protocol 
Amendment 04
10-MAR-2021
Add back the clarification sentence for inclusion 
criteria applicable only to maintenance phase, 
update Section 6.6.3 to align with pembrolizumab 
USPI, and correct reference in Table 13 to link 
DL header with Table 11 instead of Table 10.
Protocol 
Amendment 03
04-DEC-2020
Updated the RECIST and iRECIST language to 
make the study intervention decision process 
following disease progression consistent 
throughout the protocol, updated language to 
improve clarity and decrease redundancy
throughout the protocol.
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Document
Date of Issue
Overall Rationale
Protocol 
Amendment 02
29-AUG-2019
Further defined inclusion criteria #5 to ensure 
adequate tissue collection prior to patient 
enrollment, changing collection times of plasma 
and serum biomarkers, and clarifying that if there 
is any new diagnosis of MDS or AML this should 
be reported throughout the Maintenance Phase 
including the follow-up phase.
Protocol 
Amendment 01
01-JUL-2019
To remove entry into long-term follow-up for 
participants who discontinue for any reason in the 
Induction Phase, provide clarity that long-term 
follow-up for disease status monitoring and 
overall survival will only be conducted for 
randomized participants, and to align the time of 
Long-term Follow-up visits with the imaging 
schedule.
Original Protocol
24-JAN-2019
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 08
Overall Rationale for the Amendment:
To rectify the incorrect standard text mistakenly added in last amendment.
Summary of Changes Table
Section Number and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 4.2.2 Rationale for the 
Use of an Active Comparator
Removed text on using the C-SSRS.
To rectify the incorrect standard text 
mistakenly added in last amendment.
Section Number and Name
Description of Change
Brief Rationale
Additional Changes
Throughout document
Minor administrative, formatting, 
grammatical, and/or typographical 
changes were made throughout the 
document.
To ensure clarity and accurate 
interpretation of the intent of the 
protocol.
Title Page
Added study NCT number.
To provide additional study 
identification number.
Section 1.3.2, Maintenance 
Phase - Schedule of Assessments
Added information regarding biomarker 
collection through EOT visit.
To provide information regarding last
required biomarker collection.
Section 1.3.3, End-of-Treatment 
and Long-term Follow-up -
Schedule of Assessments
Notes column text added to highlight 
that ePRO and efficacy assessments are 
no longer required per Amendment 07.
To ensure assessment changes are 
noted.
Added that participants in follow-up not 
eligible for second course treatment are 
to be discontinued.
To provide guidance on participants to 
be discontinued.
Removed collection of prior/concomitant 
medications in Long-term Follow-up.
To remove unnecessary collection.
Added note that survival status 
assessments will not be collected past 
EOT.
To instruct that survival status 
assessments are not to be done after 
EOT.
Shortened arrow in survival status row to 
only include EOT.
See rationale for survival status above.
Added note that efficacy assessments 
will not be collected past EOT.
To instruct that efficacy assessments 
are not to be done after EOT.
Removed ePRO assessments will not be 
collected past EOT and added note on 
this.
To instruct that ePRO assessments are 
not to be done after EOT.
Removed biomarker collection after 
EOT.
To stop unneeded biomarker 
collections.
Footnotes updated to reflect collections 
that are not needed past EOT.
To align with SoA.
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Section Number and Name
Description of Change
Brief Rationale
Section 1.3.4, Second Course 
Phase
Removed collection of new anticancer 
treatment at imaging and survival 
follow-ups.
To instruct that these assessments are 
not to be done after EOT.
Added note that vital status assessments 
will not be collected past EOT.
See rationale for Section 1.3.3 for vital 
status.
Added note that efficacy assessments 
will not be collected past EOT.
See rationale for Section 1.3.3 for 
efficacy assessments.
Footnote for imaging updated to reflect 
collections that are not needed past EOT.
To align with SoA.
Section 4.2.1.6.1, Planned 
Genetic Analysis
Section deleted.
This text is not needed since there is no 
requirement for any other genetic 
analyses than the one explained in 
Section 4.2.1.6.
Section 4.2.2, Rationale for the 
Use of an Active Comparator
Removed text on suicidal ideation.
See rationale for primary amendment.
Section 5.2, Exclusion Criteria
Deleted exclusion criterion #16.
This was added in error in the last 
amendment but was deleted in this 
amendment as it is redundant to 
existing criteria.
Added reference to Section 6.5 to 
exclusion criterion #21.
To provide reference for information on 
COVID-19 vaccinations.
Deleted exclusion criterion #27.
See rationale for Sec 5.2, deletion of 
exclusion criterion #16.
Deleted exclusion criterion #28.
See rationale for Sec 5.2, deletion of 
exclusion criterion #16.
Deleted exclusion criterion #29.
See rationale for Sec 5.2, deletion of 
exclusion criterion #16.
Deleted exclusion criterion # 31.
See rationale for Sec 5.2, deletion of 
exclusion criterion #16.
Deleted exclusion criterion #33.
See rationale for Sec 5.2, deletion of 
exclusion criterion #16.
Deleted exclusion criterion #34.
See rationale for Sec 5.2, deletion of 
exclusion criterion #16.
Deleted exclusion criterion #35.
See rationale for Sec 5.2, deletion of 
exclusion criterion #16.
Deleted exclusion criterion #36.
See rationale for Sec 5.2, deletion of 
exclusion criterion #16.
Deleted exclusion criterion #37.
See rationale for Sec 5.2, deletion of 
exclusion criterion #16.
Deleted exclusion criterion #38.
See rationale for Sec 5.2, deletion of 
exclusion criterion #16.
Deleted exclusion criterion #39.
See rationale for Sec 5.2, deletion of 
exclusion criterion #16.
Deleted exclusion criterion #40.
See rationale for Sec 5.2, deletion of 
exclusion criterion #16.
Deleted exclusion criterion #41.
See rationale for Sec 5.2, deletion of 
exclusion criterion #16.
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Section Number and Name
Description of Change
Brief Rationale
Deleted exclusion criterion #48.
See rationale for Sec 5.2, deletion of 
exclusion criterion #16.
Deleted exclusion criterion #49.
See rationale for Sec 5.2, deletion of 
exclusion criterion #16.
Section 8.1.1, Informed Consent
Moved and revised text regarding 
obtaining and documenting informed 
consent from Section 8.1.1.1.  
To ensure information in this section is 
applicable for all informed consents.
Section 8.1.1.1, General Informed 
Consent
Moved text regarding obtaining and 
documenting informed consent from 
Section 8.1.1.1. 
See rationale for Section 8.1.1.
Section 8.2.1.3, End-of-treatment 
and Follow-up Tumor Imaging
Added that participants should continue 
with imaging per local standard of care 
after the EOT Visit.
To align with SoA.
Section 8.3.4.1, Bone Marrow or 
Blood Cytogenic Samples
Removed text regarding collection of 
blood samples.
See rationale for primary amendment
item.
Section 8.4.3, Follow-up of AE, 
SAE, and Other Reportable 
Safety Event Information
Removed reporting for nonserious AEs.
To be consistent with regulatory 
reporting requirements as reporting on 
nonserious AEs is not required.
Section 8.4.7, Events of Clinical 
Interest
Reverted to original text.
See rationale for primary amendment
item.
Section 8.8.1, Planned Genetic 
Analysis Sample Collection
Deleted redundant text.
See rationale for Section 8.1.1.1.
Section 8.11.6.3, Survival 
Follow-up Contacts
Removed text requiring participants to 
return for a Day 14 poststudy visit.
See rationale for primary amendment
item.
Section 10.1.1, Code of Conduct 
for Clinical Trials
Reverted to original text.
See rationale for primary amendment
item.
Section 10.1.7, Compliance with 
Law, Audit, and Debarment
Reverted to original text.
See rationale for primary amendment
item.
Section 10.1.8, Data Quality 
Assurance
Added example of EU CTR retention 
period.
To address HA requirement.
Section 10.1.10, Study and Site 
Closure
Added that participants in survival 
follow-up will be discontinued from the 
study.
To clarify that participants in survival 
follow-up will be discontinued from the 
study.
Added that participants in follow-up not 
eligible for second course treatment are 
to be discontinued.
See rationale for Section 1.3.3, End of 
Treatment and Long-term Follow-up -
Schedule of Assessments for second 
course treatment discontinuation.
Section 10.4, Appendix 4: 
Medical Device and Drug–Device 
Combination Products: Product 
Quality Complaints/Malfunctions: 
Definitions, Recording, and 
Follow-up
Removed text in this section and updated 
it as not applicable.
See rationale for primary amendment
item...
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................5
1
PROTOCOL SUMMARY ............................................................................................17
1.1
Synopsis.................................................................................................................17
1.2
Schema ..................................................................................................................25
1.3
Schedule of Activities (SoA)................................................................................26
1.3.1
Screening and Induction Phases: ALL PARTICIPANTS ...........................26
1.3.2
Maintenance Phase.......................................................................................30
1.3.3
End-of-treatment and Long-term Follow-up ...............................................34
1.3.4
Second Course Phase...................................................................................39
2
INTRODUCTION..........................................................................................................42
2.1
Study Rationale....................................................................................................42
2.2
Background ..........................................................................................................43
2.2.1
Olaparib........................................................................................................43
2.2.2
Pembrolizumab ............................................................................................44
2.2.3
Non–small-Cell Lung Cancer ......................................................................44
2.2.4
Current Treatment Options and Unmet Medical Need................................45
2.2.5
Pharmaceutical and Therapeutic Background .............................................47
2.2.5.1
Inhibition of PARP as a Target for Cancer Therapy..........................47
2.2.5.2
Inhibition of PD-1 as a Target for Cancer Therapy...........................48
2.2.5.3
Homologous Recombination Repair in Solid Tumors.......................49
2.2.6
Preclinical and Clinical Studies ...................................................................50
2.2.7
Ongoing Clinical Studies.............................................................................50
2.2.8
Other Study-related Therapies .....................................................................50
2.3
Benefit/Risk Assessment......................................................................................50
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................51
4
STUDY DESIGN............................................................................................................54
4.1
Overall Design......................................................................................................54
4.2
Scientific Rationale for Study Design.................................................................57
4.2.1
Rationale for Endpoints ...............................................................................58
4.2.1.1
Efficacy Endpoints.............................................................................58
4.2.1.1.1
RECIST 1.1..............................................................................59
4.2.1.1.2
iRECIST...................................................................................59
4.2.1.2
Safety Endpoints................................................................................59
4.2.1.3
Patient-reported Outcomes.................................................................60
4.2.1.4
EORTC QLQ-C30 and QLQ-LC13...................................................60
4.2.1.5
EQ-5D-5L ..........................................................................................60
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4.2.1.6
Planned Exploratory Biomarker Research.........................................61
4.2.1.7
Future Biomedical Research..............................................................62
4.2.2
Rationale for the Use of an Active Comparator...........................................63
4.3
Justification for Dose...........................................................................................63
4.3.1
Starting Dose for Olaparib...........................................................................63
4.3.2
Starting Dose for Pembrolizumab................................................................64
4.3.2.1
Starting Dose for Chemotherapy .......................................................65
4.3.3
Maximum Dose Exposure for This Study ...................................................65
4.3.3.1
Pembrolizumab ..................................................................................65
4.3.3.2
Olaparib..............................................................................................65
4.3.3.3
Pemetrexed.........................................................................................65
4.3.3.4
Cisplatin.............................................................................................65
4.3.3.5
Carboplatin.........................................................................................65
4.4
Beginning and End-of-Study Definition ............................................................66
4.4.1
Clinical Criteria for Early Study Termination .............................................66
5
STUDY POPULATION ................................................................................................67
5.1
Inclusion Criteria.................................................................................................67
5.2
Exclusion Criteria................................................................................................71
5.3
Lifestyle Considerations......................................................................................74
5.3.1
Meals and Dietary Restrictions....................................................................74
5.3.2
Contraception...............................................................................................74
5.3.3
Pregnancy.....................................................................................................74
5.3.4
Use in Nursing Women................................................................................74
5.3.5
Activity Restrictions ....................................................................................75
5.4
Screen Failures.....................................................................................................75
5.5
Participant Replacement Strategy......................................................................75
6
STUDY INTERVENTION............................................................................................76
6.1
Study Intervention(s) Administered...................................................................76
6.1.1
Treatment .....................................................................................................79
6.2
Preparation/Handling/Storage/Accountability .................................................79
6.2.1
Dose Preparation..........................................................................................79
6.2.2
Handling, Storage, and Accountability........................................................79
6.3
Measures to Minimize Bias: Randomization and Blinding..............................80
6.3.1
Intervention Assignment..............................................................................80
6.3.2
Stratification.................................................................................................80
6.3.3
Blinding........................................................................................................81
6.4
Study Intervention Compliance..........................................................................81
6.4.1
Olaparib Compliance ...................................................................................81
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6.4.2
Pembrolizumab, Carboplatin/Cisplatin, and Pemetrexed Compliance........81
6.5
Concomitant Therapy..........................................................................................82
6.5.1
Rescue Medications and Supportive Care ...................................................84
6.6
Dose Modification (Escalation/Titration/Other)...............................................84
6.6.1
Management of Overlapping Toxicities of Olaparib and Pembrolizumab..84
6.6.2
Olaparib Dosing Modifications....................................................................85
6.6.2.1
Management of Hematological Toxicities.........................................85
6.6.2.2
Management of Prolonged Hematological Toxicities .......................86
6.6.2.3
Management of Nonhematologic Toxicity........................................87
6.6.2.3.1
Management of New or Worsening Pulmonary Symptoms ....87
6.6.2.3.2
Management of Nausea and Vomiting ....................................87
6.6.2.3.3
Management of Renal Impairment ..........................................88
6.6.2.4
Interruptions for Intercurrent Nontoxicity-related Events.................88
6.6.2.5
Dose Reductions for Concurrent CYP3A4 Inhibitor Use..................89
6.6.3
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................89
6.6.4
Chemotherapeutic (Pemetrexed/Platinum) Dose Modifications .................94
6.6.4.1
Creatinine Clearance..........................................................................98
6.7
Intervention After the End of the Study............................................................98
6.8
Clinical Supplies Disclosure................................................................................98
6.9
Standard Policies..................................................................................................99
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL..........................................................................................................100
7.1
Discontinuation of Study Intervention.............................................................100
7.2
Participant Withdrawal From the Study.........................................................101
7.3
Lost to Follow-up ...............................................................................................102
8
STUDY ASSESSMENTS AND PROCEDURES......................................................103
8.1
Administrative and General Procedures .........................................................103
8.1.1
Informed Consent.......................................................................................103
8.1.1.1
General Informed Consent...............................................................104
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research...........................................................................................104
8.1.2
Inclusion/Exclusion Criteria ......................................................................104
8.1.3
Participant Identification Card...................................................................104
8.1.4
Medical History .........................................................................................105
8.1.4.1
Non–small-Cell Lung Cancer History .............................................105
8.1.5
Prior and Concomitant Medications Review.............................................105
8.1.5.1
Prior Medications.............................................................................105
8.1.5.2
Concomitant Medications................................................................105
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8.1.5.3
Subsequent Antineoplastic Therapy ................................................105
8.1.6
Assignment of Screening Number.............................................................105
8.1.6.1
Treatment Eligibility Assessment (TEA) Form...............................106
8.1.7
Assignment of Treatment/Randomization Number...................................106
8.1.8
Study Intervention Administration ............................................................106
8.1.8.1
Timing of Dose Administration.......................................................107
8.1.8.1.1
Pembrolizumab ......................................................................107
8.1.8.1.2
Pemetrexed.............................................................................107
8.1.8.1.3
Platinum-based Chemotherapy ..............................................108
8.1.8.1.3.1
Carboplatin...................................................................108
8.1.8.1.3.2
Cisplatin.......................................................................108
8.1.8.1.4
Olaparib..................................................................................109
8.1.8.1.5
Colony-stimulating Factors....................................................109
8.1.8.1.6
Antiemetic Therapy ...............................................................109
8.1.9
Discontinuation and Withdrawal ...............................................................109
8.1.9.1
Withdrawal From Future Biomedical Research ..............................110
8.1.10
Participant Blinding/Unblinding................................................................110
8.1.11
Calibration of Equipment...........................................................................110
8.1.12
Tissue Collection .......................................................................................110
8.1.12.1
Tumor Tissue for Biomarker Status.................................................110
8.2
Efficacy Assessments .........................................................................................111
8.2.1
Tumor Imaging and Assessment of Disease..............................................111
8.2.1.1
Initial Tumor Imaging......................................................................112
8.2.1.2
Tumor Imaging During the Study....................................................112
8.2.1.3
End-of-treatment and Follow-up Tumor Imaging ...........................113
8.2.1.4
Second Course Phase (Retreatment) Tumor Imaging......................113
8.2.1.4.1
Brain Imaging During Second Course Phase.........................114
8.2.1.5
RECIST 1.1 Assessment of Disease................................................114
8.2.1.6
iRECIST Assessment of Disease.....................................................116
8.2.2
Patient-reported Outcomes.........................................................................117
8.3
Safety Assessments.............................................................................................117
8.3.1
Physical Examinations...............................................................................117
8.3.2
Vital Signs..................................................................................................117
8.3.3
Electrocardiograms ....................................................................................118
8.3.4
Clinical Safety Laboratory Assessments ...................................................118
8.3.4.1
Bone Marrow or Blood Cytogenetic Samples .................................118
8.3.5
Performance Assessments: Eastern Cooperative Oncology Group 
Performance Status ....................................................................................118
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8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................119
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................119
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....121
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.122
8.4.4
Regulatory Reporting Requirements for SAE ...........................................122
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................122
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................123
8.4.7
Events of Clinical Interest..........................................................................123
8.5
Treatment of Overdose......................................................................................123
8.6
Pharmacokinetics...............................................................................................124
8.7
Pharmacodynamics............................................................................................124
8.8
Biomarkers .........................................................................................................124
8.8.1
Planned Genetic Analysis Sample Collection............................................124
8.9
Future Biomedical Research Sample Collection.............................................125
8.10
Health Economics Medical Resource Utilization and Health Economics.....125
8.11
Visit Requirements.............................................................................................125
8.11.1
Screening....................................................................................................125
8.11.2
Pre-Randomization Visit............................................................................125
8.11.3
Treatment Period........................................................................................126
8.11.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ..............................................................................126
8.11.5
Second Course Phase (Retreatment Period) ..............................................126
8.11.6
Posttreatment Visit.....................................................................................127
8.11.6.1
Safety Follow-up Visit.....................................................................127
8.11.6.2
Efficacy Follow-up Visits................................................................127
8.11.6.3
Survival Follow-up Contacts ...........................................................127
8.11.7
Vital Status.................................................................................................127
9
STATISTICAL ANALYSIS PLAN ...........................................................................129
9.1
Statistical Analysis Plan Summary...................................................................129
9.2
Responsibility for Analyses/In-house Blinding ...............................................131
9.3
Hypotheses/Estimation ......................................................................................131
9.4
Analysis Endpoints.............................................................................................132
9.4.1
Efficacy Endpoints.....................................................................................132
9.4.2
Safety Endpoints........................................................................................132
9.4.3
Patient-reported Outcome Endpoints.........................................................133
9.5
Analysis Populations..........................................................................................133
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9.5.1
Efficacy Analysis Populations...................................................................133
9.5.1.1
Safety Analysis Populations ............................................................133
9.5.2
Patient-reported Outcomes Analysis Population .......................................134
9.6
Statistical Methods.............................................................................................134
9.6.1
Statistical Methods for Efficacy Analyses.................................................134
9.6.1.1
Progression-free Survival.................................................................134
9.6.1.2
Overall Survival (OS) ......................................................................136
9.6.1.3
Analysis Strategy for Key Efficacy Endpoints................................137
9.6.2
Statistical Methods for Safety Analyses ....................................................137
9.6.3
Statistical Methods for PRO Analyses.......................................................139
9.6.4
Summaries of Baseline Characteristics and Demographics.......................140
9.7
Interim Analyses ................................................................................................140
9.7.1
.........................................................................141
9.7.2
............................................................................141
9.8
Multiplicity .........................................................................................................142
9.8.1
.......................................................142
9.8.2
.....................................................................143
9.8.3
Safety Analyses..........................................................................................145
9.9
Sample Size and Power Calculations ...............................................................146
9.10
.............................................................................................146
9.11
Compliance (Medication Adherence)...............................................................147
9.12
Extent of Exposure.............................................................................................147
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................148
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......148
10.1.1
Code of Conduct for Interventional Clinical Trials ...................................148
10.1.2
Financial Disclosure...................................................................................151
10.1.3
Data Protection...........................................................................................151
10.1.3.1
Confidentiality of Data ....................................................................151
10.1.3.2
Confidentiality of Participant Records.............................................151
10.1.3.3
Confidentiality of IRB/IEC Information..........................................152
10.1.4
Committees Structure.................................................................................152
10.1.4.1
Steering Committee .........................................................................152
10.1.4.2
Executive Oversight Committee......................................................152
10.1.4.3
External Data Monitoring Committee .............................................152
10.1.5
Publication Policy......................................................................................153
10.1.6
Compliance with Study Registration and Results Posting Requirements .153
10.1.7
Compliance with Law, Audit, and Debarment ..........................................153
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10.1.8
Data Quality Assurance .............................................................................154
10.1.9
Source Documents .....................................................................................155
10.1.10
Study and Site Closure...............................................................................155
10.2
Appendix 2: Clinical Laboratory Tests............................................................156
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................158
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................158
10.3.2
Definition of AE ........................................................................................158
10.3.3
Definition of SAE ......................................................................................159
10.3.4
Additional Events Reported in the Same Manner as SAE.........................160
10.3.5
Recording AE and SAE .............................................................................160
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................164
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................165
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................166
10.5.1
Definitions..................................................................................................166
10.5.2
Contraceptive Requirements......................................................................167
10.5.3
Pregnancy Testing......................................................................................168
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................169
10.7
Appendix 7: Country-specific Requirements..................................................175
10.7.1
France Country-specific Requirements......................................................175
10.7.2
Germany Country-specific Requirements..................................................175
10.7.3
Japan Country-specific Requirements .......................................................176
10.7.4
United Kingdom Country-specific Requirements .....................................176
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................178
10.9
Appendix 9: Abbreviations ...............................................................................182
11
REFERENCES.............................................................................................................187
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LIST OF TABLES
Table 1
Summary of Study Interventions .................................................................21
Table 2
Treatment Plan.............................................................................................55
Table 3
Adequate Organ Function Laboratory Values .............................................68
Table 4
Study Interventions......................................................................................77
Table 5
Management of Anemia...............................................................................85
Table 6
Management of Neutropenia, Leukopenia, and Thrombocytopenia ...........86
Table 7
Dose Reduction of Olaparib to Manage Moderate Renal Impairment ........88
Table 8
Dose Reduction of Olaparib with a Strong or Moderate CYP3A4 
Inhibitor ......................................................................................................................89
Table 9
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...........................................................................90
Table 10
Pembrolizumab Monotherapy, Coformulations, or IO Combinations 
Infusion Reaction Dose Modification and Treatment Guidelines ...............................93
Table 11
Dose Modifications for Chemotherapeutic Agents......................................97
Table 12
Recommended Chemotherapy Dose Modifications for Hematological 
Toxicity ......................................................................................................................97
Table 13
Recommended Dose Modifications for Chemotherapy Non-
Hematological Toxicity ...............................................................................................98
Table 14
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................................121
Table 15
Censoring Rules for Primary and Secondary Analyses of PFS.................135
Table 16
Efficacy Analysis Methods for Key Efficacy Endpoints...........................137
Table 17
Analysis Strategy for Safety Parameters....................................................138
.........141
.........143
.........144
Table 21
Protocol-required Safety Laboratory Assessments....................................156
Table 22
Highly Effective Contraception Methods..................................................168
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LIST OF FIGURES
Figure 1
Study Design Overview ...............................................................................25
Figure 2
Study Intervention Decision Making Process When Progression per 
RECIST 1.1 is Observed by Investigator...................................................................116
Figure 3
..............................................142
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Study of Pembrolizumab in Combination with 
Pemetrexed/Platinum (Carboplatin or Cisplatin) Followed by Pembrolizumab and 
Maintenance Olaparib vs Maintenance Pemetrexed in the First-Line Treatment of 
Participants with Metastatic Nonsquamous Non-Small-Cell Lung Cancer (NSCLC)
Short Title: Phase 3 Study of Pembrolizumab with Maintenance Olaparib or Maintenance
Pemetrexed in 1L Metastatic Nonsquamous NSCLC
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In male and female participants with Stage IV nonsquamous non–small-cell lung cancer 
(NSCLC) with stable disease (SD), partial response (PR), or complete response (CR) 
following induction treatment with pembrolizumab combined with pemetrexed and platinum 
(carboplatin or cisplatin):
Primary Objective
Primary Endpoint
•
Objective: To compare pembrolizumab 
plus maintenance olaparib with 
pembrolizumab plus maintenance 
pemetrexed with respect to progression-
free survival (PFS) assessed according 
to Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 by blinded 
independent central review (BICR).
•
Hypothesis (H1): Pembrolizumab plus 
maintenance olaparib is superior to 
pembrolizumab plus maintenance 
pemetrexed with respect to PFS per 
RECIST 1.1 (Section 4.2.1.1) by BICR.
•
PFS, the time from the date of 
randomization until either documented 
disease progression or death due to any 
cause, whichever occurs first.
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•
Objective: To compare pembrolizumab 
plus maintenance olaparib with 
pembrolizumab plus maintenance 
pemetrexed with respect to overall 
survival (OS).
•
Hypothesis (H2): Pembrolizumab plus 
maintenance olaparib is superior to 
pembrolizumab plus maintenance 
pemetrexed with respect to OS.
•
OS, the time from the date of 
randomization to death due to any 
cause.
Secondary Objectives
Secondary Endpoints
•
Objective: To evaluate the safety and 
tolerability of pembrolizumab plus 
maintenance olaparib compared to 
pembrolizumab plus maintenance 
pemetrexed.
•
Adverse events (AEs)
•
Discontinuation of study intervention 
due to AEs.
•
Objective: To evaluate the change from 
baseline (at randomization) and the time 
to true deterioration (TTD) in global 
health status/quality of life (QoL), 
cough, chest pain, dyspnea and physical 
functioning following treatment with 
pembrolizumab plus maintenance 
olaparib compared with pembrolizumab 
plus pemetrexed.
•
Change from baseline (at 
randomization) and the TTD defined as 
the time from baseline (at 
randomization) to the first onset of a 
≥10-point deterioration with 
confirmation by the subsequent visit of 
a ≥10-point deterioration in the 
following European Organization for 
Research and Treatment of Cancer 
Quality of Life Questionnaire (EORTC 
QLQ) and QLQ Lung Cancer Module 
13 (LC13) scales/items:
Global health status/QoL (Core 30 
[C30]/Items 29 and 30)
Cough (LC13/Item 1)
Chest pain (LC13/Item 10)
Dyspnea (C30/Item 8)
Physical functioning (C30/Items 1 
through 5)
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Non-small cell lung cancer
Population
Adult participants with treatment-naïve, 
Stage IV nonsquamous NSCLC
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Active Control Without Placebo
Study Blinding
Unblinded open-label
Blinding Roles
No blinding
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 60 months from the 
time the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 1005 participants were enrolled into the Induction Phase, with approximately 
672 participants required for randomization into the Maintenance Phase, as described in 
Section 9.9.
Intervention Groups and Duration:
Induction Phase (4 Cycles)
All participants will receive the study intervention (pembrolizumab plus 
pemetrexed/platinum) in a nonrandomized Induction Phase:
•
Pembrolizumab 200 mg intravenous (IV) every 3 weeks (Q3W) on Day 1 (Cycles 1 
through 4)
•
Pemetrexed 500 mg/m2 IV Q3W on Day 1 (Cycles 1 through 4)
•
Platinum chemotherapy, investigator’s choice: carboplatin or cisplatin
o
Carboplatin titrated to an area under the plasma drug concentration-time curve of 
5 mg/mL/min IV Q3W on Day 1 (Cycles 1 through 4)
OR
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o
Cisplatin 75 mg/m2 IV Q3W on Day 1 (Cycles 1 through 4)
Maintenance Phase (Up to 31 Cycles of Pembrolizumab Intervention)
Participants with a PR or CR or with SD who meet the eligibility criteria after the fourth 
cycle of the Induction Phase will be randomly assigned to pembrolizumab plus maintenance 
olaparib or pembrolizumab plus maintenance pemetrexed.
•
Pembrolizumab 200 mg IV Q3W will continue for a maximum of 31 cycles, or until 
specific discontinuation criteria are met (Section 7.1).
•
Olaparib 300 mg twice daily will continue, until specific discontinuation criteria are met 
(Section 7.1).
•
Pemetrexed 500 mg/m2 IV Q3W will continue, until specific discontinuation criteria are 
met (Section 7.1).
Note: Eligible participants who enter the Maintenance Phase may receive a maximum of 
35 cycles of pembrolizumab during the study (4 cycles during the Induction Phase and 
31 cycles during the Maintenance Phase). If pembrolizumab is stopped due to toxicity or 
completion of 31 cycles during the Maintenance Phase, the participant may continue with 
maintenance olaparib or pemetrexed until specific discontinuation criteria are met 
(Section 7.1). If maintenance olaparib or pemetrexed is stopped due to toxicity, the 
participant may continue to receive pembrolizumab for a maximum of 31 cycles during the 
Maintenance Phase or until specific discontinuation criteria are met (Section 7.1).
Note: Consultation with the Sponsor is required if a participant receives fewer than 4 cycles 
of study intervention during the Induction Phase without progressive disease, and the 
investigator would like to randomize the participant to the Maintenance Phase.
End-of-treatment and Long-term Follow-up
After the end-of-treatment (EOT) visit, those randomized participants who discontinue for 
reasons other than radiographic progressive disease will have long-term follow up for disease 
status (every 6 weeks up to 60 weeks post-randomization and thereafter every 9 weeks) until 
experiencing progressive disease, initiating a non-study cancer treatment, withdrawal of 
consent, becoming lost to follow-up, or end of study (EOS). All participants will be followed 
by telephone for OS every 3 months, until death, withdrawal of consent, or EOS.
A summary of the study interventions, including dose formulation, dose strength, dose 
frequency, route of administration, treatment period, and use is presented in Table 1.
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Table 1
Summary of Study Interventions
Drug Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Pembrolizumab Active
25 mg/mL
200 mg
IV Infusion
Q3W/Induction 
and 
Maintenance 
Phases for a 
maximum of 
35 cycles
Test Product
Carboplatin
Chemo
-therapy
10 mg/mLa
AUC 5 
mg/mL/min
IV Infusion
Q3W/Induction 
Phase 
(4 cycles)
Background 
Treatment
Cisplatin
Chemo
-therapy
1 mg/mL
75 mg/m2
IV Infusion
Q3W/Induction 
Phase 
(4 cycles)
Background 
Treatment
Pemetrexed
Chemo
-therapy
500 mgb
500 mg/m2
IV Infusion
Q3W/Induction 
and 
Maintenance 
Phases
Background 
Treatment
Olaparib
Active
150 mg,
100 mgc
300 mg BID
Oral
BID/
Maintenance 
Phase
Test Product
Abbreviations: BID = twice daily; IM = intramuscular; IV = intravenous(ly); MASCC = Multinational Association of 
Supportive Care in Cancer; Q3W = every 3 weeks.
a
For locally sourced supplies, the unit dose strength may vary, depending on market availability.
b
All participants taking pemetrexed should receive the appropriate supplementation of vitamin B12, folic acid, and 
corticosteroid prophylaxis, as listed below (or as per local label):
•
Folic acid 350-1000 µg PO: at least 5 doses of folic acid must be taken during the 7 days preceding the first dose 
of pemetrexed, and folic acid dosing must continue during the full course of therapy and for 21 days after the last 
dose of pemetrexed.
•
Vitamin B12 1000 µg IM injection in the week preceding the first dose of pemetrexed and once every 3 cycles 
thereafter. Subsequent vitamin B12 injections may be given on the same day as pemetrexed administration.
•
Dexamethasone prophylaxis 4 mg, PO BID (or equivalent). Taken the day before, day of, and day after 
pemetrexed administration. Higher or additional doses are permitted for antiemetic prophylaxis during Cycles 1 
through 4, but not to exceed the doses in the MASCC guidelines (Section 8.1.8.1.6).
c
300-mg dose will be made up of 2 × 150 mg tablets; 100 mg tablets are provided for dose reductions, as outlined in 
Section 6.6.2.
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Total Number of Intervention 
Groups/Arms
2 arms
Duration of Participation
Each participant will participate in the study
from the time the participant provides 
documented informed consent through the final 
protocol-specific contact.
Induction Phase:
After the Screening Phase , participants will 
enter the nonrandomized Induction Phase and 
will receive 4 cycles of assigned study 
intervention for approximately 3 months: 
pembrolizumab in combination with 
pemetrexed and either carboplatin or cisplatin.
Maintenance Phase:
Only participants who have received 4 cycles of 
study intervention during the Induction Phase, 
have at least 1 evaluable imaging time point 
during the Induction Phase, have no imaging 
visit with an overall response of progressive 
disease (as verified by BICR), are clinically 
stable, and meet eligibility criteria to participate 
in the Maintenance Phase will be randomized to 
receive pembrolizumab with maintenance 
olaparib, or pembrolizumab with maintenance 
pemetrexed. Participants entering the 
Maintenance Phase will receive randomly 
assigned study intervention until centrally 
verified disease progression is radiographically 
documented per RECIST 1.1 (verified by 
BICR) and, when clinically appropriate, 
confirmed by the site per modified RECIST 1.1, 
for immune-related therapeutics, unacceptable 
AEs, intercurrent illness that prevents further 
administration of study intervention, 
investigator’s decision to discontinue the 
participant, noncompliance with study 
intervention or procedure requirements, or 
administrative reasons requiring cessation of 
study intervention. Eligible participants who 
enter the Maintenance Phase may receive a 
maximum of 35 cycles of pembrolizumab 
during the study (4 cycles during the Induction 
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Phase and 31 cycles during the Maintenance 
Phase). If pembrolizumab is stopped due to 
toxicity or completion of 31 cycles, the 
participant may continue with maintenance 
olaparib or pemetrexed until specific 
discontinuation criteria are met (Section 7.1). If 
maintenance olaparib or pemetrexed is stopped 
due to toxicity, the participant may continue to 
receive pembrolizumab for a maximum of 31 
cycles during the Maintenance Phase or until 
specific discontinuation criteria are met 
(Section 7.1).
End-of-treatment and Long-term Follow-up:
After the EOT, each participant will be 
followed for the occurrence of AEs and 
spontaneously reported pregnancy as described 
under Section 8.4.
Randomized participants who discontinue for 
reasons other than radiographic disease 
progression will have long-term follow-up 
imaging for disease status until centrally 
verified disease progression is documented 
radiographically per RECIST 1.1, initiating a 
nonstudy cancer treatment, withdrawing 
consent, becoming lost to follow-up, or EOS. 
All randomized participants will be followed by 
telephone call every 3 months for OS until 
death, withdrawal of consent, or the EOS.
Each randomized participant is expected to 
participate in the study for approximately 60
months, including the Long-term Follow-up 
Phase.
Second Course Phase:
Participants in each arm who stop study 
intervention after receiving 35 cycles of 
pembrolizumab for reasons other than disease 
progression or intolerability may be eligible for 
up to an additional 1 year (17 cycles) of 
pembrolizumab after experiencing disease 
progression (Second Course Phase; Section 
8.12.5).
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Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Steering Committee
Yes
Study governance considerations are outlined in the protocol Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations used in this document can be found in the protocol Appendix 9.
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1.2
Schema
The study design (Screening, Induction, Maintenance, and Posttreatment Phases) is depicted in Figure 1.
Figure 1
Study Design Overview
Abbreviations: CR = complete response; ECOG = Eastern Cooperative Oncology Group; NSCLC = non–small-cell lung cancer; PD = progressive disease; 
PR = partial response; SD = stable disease.
* Participants with SD/PR/CR after receiving 4 induction cycles will be randomized to receive pembrolizumab plus maintenance olaparib, or pembrolizumab 
plus maintenance pemetrexed.
Note: Participants may receive a maximum of 35 cycles of pembrolizumab treatment during the study (4 cycles during the Induction Phase and 31 cycles during 
the Maintenance Phase). If pembrolizumab is stopped due to toxicity or completion of 31 cycles during Maintenance Phase, the participant may continue with 
maintenance olaparib or maintenance pemetrexed, until specific discontinuation criteria are met (Section 7.1). If maintenance olaparib or maintenance 
pemetrexed is stopped due to toxicity, the participant may continue to receive pembrolizumab for a maximum of 31 cycles during the Maintenance Phase, or 
until specific discontinuation criteria are met (Section 7.1).
Imaging should be performed within 28 days of entering Maintenance Phase.
In the Posttreatment Phase, participants who discontinue study intervention for reasons other than PD will move into the follow-up phase (Section 8.12.6). All 
participants may be eligible for up to 1 additional year (17 cycles) of pembrolizumab treatment if they progress after having received 35 cycles of 
pembrolizumab and with SD, PR, or CR in either arm (Section 8.11.5). The second course of pembrolizumab is optional.
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1.3
Schedule of Activities (SoA)
1.3.1
Screening and Induction Phases: ALL PARTICIPANTS
Study Period
Screening 
Phase
Induction Phase (3-week Cycles)a
Notes
Cycle No.
1
2
3
4
Day (in Cycle)
1
1
1
1
Visit Number/Title
1
2
3
4
5
Scheduling Window (Days):
-28 to -1
+ 3
± 3
± 3
± 3
Administrative Procedures
Informed Consent
X
Consent must be obtained prior to performing any protocol-specific 
procedures. 
FBR ICF (optional)
X
Participants can still participate in the study if they decline to sign 
the FBR ICF.
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
X
At the time of Visit 2/Cycle 1, Day 1, site personnel should add the 
screening number to the Participant ID card.
Demographics and Medical History
X
History of Blood Transfusions
X
Include history of blood transfusion within previous 120 days from 
start of study intervention and the reasons (eg, bleeding or 
myelosuppression)
Prior/Concomitant Medication 
Review
X
X
X
X
X
Include blood transfusions during review of concomitant medications
NSCLC Disease Details
X
TEA
X
The investigator must complete this form in eCRF and provide 
rationale to document the choice of platinum chemotherapy 
(carboplatin or cisplatin) prior to randomization
Obtain Study Treatment 
Assignment Using IRT
X
Cycle 1, Day 1 study intervention must be administered within 
3 days of enrolling the participant in the study.
Administration of Study Intervention
Pembrolizumab
X
X
X
X
200 mg Q3W
Pemetrexed
X
X
X
X
500 mg/m2 Q3W; see Section 4.3.3.3 regarding B12, folate, and 
dexamethasone supplementation with pemetrexed administration.
Carboplatin or Cisplatin
X
X
X
X
Carboplatin: AUC 5 mg/ml/min IV Q3W or Cisplatin: 75 mg/m2 IV 
Q3W.
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Study Period
Screening 
Phase
Induction Phase (3-week Cycles)a
Notes
Cycle No.
1
2
3
4
Day (in Cycle)
1
1
1
1
Visit Number/Title
1
2
3
4
5
Scheduling Window (Days):
-28 to -1
+ 3
± 3
± 3
± 3
Tumor Tissue Collection
Archival or Newly Obtained Tissue 
Collection for PD-L1 IHC and 
Other Biomarkers
X
A new incisional or core biopsy will be required if archival tissue is 
not available. PD-L1 IHC will be mandatory to stratify participants 
prior to randomization for the Maintenance Phase.
Efficacy Proceduresb
CT/MRI Imaging of Chest, 
Abdomen, and Pelvis
X
X
Xd
Screening images are to be captured within 28 days of first dose.
The first on study imaging visit has a window of +7 days. All other 
imaging visits have a visit window of ±7 days.
During Induction Phase, images will be captured Q6W from date of 
first dose (Cycle 1). Imaging timing should follow calendar days and 
should not be adjusted for delays in study intervention. All imaging 
must be submitted to central imaging vendor as soon as possible for 
expedited central review to determine eligibility for randomization 
into Maintenance Phase.
MRI of Brainc
X
X
X
Safety Procedures
AE Monitoring
X
----------------------------------------------------
AEs: Report all AEs occurring from the start of study intervention 
through 30 days following the last dose of study intervention.
SAEs: Report all SAEs from the start of study intervention through 
90 days following the last dose of study intervention, or 30 days 
following the last dose of study intervention if the participant 
initiates new anticancer therapy, whichever is earlier. 
Complete Physical Examination 
(Including Height)
X
Height at screening only
Directed Physical Examination
X
X
X
X
Directed physical examination performed as clinically indicated prior 
to intervention administration.
Weight
X
X
X
X
X
Vital Signs (heart rate, DBP, SBP, 
RR, temperature)
X
X
X
X
X
Assessments performed prior to intervention administration.
12-lead ECG
X
12-lead ECG performed using local standard procedures. Additional 
ECGs performed as clinically indicated.
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Study Period
Screening 
Phase
Induction Phase (3-week Cycles)a
Notes
Cycle No.
1
2
3
4
Day (in Cycle)
1
1
1
1
Visit Number/Title
1
2
3
4
5
Scheduling Window (Days):
-28 to -1
+ 3
± 3
± 3
± 3
Hematology
X
X
X
X
X
Screening samples to be collected within 10 days prior to the first 
dose of study intervention.
On treatment samples to be collected prior to administration of study
intervention, which can be conducted within 72 hours prior to the
first dose of study intervention in each cycle.
Urinalysis
X
Chemistry
X
X
X
X
X
Thyroid Function Tests (Total T3 or 
Free T3, FT4, TSH)
X
X
Tests performed every other cycle. Participants may be dosed while 
thyroid function tests are pending.
HBV, HCV, and HIV Testing
X
Testing at screening only required if mandated by local health 
authority or institutional guidelines. Refer Appendix 7, for country-
specific requirements.
Urine Pregnancy Test 
(WOCBP only)
X
WOCBP require a negative highly sensitive urine test within 24 
hours (72 hours for serum) prior to first dose of study intervention. 
Testing during Induction Phase must be conducted as clinically 
indicated and per local regulations where applicable. Serum test is 
only required if urine test is positive or not evaluable. More frequent 
pregnancy testing may be indicated, as dictated by local regulations. 
PT or INR and aPTT
X
Screening samples collected within 10 days of intervention initiation. 
PT or INR and aPTT should be monitored more closely in 
participants receiving anticoagulant therapy during intervention and 
safety Follow-up Phase. 
CrCl Calculation
X
X
X
X
X
CrCl is calculated using the Cockcroft-Gault method (Table 3). As an 
alternative, CrCl can be determined from a 24-hour urine collection. 
ECOG Performance Status
X
X
X
X
X
Screening assessment is to be performed within 7 days prior to 
administration of study intervention. 
Biomarkers
Blood for Genetic Analysis
X
To be collected prior to administration of study intervention. 
Blood for RNA Analysis
X
X
To be collected prior to administration of study intervention. These 
collections are to correspond to the imaging time points.
Blood for Plasma Biomarker 
Analysis
X
X
To be collected prior to administration of study intervention. These 
collections are to correspond to the imaging time points.
Blood for Serum Biomarker 
Analysis
X
X
To be collected prior to administration of study intervention. These 
collections are to correspond to the imaging time points.
Blood for ctDNA
X
X
To be collected prior to administration of study intervention. These 
collections are to correspond to the imaging time points.
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Study Period
Screening 
Phase
Induction Phase (3-week Cycles)a
Notes
Cycle No.
1
2
3
4
Day (in Cycle)
1
1
1
1
Visit Number/Title
1
2
3
4
5
Scheduling Window (Days):
-28 to -1
+ 3
± 3
± 3
± 3
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; AUC = area under the concentration-time curve; CrCl = creatinine clearance; ctDNA = 
circulating tumor DNA; DBP = diastolic blood pressure; DC = discontinue/discontinuation; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = 
end-of-treatment; FBR = Future Biomedical Research; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; ICF = informed consent 
form; ID = identification; IHC = immunohistochemistry; INR = international normalized ratio; IRT = interactive response system; PD = progressive disease; PD-L1 = 
programmed death ligand 1; PT = prothrombin time; Q3W = every 3 weeks; Q6W = every 6 weeks; RR = respiratory rate; SAE = serious adverse event; SBP = systolic blood 
pressure; TEA = Treatment Eligibility Assessment; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential.
a
Participants who do not continue to the randomization phase are to complete the 30-day Safety Follow-up Visit; refer to Section 1.3.3.
b
Imaging should continue to be performed until PD is centrally verified, the start of new anticancer treatment, withdrawal of consent, pregnancy, or death, whichever occurs 
first.
c
Participants with treated brain lesions and participants with known, asymptomatic, untreated brain lesions at diagnosis may participate, but require regular imaging of the 
brain as a site of disease. Participants without brain lesions at baseline should be imaged as clinically indicated.
d
Imaging must occur at Week 12. Imaging should be performed within 28 days of entering the Maintenance Phase.
Note: For country-specific requirements see Appendix 7.
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1.3.2
Maintenance Phase
Study Period
Post-induction/
Pre-randomization
Visita
Maintenance 
Phase
(3-week Cycles)b
Notes
As of Amendment 07, tumor imaging will be assessed locally based on the site’s standard of 
care imaging schedule. Biomarkers will only be collected through the EOT visit (see Section 
1.3.3). Also, participants who are still on study treatment will no longer require ePRO 
assessments.
Cycle
-
1+
Day (in Cycle)
-
1
Visit Number/Title
6
7+
Scheduling Window (Days):
± 3
± 3
Administrative Procedures
Maintenance Phase Checklist
X
Pre-randomization visit is to occur 4 weeks ±7 days from Cycle 4, Day 1 of Induction.
Checklist must be reviewed by the Sponsor. Participants with PD must be excluded from the 
Maintenance Phase and should enter 30-day Safety Follow-up Visit (refer to Section 1.3.3).
Inclusion/exclusion criteria
X
Prior/Concomitant Medication 
Review
X
X
Include blood transfusions during review of concomitant medication.
Randomization
X
Study drug administration should begin on the day of randomization, but no later than 3 days 
after randomization
Administration of Study Intervention
Olaparib
X
To initiate maintenance olaparib, creatinine clearance (CrCl) must be ≥51 mL/min. Only for 
participants randomized to olaparib. Continuous daily dose of 300 mg BID until progression of 
disease, intolerable toxicities, or physician decision. Maintenance olaparib to start at least 4 
weeks and no later than 6 weeks from Cycle 4, Day 1 of study medication in the Induction 
Phase.
Olaparib Container Return
X
Only for participants randomized to olaparib.
Pembrolizumab
X
Participants will need to return to the site Q3W for dosing at 200mg for a maximum of 
31 cycles or until progression of disease, intolerable toxicities, or physician decision. 
Pembrolizumab to restart at least 4 weeks and no later than 6 weeks from Cycle 4, Day 1 of 
study medication in the Induction Phase.
Pemetrexed
X
Only for participants randomized to pemetrexed. 500 mg/m2; participants will need to return to 
the site Q3W for dosing until progression of disease, intolerable toxicities, or physician 
decision. Maintenance pemetrexed to start at least 4 weeks and no later than 6 weeks from 
Cycle 4, Day 1 of study medication in the Induction Phase. See Section 4.3.3.3 regarding B12, 
folate, and dexamethasone supplementation with pemetrexed administration.
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Study Period
Post-induction/
Pre-randomization
Visita
Maintenance 
Phase
(3-week Cycles)b
Notes
As of Amendment 07, tumor imaging will be assessed locally based on the site’s standard of 
care imaging schedule. Biomarkers will only be collected through the EOT visit (see Section 
1.3.3). Also, participants who are still on study treatment will no longer require ePRO 
assessments.
Cycle
-
1+
Day (in Cycle)
-
1
Visit Number/Title
6
7+
Scheduling Window (Days):
± 3
± 3
Efficacy Procedures
Imaging should continue to be performed until PD is centrally verified, the start of new 
anticancer treatment, withdrawal of consent, pregnancy, or death, whichever occurs first. 
Imaging can continue to be performed after PD is centrally verified if the investigator elects to 
continue treatment and follow iRECIST.
See Section 8.2.1.5.
CT/MRI Imaging of Chest, 
Abdomen, and Pelvis
X
The first imaging visit has a visit window of + 7 days, all subsequent imaging visits have a 
visit window of ± 7 days. During Maintenance Phase, images will be captured Q6W for the 
first 60 weeks from the date of randomization, followed by Q9W thereafter until centrally 
verified disease progression, or the start of new anticancer treatment.
A new baseline CT scan of the chest/abdomen/pelvis will be needed prior to initiating Cycle 1 
of the Maintenance Phase if the last imaging was obtained >28 days before the date of 
randomization. Imaging timing should follow calendar days and should not be adjusted for 
delays in study intervention.
Note: As of Amendment 07, tumor imaging will be assessed locally based on the site’s 
standard of care schedule.
MRI of Brainc
X
Safety Procedures
AE Monitoring
X
X
AEs: Report all AEs occurring from the start of study intervention through 30 days following 
the last dose of study intervention.
SAEs: Report all SAEs from the start of study intervention through 90 days following the last 
dose of study intervention, or 30 days following the last dose of study intervention if the 
participant initiates new anticancer therapy, whichever occurs first. New diagnosis of MDS or 
AML should be reported throughout the study including the follow-up phase.
Directed Physical Examination
X
X
Directed physical examination performed as clinically indicated prior to study intervention 
administration.
Weight
X
X
Vital Signs (heart rate, DBP, 
SBP, RR, Temperature)
X
X
Assessments performed prior to study intervention administration.
Hematology
X
X
Laboratory tests performed within 3 days of Cycle 1 (ie, pre-randomization) do not need to be 
repeated at Cycle 1. On-treatment samples collected prior to administration of study 
intervention. Thyroid function tests at Cycle 1 followed by every other cycle through Cycle 31. 
Participants may be dosed while thyroid function tests are pending.
Chemistry
X
X
Thyroid Function Tests (Total 
T3 or Free T3, FT4, TSH)
X
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Study Period
Post-induction/
Pre-randomization
Visita
Maintenance 
Phase
(3-week Cycles)b
Notes
As of Amendment 07, tumor imaging will be assessed locally based on the site’s standard of 
care imaging schedule. Biomarkers will only be collected through the EOT visit (see Section 
1.3.3). Also, participants who are still on study treatment will no longer require ePRO 
assessments.
Cycle
-
1+
Day (in Cycle)
-
1
Visit Number/Title
6
7+
Scheduling Window (Days):
± 3
± 3
Urine Pregnancy Test 
(WOCBP Only)
X
X
WOCBP require a negative highly sensitive urine test at the pre-randomization visit and within 
24 hours (72 hours for serum) prior to first dose of study intervention. Serum test only required 
if urine test is positive or not evaluable. Testing during Maintenance Phase must be conducted 
as clinically indicated and as per local regulations, where applicable. More frequent pregnancy 
testing may be indicated, as dictated by local regulations. 
CrCl Calculation
X
X
CrCl is calculated using the Cockcroft-Gault formula (Table 3). As an alternative, CrCl can be 
determined from a 24-hour urine collection. To initiate maintenance olaparib, CrCl must be 
≥51 mL/min. To initiate maintenance pemetrexed arm, CrCl must be ≥45 mL/min.
ECOG Performance Status
X
X
ECOG performance status will be evaluated prior to first administration of study intervention 
(within 7 days) and before administration of study intervention in each cycle.
Patient-Reported Outcomes
EORTC QLQ-C30
EORTC QLQ-LC13
EQ-5D-5L
Biomarkers
Blood for ctDNA
X
X
ctDNA will be collected at the Post-induction/Pre-Randomization Visit, Cycle 1, Day 1, and 
Q6W for the first 60 weeks from the date of randomization, followed by Q9W thereafter, until 
disease progression, or the start of new anticancer treatment. These collections are to 
correspond to the imaging time points.
Blood for RNA analysis
X
X
To be collected at Post-induction/Pre-Randomization Visit, Cycle 1, Day 1 and Q6W for the 
first 60 weeks from the date of randomization, followed by Q9W thereafter, until centrally 
verified disease progression, or the start of new anticancer treatment. These collections are to 
correspond to the imaging time points.
Blood for plasma biomarker 
analysis
X
X
To be collected at Post-induction/Pre-Randomization Visit, Cycle 1, Day 1 and Q6W for the 
first 60 weeks from the date of randomization, followed by Q9W thereafter, until centrally 
verified disease progression, or the start of new anticancer treatment. These collections are to 
correspond to the imaging time points.
Blood for serum biomarker 
analysis
X
X
To be collected at Post-induction/Pre-Randomization Visit, Cycle 1, Day 1 and Q6W for the 
first 60 weeks from the date of randomization, followed by Q9W thereafter, until centrally 
verified disease progression, or the start of new anticancer treatment. These collections are to 
correspond to the imaging time points.
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Study Period
Post-induction/
Pre-randomization
Visita
Maintenance 
Phase
(3-week Cycles)b
Notes
As of Amendment 07, tumor imaging will be assessed locally based on the site’s standard of 
care imaging schedule. Biomarkers will only be collected through the EOT visit (see Section 
1.3.3). Also, participants who are still on study treatment will no longer require ePRO 
assessments.
Cycle
-
1+
Day (in Cycle)
-
1
Visit Number/Title
6
7+
Scheduling Window (Days):
± 3
± 3
Abbreviations: AE = adverse event; AUC = area under the curve; BID = twice daily; CrCl = creatinine clearance; DBP = diastolic blood pressure; 
DC = discontinue/discontinuation; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality 
of Life Core 30; EORTC QLQ-LC13 = European Organisation for Research and Treatment of Cancer Quality of Life Cancer Quality of Life Questionnaire Lung Cancer 13; 
EOT = end-of-treatment; ePRO = electronic patient-reported outcome; EQ-5D-5L = European Quality of Life Five-dimension Five-level Scale Questionnaire; PD = progressive 
disease; PRO = patient-reported outcome; Q3W = every 3 weeks; Q6W = every 6 weeks; Q9W = every 9 weeks; Q12W = every 12 weeks; RNA = ribonucleic acid; 
RR = respiratory rate; SAE = serious adverse event; SBP = systolic blood pressure; WOCBP = women of childbearing potential.
a
Participants who do not qualify for the Maintenance Phase will proceed to the 30-day Safety Follow-up (refer to Section 1.3.3).
b
Study intervention administration should begin on the day of randomization, but no later than 3 days after randomization.
c
Participants with treated brain lesions and participants with known, asymptomatic, untreated brain lesions at diagnosis will require regular imaging of the brain during the 
Maintenance Phase as a site of disease. Participants without brain lesions at baseline should be imaged as clinically indicated.
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1.3.3
End-of-treatment and Long-term Follow-up
Participants Who Receive Induction 
Phase Treatment and are Not 
Randomized
Participants Randomized to Maintenance Phase
Notes
Effective with Amendment 7, 
ePROs and all efficacy follow-up 
will continue to be collected at the 
EOT visits but will not be 
collected during long-term follow-
up.
Effective with Amendment 08, 
participants who are in follow-up 
and did not receive 35 doses of 
pembrolizumab during the initial 
treatment period and/or are not 
eligible for second course 
treatment should be discontinued.
Study Period
Safety Follow-up
EOT
Long-Term Follow-up
Visit Number/Title
Safety
DC
Safetya
Follow-Upa,b
Survival
Follow-upc
Scheduling 
Window (Days):
30 Days After Last Dose (+ 7 days)
At Time of 
DC
(± 3 days)
30 Days 
After Last 
Dose 
(+ 7 days)
Q6W up to 60 
weeks Post-
randomization, 
thereafter Q9W 
(± 7 days)
Q12W 
(± 14 days)
Administrative Procedures
Prior/concomitant 
medication review
X
X
X
Include blood transfusions during 
review of concomitant medication.
Survival status
Continued after centrally verified 
PD or start of new anticancer 
treatment through the EOT Visit. In 
addition, upon Sponsor request, 
participants may be contacted for 
survival status at any time during 
the study.
Efficacy Procedures
Imaging should continue to be 
performed until PD is centrally 
verified, the start of new anticancer 
treatment, withdrawal of consent, 
pregnancy, or death, whichever 
occurs first, through the EOT Visit.
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Participants Who Receive Induction 
Phase Treatment and are Not 
Randomized
Participants Randomized to Maintenance Phase
Notes
Effective with Amendment 7, 
ePROs and all efficacy follow-up 
will continue to be collected at the 
EOT visits but will not be 
collected during long-term follow-
up.
Effective with Amendment 08, 
participants who are in follow-up 
and did not receive 35 doses of 
pembrolizumab during the initial 
treatment period and/or are not 
eligible for second course 
treatment should be discontinued.
Study Period
Safety Follow-up
EOT
Long-Term Follow-up
Visit Number/Title
Safety
DC
Safetya
Follow-Upa,b
Survival
Follow-upc
Scheduling 
Window (Days):
30 Days After Last Dose (+ 7 days)
At Time of 
DC
(± 3 days)
30 Days 
After Last 
Dose 
(+ 7 days)
Q6W up to 60 
weeks Post-
randomization, 
thereafter Q9W 
(± 7 days)
Q12W 
(± 14 days)
CT/MRI imaging of 
chest, abdomen, and 
pelvis
Xd
Xd
All imaging visits have a visit 
window of ±7 days. Imaging will be 
captured Q6W for the first 60 weeks 
from the date of randomization, 
followed by Q9W thereafter until 
centrally verified disease 
progression, or the start of new 
anticancer treatment. Imaging 
timing should follow calendar days
and should not be adjusted for 
delays in study intervention.
MRI of braine
Xd
Xd
X
Safety Procedures
AE monitoring
X
X
X
X
AEs: Report all AEs occurring 
through 30 days following the last 
dose of study intervention.
SAEs: Report all SAEs through 
90 days following the last dose of 
study intervention, or 30 days 
following the last dose of study 
intervention if the participant 
initiates new anticancer therapy, 
whichever occurs first. New 
diagnosis of MDS or AML should 
be reported throughout the study 
including the follow-up phase.
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Participants Who Receive Induction 
Phase Treatment and are Not 
Randomized
Participants Randomized to Maintenance Phase
Notes
Effective with Amendment 7, 
ePROs and all efficacy follow-up 
will continue to be collected at the 
EOT visits but will not be 
collected during long-term follow-
up.
Effective with Amendment 08, 
participants who are in follow-up 
and did not receive 35 doses of 
pembrolizumab during the initial 
treatment period and/or are not 
eligible for second course 
treatment should be discontinued.
Study Period
Safety Follow-up
EOT
Long-Term Follow-up
Visit Number/Title
Safety
DC
Safetya
Follow-Upa,b
Survival
Follow-upc
Scheduling 
Window (Days):
30 Days After Last Dose (+ 7 days)
At Time of 
DC
(± 3 days)
30 Days 
After Last 
Dose 
(+ 7 days)
Q6W up to 60 
weeks Post-
randomization, 
thereafter Q9W 
(± 7 days)
Q12W 
(± 14 days)
Complete physical 
examination 
X
X
Directed physical 
examination
X
Weight
X
X
X
Vital signs (heart 
rate, DBP, SBP, 
RR, temperature)
X
X
X
12-lead ECG
X
12-lead ECG is to be performed 
using local standard procedures. 
Additional ECGs are to be 
performed, as clinically indicated.
Hematology
X
X
X
Urinalysis
X
X
Chemistry
X
X
X
Thyroid function 
tests (total T3 or 
free T3, FT4, TSH)
X
X
X
Urine pregnancy 
test 
(WOCBP only)
X
X
X
Testing during EOT and Long-term 
Follow-up Phase must be conducted 
as clinically indicated and per local 
regulations, where applicable. 
Serum test is only required if urine 
test is positive, or not evaluable.
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Participants Who Receive Induction 
Phase Treatment and are Not 
Randomized
Participants Randomized to Maintenance Phase
Notes
Effective with Amendment 7, 
ePROs and all efficacy follow-up 
will continue to be collected at the 
EOT visits but will not be 
collected during long-term follow-
up.
Effective with Amendment 08, 
participants who are in follow-up 
and did not receive 35 doses of 
pembrolizumab during the initial 
treatment period and/or are not 
eligible for second course 
treatment should be discontinued.
Study Period
Safety Follow-up
EOT
Long-Term Follow-up
Visit Number/Title
Safety
DC
Safetya
Follow-Upa,b
Survival
Follow-upc
Scheduling 
Window (Days):
30 Days After Last Dose (+ 7 days)
At Time of 
DC
(± 3 days)
30 Days 
After Last 
Dose 
(+ 7 days)
Q6W up to 60 
weeks Post-
randomization, 
thereafter Q9W 
(± 7 days)
Q12W 
(± 14 days)
CrCl calculation
X
X
X
CrCl is calculated using the 
Cockcroft-Gault formula (Table 3). 
As an alternative, CrCl can be 
determined from a 24-hour urine 
collection.
ECOG Performance 
Status
X
X
X
Patient-Reported Outcomes
EORTC QLQ-C30
X
Perform ePROs in the order listed in 
the SoA (ie, EORTC QLQ-C30 
first). Effective with Amendment 7, 
ePROs will continue to be collected 
at the EOT visit but will not be 
collected during long-term follow-
up.
EORTC QLQ-
LC13
X
EQ-5D-5L
X
Biomarkers
Blood for RNA 
analysis
X
Biomarkers will continue to be 
collected at the EOT visit but will 
not be collected during long-term 
follow-up. Once centrally verified 
PD occurs, the final biomarker 
samples are collected. If participant 
discontinues due to PD, biomarker 
samples will be collected at EOT 
visit.
Blood for plasma 
biomarker analysis
X
Blood for serum 
biomarker analysis
X
Blood for ctDNA
X
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Participants Who Receive Induction 
Phase Treatment and are Not 
Randomized
Participants Randomized to Maintenance Phase
Notes
Effective with Amendment 7, 
ePROs and all efficacy follow-up 
will continue to be collected at the 
EOT visits but will not be 
collected during long-term follow-
up.
Effective with Amendment 08, 
participants who are in follow-up 
and did not receive 35 doses of 
pembrolizumab during the initial 
treatment period and/or are not 
eligible for second course 
treatment should be discontinued.
Study Period
Safety Follow-up
EOT
Long-Term Follow-up
Visit Number/Title
Safety
DC
Safetya
Follow-Upa,b
Survival
Follow-upc
Scheduling 
Window (Days):
30 Days After Last Dose (+ 7 days)
At Time of 
DC
(± 3 days)
30 Days 
After Last 
Dose 
(+ 7 days)
Q6W up to 60 
weeks Post-
randomization, 
thereafter Q9W 
(± 7 days)
Q12W 
(± 14 days)
Abbreviations: AE = adverse event; DBP = diastolic blood pressure; DC = discontinue/discontinuation; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Core 30; EORTC QLQ-LC13 = European Organisation for Research 
and Treatment of Cancer Quality of Life; EOS = end of study; EOT = end-of-treatment; EQ-5D-5L = European Quality of Life Five-dimension Five-level Scale Questionnaire; 
PD = progressive disease; PRO = patient reported outcome; Q9W = every 9 weeks; Q12W = every 12 weeks; RR = respiratory rate; SAE = serious adverse event; 
SBP = systolic blood pressure; WOCBP = women of childbearing potential.
a
If the DC visit occurs ≥30 days from last dose of study intervention, a Safety Follow-up Visit is not required.
b
Follow-up visits may be scheduled to coincide with the Long-term Follow-up Phase imaging. For participants who DC for reasons other than centrally verified PD, 
imaging continues until centrally verified PD or initiation of a new antineoplastic therapy through the EOT Visit.
c
Participants who either DC for centrally verified PD or start a new anticancer therapy will enter the Survival Follow-up Phase and will be monitored approximately every 
12 weeks (84 ± 14 days) by telephone call to assess for survival status until death, withdrawal of consent, or the EOS, whichever occurs earlier. Effective with Amendment 
7, Survival Follow-up ends after the EOT Visit.
d
Imaging to be performed at DC (± 4 weeks [28 days]). If an imaging assessment was obtained within 4 weeks (28 days) prior to the date of DC, imaging is not required at 
the EOT visit. For participants who DC for PD, this is the final required tumor imaging.
e
Participants with treated brain lesions and participants with known, asymptomatic, untreated brain lesions at diagnosis, will require imaging of the brain as a site of disease 
at DC (± 4 weeks [28 days]). If an imaging assessment was obtained within 4 weeks (28 days) prior to the date of DC, imaging is not required at the EOT visit. For 
participants who DC for PD, this is the final required tumor imaging.
Note: For country-specific requirements see Appendix 7.
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1.3.4
Second Course Phase
Study Period
Second Course Treatment
EOT
Posttreatment
Notes
Effective with Amendment 7, all efficacy 
follow-up will continue to be collected at the 
EOT visits but will not be collected during 
posttreatment follow-up.
Treatment Cycle
C1
C2
C3
C4
C5
C6+
At 
Time 
of DC
Safety 
Follow-
upa,
Imaging 
Follow-
upb
Survival 
Follow-up
Cycle Day
1
1
1
1
1
1
30 Days 
from Last 
Dose (+ 7)
Q12W 
(± 7)
Q12W
(± 7)
Scheduled Days
± 3
± 3
± 3
± 3
± 3
Administrative Procedures
Review Eligibility Criteria
X
Review Concomitant 
Medication
X
X
X
X
X
X
X
X
Review New Anticancer 
Treatment
X
X
All anticancer therapy will be recorded until 
time of death or termination of survival follow-
up. If a clinical visit is not feasible, this 
information may be obtained by phone or 
email.
Vital Status
------------------------------------------------------------------------------------------------------
All participants may be contacted for vital 
status at any time during the study through the 
EOT Visit.
Clinical Assessments or Procedures
Review Adverse Events
X
X
X
X
X
X
X
X
X
AEs: Report all AEs occurring through 30 days 
following the last dose of study intervention. 
SAEs: Report all SAEs occurring through 
90 days following the last dose of study 
intervention, or 30 days following the last dose 
of study intervention if the participant initiates 
new anticancer therapy, whichever is earlier. 
New diagnosis of MDS or AML should be 
reported throughout the study including the 
follow-up phase.
Full Physical Examination
X
X
Directed Physical 
Examination
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
ECOG Performance Status
X
X
X
X
X
X
X
X
Perform within 3 days prior to Second Course 
Cycle 1 and prior to treatment during treatment 
visits.
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Study Period
Second Course Treatment
EOT
Posttreatment
Notes
Effective with Amendment 7, all efficacy 
follow-up will continue to be collected at the 
EOT visits but will not be collected during 
posttreatment follow-up.
Treatment Cycle
C1
C2
C3
C4
C5
C6+
At 
Time 
of DC
Safety 
Follow-
upa,
Imaging 
Follow-
upb
Survival 
Follow-up
Cycle Day
1
1
1
1
1
1
30 Days 
from Last 
Dose (+ 7)
Q12W 
(± 7)
Q12W
(± 7)
Scheduled Days
± 3
± 3
± 3
± 3
± 3
Laboratory Assessments or Procedures
Pregnancy Test (WOCBP 
only), Urine or HCG
X
X
X
X
X
X
X
X
X
WOCBP require a negative highly sensitive 
urine test within 24 hours (72 hours for serum) 
prior to first dose of study intervention. Testing 
during Second Course must be conducted as 
clinically indicated and per local regulations 
where applicable. Serum test is only required if 
urine test is positive or not evaluable. More 
frequent pregnancy testing may be indicated, as 
dictated by local regulations.
PT/INR and aPTT/PTT
X
Perform within 3 days prior to Second Course 
Cycle 1. Participants receiving coumadin-based 
anticoagulants should have more frequent INR 
monitoring, as clinically indicated.
Chemistry Panel
X
X
X
X
X
X
X
X
Perform within 3 days prior to Second Course 
Cycle 1.
Hematology Panel
X
X
X
X
X
X
X
X
Perform within 3 days prior to Second Course 
Cycle 1.
T3/FT3, FT4, and TSH
X
X
X
X
X
Perform within 3 days prior to Second Course 
Cycle 1 and every other cycle thereafter (eg, 
C3, C5, C7, etc.).
Efficacy Measurements
CT/MRI Imaging of Chest, 
Abdomen, and Pelvis
X
X
X
X
Perform within 28 days prior to Second Course 
Cycle 1. Q12W from Second Course Cycle 1 
onward or more frequently, as clinically 
indicated. If imaging was obtained within 
28 days prior to DC, an additional scan is not 
needed at DC. Effective with Amendment 7, no 
further imaging is to be performed after the 
EOT Visit. 
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Study Period
Second Course Treatment
EOT
Posttreatment
Notes
Effective with Amendment 7, all efficacy 
follow-up will continue to be collected at the 
EOT visits but will not be collected during 
posttreatment follow-up.
Treatment Cycle
C1
C2
C3
C4
C5
C6+
At 
Time 
of DC
Safety 
Follow-
upa,
Imaging 
Follow-
upb
Survival 
Follow-up
Cycle Day
1
1
1
1
1
1
30 Days 
from Last 
Dose (+ 7)
Q12W 
(± 7)
Q12W
(± 7)
Scheduled Days
± 3
± 3
± 3
± 3
± 3
MRI of Brain
X
X
X
X
Perform within 28 days prior to Second Course 
Cycle 1 for participants who are known to be 
positive for brain metastases or are clinically 
symptomatic. If positive for brain metastases at 
start of Second Course, continue imaging 
Q12W from Second Course Cycle 1 onward or 
more frequently, as clinically indicated. If 
imaging was obtained within 28 days prior to 
DC, an additional scan is not needed at DC. 
Effective with Amendment 7, no further 
imaging is to be performed after the EOT Visit.
Dispensing and Administration of Study Intervention
Pembrolizumab 
X
X
X
X
X
X
200 mg IV Q3W
Abbreviations: AE = adverse event; HCG = human chorionic gonadotropin; BP = blood pressure; C1 = Cycle 1; C2 = Cycle 2; CR = complete response; CT = computed 
tomography; DC = discontinued/discontinuation; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end-of-treatment; FT4 = free thyroxine; 
MRI = magnetic resonance imaging; Q3W = every 3 weeks; Q12W = every 12 weeks; SAE = serious adverse event; T3 = triiodothyronine; TSH = thyroid stimulating 
hormone; WOCBP = women of childbearing potential.
a
If Discontinuation Visit occurs ≥30 days from last dose of study intervention, a Safety Follow-up Visit is not required. All procedures for both visits will be performed at 
the Discontinuation Visit.
b
Follow-up visits are to be scheduled to coincide with follow-up imaging.
c
Participants who discontinue for reasons other than radiographic disease progression will have posttreatment follow-up imaging for disease status until centrally verified 
disease progression is documented radiographically per RECIST 1.1, confirmed by the site per iRECIST when clinically appropriate, initiating a new anticancer treatment, 
withdrawing consent, becoming lost to follow-up, pregnancy, or death. Effective with Amendment 7, no further imaging is to be performed after the EOT Visit.
Note: For country-specific requirements see Appendix 7.
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2
INTRODUCTION
This clinical study will evaluate the polyadenosine 5′-diphosphoribose polymerization 
(PARP) inhibitor, olaparib, in combination with pembrolizumab for the treatment and 
maintenance of nonsquamous non–small-cell lung cancer (NSCLC).
2.1
Study Rationale
Nonsquamous NSCLC accounts for approximately 65% to 70% of all NSCLC, with the 
majority of patients having advanced disease at diagnosis that is not amenable to surgical 
resection, as such additional treatment options are needed.
Pembrolizumab monotherapy has changed the treatment paradigm for those patients with 
NSCLC whose tumors express PD-L1 ≥50% in the Phase 3 study, KEYNOTE-024. In this 
study, pembrolizumab showed statistically significant increases in OS and PFS compared 
with platinum-based chemotherapy for treatment-naïve participants with metastatic NSCLC 
whose tumors expressed high levels of the programmed cell death ligand 1 (PD-L1; tumor 
proportion score [TPS] ≥50%) with no epidermal growth factor receptor (EGFR) or 
anaplastic lymphoma kinase (ALK) genomic tumor aberrations., leading to regulatory 
approval for this indication in the US and other countries around the world. Approximately 
30% of patients with newly diagnosed, advanced NSCLC highly express PD-L1 to a TPS 
≥50% [Reck, M., et al 2016]; therefore, only a subset of patients with metastatic 
nonsquamous NSCLC are potential candidates. With the findings from KEYNOTE-042, the 
TPS cutoff has been lowered, as pembrolizumab monotherapy significantly improved OS for 
participants with NSCLC who had TPS ≥1% (16.7 months vs. 12.1 months; HR: 0.81) and 
TPS ≥20% (17.7 months vs. 13.0 months; HR: 0.77), compared with chemotherapy alone, 
while continuing to show an OS benefit in those with TPS ≥50% (20.0 months vs. 
12.2 months; HR: 0.69). Thus, both KEYNOTE-024 and KEYNOTE-042 showed that 
pembrolizumab monotherapy is effective in participants with PD-L1 positive metastatic 
NSCLC. Yet, despite these encouraging data, there is still substantial room for improvement 
of the treatment options available to these patients.
To expand on the efficacy of pembrolizumab, KEYNOTE-21 Cohort G and KEYNOTE-189 
were designed to combine the agent with pemetrexed and a platinum in patients with 
metastatic nonsquamous NSCLC, as chemotherapy has been shown to augment the antitumor 
immune response. KEYNOTE-21G is a Phase 2 study that randomized 123 patients to 
pembrolizumab with pemetrexed and carboplatin versus pemetrexed with carboplatin in 
patients with metastatic nonsquamous NSCLC in whom there were no EGFR or ALK
genomic tumor aberrations who had not previously received systemic therapy for their 
advanced disease. The study met its primary endpoint of improvement in objective response 
rate (ORR), as well as the key secondary endpoint of PFS, leading to Food and Drug 
Administration (FDA) accelerated approval of pembrolizumab in combination with 
pemetrexed/carboplatin. In an updated analysis, the following were noted: improvement in 
ORR was 24.8% (95% confidence interval [CI]: 7.2 to 40.9) with 56.7% for the 
pembrolizumab with chemotherapy arm and 31.7% for the control; PFS HR 0.54 (95% 
CI: 0.33 to 0.88) with median PFS 19.0 versus 8.9 months, for the pembrolizumab with
chemotherapy arm compared with the control, respectively; and OS HR 0.59 (95% CI: 0.34 
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to 1.05) with median OS not reached in the pembrolizumab combination arm and 
20.9 months in the control [Borghaei, H., et al 2017].
KEYNOTE-189 is a global, multicenter, placebo-controlled trial that randomized 
616 participants with untreated Stage IV nonsquamous NSCLC in a 2:1 fashion to receive 
pemetrexed and investigator’s choice of either carboplatin or cisplatin in combination with 
pembrolizumab or saline placebo for 4 cycles, followed by pembrolizumab or saline for a 
total of 35 cycles, plus pemetrexed maintenance therapy. Patients in the saline placebo arm 
had the option to cross over to pembrolizumab monotherapy if progressive disease had been 
verified by BICR and other safety criteria were met. The study showed a clinically 
meaningful and statistically significant improvement in OS with an HR of 0.49 (95% 
CI: 0.38 to 0.64, p<0.00001) and a median OS of not reached in the pembrolizumab 
combination arm compared with 11.3 months in the chemotherapy alone arm. Similarly, 
there was significant PFS benefit with an HR of 0.52 (95% CI: 0.43 to 0.64, p<0.0001) with 
a median PFS of 8.8 months and 4.9 months in the pembrolizumab combination arm vs. 
chemotherapy alone arm, respectively. ORR also was significantly improved in the 
pembrolizumab combination arm (47.6%) compared with chemotherapy alone (18.9%), 
p<0.00001. Importantly, all subgroups benefited from pembrolizumab in combination with 
pemetrexed and carboplatin or cisplatin, including patients whose tumors did not express PD-
L1; therefore, extending the benefit of pembrolizumab to those with PD-L1 negative tumors.
Unfortunately, while these results have changed the paradigm in lung cancer treatment, 
patients do continue to progress and succumb to this disease and as such, there can be further 
improvement on the available therapeutic options. As PARP-inhibition has been established 
as maintenance therapy in platinum-sensitive ovarian cancer, there is potential for improved 
outcomes in lung cancers by adding maintenance olaparib to pembrolizumab in those 
demonstrating platinum-sensitivity after induction pembrolizumab with chemotherapy. 
NSCLC also is a prime candidate for olaparib use as homologous recombination deficiency 
loss of heterozygosity (HRD-LOH) scores are as high as in breast and ovarian cancers, as per 
The Cancer Genome Atlas. Further, preclinical data suggest that olaparib and anti-PD(L)-1 
inhibitors show synergistic therapeutic benefit. Therefore, adding olaparib as maintenance 
therapy to pembrolizumab in the treatment of patients with platinum-sensitive lung cancers 
has the potential for further treatment benefit, which is clearly necessary.
2.2
Background
2.2.1
Olaparib
Olaparib (AZD2281, KU-0059436) is a potent PARP inhibitor (PARP1, 2, and 3) that is 
being developed as an oral anticancer therapy, as monotherapy (including maintenance) and 
in combination with chemotherapy and other anticancer agents.
PARP inhibition is a novel approach to targeting tumors with deficiencies in DNA repair 
mechanisms. The PARP enzymes are essential for repairing DNA single-strand breaks 
(SSBs). Inhibiting PARPs leads to the persistence of SSBs, which are then converted to the 
more serious DNA double-strand breaks (DSBs) during DNA replication. During cell 
division, DSBs can be efficiently repaired in normal cells by homologous recombination 
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repair (HRR). Tumors with homologous recombination deficiency (HRD), such as ovarian 
cancers in patients with the breast cancer susceptibility gene 1/2 (BRCA1/2) mutations 
(BRCAm), cannot accurately repair the DNA damage, which may become lethal to cells as it 
accumulates. In such tumor types, olaparib may offer a potentially efficacious and less toxic 
cancer treatment compared with currently available chemotherapy regimens.
Olaparib traps the inactive form PARP on DNA at sites of SSBs, thus preventing their repair 
[Helleday, T. 2011] [Murai, J., et al 2012]. Olaparib has shown efficacy in ovarian, prostate, 
and pancreatic tumors with BRCA1 and BRCA2 mutations and proof-of-concept in tumors 
with ataxia-telangiectasia mutated (ATM) and other indicators of HRD. The specificity of 
olaparib for binding PARP at the replication fork during DNA replication is believed to have 
applicability to tumors associated with mutations in HRR.
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on olaparib.
2.2.2
Pembrolizumab
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated 
for the treatment of patients across several indications. For more details on specific 
indications refer to the IB.
2.2.3
Non–small-Cell Lung Cancer
Lung cancer is the most common malignancy in the world, with an estimated incidence in 
2012 of 2.1 million and an associated 1.8 million deaths [Bray, F., et al 2018]. Among males, 
the estimated incidence rates of new diagnoses are highest in Central and Eastern Europe 
(53.5 per 100,000/year) and Eastern Asia (50.4), while the incidence rates among females are 
highest in North America (33.8), Northern Europe (23.7), and Eastern Asia (19.2) [Ferlay, J., 
et al 2015]. Mortality from lung cancer is the leading cause of cancer death in men and the 
second leading cause in women [Torre, L. A., et al 2015]. In the United States (US) in early 
2018, there were an estimated 234,000 new cases and 154,000 deaths from lung cancer 
[Siegel, R. L., et al 2018].
Non–small-cell lung cancer represents approximately 80% to 85% of all lung cancers 
[National Cancer Institute 2016] and consists of 2 major types: nonsquamous carcinoma 
(~65% to 70% of cases) and squamous carcinoma (~30% to 35% of cases) [Ferlay, J., et al
2015] [Arnold, M., et al 2015]. At the time of diagnosis, approximately 80% of patients with 
lung cancer have locally advanced or metastatic disease that is not amenable to surgical 
resection [National Cancer Institute 2012]. Of those patients diagnosed with early stage 
NSCLC and treated with surgery, a significant percentage subsequently develop distant 
recurrence [Pisters, K. M. W. and Le Chevalier, T. 2005]. These factors contribute to the 
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dismal 5-year relative survival rates of 17.7% in patients diagnosed with NSCLC, and a mere 
4.3% in those with advanced/metastatic disease [National Cancer Institute 2016a].
2.2.4
Current Treatment Options and Unmet Medical Need
There remains a high unmet medical need for patients with previously untreated metastatic 
nonsquamous NSCLC.
Importantly, in nonsquamous NSCLC, molecular profiling and availability of targeted 
therapy have helped change the treatment approach for a subset of patients. The EGFR 
tyrosine kinase inhibitors gefitinib, erlotinib, and afatinib have showed marked superiority 
over chemotherapy in patients with activating EGFR mutations; and osimertinib in front line 
has shown improved outcomes over earlier generations of EGFR tyrosine kinase inhibitors. 
Similarly, multiple ALK inhibitors, including crizotinib, ceritinib, alectinib, and brigantinib 
have shown significant activity in ALK-rearranged NSCLC and have received regulatory 
approval for use. Interestingly, the ALK inhibitors are also active in a rare subgroup of 
ROS-1-rearranged NSCLC patients. Data have shown poorer outcomes in patients with 
tumors harboring a targetable mutation that are not treated with a tyrosine kinase inhibitor 
[Kris, M. G., et al 2014].
Prior to the use and availability of pembrolizumab, platinum-based chemotherapy, with or 
without maintenance therapy, was the standard first-line (1L) therapy for patients with 
advanced/metastatic NSCLC with good Eastern Cooperative Oncology Group (ECOG) 
performance status scores (0 or 1), without EGFR or ALK genomic tumor aberrations [Oken, 
M. M., et al 1982]. Chemotherapy regimens used in the 1L treatment of metastatic NSCLC 
include cisplatin or carboplatin in combination with paclitaxel, nab-paclitaxel, gemcitabine, 
pemetrexed, or docetaxel [Peters, S., et al 2012] [Peters, S., et al 2012]. Multiple Phase 3 
studies have showed similar efficacy for most platinum-based chemotherapy in participants 
with NSCLC; response rates have ranged from 15% to 33%, with median PFS values of 
approximately 4.5 to 6.3 months and median OS values of 10.3 to 12.6 months [Socinski, 
Mark A., et al 2012] [Sandler, A., et al 2006] [Scagliotti, G. V., et al 2008] [Thatcher, N., et 
al 2015] A meta-analysis of randomized, controlled clinical studies compared chemotherapy 
regimens containing cisplatin or carboplatin in combination with third-generation 
antineoplastic agents, including docetaxel, paclitaxel, and gemcitabine. No clinically 
meaningful difference in the safety and efficacy of carboplatin versus cisplatin-containing 
regimens was found [Ardizzoni, A., et al 2007], with a median OS of 8.4 months compared
with 9.1 months, and 1-year survival rates of 34% versus 37%, for carboplatin and cisplatin, 
respectively. These data support the interchangeable use of carboplatin and cisplatin in 
combination with standard-of-care (SOC) antineoplastic agents, which also is reflected in 
clinical utilization data and supported by National Comprehensive Cancer Network (NCCN) 
recommendations [National Comprehensive Cancer Network 2016] and The European 
Society for Medical Oncology (ESMO) Guidelines [Novello, S., et al 2016]. Studies have 
assessed differences in outcomes if 6 or fewer cycles of platinum-doublet-containing 
regimens are administered [Park, J. O., et al 2007] [Rossi, A., et al 2014]. Although PFS is 
longer with 6 cycles of chemotherapy compared with 3 or 4, increased toxicities are seen 
without a statistically significantly improved OS [Park, J. O., et al 2007] [Rossi, A., et al 
2014]. Therefore, the ESMO Guidelines specifically state that patients should receive 4 
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cycles of platinum-based doublets followed by maintenance therapy, or a maximum of 6 
cycles if maintenance intervention is not appropriate [Novello, S., et al 2016].
The results of a landmark Phase 3 study evaluating cisplatin and pemetrexed compared with 
cisplatin and gemcitabine underscored that knowledge of histologic subtypes are important to 
determine the appropriate treatment choice in NSCLC [Scagliotti, G. V., et al 2008]. The 
study had a noninferiority design and enrolled 1725 patients with previously untreated 
NSCLC. Although OS was noninferior with cisplatin and pemetrexed compared with 
cisplatin and gemcitabine (median survival 10.3 months versus 10.3 months; HR 0.94; 95% 
CI 0.84 to 1.05%), planned subgroup analyses showed that cisplatin and pemetrexed was 
superior in patients with nonsquamous NSCLC (n=1000; HR 0.81; 95% CI: 0.7 to 0.94; 
p=0.005), and cisplatin and gemcitabine led to improved survival in patients with squamous 
cell histology (n=473; 10.8 months versus 9.4 months, respectively, p=0.05) [Scagliotti, G. 
V., et al 2008]. Pemetrexed and platinum therapy has become a significant treatment of 
choice for metastatic nonsquamous NSCLC.
The PARAMOUNT study showed that continuation of pemetrexed after achieving stable 
disease or response with the initial 4 cycles of pemetrexed/cisplatin in participants with 
advanced nonsquamous NSCLC confers a significant survival benefit compared with placebo 
(median OS 13.9 months versus 11.0 months from randomization at the initiation of 
maintenance therapy [Paz-Ares, L., et al 2012] [Paz-Ares, L. G., et al 2013]). Subsequently, 
maintenance therapy with pemetrexed became the SOC in patients with nonsquamous 
NSCLC who had not progressed during pemetrexed/cisplatin induction therapy.
While the addition of bevacizumab to carboplatin/paclitaxel followed by bevacizumab 
maintenance therapy in eligible patients with NSCLC showed improved OS (HR: 0.79) 
[Sandler, A., et al 2006], the combination of bevacizumab to cisplatin/gemcitabine revealed 
no survival benefit (HR: 0.93 and 1.03 for low- and high-dose bevacizumab regimens, 
respectively) [Reck, M., et al 2010]. Additionally, given the safety profile of bevacizumab, 
use of the drug has been variable worldwide. In summary, observed results for these modern 
chemotherapy regimens, with or without maintenance therapy, have shown only modest 
improvements in survival and indicate that effective and tolerable treatment options are 
needed for patients with advanced nonsquamous NSCLC without actionable genetic 
aberrations.
Pembrolizumab has led to a paradigm shift from standard platinum-based doublets for 
NSCLC. KEYNOTE-21 Cohort G and KEYNOTE-189 have further re-defined the standard 
of care for patients with nonsquamous NSCLC. Cohort G of KEYNOTE-21 evaluated 
pembrolizumab combined with pemetrexed/carboplatin versus pemetrexed/carboplatin alone 
in previously untreated patients with nonsquamous NSCLC in the setting of a Phase 2 study. 
The prespecified analysis of KEYNOTE-21 Cohort G showed a statistically significant and 
clinically meaningful benefit in ORR and PFS, which was the basis for FDA accelerated 
approval of pembrolizumab in combination with pemetrexed/carboplatin for the 1L treatment 
of patients with metastatic nonsquamous NSCLC irrespective of PD-L1 tumor expression 
[Langer, C. J., et al 2016].
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KEYNOTE-189 was the confirmatory Phase 3 study intended to enforce and expand upon 
the results of KEYNOTE-21 Cohort G. In KEYNOTE-189, treatment with pembrolizumab in 
combination with pemetrexed/platinum chemotherapy (cisplatin or carboplatin) provided a 
clinically meaningful and significant improvement in OS (HR: 0.49; p<0.00001; median OS 
not reached vs. 11.3 months), PFS (HR: 0.52; p<0.00001; median PFS 8.8 months vs. 
4.9 months), and objective response rate (ORR; 47.6% vs. 18.9%; p<0.001) for previously 
untreated patients with metastatic nonsquamous NSCLC. Importantly, in KEYNOTE-189, all 
subgroups benefited from pembrolizumab in combination with chemotherapy, including 
patients whose tumors did not express PD-L1; therefore, extending the benefit of 
pembrolizumab to those with PD-L1 negative tumors. The magnitude of benefit observed in 
this study is unprecedented in NSCLC clinical trials, and regulatory agencies have begun to 
approve pembrolizumab in combination with pemetrexed and platinum for this indication. 
Median OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 
10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio [HR], 0.56; 95% 
CI, 0.45 to 0.70]). Median PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, 
respectively (HR, 0.48; 95% CI, 0.40 to 0.58) [Gadgeel, S., et al 2020].
More recently, results have been reported for a 3-arm, randomized study of the anti-PD-L1 
inhibitor atezolizumab combined with carboplatin/paclitaxel chemotherapy and bevacizumab 
in patients with nonsquamous NSCLC. The comparison of atezolizumab combined with 
chemotherapy and bevacizumab to chemotherapy and bevacizumab alone showed a 38% 
improvement in PFS (8.3 vs. 6.8 months; HR 0.62 (95% CI: 0.52 to 0.74): p<0.001) and OS 
(19.2 vs. 14.7 months; HR 0.78 (95% CI: 0.64 to 0.96); p=0.02) favoring the atezolizumab-
containing arm, with a comparable safety profile in both treatment groups [Socinski, M. A., 
et al 2018]. These results provided further evidence that the combination of standard 
chemotherapy with immunotherapy, which is a well-understood and broadly used treatment 
in NSCLC, is a clinically meaningful approach.
Despite these impressive results, for patients with advanced nonsquamous NSCLC there is a 
need for new agents that can be combined with a pembrolizumab backbone to increase 
response rates, decrease the risk of progression, and decrease the risk of death [Gandhi, L., et 
al 2018].
2.2.5
Pharmaceutical and Therapeutic Background
2.2.5.1
Inhibition of PARP as a Target for Cancer Therapy
PARP1 and PARP2 are zinc-finger DNA-binding enzymes that play a critical role in DNA 
repair [Ame, J. C., et al 2004] by sensing DNA damage and converting it into intracellular 
signals that activate the base excision repair and SSB repair pathways. When a break in DNA 
occurs, PARP enzymes are recruited to, and bind at, the end of the broken DNA strands, 
activating their enzymatic activity. PARP subsequently catalyzes the addition of long 
polymers of ADP-ribose onto several other proteins associated with chromatin (eg, PARP, 
histones, DNA repair proteins), resulting in chromatin relaxation, rapid recruitment of DNA 
repair proteins, and efficient repair of the break.
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Under normal conditions, HRR is the preferred pathway for repairing DNA damage, as it is 
associated with a lower error rate compared with other forms of DNA repair [Prakash, R., et 
al 2015]. During DNA replication (S phase), pre-existing or chemotherapy-induced SSBs are 
converted to DSBs if not adequately repaired by intracellular mechanisms [Fong, Peter C., et 
al 2009], such as HRR. Cells unable to perform HRR (eg, due to inactivation of genes 
required for homologous recombination, such as BRCA1 or BRCA2) are more likely to use 
the error-prone nonhomologous end-joining (NHEJ) or alternative (alt)-NHEJ pathways to 
repair these DSBs and risk accumulating multiple lesions or loss of heterozygosity (LOH) 
due to an increase in deletions and accompanying genomic instability. Over time, the 
accumulation of excessive DNA errors in combination with the inability to complete S phase 
(ie, because of stalled replication forks due to PARP inhibitor administration) leads to cell 
death, demonstrating that PARP inhibition is synthetically lethal in the context of BRCAm 
[Farmer, H., et al 2005] [Bryant, H. E., et al 2005]. Cells without SSBs or with intact HRR, 
such as somatic tissue, replicate normally in the presence of a PARP inhibitor, thereby 
minimizing toxicity.
Thus, treatment with PARP inhibitors could represent a novel opportunity to selectively kill 
cancer cells with deficiencies in DNA repair pathways.
Additionally, PARP inhibitors, by causing DNA damage can activate the cyclic guanosine 
monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway, 
increasing type I interferons, immunomodulatory molecules (eg, CXCL10, CCL5), and 
CD4+/CD8+ lymphocytes and upregulating PD-L1 and other checkpoint inhibitors in both 
BRCA-proficient and BRCA-deficient cells. Preclinically, the combination of olaparib and 
anti-PD(L)1 inhibitors show improved therapeutic benefit than each alone, likely being 
synergistic. Therefore, there is rationale for the combination of olaparib and pembrolizumab.
2.2.5.2
Inhibition of PD-1 as a Target for Cancer Therapy
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and 
favorable prognosis in various malignancies [Dong, H., et al 2002] [Hino, R., et al 2010] 
[Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC. 2012] [Patnaik, A., et al 2012] 
[Hodi, F. S., et al 2010] [Chapman, P. B., et al 2011] [Robert, C., et al 2011]. In particular, 
the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells to FoxP3+ regulatory T-
cells seems to correlate with improved prognosis and long-term survival in solid 
malignancies, including ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma 
(HCC); malignant melanoma; and renal cell carcinoma (RCC). TILs can be expanded ex vivo 
and re-infused, inducing durable objective tumor responses in cancers such as melanoma 
[Sasaki, A., et al 2008] [Shen, Z., et al 2010].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to downmodulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4, which has been shown to negatively 
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regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Talmadge, J. E., et al 2007] [Usubütün, A., et al 1998]. The mechanism by which PD-1 
downmodulates T-cell responses is similar to, but distinct from, that of CTLA-4, as both 
molecules regulate an overlapping set of signaling proteins [Nobili, C., et al 2008] [Hiraoka, 
N. 2010]. 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 [Hodi, F. S. and Dranoff, G. 
2010] [Kloor, M. 2009]. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively 
expressed or can be induced in a variety of cell types, including nonhematopoietic tissues and 
various tumors. Both ligands are type I transmembrane receptors, containing IgV- and IgC-
like domains in the extracellular region and short cytoplasmic regions with no known 
signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered 
through the T-cell receptor. PD-L1 is expressed at low levels on various nonhematopoietic 
tissues, most notably on vascular endothelium, whereas the PD-L2 protein 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 PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues [Lee, H. 
E., et al 2008]. Although healthy organs express little (if any) PD-L1, a variety of cancers 
were shown 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 RCC 17 [Liotta, F., et al 2011], pancreatic 
carcinoma [Suzuki, H., et al 2010], HCC [Chew, V., et al 2010], and ovarian carcinoma. 
[Pölcher, M., et al 2010]. Further, PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in participants with melanoma [Oble, D. A., et al 2009].
2.2.5.3
Homologous Recombination Repair in Solid Tumors
Defects in DNA repair drive the genesis of several solid tumors, most notably ovarian and 
pancreatic. DNA strand breaks occur both as part of the recombination and replication 
process as well as following intercalating chemotherapy or DNA damaging radiotherapy. 
HRR defective tumors are intrinsically sensitive to PARP inhibitors, both in tumor models in 
vivo [Rottenberg, S., et al 2008] [Hay, T., et al 2009] and in the clinic [Fong, Peter C., et al 
2009] [Tutt, A., et al 2010] [Mateo, J., et al 2015] [Kaufman, B., et al 2015]. The main 
mechanism of action for olaparib results from the trapping inactive PARP on SSBs
preventing their repair [Helleday, T. 2011] [Murai, J., et al 2012] and excessive conversion 
into the more serious DSBs, which are lethal, or results in incomplete/inaccurate repair of the 
damaged strand leading to a LOH with subsequent aberrant protein translation and function.
Normally, the process of HRR corrects DSBs using proteins such as BRCA1 and BRCA2; 
however, the HRR armamentarium includes proteins coded by at least 13 other genes 
including ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, 
RAD51B, RAD51C, RAD51D, and RAD54L. For example, the protein coded by the ATM
gene also is involved in the repair of DSB. ATM is activated by DSB and phosphorylates 
diverse cellular proteins, leading to cell-cycle arrest (eg, mediator of DNA damage 
checkpoint 1, checkpoint kinase 2), activates the tumor suppressor p53, contributes to 
chromatin relaxation and remodeling, and activates nuclear factor kappa-light-chain-
enhancer of activated B cells. Defective ATM increases the risk of breast, gastrointestinal, 
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lung, and lymphoid cancers. Moreover, defective ATM also appears to correlate with a poor 
prognosis, but the conferred risk has not been quantified.
A small percentage of tumors have loss-of-function mutations in HRR genes, with BRCA1, 
BRCA2, and ATM being the best characterized and most frequently mutated [Watkins, J. A., 
et al 2014] [Marquard, A. M., et al 2015] [Choi, M., et al 2016] [Lord, C. J. 2016]. 
Approximately half of the detected HRRm are germline mutations [Mateo, J., et al 2015]. 
While an adverse prognostic impact of germline BRCA2 mutations has been described in 
prostate cancer [Castro, E., et al 2015], it is less clear if other germline or somatic HRR gene 
mutations are associated with similar adverse clinical outcomes. To date, HRRm has not 
been associated with specific patient or tumor characteristics.
Notably, in NSCLC, HRD-LOH scores are as high as in breast and ovarian cancers, as per 
The Cancer Genome Atlas Network data [Cerami, E., et al 2012] [Gao, J., et al 2013].
2.2.6
Preclinical and Clinical Studies
A summary of preclinical and clinical study data for pembrolizumab and olaparib is provided 
in their respective IBs.
2.2.7
Ongoing Clinical Studies
A summary of ongoing clinical study data for pembrolizumab and olaparib is provided in 
their respective IBs.
2.2.8
Other Study-related Therapies
A platinum doublet with pemetrexed is the most frequently used 1L chemotherapy for 
chemotherapy-naïve metastatic nonsquamous NSCLC patients. Pembrolizumab in 
combination with pemetrexed and cisplatin or carboplatin is also being evaluated in a 
randomized Phase 3 study, KN189, and those data were positive at the interim analysis [Paz-
Ares, L., et al 2018]. Based on safety and efficacy data from these combination studies with 
pembrolizumab and other PD-1/PD-L1 inhibitors, the current study will utilize 
pembrolizumab in combination with pemetrexed and cisplatin or carboplatin.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In male and female participants with Stage IV nonsquamous non–small-cell lung cancer 
(NSCLC) with stable disease (SD), partial response (PR), or complete response (CR) 
following induction treatment with pembrolizumab combined with pemetrexed and platinum 
(carboplatin or cisplatin):
Primary Objective
Primary Endpoint
•
Objective: To compare pembrolizumab 
plus maintenance olaparib with 
pembrolizumab plus maintenance 
pemetrexed with respect to progression-
free survival (PFS) assessed according 
to Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 by blinded 
independent central review (BICR).
•
Hypothesis (H1): Pembrolizumab plus 
maintenance olaparib is superior to 
pembrolizumab plus maintenance 
pemetrexed with respect to PFS per 
RECIST 1.1 (Section 4.2.1.1) by BICR.
•
PFS, the time from the date of 
randomization until either documented 
disease progression or death due to any 
cause, whichever occurs first.
•
Objective: To compare pembrolizumab 
plus maintenance olaparib with 
pembrolizumab plus maintenance 
pemetrexed with respect to overall 
survival (OS).
•
Hypothesis (H2): Pembrolizumab plus 
maintenance olaparib is superior to 
pembrolizumab plus maintenance 
pemetrexed with respect to OS.
•
OS, the time from the date of 
randomization to death due to any 
cause.
At the final analysis, the pembrolizumab plus olaparib arm did not meet the primary 
endpoint of OS. PFS was not statistically significant compared with the control arm.
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Secondary Objectives
Secondary Endpoints
•
Objective: To evaluate the safety and 
tolerability of pembrolizumab plus 
maintenance olaparib compared to 
pembrolizumab plus maintenance 
pemetrexed.
•
Adverse events (AEs)
•
Discontinuation of study intervention 
due to AEs.
•
Objective: To evaluate the change from 
baseline (at randomization) and the time 
to true deterioration (TTD) in global 
health status/quality of life (QoL), 
cough, chest pain, dyspnea and physical 
functioning following treatment with 
pembrolizumab plus maintenance 
olaparib compared with pembrolizumab 
plus pemetrexed.
•
Change from baseline (at 
randomization) and the TTD defined as 
the time from baseline (at 
randomization) to the first onset of a 
≥10-point deterioration with 
confirmation by the subsequent visit of 
a ≥10-point deterioration in the 
following European Organization for 
Research and Treatment of Cancer 
Quality of Life Questionnaire (EORTC 
QLQ) and QLQ Lung Cancer Module 
13 (LC13) scales/items:
Global health status/QoL (Core 30 
[C30]/Items 29 and 30)
Cough (LC13/Item 1)
Chest pain (LC13/Item 10)
Dyspnea (C30/Item 8)
Physical functioning (C30/Items 1 
through 5)
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
•
Objective: To evaluate pembrolizumab 
plus maintenance olaparib compared to 
pembrolizumab plus maintenance 
pemetrexed with respect to objective 
response rate (ORR) and duration of 
response (DOR) assessed according to 
RECIST 1.1 (Section 4.2.1.1) by BICR.
•
Objective response (OR), complete 
response (CR) or partial response (PR) 
after the date of randomization.
•
DOR, the time from first documented 
evidence of CR or PR after the date of 
randomization until either documented 
disease progression or death due to any 
cause, whichever occurs first.
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•
Objective: To evaluate the effect of PD-
L1 expression levels on the efficacy 
endpoints of OS and PFS assessed 
according to RECIST 1.1 (Section 
4.2.1.1) by BICR.
•
PFS
•
OS
•
Objective: To evaluate pembrolizumab 
plus maintenance olaparib compared to 
pembrolizumab plus maintenance 
pemetrexed with respect to new 
anticancer therapy (PFS2), as assessed 
by the investigator using RECIST 1.1.
•
PFS2, the time from randomization to 
subsequent disease progression after 
initiation of new anticancer therapy, or 
death from any cause, whichever occurs 
first.
•
Objective: To evaluate pembrolizumab 
plus maintenance olaparib compared to 
pembrolizumab plus pemetrexed with 
respect to the time to first subsequent 
anticancer therapy (TFST) and the time 
to second subsequent anticancer 
treatment (TSST)
•
TFST, the time from the date of 
randomization to initiation of first 
subsequent anticancer treatment or 
death due to any cause, whichever 
occurs first
•
TSST, the time from the date of 
randomization to initiation of second 
subsequent anticancer treatment or 
death due to any cause, whichever 
occurs first
•
Objective: To characterize health 
utilities using the 5-level version of the 
European Quality of Life 5-dimension 
Questionnaire (EQ-5D-5L) to generate 
utility scores for use in economic 
models.
Health utilities using the EQ-5D-5L.
•
Objective: To identify molecular 
(genomic, metabolic, and/or proteomic) 
biomarkers that may be indicative of 
clinical response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action of pembrolizumab 
in combination with maintenance 
olaparib.
•
Germline genetic variation, genetic 
(DNA) mutations from tumor, tumor 
and blood RNA variation, proteomics 
and immunohistochemistry, and other 
blood-derived biomarkers.
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3, randomized, active-controlled, parallel-group, multisite, unblinded study of 
the combination of pembrolizumab plus pemetrexed plus platinum (carboplatin or cisplatin) 
followed by continued pembrolizumab and maintenance olaparib compared with continued 
pembrolizumab and maintenance pemetrexed in participants with metastatic nonsquamous 
NSCLC maintenance in need of 1L intervention.
This study will be conducted in 4 phases: Screening, an Induction Phase, a Maintenance 
Phase, and a Long-term Follow-up. An optional Second Course Phase is also available. The 
study design overview is presented in Figure 1 and described below.
The Induction Phase was an open-label 12-week period, during which approximately 
1005 eligible participants were enrolled to receive 4 cycles of pembrolizumab 200 mg IV 
every 3 weeks (Q3W) in combination with pemetrexed and carboplatin or cisplatin; refer to 
Table 2 for dosing information. During the Induction Phase, participants had study visits 
every 3 weeks for assessments. Tumor response during the Induction Phase was evaluated 
using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, with radiographic 
imaging at enrollment and at Weeks 6 and 12 (± 7 days) from the date of the first dose 
(Cycle 1) of study intervention. All imaging must be submitted to the central imaging vendor 
as soon as possible for expedited BICR to determine overall response for each Induction 
Phase scan prior to randomization into the Maintenance Phase.
Note: As of Amendment 07, disease progression will no longer be centrally verified; 
participants will only be assessed locally.
The Maintenance Phase is a randomized, unblinded period, during which approximately 
672 participants were eligible for randomization to pembrolizumab combined with 
maintenance olaparib, or pembrolizumab combined with maintenance pemetrexed 
(Table 2), if they met all of the following key requirements:
•
Received 4 cycles of study intervention during the Induction Phase with at least 
1 evaluable scan and no overall responses of PD by RECIST 1.1, as determined by 
central imaging review (Consultation with the Sponsor is required if a participant 
receives fewer than 4 cycles of study intervention during the Induction Phase without PD, 
and the investigator would like to randomize the participant to the Maintenance Phase)
•
Have an ECOG performance status score of 0 or 1 at Pre-randomization Visit
•
All adverse events (AEs; except alopecia, Grade 2 fatigue, and endocrine-related AEs 
Grade ≤2 requiring treatment or hormone replacement) have resolved to Grade ≤1 or 
baseline following Induction Phase Treatment
•
Have adequate organ function, as indicated by the laboratory values in Table 3
•
Are taking no medications or vaccinations specifically prohibited in the exclusion criteria 
(Section 5.2).
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A detailed list of inclusion criteria specific for entering the Maintenance Phase is provided in 
Section 5.1.
Randomization will be stratified by ECOG performance status score (0 or 1) at 
Pre-randomization Visit, PD-L1 expression (TPS <50% vs. ≥50%), and response at 
randomization (CR/PR vs. SD).
Eligible participants who enter the Maintenance Phase may receive a maximum of 35 cycles 
of pembrolizumab during the study (4 cycles during the Induction Phase and 31 cycles during 
the Maintenance Phase). If pembrolizumab is stopped due to toxicity or completion of 
31 cycles during the Maintenance Phase, the participant may continue with maintenance 
olaparib or pemetrexed until specific discontinuation criteria are met (Section 7.1). If 
maintenance olaparib or pemetrexed is stopped due to toxicity, the participant may continue 
to receive pembrolizumab for a maximum of 31 cycles during the Maintenance Phase or until 
specific discontinuation criteria are met (Section 7.1).
Table 2
Treatment Plan
Induction Phase
(Cycles 1 through 4)
Maintenance Phase
(Up to 31 Cycles)
•
Pembrolizumab 200 mg IV Q3W on Day 1
•
Pemetrexed 500 mg/m2 IV Q3W on Day 1
•
Platinum, investigator’s choice (carboplatin 
or cisplatin)
•
Carboplatin titrated to an AUC of 
5 mg/mL/min IV Q3W on Day 1
OR
•
Cisplatin 75 mg/m2 IV Q3W on Day 1 
•
Pembrolizumab 200 mg IV Q3W on Day 1 
for a maximum of 31 cycles, or until 
specific discontinuation criteria are met 
(Section 7.1)
•
Olaparib 300 mg PO BID daily to continue 
until specific discontinuation criteria are 
met (Section 7.1)
OR
•
Pembrolizumab 200 mg IV Q3W on Day 1 
for a maximum of 31 cycles, will continue 
until specific discontinuation criteria are 
met (Section 7.1)
•
Pemetrexed 500 mg/m2 IV Q3W on Day 1, 
will continue until specific discontinuation 
criteria are met (Section 7.1)
Abbreviations: AUC = area under the concentration-time curve; BID = twice daily; IV = intravenous(ly); PO = oral(ly); 
Q3W = every 3 weeks.
Efficacy will be evaluated using PFS per RECIST 1.1, as determined by BICR and OS.
Participants randomized into the Maintenance Phase will be evaluated with radiographic 
imaging to assess response to study intervention at regular intervals throughout the study, as 
described in Section 8.2.1. The images obtained prior to initiating the Maintenance Phase 
should be performed within 28 days of the date of randomization; these imaging studies will 
serve as the new baseline. All imaging obtained on study will be submitted to the central 
imaging vendor, including imaging showing investigator-assessed progressive disease (PD), 
will be submitted to the central imaging vendor for review, which will assess images using 
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RECIST 1.1 for verification of PD and determination of ORR (Section 8.2). Initial tumor 
imaging showing site-assessed PD should be immediately submitted for verification by BICR 
prior to study intervention discontinuation.
Participants in the Maintenance Phase will receive randomly assigned study intervention 
until centrally verified disease progression is radiographically documented and, when 
clinically appropriate, confirmed by the site per modified RECIST 1.1 for immune-based 
therapeutics (iRECIST), or unacceptable AEs, intercurrent illness that prevents further 
administration of study intervention, investigator’s decision to discontinue the participant, 
noncompliance with study intervention or procedure requirements, or administrative reasons 
requiring cessation of study intervention. Pembrolizumab will continue for a maximum of 
31 cycles, or until specific discontinuation criteria are met (Section 7.1). Olaparib and 
pemetrexed will continue until specific discontinuation criteria are met (Section 7.1).
Participants treated with pembrolizumab who complete a total of 35 cycles of 
pembrolizumab during the study (4 cycles during the Induction Phase and 31 cycles during 
the Maintenance Phase) with SD, CR, or PR, and without a current AE, may be eligible for 
retreatment with up to 17 additional cycles (approximately 1 year) of pembrolizumab if they 
experience radiographic disease progression after stopping treatment in the Maintenance 
Phase. This retreatment is termed the Second Course Phase and is only available if the study 
remains open and the participant meets the criteria listed in Section 7.1. Responses or events 
of progression occurring during Second Course Phase will not be counted toward the ORR 
and PFS endpoints.
Adverse event monitoring will be ongoing during the study and graded in severity according 
to the guidelines in the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) v 4.0 (Section 8.4). Adverse events will be reported by the investigator 
or delegate from the start of induction treatment through 30 days following cessation of study 
intervention. Serious AEs (SAEs) will be reported by the investigator or delegate from the 
start of study intervention through 90 days following cessation of study intervention, or 
30 days following cessation of study intervention if the participant initiates new anticancer 
therapy, whichever is earlier. Patient-reported outcomes (PROs) will be used to assess 
symptomatic improvement and participants will provide information regarding their 
health-related quality of life (HRQoL). Participants will be evaluated for time to true 
deterioration (TTD) in global health status/QoL, cough, chest pain, dyspnea, and physical 
functioning.
Note: As of Amendment 07, ePRO assessments will no longer be collected.
In addition, blood for identification of molecular biomarkers (eg, genomic, metabolic, and/or 
proteomic) that may be indicative of clinical response/resistance, safety, pharmacodynamic 
activity, and/or the mechanism of action of olaparib will be collected at regular intervals (see 
Section 4.2.1.4).
Participants who discontinue study intervention for reasons other than centrally verified PD 
will have Long-term Follow-up for disease status (including imaging), until PD, initiating a 
new anticancer therapy, withdrawing informed consent for study participation, or becoming 
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lost to follow-up. After documented PD each participant will be contacted by telephone 
approximately every 12 weeks (84 ± 14 days) for survival until withdrawal of consent to 
participate in the study, becoming lost to follow-up, death, or end of the study, whichever 
occurs first.
Three interim efficacy analyses and 1 final analysis are planned in this study. Details 
regarding interim analyses are provided in Section 9.7. An external Data Monitoring 
Committee (eDMC) will serve as the primary reviewer of the treatment-level results and will 
make recommendations for discontinuation of the study or modification to an Executive 
Oversight Committee (EOC) of the Sponsor (Section 10.1.4). The eDMC responsibilities and 
review schedules will be outlined in the eDMC charter.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
KEYLYNK-006 was designed to evaluate the efficacy and safety of pembrolizumab plus 
maintenance olaparib compared with pembrolizumab plus maintenance pemetrexed after 
induction therapy with pembrolizumab and chemotherapy with the dual primary endpoints of 
PFS by BICR and OS.
At the final analysis, the pembrolizumab plus olaparib arm did not meet the primary endpoint 
of OS. PFS was not statistically significant compared with the control arm. No new safety 
signals were observed in any of the treatment arms. Note: All study participants still 
receiving study treatment will discuss next steps with the investigator. If continuing to 
receive therapy on study the participant should follow the modified study procedures. 
Participants currently on study treatment will have continued access to olaparib, pemetrexed, 
and pembrolizumab if they qualify per protocol. There will be no further analyses for 
efficacy and ePRO endpoints.
4.2
Scientific Rationale for Study Design
Further improvements can be made on the therapeutic options available for patients with 
previously untreated metastatic nonsquamous NSCLC, notwithstanding the progress made 
with the use of molecularly targeted agents in patients with actionable mutations and with the 
use of the use of the anti-PD1/anti-PD-L1 antibodies to inhibit suppression of the immune 
system, which have begun to change outcomes in this patient population.
A potential opportunity to improve upon the current therapeutic strategy in nonsquamous 
NSCLC is by adding a PARP inhibitor to pembrolizumab in the maintenance setting. PARP 
inhibition has been established as a maintenance therapy for platinum-sensitive populations 
in ovarian cancer, regardless of BRCA status. Clinical benefit from platinum may predict for 
sensitivity to olaparib maintenance, which may extend beyond ovarian cancer. Olaparib, 
when added to pembrolizumab, may continue to induce DNA damage and upregulate PD-L1, 
leading to synergism and further delaying progressive disease in nonsquamous NSCLC. 
Notably, in the MEDIOLA trial, a Phase 2 basket study that included patients with small-cell 
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lung cancer, an improvement in overall survival was demonstrated when olaparib-
durvalumab was administered following olaparib in those with relapsed disease.
Importantly, olaparib in combination with pembrolizumab is being evaluated in an ongoing 
nonrandomized, multicenter, multicohort, open-label, Phase 1b/2 study (KEYNOTE-365) in 
participants with metastatic castration-resistant prostate cancer and the combination has been 
generally well tolerated, with no new safety signals identified for either compound.
This open-label, active-controlled Phase 3 study will build on the current SOC in the 
front-line treatment of patients with Stage IV NSCLC established by the results of 
KEYNOTE-189 utilizing 4 cycles of pembrolizumab combined with pemetrexed and 
platinum followed by pembrolizumab for up to a total of 35 cycles plus pemetrexed 
maintenance. However, this study design will utilize a novel strategy to prevent progression 
of disease by replacing pemetrexed with olaparib. Participants with platinum-sensitive 
disease (SD, CR, or PR) to 4 cycles of pembrolizumab, pemetrexed, and platinum will be 
randomized to pembrolizumab and maintenance olaparib or pembrolizumab and maintenance 
pemetrexed. By using a different mechanism of action and continuing to induce DNA 
damage and to upregulate PD-L1, the combination of pembrolizumab and maintenance 
olaparib will lead to improved tumor control compared with pembrolizumab and 
maintenance pemetrexed.
Replacing pemetrexed with olaparib may decrease toxicity, eliminate the need for pre-
medication, and provide a more convenient route of drug administration. Randomization to 
the Maintenance Phase after all participants complete induction therapy isolates the treatment 
effect of the combination of continued pembrolizumab and maintenance olaparib compared 
with continued pembrolizumab and maintenance pemetrexed.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
This study has dual primary endpoints of PFS and OS.
This study will use PFS as assessed by BICR, according to RECIST 1.1 (see 
Section 4.2.1.1.1) as a primary endpoint. Progression-free survival is an acceptable measure 
of clinical benefit for a late-stage study that demonstrates superiority of a new antineoplastic 
therapy, especially if the magnitude of the effect is large and the therapy has an acceptable 
risk/benefit profile. The use of BICR and RECIST 1.1 to assess PFS is typically considered 
acceptable by regulatory authorities. Images will be read by a central imaging vendor blinded 
to treatment assignment to minimize bias in the response assessments. The final 
determination of radiologic progression will be based on the central assessment of 
progression, rather than a local site investigator/radiology assessment. Real-time verification 
of site-detected radiologic progression by central review will be communicated to the site.
Overall survival has been recognized as the gold standard for the demonstration of 
superiority of a new antineoplastic therapy in randomized clinical studies.
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4.2.1.1.1
RECIST 1.1
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures and by 
the local site when determining eligibility (Section 8.2.1.4). Although traditional RECIST 1.1 
references a maximum of 5 target lesions in total and 2 per organ, this protocol has 
implemented a modification to RECIST 1.1 to allow a maximum of 10 target lesions in total 
and 5 per organ.
4.2.1.1.2
iRECIST
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab (Section 8.2.1.4.1). Immunotherapeutic agents such 
as pembrolizumab may produce antitumor effects by potentiating endogenous cancer-specific 
immune responses. The response patterns seen with such an approach may extend beyond the 
typical time course of responses seen with cytotoxic agents, and patients treated with 
pembrolizumab may manifest a clinical response after an initial increase in tumor burden or 
even the appearance of new lesions. Thus, standard RECIST 1.1 may not provide an accurate 
response assessment of immunotherapeutic agents such as pembrolizumab. Based on an 
analysis of participants with melanoma enrolled in study KEYNOTE-001 (KN001), 7% of 
evaluable participants experienced delayed or early tumor pseudo-progression. Of note, 
participants who had PD by RECIST 1.1 but not by the immune-related response criteria 
[Wolchok, J. D., et al 2009] had longer OS than participants with PD by both criteria [Hodi, 
F. S., et al 2014]. Additionally, the data suggest that RECIST 1.1 may underestimate the 
benefit of pembrolizumab in approximately 15% of participants. These findings support the 
need to apply a modification to RECIST 1.1 that takes into account the unique patterns of 
atypical responses in immunotherapy and enables treatment beyond initial radiographic 
progression, if the participant is clinically stable.
Modified RECIST 1.1 for immune-based therapeutics (ie, iRECIST) assessment has been 
developed and published by the RECIST Working Group, with input from leading experts 
from industry and academia, along with participation from the US FDA and the European 
Medicines Agency (EMA) [Seymour, L., et al 2017]. The unidimensional measurement of 
target lesions, qualitative assessment of nontarget lesions, and response categories are 
identical to RECIST 1.1, until progression is seen by RECIST 1.1. However, if a participant 
is clinically stable, additional imaging may be performed to confirm radiographic 
progression. iRECIST will be used by investigators to assess tumor response and progression 
and make treatment decisions.
4.2.1.2
Safety Endpoints
Safety parameters frequently used for evaluating investigational-systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs, and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version v 4.0.
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4.2.1.3
Patient-reported Outcomes
Note: As of Amendment 07, participants who are still on study treatment will no longer 
require ePRO assessments.
Symptomatic improvement is considered a clinical benefit and accepted by health authorities 
as additional evidence of risk-benefit profile of any new study intervention. As part of the 
analyses for this study, health-related quality of life (HRQoL) and disease-related symptoms 
will be investigated among all participants using the following assessment questionnaires: 
European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire (QLQ) Core 30 (C30), EORTC QLQ Lung Cancer Module 13 (LC13), and 
European Quality of Life Five-dimension Five-level Scale Questionnaire (EQ-5D-5L). 
Patient-reported outcomes are not pure efficacy or safety endpoints because they are affected 
by disease progression and treatment tolerability.
4.2.1.4
EORTC QLQ-C30 and QLQ-LC13
The EORTC QLQ C30 is a psychometrically and clinically validated instrument appropriate 
for assessing QoL in oncology studies [Aaronson, N. K., et al 1993]. EORTC QLQ-C30 is 
the most widely used, cancer-specific, HRQoL instrument. It contains 30 items and measures 
5 functional dimensions (physical, role, emotional, cognitive, and social); 3 symptom items 
(fatigue, nausea/vomiting, and pain); 6 single items (dyspnea, sleep disturbance, appetite 
loss, constipation, diarrhea, and financial impact); and a global health and QoL scale 
[Aaronson, N. K., et al 1993]. For the global health status or QoL and function scales, a 
higher value indicates a better level of function; for symptom scales and items, a higher value 
indicates increased severity of symptoms. TTD and mean change from baseline in global 
health status or QoL scale of the EORTC QLQ-C30, will be evaluated as secondary 
objectives.
The EORTC QLQ-LC13, a supplemental lung cancer-specific module used in combination 
with QLQ-C30, is comprised of multi- and single-item measures of lung cancer-associated 
symptoms (cough, hemoptysis, dyspnea, and site-specific pain) and treatment-related 
symptoms (sore mouth, dysphagia, peripheral neuropathy, and alopecia) [Bergman, B., et al 
1994]. It is scored on a 4-point scale (1 = not at all, 2 = a little, 3 = quite a bit, and 4 = very 
much) and has been translated and validated into more than 60 languages.
The EORTC QLQ-C30 and QLQ-LC13 are the most frequently used and reported PRO 
measures in lung cancer clinical studies. The reliability, validity, and practicality of these 
instruments have been reported [Bergman, B., et al 1994] [Aaronson, N. K., et al 1993].
4.2.1.5
EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [Rabin, R. and de 
Charro, F. 2001]. The 5 health state dimensions in the EQ-5D-5L include the following: 
Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each 
dimension is rated on a 5-point scale from 1 (no problem) to 5 (unable to/extreme problems). 
The EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the 
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participant rates his or her general state of health at the time of the assessment. This 
instrument has been used extensively in cancer studies and published results from these 
studies support its validity and reliability [Pickard, A. S., et al 2007].
4.2.1.6
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/pharmacodynamic biomarkers and generate information that may better guide 
single-agent and combination therapy with immuno-oncology drugs. To identify novel 
biomarkers, biospecimens (ie, blood components, tumor material) will be collected to support 
analyses of cellular components (eg, protein, DNA, RNA, metabolites) and other circulating 
molecules. Investigations may include, but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome to interpret tumor-specific DNA mutations. In addition to studying variation across 
the human genome, mutations in DNA damage repair genes including, but not limited to 
BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, 
PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L, as well as genome scars, including 
LOH, may be investigated. Based on data from participants in several olaparib studies in 
multiple cancer types, known or suspected deleterious mutations in these genes and LOH 
may be predictive of a response to the combination of olaparib and pembrolizumab. Finally, 
MSI may be evaluated as this is an important biomarker for some cancers (ie, colorectal 
cancer).
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes called a ‘hyper-mutated’ 
state) may generate neoantigen presentation in the tumor microenvironment. To conduct this 
type of research, it is important to identify tumor-specific mutations that occur across all 
genes in the tumor genome. Thus, genome-wide approaches may be used for this effort. Note 
that to understand tumor-specific mutations, it is necessary to compare the tumor genome 
with the germline genome. Microsatellite instability may also be evaluated as this is an 
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important biomarker for some cancers (ie, colorectal cancer). Circulating tumor DNA and/or 
RNA may also be evaluated from blood samples.
Tumor and/or blood RNA analyses
Both genome-wide and targeted mRNA expression profiling and sequencing in tumor tissue 
and/or in blood may be performed to define gene signatures that correlate to clinical response 
to treatment with pembrolizumab or other immunotherapies. Pembrolizumab induces a 
response in tumors that likely reflects an inflamed/immune phenotype. Specific 
immune-related gene sets (ie, those capturing interferon-gamma transcriptional pathways) 
may be evaluated and new signatures may be identified. Individual genes related to the 
immune system may also be evaluated (eg, IL-10). MicroRNA profiling may also be pursued 
as well as exosomal profiling.
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor, tissue, and blood samples from this study may undergo proteomic analyses (eg, PD-
L1 IHC). PD-L1 protein level in tumor sections, assessed by IHC, has been shown to 
correlate with response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic 
(IVD) device has been developed for use with pembrolizumab in NSCLC. Preliminary data 
indicates that this association may also be true in additional cancer types (ie, triple negative 
breast cancer, head and neck, and gastric). Additional tumor or blood-derived proteins may 
also correlate with response to olaparib and pembrolizumab. Therefore, tumor tissue may be 
subjected to proteomic analyses using a variety of platforms that could include but are not 
limited to immunoassays and liquid chromatography/mass spectrometry. This approach could 
identify novel protein biomarkers that could aid in patient selection for olaparib (MK-7339) 
and pembrolizumab (MK-3475) therapy.
Other biomarkers
In addition to expression on the tumor tissue, other tumor derived cells, proteins and 
DNA/RNA can be shed from tumor and released into the blood. Assays such as enzyme-
linked immunoassay (ELISA) that measure proteins and assays that measure cell-free 
DNA/RNA (cfDNA/cfRNA) may also be evaluated from blood samples. Correlation of these 
biomarkers with response to treatments may identify new approaches for predictive 
biomarkers in blood, representing a major advance from today’s reliance on assessing tumor 
biomarkers. This research would serve to develop such assays for future clinical use.
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
4.2.1.7
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
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Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in 
Appendix 6.
4.2.2
Rationale for the Use of an Active Comparator
The use of the active comparator combination of pembrolizumab with pemetrexed in the 
Maintenance Phase ensures that participants receive the current SOC. In this study, 
pembrolizumab plus maintenance olaparib following the Induction Phase with 
pembrolizumab combined with pemetrexed and platinum in those participants with SD, PR, 
or CR, will be evaluated to show superiority to pembrolizumab plus maintenance pemetrexed 
with regard to PFS and OS.
4.3
Justification for Dose
4.3.1
Starting Dose for Olaparib
The safety and efficacy of olaparib have been showed in the clinical programs using 
predominantly the capsule formulation (400 mg [8 capsules] twice daily [BID]). However, an 
improved tablet formulation (2 tablets BID) has been developed and will be used in this 
study. The recommended tablet formulation of olaparib as monotherapy is 300 mg BID, 
which is considered similar in terms of efficacy and safety to the capsule 400 mg BID dose. 
However, the capsule and the tablet formulations are not bioequivalent, as observed in 
Study 24, in which 300 mg BID tablet dose matched or exceeded the exposure of the 400 mg 
capsule in terms of area under concentration-time curve (AUC), maximum concentration 
(Cmax), and minimum concentration (Cmin). The tolerability profile of the 300 mg BID tablet 
dose in Study 24 was considered similar to the 400 mg BID capsule formulation. The most 
common AEs were consistent with the known safety profile of olaparib, namely low-grade 
nausea, vomiting, fatigue, and anemia. Tablet formulation is used across the olaparib Phase 3 
program. Olaparib, when given in the tablet formulation has a time to maximum plasma 
concentration (tmax) typically of 0.5 to 2 hours and a mean terminal half-life (t1/2) of 
approximately 12 to 15 hours. Based on the average single-dose t1/2, it would be expected 
that steady-state exposure would be achieved within approximately 3 days of commencing 
dosing with olaparib. It is metabolized primarily by the CYP3A4 enzyme and is excreted 
through the urine (35% to 50%) and feces (12% to 60%).
Further information is provided in the olaparib IB.
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4.3.2
Starting Dose for Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda development program, 200 mg Q3W is the appropriate dose 
of pembrolizumab for adults across all indications and regardless of tumor type. As outlined 
below, this dose is justified by:
•
Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 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 PK 
[PBPK] analysis) at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and 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 versus 10 mg/kg 
Q3W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and 
KN006). All these studies showed flat dose- and exposure-response relationships across the 
studied doses, 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 by direct binding to cancer cells.
Additionally, pharmacology data clearly showed target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively showed 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Second, 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 participant 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.
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4.3.2.1
Starting Dose for Chemotherapy
The doublet chemotherapy treatment (pemetrexed and carboplatin or cisplatin) used in this 
study is a well-established regimen for nonsquamous NSCLC. See Section 6.1 for 
information on the order in which study interventions should be administered.
4.3.3
Maximum Dose Exposure for This Study
4.3.3.1
Pembrolizumab
The maximum duration of exposure for pembrolizumab is 35 administrations (~ 2 years).
4.3.3.2
Olaparib
There is no maximum duration of exposure for olaparib.
4.3.3.3
Pemetrexed
Pemetrexed 500 mg/m2 will be administered as an IV infusion over 10 minutes Q3W 
according to local practice and labels until progression or unacceptable toxicity. All
participants should receive the appropriate supplementation of vitamin B12, folic acid, and 
corticosteroid prophylaxis, as listed below (or as per local label):
•
Folic acid 350 to 1000 μg orally (PO): at least 5 doses of folic acid must be taken during 
the 7 days preceding the first dose of pemetrexed, and folic acid dosing must continue 
during the full course of therapy and for 3 weeks after the last dose of pemetrexed.
•
Vitamin B12 1000 μg intramuscular (IM) injection in the week preceding the first dose of 
pemetrexed and once every 3 cycles thereafter. Subsequent vitamin B12 injections may 
be given the same day as pemetrexed administration.
•
Dexamethasone prophylaxis 4 mg PO BID (or equivalent). Taken the day before, day of, 
and day after pemetrexed administration. Higher or additional doses are permitted for 
antiemetic prophylaxis during Cycles 1 through 4, but not to exceed the doses in the 
Multinational Association of Supportive Care in Cancer (MASCC) guidelines (Section 
8.1.8.1.6).
4.3.3.4
Cisplatin
Cisplatin 75 mg/m2 should be infused after the pemetrexed infusion for the first 4 cycles and 
should be immediately preceded and followed by hydration procedures and administered 
according to local practice and labels.
4.3.3.5
Carboplatin
Carboplatin AUC 5 mg/mL/min will be administered as an IV infusion over 15 to 60 minutes 
Q3W for 4 cycles immediately after maintenance pemetrexed, according to local practice and 
labels.
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4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3), or the last participant on active treatment is consented in the extension study. For 
purposes of analysis and reporting, the overall study ends when the Sponsor receives the last 
laboratory test result or at the time of final contact with the last participant, whichever comes
last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects is such that the risk/benefit ratio to the study population as a whole is 
unacceptable. In addition, further recruitment in the study or at (a) particular study site(s) 
may be stopped as described in Appendix 1.10.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Have a histologically confirmed or cytologically confirmed diagnosis of nonsquamous 
NSCLC.
2. Have Stage IV (T any, N any, M1a, M1b, or M1c - American Joint Committee on Cancer 
(AJCC) 8th Edition) nonsquamous NSCLC.
3. Have confirmation that EGFR, ALK, or ROS1-directed therapy is not indicated 
(documentation of absence of tumor-activating EGFR mutations AND absence of ALK
and ROS1 gene rearrangements, OR presence of a K-Ras mutation).
4. Have measurable disease, based on RECIST 1.1, as determined by the local site 
investigator/radiology assessment. Lesions that appear measurable, but are situated in a 
previously irradiated area, can be considered measurable (eligible for selection as target 
lesions) if they have shown documented growth since the completion of radiation.
5. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy 
of a tumor lesion not previously irradiated. Formalin-fixed, paraffin-embedded (FFPE) 
tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived 
tissue.
Note: Details pertaining to tumor tissue submission can be found in the Procedures 
Manual.
Note: Adequacy of biopsy specimen for the above analyses must be confirmed by the 
central laboratory before the participant can start the Induction Phase. Submission of 
another tumor specimen may be required prior to enrolling the participant, if adequate 
tumor tissue was not provided the first time.
6. Have a life expectancy of at least 3 months.
7. Have an ECOG performance score of 0 or 1 assessed within 7 days prior to the 
administration of study intervention.
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8. Have not received prior systemic treatment for their advanced/metastatic NSCLC. 
Participants who received adjuvant or neoadjuvant therapy are eligible if the 
adjuvant/neoadjuvant therapy was completed at least 12 months prior to the development 
of metastatic disease.
9. Have adequate organ function, as indicated by the following laboratory values (Table 3). 
All screening laboratory tests should be performed within 10 days prior to the first dose 
of study intervention.
Table 3
Adequate Organ Function Laboratory Values
Systems
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500 cells/µL
Platelets
≥100 000 cells/µL
Hemoglobin
≥9.0 g/dL, or ≥5.6 mmol/L1
Renal
Estimated CrCl using the Cockcroft-Gault 
equation2 or a 24-hour urine test 
≥51 mL/min 
Hepatic
Total bilirubin
≤1.5 × ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation (only required at Screening)
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time 
(aPTT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants
Abbreviations: ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) = 
aspartate aminotransferase (serum glutamic oxaloacetic transaminase); CrCl = creatinine clearance; ULN = upper 
limit of normal.
1.
For screening, criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 28 days prior to initiation of study intervention. For post-Induction/pre-Randomization, 
criteria must be met without erythropoietin dependency within last 14 days prior to randomization.
2.
Estimated CrCl using Cockcroft-Gault:
(140-age [years] × weight (kg) (×F)*
Serum creatinine (mg/dL) × 72
*where F = 0.85 for females and F = 1 for males
As an alternative, CrCl can be determined from a 24-hour urine collection.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of specific 
chemotherapies.
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Demographics
10. Be at least 18 years of age at the time of signing the informed consent.
Male Participants
11. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 180 days after the last dose of study intervention:
•
Refrain from donating sperm
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent
OR
•
Agree to use contraception, unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [Appendix 5]), as detailed below:
•
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a woman of childbearing potential 
(WOCBP) who is not currently pregnant. Note: Men with a pregnant or breastfeeding 
partner must agree to remain abstinent from penile-vaginal intercourse or use a male 
condom during each episode of penile-vaginal penetration.
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies. If the contraception requirements 
in the local label for any of the study interventions is more stringent than the requirements 
above, the local label requirements are to be followed.
Female Participants
12. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least 1 of the following conditions applies:
a.
Is not a WOCBP
OR
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b. Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate <1% per year), or be abstinent from heterosexual intercourse as their preferred 
and usual lifestyle (abstinent on a long-term and persistent basis), as described in 
Appendix 5 during the intervention period and for at least 180 days after the last dose 
of study intervention and agrees not to donate eggs (1ova, oocytes) to others or 
freeze/store for her own use for the purpose of reproduction during this period. The 
investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention.
-
A WOCBP must have a negative highly sensitive urine pregnancy test as required by 
local regulations) within 24 hours (72 hours for serum) before the first dose of study 
intervention.
-
Additional requirements for pregnancy testing during and after study intervention are 
in Appendix 5.
-
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions is more stringent than the 
requirements above, the local label requirements are to be followed.
Informed Consent
13. Have (or legally acceptable representative) provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for future 
biomedical research. However, the participant may participate in the main study without 
participating in future biomedical research.
Additional Criteria Applicable to Maintenance Phase Only, Prior to Randomization
14. Have a CR/PR or SD of their NSCLC after completion of the study-specified Induction 
Phase, as determined by central imaging review.
15. Have an ECOG performance status score at randomization of 0 or 1 as assessed at 
Pre-randomization Visit (most recent assessment within the visit).
16. All AEs (with the exception of alopecia, Grade 2 fatigue, and Grade ≤2 endocrine-related 
AEs requiring treatment or hormone replacement. For anemia and creatinine clearance, 
the guidelines provided in Table 3 may be followed) resolved to Grade ≤1 or baseline 
following Induction Phase treatment.
17. Have adequate organ function, as indicated by the laboratory values in Table 3 above.
18. Are not taking medications or vaccinations specifically prohibited in the exclusion 
criteria (Section 5.2).
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19. Are not pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting from the pre-randomization visit through 180 
days after the last dose of study intervention.
20. Have not withdrawn consent to continue treatment.
21. Continue to derive clinical benefit from study participation according to investigator’s 
discretion.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Has predominantly squamous cell histology NSCLC. Mixed tumors will be categorized 
by the predominant cell type; if small cell elements are present, the participant is 
ineligible.
2. Has a known additional malignancy that is progressing or has progressed within the past 
3 years requiring active treatment.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
3. Has known active central nervous system metastases and/or carcinomatous meningitis. 
Participants with previously treated brain metastases may participate provided they are 
clinically stable for at least 2 weeks and, have no evidence of new or enlarging brain 
metastases, and also are off steroids 3 days prior to dosing with study medication. Stable 
brain metastases by this definition should be established prior to the first dose of study 
medication. Participants with known untreated, asymptomatic brain metastases (ie, no 
neurological symptoms, no requirements for corticosteroids, no or minimal surrounding 
edema, and no lesion >1.5 cm) may participate, but will require regular imaging of the 
brain as a site of disease.
4. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
5. Participant has a known hypersensitivity to any components or excipients of cisplatin, 
carboplatin, pemetrexed, or olaparib.
6. Has active autoimmune disease that has required systemic treatment in past 2 years (ie, 
with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed.
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study intervention.
8. Has a history of (noninfectious) pneumonitis that required steroids or has current 
pneumonitis.
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9. Has an active infection requiring systemic therapy.
10. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing 
is required, unless mandated by local health authority.
11. Has a known history of hepatitis B (defined as hepatitis B surface antigen reactive) or 
known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
Note: No testing for hepatitis B or hepatitis C is required unless mandated by local health 
authority.
12. Has a known history of active tuberculosis (TB; Mycobacterium tuberculosis).
13. Has symptomatic ascites or pleural effusion. A participant who is clinically stable 
following treatment for these conditions (including therapeutic thoraco- or paracentesis) 
is eligible.
14. Has a known history of interstitial lung disease. Lymphangitic spread of the NSCLC is 
not exclusionary.
15. Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features 
suggestive of MDS/AML.
Prior/Concomitant Therapy
16. Before the first dose of study intervention:
a.
Has received prior systemic cytotoxic chemotherapy for metastatic disease.
b. Has received antineoplastic biological therapy (eg, erlotinib, crizotinib, cetuximab) 
for metastatic disease.
c.
Had major surgery (<3 weeks prior to study intervention) or has not recovered from 
any effects of any major surgery.
17. Has received prior therapy with olaparib or with any other PARP inhibitor.
18. Has received radiation therapy to the lung that is >30 Gy within 6 months of the first dose 
of study intervention.
19. Is expected to require any other form of antineoplastic therapy while on study.
20. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA 4, OX 
40, CD137).
21. Received a live or live-attenuated vaccine within 30 days before the first dose of study 
intervention. Administration of killed vaccines are allowed.
Refer to Section 6.5 for information on COVID-19 vaccines.
22. Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs, other than an 
aspirin dose ≤1.3 g per day, for a 5-day period (an 8-day period for long-acting agents, 
such as piroxicam).
23. Is unable or unwilling to take folic acid or vitamin B12 supplementation.
24. Received colony-stimulating factors (eg, granulocyte colony-stimulating factor [G-CSF], 
granulocyte-macrophage colony-stimulating factor or recombinant erythropoietin) within 
28 days prior to the first dose of study intervention. Note: For post-Induction/ 
pre-Randomization, within 14 days prior to randomization.
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25. Is currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin, 
protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, 
boceprevir, telaprevir) or moderate (eg, ciprofloxacin, erythromycin, diltiazem, 
fluconazole, verapamil) inhibitors of cytochrome P450 (CYP)3A4 that cannot be 
discontinued for the duration of the study. The required washout period prior to starting 
olaparib is 2 weeks.
Note: a current list of strong/moderate inhibitors of CYP3A4 can be found at the 
following website:
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm
26. Is currently receiving either strong (eg, phenobarbital, enzalutamide, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or 
moderate (eg, bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be 
discontinued for the duration of the study. The required washout period prior to starting 
olaparib is 5 weeks for phenobarbital and 3 weeks (21 days) for other agents.
Note: a current list of strong/moderate inducers of CYP3A4 can be found at the following 
website: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm
Prior/Concurrent Clinical Study Experience
27. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
treatment.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
28. The presence of uncontrolled, potentially reversible cardiac conditions, as judged by the 
investigator (eg, unstable ischemia, uncontrolled symptomatic arrhythmia, congestive 
heart failure, electrolyte disturbances, etc.), or participant has congenital long QT 
syndrome.
Other Exclusions
29. Is considered a poor medical risk, in the opinion of the treating investigator, due to a 
serious, uncontrolled medical disorder or nonmalignant systemic disease. Examples 
include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 
3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal 
cord compression, or superior vena cava syndrome.
30. Has a known psychiatric or substance abuse disorder that would interfere with 
cooperation with the requirements of the study.
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31. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the Screening Visit through 180 days after 
the last dose of study intervention.
32. Is unable to swallow orally administered medication, or has a gastrointestinal disorder 
affecting absorption (eg, gastrectomy, partial bowel obstruction, or malabsorption).
33. Has had an allogeneic-tissue/solid-organ transplant.
34. Completed palliative radiotherapy within 7 days of the first dose. Participants must have 
recovered from all radiation-related toxicities and not require corticosteroids.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
During the Maintenance Phase, participants should avoid grapefruit, grapefruit juice, and St. 
John’s Wort (tablet or tea) while receiving study intervention. Otherwise, participants should 
maintain a normal diet unless modifications are required to manage an AE such as diarrhea, 
nausea, or vomiting.
5.3.2
Contraception
The study intervention may have adverse effects on a fetus in utero. Refer to Appendix 5 for 
approved methods of contraception.
Participants should be informed that taking the study intervention may involve unknown 
risks to the fetus (unborn baby) if pregnancy were to occur during the study. In order to 
participate in the study, participants of childbearing potential must adhere to the 
contraception requirement (Appendix 5) from the day of study intervention initiation (or 
14 days prior to the initiation of study intervention for oral contraception) throughout the 
study period up to 180 days after the last dose of study intervention. If there is any question 
that a participant of childbearing potential will not reliably comply with the requirements for 
contraception, that participant should not be entered into the study.
5.3.3
Pregnancy
If a participant inadvertently becomes pregnant during the study, the participant will be 
immediately discontinued from study intervention. The site will contact the participant at 
least monthly and document the participant’s status until the pregnancy has been completed 
or terminated. The outcome of the pregnancy will be reported to the Sponsor as described in 
Section 8.4.
5.3.4
Use in Nursing Women
It is unknown whether any of the study medications are excreted in human milk. Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions 
in the nursing infant, participants who are breastfeeding are not eligible for enrollment.
No restrictions are required.
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5.3.5
Activity Restrictions
Adverse events related to olaparib may include asthenia, fatigue, and dizziness. Therefore, 
participants should be advised to use caution while driving or using machinery if these 
symptoms occur.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently enrolled in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from the study intervention OR withdraws from the study
will not be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies will be packaged to support enrollment. Clinical supplies will be affixed 
with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 4.
In the Induction Phase, pembrolizumab should be given prior to chemotherapy; pemetrexed 
and platinum should be given as per SOC.
For the Maintenance Phase, olaparib on Day 1 should be given prior to pembrolizumab.
Note: At the final analysis, the pembrolizumab plus olaparib arm did not meet the primary 
endpoint of OS. PFS was not statistically significant compared to the control arm. 
Participants taking olaparib or pemetrexed should continue receiving it per the investigator’s 
discretion after discussion. Participants currently undergoing or who will undergo Second 
Course with pembrolizumab monotherapy can continue or start treatment per investigator’s 
discretion under this protocol. Participants who are potential candidates for Second Course 
treatment will continue in Efficacy Follow-up.
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Table 4
Study Interventions
Drug Name
Drug Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Pembrolizumab Experimental Active
Drug
Solution
25 mg/mL
200 mg
IV Infusion
Q3W/Induction 
and 
Maintenance 
Phases for a 
maximum of 
35 cycles
Test Product IMP
Centrally
Carboplatin
Other
Chemo
-therapy
Drug
Solution
10 mg/mLa
AUC 5 
mg/mL/min
IV Infusion
Q3W/Induction 
Phase 
(4 cycles)
Background 
Treatment
NIMP/AxMP Centrally 
or locally
Cisplatin
Other
Chemo
-therapy
Drug
Solution
1 mg/mL
75 mg/m2
IV Infusion
Q3W/Induction 
Phase 
(4 cycles)
Background 
Treatment
NIMP/AxMP Centrally 
or locally
Pemetrexed
Other
Chemo
-therapy
Drug
Injection, 
Powder, 
Lyophilized, 
For Solution
500 mgb
500 mg/m2
IV Infusion
Q3W/Induction 
and 
Maintenance 
Phases
Background 
Treatment
IMP
Centrally 
or locally
Olaparib
Experimental Active
Drug
Tablet
150 mg,
100 mgc
300 mg BID Oral
BID/
Maintenance 
Phase
Test Product IMP
Centrally
Abbreviations: AUC = area under the plasma drug concentration time curve; BID = twice daily; D1 = Day 1; IM = intramuscular; IMP = investigational medicinal product; IV = 
intravenous(ly); MASCC = Multinational Association of Supportive Care in Cancer; N/A = not applicable; NIMP = non-investigational medicinal product; Q3W = every 3 weeks; 
SOC = standard of care.
Definitions of IMP and NIMP are based on guidance issued by the European Commission. Regional and/or country differences of the definition of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
a
For locally sourced supplies, the unit dose strength may vary, depending on market availability.
b
All participants taking pemetrexed should receive the appropriate supplementation of vitamin B12, folic acid, and corticosteroid prophylaxis, as listed below (or as per local 
label):
•
Folic acid 350-1000 µg PO: at least 5 doses of folic acid must be taken during the 7 days preceding the first dose of pemetrexed, and folic acid dosing must continue 
during the full course of therapy and for 21 days after the last dose of pemetrexed.
•
Vitamin B12 1000 µg IM injection in the week preceding the first dose of pemetrexed and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be 
given on the same day as pemetrexed administration.
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•
Dexamethasone prophylaxis 4 mg, PO BID (or equivalent). Taken the day before, day of, and day after pemetrexed administration. Higher or additional doses are 
permitted for antiemetic prophylaxis during Cycles 1 through 4, but not to exceed the doses in the MASCC guidelines (Section 8.1.8.1.6).
c
300-mg dose will be made up of 2 × 150 mg tablets; 100 mg tablets are provided for dose reductions, as outlined in Section 6.6.2.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 4 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary, or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 6.1 for details regarding administration of the study intervention.
6.1.1
Treatment
The initial treatment or first course of pembrolizumab consists of 35 treatments. Note: The 
number of treatments is calculated starting with the first dose.
These participants may be eligible for Second Course described in Section 8.11.5.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual.
Olaparib is a tablet for oral administration; no preparation is required. Refer to the olaparib 
Pharmacy Manual for further instructions. Olaparib will be provided in high-density 
polyethylene bottles with child-resistant closures. Each bottle will be labeled in accordance 
with Good Manufacturing Practice Annex 13 and per country regulatory requirement.
Pemetrexed and carboplatin/cisplatin should be prepared per local and institutional guidelines 
according to the approved product labels.
The rationale for selection of doses to be used in this study is provided in Section 4.3
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
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accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study 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 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Treatment allocation will occur centrally using an interactive response technology (IRT) 
system. The allocation numbers will be given to each participant at the start of the study.
Randomization will occur after participants complete the Induction Phase and imaging shows 
SD, PR, or CR, as verified by central vendor. All participants will undergo a pre-
randomization visit, during which a checklist will be completed by the investigator and 
approved by the Sponsor. Randomization will be performed via the IRT system.
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:
•
Most recent ECOG at Pre-randomization Visit (0 vs. 1)
•
PD-L1 expression (TPS <50% vs. ≥50%)
o
PD-L1 nonevaluable subjects will be grouped with the TPS <50% group.
•
Response at randomization (CR/PR vs. SD)
o
Confirmed and unconfirmed CR/PR will be stratified together. That is, initial CR or 
PR in response to induction therapy does not need to be confirmed by imaging at least 
4 weeks later. All responses will need to be centrally assessed (ie, BICR). See Section 
8.2.1.2 for stratification guidelines for non-evaluable imaging.
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6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the study intervention administered.
6.4
Study Intervention Compliance
6.4.1
Olaparib Compliance
Participants will take their dose of olaparib BID without regard to food. Participants will 
self-administer olaparib, except on Day 1 of the first cycle, when the dose will be given at the 
study site clinic prior to pembrolizumab infusion. For all other cycles, olaparib will be given 
prior to pembrolizumab infusion.
Site staff will perform tablet counts at regular intervals during treatment. After the tablet 
count has been performed, the remaining tablets will not be returned to the participant, but 
will be retained by the investigative site, until the study monitor completes reconciliation. 
Olaparib compliance will be calculated by the Sponsor, based on the drug accountability 
documented by the site staff, and monitored by the Sponsor/designee. All participants will be 
instructed to return their bottle of olaparib at the appropriate scheduled visit, when a new 
bottle will be dispensed. Participants will be instructed to notify study site personnel of 
missed doses.
Interruptions from the protocol-specified olaparib treatment plan for >21 consecutive days 
require consultation between the investigator and the Sponsor and written documentation of 
the collaborative decision on participant management.
6.4.2
Pembrolizumab, Carboplatin/Cisplatin, and Pemetrexed Compliance
Pembrolizumab and chemotherapy will be administered on an outpatient basis.
Interruptions from the protocol-specified pembrolizumab, carboplatin/cisplatin, or 
pemetrexed intervention plan require consultation between the investigator and the Sponsor 
and written documentation of the collaborative decision on participant management 
(Section 7.1).
Pembrolizumab may be interrupted for a maximum of 12 weeks from last dose; 
chemotherapy may be interrupted for a maximum of 6 weeks from last dose.
If there are interruptions in the study intervention schedule or infusion/injection was stopped, 
the details of and reason for any interruption or infusion/injection cessation of study 
intervention will be documented in the participant’s medical record.
Refer to Section 6.6.3 for Dose Modification and Toxicity Management Guidelines for irAEs 
associated with pembrolizumab monotherapy, coformulations, or IO combinations and for 
other allowed dose interruptions.
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6.5
Concomitant Therapy
If there is a clinical indication for any medications or vaccinations prohibited, the 
investigator must discuss any questions regarding this with the Sponsor’s Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator and the Sponsor.
The following medications and vaccinations are prohibited during the study:
•
Live or live-attenuated vaccines within 30 days before the first dose of study intervention 
and while participating in the study, and for 30 days after the last dose of study 
intervention. See Appendix 7 for country-specific requirements.
Note: Killed vaccines are allowed.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated 
just as any other concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.
•
Anticancer hormonal therapy (eg, androgen deprivation, androgen receptor blockade, 
anti-estrogens).
Note: Hormonal replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is allowed.
•
Strong and moderate inducers or inhibitors of CYP3A4 that cannot be discontinued for 
the duration of the study.
Note: a current list of strong/moderate inducers/inhibitors of CYP3A4 can be found at the 
following website: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm
Note: Exceptions are outlined in Section 6.6.2.5.
•
Note: Only applicable to participants taking olaparib concomitantly.
•
Systemic glucocorticoids are permitted for the following purposes:
-
To modulate symptoms of an AE that is suspected to have an immunologic etiology
-
As needed for the prevention of emesis
-
Premedication for IV contrast allergies
-
Short-term oral or IV use in doses >10 mg/day prednisone-equivalent for COPD 
exacerbations
-
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent
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•
In addition, the following glucocorticoid use is allowed
-
For topical use or ocular use
-
Intraarticular joint use
-
For inhalation in the management of asthma or COPD
•
Phenytoin during therapy with cisplatin/carboplatin.
In addition to the medications listed here, study site staff should refer to the approval product 
labels for prohibited medications, as well as drug-drug interactions for each 
chemotherapeutic agent used in this study.
No therapies are prohibited during the Long-term Follow-up Phase.
If the investigator determines that a participant requires any of the following prohibited 
medications and vaccinations for any reason during the study, study intervention must be 
discontinued:
•
Systemic antineoplastic chemotherapy, immunotherapy, or biological therapy not 
specified in this protocol
•
Investigational agents other than those specified in this protocol
•
Radiation therapy for disease control
Note: Participants are allowed to receive palliative radiotherapy for painful bone lesions. 
Targeted external beam irradiation should not be used in the primary lung field where 
assessment for tumor is indicated.
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
at the investigator’s discretion.
•
Surgery for tumor control.
Based on in vitro data, olaparib may increase the exposure to substrates of CYP3A4, organic-
anion-transporting polypeptide 1B1, organic cation transporter 1/2/3, and multidrug and toxic 
compound extrusion 1/2 and reduce exposure to substrates of CYP2B6. Caution should be 
observed if substrates of these isoenzymes or transporter proteins are co-administered. A 
current list of substrates can be found at the following website: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter
actionsLabeling/ucm093664.htm
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medications will be recorded on the eCRF including all 
prescriptions, OTC products, herbal supplements, and IV medications, and fluids. If changes 
occur during the study period, documentation of drug dosage, frequency, route, and date 
should also be included on the eCRF.
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All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
All concomitant medications administered during SAEs or ECIs are to be recorded. SAEs 
and ECIs are defined in Section 8.4.
6.5.1
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
Suggested supportive care measures for the management of AEs with potential immunologic 
etiology are outlined along with the dose modification guidelines in Table 9. Where 
appropriate, these guidelines include the use of oral or IV 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 of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 9 for 
guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures, such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Management of Overlapping Toxicities of Olaparib and Pembrolizumab
Both olaparib and pembrolizumab treatment may be associated with the development of 
pneumonitis and renal toxicity.
For renal dysfunction, follow the dose modification guidelines provided in Table 7 (olaparib) 
and Table 9 (pembrolizumab). A kidney biopsy is strongly recommended to help to 
determine etiology of renal dysfunction.
If pneumonitis is confirmed, treatment with olaparib must be withheld. Olaparib may be 
restarted once pneumonitis has completely resolved. Treatment with pembrolizumab must be 
withheld for pneumonitis ≥Grade 2 (Table 9). When the pneumonitis resolves to <Grade 2, 
then pembrolizumab may be resumed as per guidelines in Table 9. Sponsor consultation is 
recommended if there are any doubts. Study intervention must be discontinued for recurrent 
Grade 2 pneumonitis (Section 7.1).
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6.6.2
Olaparib Dosing Modifications
The dose of olaparib can be reduced to 250 mg BID initially and then to 200 mg BID as 
needed. If the 200 mg BID dose is not tolerable, no further dose reduction is allowed and 
study intervention should be discontinued. Once the dose has been reduced, escalation is not 
permitted.
The reason for the dose interruption or reduction should be captured on the appropriate 
eCRF.
During the Maintenance Phase, if, in the opinion of the investigator, a toxicity is related to 
the combination of both olaparib and pembrolizumab, both drugs should be interrupted 
and/or discontinued according to the recommendations listed in this section. If the toxicity 
can be attributable to olaparib, pemetrexed or pembrolizumab, the respective agent may be 
reduced (if applicable), interrupted, or discontinued according to the recommendations listed 
in this section; in such situations, the other agent can continue to be administered.
6.6.2.1
Management of Hematological Toxicities
Any hematological toxicity observed during the study could be managed by a brief 
interruption of study intervention or a dose reduction of olaparib (Table 5 and Table 6). 
Repeated interruptions, not exceeding 3 weeks (21 days) duration, are allowed as required. If 
the interruption is any longer, the Sponsor must be informed.
Table 5
Management of Anemia
Toxicity
NCI CTCAE Grade
Action Taken
Hemoglobin 
(Hb)
Grade 2
(<9.0 but ≥8.0 g/dL)
First Occurrence:
Give appropriate supportive treatment and investigate causality.
Investigator judgement to either continue maintenance olaparib with 
supportive treatment (eg, transfusion) or interrupt maintenance olaparib 
dosing for a maximum of 3 weeks (21 days). Study intervention can be 
restarted if Hb has recovered to >9.0 g/dL.
Subsequent Recurrence:
Hb <9.0 but ≥8.0 g/dL: interrupt maintenance olaparib for a maximum of 
3 weeks (21 days) until Hb improves to >9.0 g/dL. Upon recovery, 
reduce the dose of maintenance olaparib to 250 mg BID. A second dose 
reduction to 200 mg BID may be considered if additional decreases in 
Hb occur
Grade 3
(<8.0 g/dL)
Give appropriate supportive treatment (eg, transfusion) and investigate 
causality.
Interrupt maintenance olaparib, for a maximum of 3 weeks (21 days), 
until Hb improves to ≥9.0 g/dL.
Upon recovery, reduce the dose of maintenance olaparib to 250 mg BID. 
A second dose reduction to 200 mg BID may be considered if additional 
decreases in Hb occur.
Abbreviations: BID = twice daily; CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer 
Institute.
Note: Common treatable causes of anemia (eg, iron, vitamin B12 or folate deficiencies and hypothyroidism) should be 
investigated and appropriately managed. In some cases, management of anemia may require blood transfusions. The 
management of prolonged hematological toxicities is detailed in Section 6.6.2.2.
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Table 6
Management of Neutropenia, Leukopenia, and Thrombocytopenia
Toxicity
NCI CTCAE Grade
Action Taken
Neutropenia, 
leukopenia, or 
thrombocytopenia
Grades 1 or 2
Investigator judgment to either continue maintenance olaparib or 
interrupt dosing for a maximum of 3 weeks (21 days). Give 
appropriate supportive treatment and investigate causality.
Grades 3 or 4
Interrupt maintenance olaparib, for a maximum of 3 weeks (21 
days), until event recovers to ≤Grade 1.
Repeated incidence: reduce the dose of maintenance olaparib to 
250 mg BID. A second dose reduction to 200 mg BID may be 
considered if additional Grade 3 or 4 events occur.
Abbreviations: AE = adverse event; BID = twice daily; G-CSF = granulocyte-colony stimulating factor; NCI CTCAE = 
National Cancer Institute Common Terminology Criteria for Adverse Events.
AEs of neutropenia and leukopenia should be managed as deemed appropriate by the investigator with close follow-up 
and interruption of study intervention if CTCAE Grade 3 or worse neutropenia occurs.
Primary prophylaxis with G-CSF is not recommended; however, if a participant develops febrile neutropenia, study 
intervention should be stopped and appropriate management, including G-CSF, should be given according to local 
hospital guidelines. Note that G-CSF should not be used within at least 24 hours (7 days for pegylated G-CSF) of the 
last dose of study intervention, unless absolutely necessary.
Platelet transfusions, if indicated, should be given according to local hospital guidelines.
The management of prolonged hematological toxicities is detailed in Section 6.6.2.2.
6.6.2.2
Management of Prolonged Hematological Toxicities
If a participant develops prolonged hematological toxicity such as:
•
≥2-week interruption/delay in study intervention due to NCI CTCAE Grade 3 or worse 
anemia and/or the development of blood transfusion dependence
•
≥2-week interruption/delay in study intervention due to NCI CTCAE Grade 3 or worse 
neutropenia (ANC <1 × 109/L)
•
≥2-week interruption/delay in study intervention due to NCI CTCAE Grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (platelets 
<50 × 109/L)
Differential blood count, including reticulocytes and peripheral blood smear, should be 
checked weekly. If any blood parameters remain clinically abnormal after the dosing of 
maintenance olaparib has been interrupted for ≥3 weeks (≥21 days), the participant should be 
referred to a hematologist for further investigations. Bone marrow analysis and/or blood 
cytogenetic analysis should be considered, according to local regulation and/or standard 
institutional hematological practice. Study intervention should be discontinued if blood 
counts do not recover to NCI CTCAE Grade 1 or better within 3 weeks (21 days) of dose 
interruption.
Development of confirmed MDS or other clonal blood disorder should be reported as an SAE 
and full reports must be provided by the investigator to the Sponsor as outlined in 
Section 8.4.4. Maintenance olaparib intervention should be discontinued for confirmed MDS 
and/or AML (Section 7.1).
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6.6.2.3
Management of Nonhematologic Toxicity
Repeated dose interruptions, not exceeding 3 weeks (21 days) duration, are allowed as 
required. If toxicity reoccurs following rechallenge with study intervention, and where 
further dose interruptions are considered inadequate for management of toxicity, either a 
dose reduction should be considered (Section 6.6.1) or the participant must permanently 
discontinue study intervention.
Maintenance olaparib treatment must be interrupted if any NCI CTCAE Grade 3 or 4 AE 
occurs that the investigator considers to be related to administration of olaparib.
6.6.2.3.1
Management of New or Worsening Pulmonary Symptoms
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormalities occur 
in the absence of a clear diagnosis, an interruption in study intervention dosing is 
recommended and further diagnostic workup (including a high resolution computed 
tomography [CT] scan) should be performed to exclude pneumonitis. Please refer to 
Table 9, which outlines the Toxicity Management Guidelines for pembrolizumab as it can 
also cause pneumonitis.
Following investigation, if no evidence of abnormality is observed on CT imaging and 
symptoms resolve, then study intervention can be restarted, if deemed appropriate by the 
investigator. If significant pulmonary abnormalities are identified, these need to be discussed 
with the Clinical Director. If pneumonitis is confirmed while on study, refer to Section 6.6.1 
for guidance on the management of olaparib and pembrolizumab.
6.6.2.3.2
Management of Nausea and Vomiting
Events of nausea and vomiting are known to be associated with maintenance olaparib. These 
events are generally mild to moderate (NCI CTCAE Grade 1 or 2) in severity, intermittent, 
and manageable on continued treatment. The first onset generally occurs in the first month of 
intervention for nausea and within the first 6 months of intervention for vomiting. For 
nausea, the incidence generally plateaus at approximately 9 months, and for vomiting at 
approximately 6 to 7 months.
No routine prophylactic antiemetic treatment is required at the start of study intervention; 
however, participants should receive appropriate anti-emetic treatment at the first onset of 
nausea or vomiting and as required thereafter, in accordance with local regulations or 
institutional guidelines. Alternatively, olaparib tablets can be taken with a light meal/snack 
(ie, 2 pieces of toast or a couple of biscuits).
As per international guidance on antiemetic use in cancer patients (ESMO, NCCN), generally 
a single-agent antiemetic should be considered (eg, dopamine receptor antagonist or 
antihistamines).
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6.6.2.3.3
Management of Renal Impairment
To initiate maintenance olaparib, creatinine clearance (CrCl) must be ≥51 mL/min. As an 
alternative, CrCl can be determined from a 24-hour urine collection.
If subsequent to study entry and/or while still on study therapy, a participant’s estimated 
CrCl falls below the threshold for study inclusion (≥51 mL/min), retesting should be 
performed promptly.
A dose reduction is recommended for participants who develop moderate renal impairment 
(calculated CrCl between 31 to 50 mL/min, as calculated with the Cockcroft-Gault formula, 
or based on a 24-hour urine test) for any reason during the course of the study (Table 7).
Table 7
Dose Reduction of Olaparib to Manage Moderate Renal Impairment
Initial Dose
Moderate Renal Impairmenta
300 mg BID
200 mg BID
Abbreviation: BID = twice daily; CrCl = creatinine clearance.
a.
CrCl of 31 to 50 mL/min, as calculated with the Cockcroft-Gault formula. As an alternative, CrCl can be determined 
from a 24-hour urine collection.
Because the CrCl determination is only an estimate of renal function, in instances where the 
CrCl falls to between 31 to 50 mL/min, the investigator should use his or her discretion in 
determining whether a dose change or discontinuation of therapy is warranted.
See Table 9, which outlines the Toxicity Management Guidelines for pembrolizumab, as it 
also can cause renal toxicity. For renal toxicity, a biopsy should be performed to determine 
the etiology of the toxicity and whether the renal toxicity is related to olaparib or 
pembrolizumab.
Olaparib has not been studied in participants with severe renal impairment (CrCl 
≤30 ml/min) or end-stage renal disease; if participants develop severe impairment or end 
stage disease, it is recommended that maintenance olaparib be discontinued.
6.6.2.4
Interruptions for Intercurrent Nontoxicity-related Events
Olaparib dose interruption for conditions other than toxicity resolution should be kept as 
short as possible. If a participant cannot restart study intervention within 3 weeks (21 days) 
for resolution of intercurrent conditions not related to disease progression or toxicity, the case 
should be discussed with the Clinical Director, and approved via a Sponsor Communication 
Form.
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions, per drug accountability and participant feedback reconciliation, are 
to be recorded in the eCRF.
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Maintenance olaparib should be stopped at least 3 days prior to planned surgery and can be 
restarted when the wound has healed. It is not required to stop maintenance olaparib for any 
needle biopsy procedure.
Maintenance olaparib should be discontinued for a minimum of 3 days before a participant 
undergoes radiation treatment and should be restarted within 3 weeks (21 days) as long as 
any bone marrow toxicity has recovered.
Because the AEs related to maintenance olaparib may include asthenia, fatigue, and 
dizziness, participants should be advised to use caution while driving or using machinery if 
these symptoms occur.
6.6.2.5
Dose Reductions for Concurrent CYP3A4 Inhibitor Use
Strong or moderate CYP3A inhibitors should not be taken with olaparib. If there is no 
suitable alternative concomitant medication, then the dose of maintenance olaparib should be 
reduced for the period of concomitant administration as described in Table 8. After the 
washout of the inhibitor is complete (Section 5.2), the maintenance olaparib dose cannot be 
re-escalated. The dose reduction of olaparib should be recorded in the eCRF with the reason 
documented as concomitant CYP3A4 inhibitor use.
Table 8
Dose Reduction of Olaparib with a Strong or Moderate CYP3A4 Inhibitor
Initial Dose
Strong CYP3A Inhibitor
Moderate CYP3A Inhibitor
300 mg BID
100 mg BID
150 mg BID
Abbreviation: BID = twice daily.
6.6.3
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated With 
Pembrolizumab
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.
Dose Modification and Toxicity Management Guidelines for irAEs Associated With 
Pembrolizumab Monotherapy, Coformulations, or IO Combinations are provided in Table 9.
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Table 9
Dose Modification and Toxicity Management Guidelines for Immune-related 
Adverse Events Associated with Pembrolizumab Monotherapy, Coformulations or IO 
Combinations
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 monotherapy, coformulations or IO combinations 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 
treatment.
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4. If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may 
resume after the irAE decreased to ≤Grade 1 after corticosteroid taper.
irAEs
Toxicity 
Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations 
or IO 
Combinations
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
Monitor participants for 
signs and symptoms of 
pneumonitis
Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
and initiate 
corticosteroid treatment
Add prophylactic 
antibiotics for 
opportunistic infections
Recurrent 
Grade 2 or 
Grade 3 or 4 
Permanently 
discontinue
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irAEs
Toxicity 
Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations 
or IO 
Combinations
Corticosteroid 
and/or Other 
therapies
Monitoring and Follow-
up
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 / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold
Administer 
corticosteroids 
(initial dose of 
0.5-1 mg/kg 
prednisone or 
equivalent) 
followed by taper
Monitor with liver 
function tests (consider 
weekly or more 
frequently until liver 
enzyme value returned 
to baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of β-cell 
failure
Withhold a
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
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irAEs
Toxicity 
Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations 
or IO 
Combinations
Corticosteroid 
and/or Other 
therapies
Monitoring and Follow-
up
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 a
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 a
Hypothyroidism
Grade 2-4
Continue
Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
standard of care
Monitor for signs and 
symptoms of thyroid 
disorders
Nephritis and 
renal 
dysfunction
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 
Withhold
Based on severity 
of AE administer 
corticosteroids
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes
Grade 2, 3 or 
4
Permanently 
discontinue
All Other irAEs
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 b
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common 
Terminology Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; 
GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO 
combinations is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, 
DRESS, SJS, TEN and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab Monotherapy, Coformulations, or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations may cause severe or life-
threatening infusion reactions including severe hypersensitivity or anaphylaxis. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. Dose modification and toxicity 
management guidelines on pembrolizumab monotherapy, coformulations, or IO 
combinations associated infusion reactions are provided in Table 10.
Table 10
Pembrolizumab Monotherapy, Coformulations, or IO Combinations Infusion 
Reaction Dose Modification and 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 participant 
is deemed medically stable in the 
opinion of the investigator
None
Grade 2
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 h
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 1 hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the original 
infusion rate (eg, from 100 mL/h to 
50 mL/h). 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 study intervention.
Participant may be premedicated 1.5 h 
(±30 min) prior to infusion of study 
intervention with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500 to 1000 mg po (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms after initial 
improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
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:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the participant 
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 intervention.
No subsequent dosing
CTCAE=Common Terminology Criteria for Adverse Events; h=hour; IV=intravenous; NCI=National Cancer 
Institute; NSAIDs=nonsteroidal anti-inflammatory drugs.
Note: Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For further information, please refer to the CTCAE v4.0 at http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab Monotherapy, Coformulations, 
or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations may be interrupted for 
situations other than treatment-related AEs such as medical or surgical events and/or 
unforeseen circumstances not related to study intervention. However, study intervention is to 
be restarted within 3 weeks (21 days) of the originally scheduled dose and within 42 days of 
the previously administered dose, unless otherwise discussed with the Sponsor. The reason 
for study intervention interruption is to be documented in the participant’s study record.
6.6.4
Chemotherapeutic (Pemetrexed/Platinum) Dose Modifications
If a participant experiences a ≥10% weight change during Cycles 1 through 4, the doses of 
pemetrexed, cisplatin, or carboplatin should be recalculated.
Dose modifications due to AEs will depend on the investigator’s assessment of causality. If 
appropriate, the investigator may attribute each toxicity event to cisplatin/carboplatin, 
pemetrexed, or pembrolizumab alone, or to the combination, and use a stepwise dose 
modification (Table 5 through Table 13).
Dose modifications must be based on the maximum toxicity experienced during an 
intervention administration cycle. Toxicity must resolve to Grade ≤1 or baseline prior to 
resuming the subsequent cycle, with the exception of alopecia, Grade 2 fatigue, and Grade ≤2 
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endocrine-related AEs requiring treatment or hormone replacement; for anemia and 
creatinine clearance, the guidelines provided in Table 3 may be followed.
If a dose reduction for toxicity occurs with any agent, the dose may not be re-escalated. 
Participants can have a maximum of 2 dose modifications (if applicable) to each of the 
components of study therapy throughout the course of the study for toxicities. If a participant 
experiences several toxicities and there are conflicting recommendations, the most 
conservative recommended dose adjustment should be followed (ie, the dose reduction 
appropriate to the most severe toxicity). Participants who require a third dose modification to 
any particular component will have that intervention discontinued. Once the dose has been 
decreased, it should remain reduced for all subsequent administrations or be further reduced, 
if necessary. There will be no dose escalations in this study.
Reduction of one chemotherapy agent and not the other agent is appropriate if, in the opinion 
of the investigator, the toxicity is clearly related to one of the treatments. If, in the opinion of 
the investigator, the toxicity is related to the combination of both chemotherapy agents, both 
agents should be reduced according to recommended dose modifications. If the toxicity is 
related to the combination of 3 agents, all 3 agents should be reduced (if applicable), 
interrupted or discontinued according to the recommended dose modifications. If all 3 agents 
are discontinued due to a toxicity, the participant cannot proceed to the Maintenance Phase. 
If pembrolizumab and/or pemetrexed are discontinued during the Induction Phase, the 
participant cannot proceed to the Maintenance Phase.
Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
delayed/interrupted for a maximum of 12 weeks. However, for participants to proceed to the 
Maintenance Phase, the toxicity must resolve to Grade ≤1 or baseline prior to resuming the 
subsequent cycle, with the exception of alopecia, Grade 2 fatigue, and Grade ≤2 endocrine-
related AEs requiring treatment or hormone replacement; for anemia and creatinine 
clearance, the guidelines provided below may be followed.
During the Induction Phase, study drug-related toxicities must be resolved to baseline or 
Grade ≤1 (with the exception of alopecia, Grade 2 fatigue, and Grade ≤2 endocrine-related 
AEs requiring treatment or hormone replacement; for anemia and creatinine clearance the 
guidelines provided below may be followed) prior to administering the next dose. 
Participants must not receive the next cycle of chemotherapy if any of the following apply:
•
Absolute neutrophil count <1,500/mm3
•
Platelet count <100,000/mm3
•
Hemoglobin level <9 g/dL
•
Total bilirubin level >1.5 × upper limit of normal (ULN)
•
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels 
≥2.5 × ULN, or ≥5 × ULN if liver metastases are present
•
CrCl <51 mL/min (CrCl will be based on the Cockcroft-Gault formula; alternatively, 
CrCl can be determined from a 24-hour urine collection)
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During Induction Phase Cycles 1 through 4 of pemetrexed plus cisplatin/carboplatin:
•
If pemetrexed dosing is delayed or interrupted on Day 1, the platinum agent and 
pembrolizumab should also be delayed/interrupted. If pemetrexed plus 
cisplatin/carboplatin is delayed or interrupted during Cycles 1 through 4, participants 
should be seen weekly until toxicity resolves.
•
If platinum dosing is delayed or interrupted on Day 1, pembrolizumab and pemetrexed 
should also be delayed/interrupted. If pemetrexed plus cisplatin/carboplatin is delayed or 
interrupted during Cycles 1 through 4, participants should be seen weekly until toxicity 
resolves.
•
If pembrolizumab dosing is delayed or interrupted, pemetrexed plus cisplatin/carboplatin 
therapy can continue as scheduled. Pembrolizumab administration should be attempted at 
the next cycle of therapy.
•
Each chemotherapy cycle may not be delayed by more than 3 weeks (>21 days) despite 
supportive treatment. If only one of the agents is thought to be causing the specified 
toxicity leading to a 21-day delay of administration of the next cycle, that 
chemotherapeutic agent can be withheld and treatment can continue with pembrolizumab 
and the remaining chemotherapy drug.
The reason for the dose interruption or reduction should be captured on the appropriate
eCRF. The chemotherapy guidance for pembrolizumab/pemetrexed arm should be followed 
during Maintenance Phase.
The NCI CTCAE 4.0 must be used to grade the severity of AEs. All dose modifications 
should be based on the AE requiring the greatest dose modification. Dose modifications are 
detailed in Table 5 through Table 13. These serve as a guide and do not replace investigator 
judgment and applicable local label recommendations, if more stringent. A participant is 
allowed to switch from cisplatin to carboplatin if the participant develops unexpected 
toxicities with the use of cisplatin (including hearing loss), becomes ineligible for further 
cisplatin therapy, and/or the investigator considers switching to carboplatin to be in the best 
interest of the participant.
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Table 11
Dose Modifications for Chemotherapeutic Agents
Drug
Dose Level 0
Dose Level -1
Dose Level -2
Dose Level -3
Cisplatin
75 mg/m2
56 mg/ m2
38 mg/ m2
Discontinue
Carboplatin
AUC 5 mg/mL/min
Maximum dose
750 mg
AUC 3.75 mg/mL/min
Maximum dose 562.5 mg
AUC 2.5 mg/mL/min
Maximum dose 375 mg
Discontinue
Pemetrexed
500 mg/m2
375 mg/m2
250 mg/m2
Discontinue
Abbreviations: AUC = area under the concentration-time curve; BID = twice daily.
For olaparib, follow dose medications as outlined in Section 6.6.2 (and all of its subsections).
For pembrolizumab, follow dose modifications as outlined in Section 6.6.3 (and all of its subsections).
Recommended dose modifications for key chemotherapy toxicities are outlined in Table 12
and Table 13. These serve as a guide and do not replace investigator judgment and applicable 
local label recommendations, if more stringent. These data are based on Day 1 cell counts.
Table 12
Recommended Chemotherapy Dose Modifications for Hematological Toxicity
Platelets
ANC
Pemetrexed
Cisplatin/Carboplatin
Dose Level (DL) from Table 11
≥50,000/mcL AND
≥ 500/mcL
DL 0
DL 0
≥50,000/mcL AND
< 500/mcL
DL -1
DL -1
<50,000/mcL without Bleeding 
AND
ANY
DL -1
DL -1
<50,000/mcL with Grade ≥2 
Bleeding AND
ANY
DL -2
DL -2
ANY AND
< 1,000/mcL + fever 
≥38.5°C (101°F)
DL -1
DL -1
Abbreviations: ANC = absolute neutrophil counts; DL = dose level; mcL = microliter(s).
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Table 13
Recommended Dose Modifications for Chemotherapy Non-Hematological 
Toxicity
Event
CTCAE Grade
Pemetrexed
Cisplatin
Carboplatin
Dose Level (DL) from Table 11
Nausea or Vomiting
Grade 3 or 4
DL 0
DL 0
DL 0
Diarrhea
Grade 3 or 4
DL -1
DL -1
DL 0
Mucositis
Grade 3 or 4
DL -2
DL 0
DL 0
Neurotoxicity
Grade 2
DL 0
DL -2
DL 0
Grade 3 or 4
DL -1
Discontinue
DL -1
Transaminase Elevation
Grade 3
DL -1
DL -1
DL -1
Grade 4
Discontinue
Discontinue
Discontinue
Other Nonhematological 
Toxicity
Grade 3 or 4
DL -1
DL -1
DL -1
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; DL = dose level.
6.6.4.1
Creatinine Clearance
Creatinine clearance will be calculated using the original weight-based Cockcroft and Gault 
formula. As an alternative, CrCl can be determined from a 24-hour urine collection.
•
During the Induction Phase, the CrCl must be ≥51 mL/min prior to the administration of 
chemotherapy.
•
During the Maintenance Phase, for those participants in the pembrolizumab and 
maintenance pemetrexed arm, the CrCl must be ≥45 mL/min prior to the administration 
of chemotherapy.
Note: Maintenance pemetrexed may be delayed for up to 42 days to allow the participant 
time to recover from the toxicity. If a participant’s CrCl value has not returned to 
≥45 mL/min within 42 days after the previous dose, maintenance pemetrexed must be 
discontinued and pembrolizumab can continue.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study (EOS).
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (pembrolizumab [25 mg/mL] and 
olaparib [150 or 100 mg]) is included in the label text; random code/disclosure envelopes or 
lists are not provided.
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6.9
Standard Policies
Not applicable. 
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period will still continue to be monitored in this study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.12.4 unless the participant has 
withdrawn from the study Section 7.2.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
Any prolonged interruption of study intervention beyond the permitted periods, for irAE 
management or other allowed dose interruptions, as noted in Section 6.6.3, require 
Sponsor consultation prior to restarting treatment. If treatment will not be restarted, the 
participant will continue to be monitored in the study and the reason for discontinuation 
of study intervention will be recorded in the medical record.
•
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 participant has a confirmed positive serum pregnancy test.
•
Radiographic disease progression outlined in Section 8.2 (after obtaining informed 
consent addendum and Sponsor communication, the investigator may elect to continue 
treatment beyond iRECIST disease progression).
•
Any progression or recurrence of malignancy, or any occurrence of another malignancy 
that requires active treatment.
•
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 6.6 (e.g. recurrent Grade 2 pneumonitis, recurrent Grade 3 colitis, recurrent 
Grade 3 diarrhea).
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•
Unacceptable AEs or toxicities (Section 6.6.1).
•
Bone marrow findings consistent with MDS or AML.
•
If a participant with liver metastasis has Grade 2 AST or ALT at the start of study 
treatment, and the AST or ALT value increases by ≥50% relative to baseline and lasts for 
≥1 week, then the participant should permanently discontinue study intervention.
•
Interruption of pemetrexed, carboplatin, or cisplatin for more than 6 weeks without 
Sponsor consultation.
•
Interruption of pembrolizumab administration for >12 consecutive weeks for an 
AE/toxicity or for >3 weeks (>21 days) for administrative reasons without Sponsor 
consultation.
•
Interruption of administration of olaparib for >21 consecutive days without Sponsor 
consultation.
•
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment.
•
Prohibited medication or vaccination required, and agreement between Sponsor, 
investigator, and participant to discontinue (Section 6.5.1).
For participants who are discontinued from study intervention, but continue to be monitored 
in the study, all visits, and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent”. Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
Participants in this study may discontinue in the Induction Phase due to progression of 
disease or not meeting eligibility criteria to proceed to the Maintenance Phase (as listed in 
Section 5.1). Upon completion of the End-of-Treatment/Safety Follow-up Visit, these 
participants are to be discontinued from the study and are no longer followed.
Note: As of Amendment 07, central tumor response assessments will no longer be 
performed. Participants on study treatment will be assessed locally by the investigator for 
disease progression, based on the site’s standard of care imaging schedule. Participants with 
PD per local investigator assessment should be discontinued (except if the Sponsor approves 
treatment continuation following PD).
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
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Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.8.2 and Section 8.1.8.3. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before providing documented informed consent may be used for 
screening or baseline purposes provided the procedures meet the protocol-specified 
criteria and were performed within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements. The ICF, any subsequent revised ICF, and any written information 
provided to the participant must receive the IRB/IEC’s approval/favorable opinion in 
advance of use.
Informed consent given by the participant (or their legally acceptable representative) must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or their legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated ICF should be given to the participant (or their legally 
acceptable representative) before participation in the study.
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The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study. If there are changes to 
the participant’s status during the study (eg, age of majority requirements or health), the 
investigator or medically qualified designee must ensure the appropriate documented 
informed consent from the participant (or their legally acceptable representative) is in place.
8.1.1.1
General Informed Consent
Specifics about the study and the study population are to be included in the ICF.
The participant (or their legally acceptable representative) should be informed in a timely 
manner if new information becomes available that may be relevant to the participant’s 
willingness to continue participation in the study. The communication of this information 
will be provided and documented via a revised consent form or addendum to the original 
consent form that captures the participant’s or the participant’s legally acceptable 
representative’s dated signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention 
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
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8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout, or run-in treatment including placebo run-in).
8.1.4.1
Non–small-Cell Lung Cancer History
The investigator or qualified designee will obtain prior and current details regarding the 
participant’s NSCLC.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the study. Treatment for the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as a prior medication.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up Visit. In addition, new medications started 
during the Second Course through the Second Course Safety Follow-up Visit should be 
recorded.
8.1.5.3
Subsequent Antineoplastic Therapy
Details of subsequent therapies for cancer and/or details of radiation therapy and surgery for 
the treatment of the cancer, after discontinuation of study intervention, will be collected. 
Reasons for starting subsequent antineoplastic therapies, including access to other PARP 
inhibitors, PD-1/PD-L1 inhibitors, or investigational drugs will be collected.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be reused 
for different participants.
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Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening visit requirements 
(screening/rescreening) are provided in Section 8.12.1.
8.1.6.1
Treatment Eligibility Assessment (TEA) Form
•
A TEA form located in the eCRF is included in this study to document the choice of 
platinum chemotherapy (carboplatin or cisplatin) and the rationale. These data may be 
required to support reimbursement efforts for pembrolizumab and maintenance olaparib 
following pembrolizumab in combination with pemetrexed/platinum (carboplatin or 
cisplatin).
•
The investigator must complete this form and provide rationale to document the choice of 
platinum chemotherapy (carboplatin or cisplatin) prior to induction.
8.1.7
Assignment of Treatment/Randomization Number
All participants eligible for study intervention will continue to be treated using the initial 
assigned screening number. All participants eligible for the Maintenance Phase who are 
randomized will receive an allocation/randomization number. The allocation/randomization 
number identifies the participant for all procedures occurring after randomization to the 
Maintenance Phase. Once a treatment/randomization number is assigned to a participant, it 
can never be re-assigned to another participant.
A single participant cannot be assigned more than 1 allocation/randomization number.
For those participants who are treated as per the Induction Phase and are not randomized to 
the Maintenance Phase, a separately devised allocation number will be assigned.
8.1.8
Study Intervention Administration
Administration of pembrolizumab, pemetrexed, carboplatin, and cisplatin during the 
Induction Phase will be monitored by the investigator and/or study staff.
During the Maintenance Phase, administration of pembrolizumab and either olaparib or 
pemetrexed will be monitored by the investigator and/or study staff on Day 1 of the first 
cycle, according to the specifications within the Pharmacy Manual. Participants will then 
self-administer olaparib orally for the remainder of the 21-day treatment cycle.
Study intervention should begin within 3 days of treatment allocation for the Induction Phase 
and within 3 days of treatment randomization in the Maintenance Phase, respectively.
Note: Participants taking olaparib or pemetrexed should continue receiving it per 
investigator’s discretion after discussion.
Participants who are potential candidates for Second Course treatment will continue in 
Efficacy Follow-up. Participants currently undergoing or who will undergo Second Course 
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with pembrolizumab monotherapy can continue or start treatment per investigator’s 
discretion under this protocol.
8.1.8.1
Timing of Dose Administration
On Day 1 of each cycle, study intervention should be administered after all procedures and 
assessments have been completed. Study intervention can be administered within ±3 days of 
the targeted Day 1 for each cycle.
Cycles 1-4 (Induction Phase)
Participants will receive pembrolizumab 200 mg (Day 1) with pemetrexed 500 mg/m2 and 
the investigator’s choice of carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2 for 
4 cycles.
Cycles 1-31 (Maintenance Phase)
Participants will continue pembrolizumab 200 mg and begin maintenance therapy with either 
olaparib 300 mg BID or pemetrexed 500 mg/m2 Q3W.
8.1.8.1.1
Pembrolizumab
Pembrolizumab will be administered as a 30-minute IV infusion Q3W, and it will be 
administered prior to chemotherapy. Sites should make every effort to target infusion timing 
to be as close to 30 minutes as possible. However, given the variability of infusion pumps 
from site to site, a window of -5 minutes and +10 minutes is permitted (ie, infusion time is 
30 minutes: -5 minutes/+10 minutes).
8.1.8.1.2
Pemetrexed
Pemetrexed 500 mg/m2 will be administered as an IV infusion over 10 minutes Q3W as per 
local practice and labels. All participants should receive the appropriate supplementation of 
vitamin B12 and folic acid and corticosteroid prophylaxis as listed below (or as per local 
label):
•
Folic acid 350 to 1000 μg PO: at least 5 doses of folic acid must be taken during the 
7 days preceding the first dose of pemetrexed, and folic acid dosing must continue during 
the full course of therapy and for 21 days after the last dose of pemetrexed.
•
Vitamin B12 1000 μg IM injection in the week preceding the first dose of pemetrexed 
and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the 
same day as pemetrexed administration.
•
Dexamethasone prophylaxis 4 mg PO BID (or equivalent). Taken the day before, day of, 
and day after pemetrexed administration. Higher or additional doses are permitted for 
antiemetic prophylaxis during Cycles 1 to 4 but not to exceed doses in MASCC 
guidelines (Section 8.1.8.1.6).
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8.1.8.1.3
Platinum-based Chemotherapy
8.1.8.1.3.1
Carboplatin
Carboplatin (AUC 5 mg/mL/min) will be administered as an IV infusion over approximately 
60 minutes Q3W on Day 1 for each of the 4 cycles (Induction Phase) and after 
pembrolizumab as per local practice and labels. The carboplatin dose should be calculated 
using the Calvert formula (see below) and should not to exceed 750 mg.
Calvert formula:
•
Total dose (mg) = (target AUC) × (CrCl + 25)
•
The estimated CrCl in the Calvert formula should not exceed 125 mL/min
•
Maximum carboplatin dose (mg)
= target AUC 5 × (125 + 25)
= 5 × 150
= 750 mg
Creatinine clearance must be calculated using either the Cockcroft-Gault formula or another 
acceptable standard formula for estimating CrCl in mL/min based on serum creatinine:
•
Men: [(140 - age (y)) × weight (kg)]/[72 × serum creatinine (mg/dL)]
•
Women: [(140 - age (y)) × weight (kg)] × 0.85/[72 × serum creatinine (mg/dL)]
Alternatively, CrCl can be determined from a 24-hour urine collection.
Note: Dose may be rounded to the nearest 50 mg at the discretion of the investigator, and 
according to institutional standards.
Unless there is a change in weight ≥10%, the same dose of carboplatin can be used 
throughout the 4 cycles of the Induction Phase (provided there are no additional toxicities).
Additional premedications should be administered as per standard practice.
8.1.8.1.3.2
Cisplatin
Cisplatin (75 mg/m2) will be administered as an IV infusion over 30 to 180 minutes Q3W on 
Day 1 for up to 4 cycles (Induction Phase) and after pembrolizumab as per local practice and 
labels.
Participants are allowed to switch from cisplatin to carboplatin if the participant becomes 
ineligible for further cisplatin therapy according to local guidelines and the investigator 
considers switching to carboplatin to be in the best interest of the participant.
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8.1.8.1.4
Olaparib
Participants must have at least one evaluable scan and no overall response of PD prior to 
starting either olaparib or pemetrexed in the Maintenance Phase. During the Maintenance 
Phase, olaparib administration will be witnessed by the investigator and/or study staff on 
Day 1 of the first cycle, and participants will then self-administer olaparib PO for the 
remainder of the 21-day treatment cycle. Participants will be instructed to self-administer
olaparib at approximately the same time of day. If vomiting occurs within 2 hours after the 
olaparib tablets are swallowed, the dose should only be replaced if all of the intact tablets can 
be seen and counted.
If a participant misses a scheduled dose for any reason (eg, as a result of forgetting to take 
the tablets or vomiting), the participant will be allowed to take the scheduled dose up to a 
maximum of 2 hours after that scheduled dose time. If more than 2 hours after the scheduled 
dose time, the missed dose is not to be taken and the participant should take their allotted 
dose at the next scheduled time.
Refer to the olaparib Pharmacy Manual for further details on dose administration.
8.1.8.1.5
Colony-stimulating Factors
During the Induction Phase, the use of CSFs is highly recommended as primary prophylaxis 
to reduce the risk of febrile neutropenia in this patient population, especially as many 
participants have multiple comorbidities and advanced disease. Granulocyte-CSF should not 
be used within 14 days prior to randomization.
During the Maintenance Phase, primary prophylaxis with G-CSF is not recommended; 
however, if a participant develops febrile neutropenia, study intervention should be 
interrupted and appropriate management including G-CSF should be given according to local 
hospital guidelines. Please note that G CSF should not be used within at least 24 hours 
(7 days for pegylated G-CSF) of the last dose of study intervention unless absolutely 
necessary.
The American Society of Clinical Oncology guidelines for use of CSFs should be followed 
for this study [Smith, T. J., et al 2015].
8.1.8.1.6
Antiemetic Therapy
Antiemetic therapy should follow the Multinational Association of Supportive Care in 
Cancer (MASCC) guidelines [Roila, F., et al 2016]. In each cycle of treatment during the 
Induction Phase, antiemetic therapy should include a 5 HT3 receptor antagonist, 
dexamethasone (or equivalent), and/or aprepitant [Roila, F., et al 2016].
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period 
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.3.
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Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
This is an open-label, unblinded study.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.12
Tissue Collection
8.1.12.1
Tumor Tissue for Biomarker Status
During the Screening Phase, participants are required to have provided a newly obtained core 
or incisional biopsy of a tumor lesion not previously irradiated or, if not available, an 
archival tumor tissue sample. FFPE tissue blocks are preferred to slides. Newly obtained 
biopsies are preferred to archived tissue. Note: details pertaining to tumor tissue submission 
are in the Procedures Manual). Tissue is needed for central determination of PD-L1, HRRm, 
HRD-LOH, tumor mutation burden, and microsatellite instability-high status.
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8.2
Efficacy Assessments
Immunogenicity assessments will not be performed in this study.
8.2.1
Tumor Imaging and Assessment of Disease
Throughout this section, the term ‘scan’ refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), medical 
photography, or other methods as specified in this protocol.
Note: As of Amendment 7, participants who are still on study treatment will no longer 
require tumor response assessments by BICR to be performed. Scans will not be submitted to 
the iCRO. Participants who are still on study treatment and who have not experienced 
radiographic disease progression will be assessed locally by the investigator for disease 
progression, based on the site’s standard of care imaging schedule. Original protocol text in 
this section has been retained for reference.
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual. Tumor imaging is strongly preferred, as follows:
•
CT with IV and oral contrast (preferred) of the chest, abdomen, and pelvis for all 
participants, or noncontrast CT of the chest and MRI of the abdomen and pelvis with IV 
gadolinium for participants in whom iodinated contrast is contraindicated
•
MRI (strongly preferred) or CT with contrast (when MRI is medically contraindicated) of 
the brain
The same imaging technique regarding modality, ideally the same scanner, and the use of 
contrast should be used in a participant throughout the study to optimize the reproducibility 
of the assessment of existing and new tumor burden and improve the accuracy of the 
assessment of response or progression based on imaging. Note: for the purposes of assessing 
tumor imaging, the term investigator refers to the local investigator at the site and/or the 
radiological reviewer at the site or at an offsite facility.
All scheduled images for all study participants from the sites will be submitted to the central 
imaging vendor. In addition, images (including via other modalities) that are obtained at an 
unscheduled time point to determine disease progression, and imaging obtained for other 
reasons, but captures radiologic progression based on investigator assessment, should also be 
submitted to the central imaging vendor.
When the investigator identifies radiographic progression per RECIST 1.1, the central 
imaging vendor will perform expedited verification of radiologic disease progression and 
communicate the results to the study site and Sponsor. Progression of disease should be 
verified centrally before intervention is discontinued if the participant is clinically stable. 
Treatment should continue until PD has been verified. Regardless of whether PD is verified, 
if the investigator considers the participant has progressed, but elects to implement iRECIST, 
the investigator will assess for confirmation of progression by iRECIST at subsequent time 
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points. Images should continue to be submitted to the central imaging vendor until VOP is 
confirmed centrally.
8.2.1.1
Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 28 days prior to the date of the 
first dose of study intervention.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality and performed within 28 days prior to 
first treatment dose.
Participants with previously treated brain metastases may participate provided they are 
clinically stable for at least 2 weeks and, have no evidence of new or enlarging brain 
metastases and also are off steroids 3 days prior to dosing with study medication. Stable brain 
metastases by this definition should be established prior to the first dose of study medication. 
Participants with known untreated, asymptomatic brain metastases (ie, no neurological 
symptoms, no requirements for corticosteroids, no or minimal surrounding edema, and no 
lesion >1.5 cm) may participate but will require regular imaging of the brain as a site of 
disease. This exception does not include carcinomatous meningitis, as participants with 
carcinomatous meningitis are excluded, regardless of clinical stability.
8.2.1.2
Tumor Imaging During the Study
During the Induction Phase, the first on-study imaging assessment should be performed at 
6 weeks (42 days + 7 days) from the date of first dose. The second on-study imaging 
assessment should be performed at 12 weeks (84 days ± 7 days) from the date of first dose. 
All imaging must be submitted to the central imaging vendor for expedited BICR to 
determine lack of progression during the Induction Phase, which is required to be eligible for 
randomization.
For stratification purposes, confirmed and unconfirmed CR/PR will be stratified together. 
Nonevaluable imaging at Week 12 (84 days ± 7 days) will use the response obtained at the 
latest evaluable scan obtained at pre-randomization (Week 6 [42 days ± 7 days]) for 
stratification. Those patients with 2 nonevaluable scans during induction at Weeks 6 and 12 
will not be randomized into the Maintenance Phase.
All imaging prior to initiating the Maintenance Phase should have been performed within 
28 days of the date of randomization, and these imaging studies will serve as the new 
baseline. For participants randomized into the Maintenance Phase, imaging will be 
performed at 6 weeks (42 days + 7 days) after randomization, then every 6 weeks (Q6W; 
42 days ± 7 days) for the first 60 weeks from the date of randomization, after which imaging 
will increase to every 9 weeks (Q9W; 63 ± 7 days). Imaging timing should follow calendar 
days and should not be adjusted for delays in cycle starts. Imaging should continue to be 
performed until centrally verified disease progression per RECIST 1.1 is identified by the 
investigator and verified by BICR (unless the investigator elects to continue treatment and 
follow iRECIST), the start of new anticancer treatment, withdrawal of consent, or death, 
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whichever occurs first. All supplemental imaging must be submitted to the central imaging 
vendor.
For participants to proceed to the Maintenance Phase, responses do not need to be confirmed. 
However, images will need to be centrally reviewed to determine that participants do not 
have progressive disease. Furthermore, if the participant is determined to be eligible for 
maintenance, the latest evaluable imaging time pointe prior to entering the Maintenance 
Phase will serve as the new baseline.
During the Maintenance Phase, objective response should be confirmed by a repeat imaging 
assessment. Tumor imaging to confirm PR or CR should be performed at least 4 weeks after 
the first indication of a response is observed. Participants will then return to regular 
scheduled imaging, starting with the next scheduled imaging time point. Participants who 
receive additional imaging for confirmation do not need to undergo the next scheduled tumor 
imaging if it is less than 4 weeks later; tumor imaging may resume at the subsequent 
scheduled imaging time point. Note: Response does not typically need to be verified in real 
time by the central imaging vendor.
8.2.1.3
End-of-treatment and Follow-up Tumor Imaging
For randomized participants who discontinue study intervention, tumor imaging should be 
performed at the time of treatment discontinuation (± 4-week window). If previous imaging 
was obtained within 4 weeks prior to the date of discontinuation, then imaging at treatment 
discontinuation is not mandatory. For participants who discontinue study intervention due to 
centrally verified disease progression, this is the final required tumor imaging if the 
investigator elects not to implement iRECIST.
For participants who enter the Maintenance Phase and discontinue study intervention without 
centrally verified disease progression, every effort should be made to continue monitoring 
disease status by tumor imaging using the same imaging schedule used while on treatment 
(every 6 weeks (42 days ±7 days) for the first 60 weeks from the date of randomization) and 
then increase to Q9W (63 ±7 days) thereafter until the start of a new anticancer treatment, 
disease progression, pregnancy, death, withdrawal of consent, or the end of the study, 
whichever occurs first.
Participants should continue with imaging per local standard of care after the EOT Visit.
8.2.1.4
Second Course Phase (Retreatment) Tumor Imaging
Tumor scans must be performed within 28 days prior to restarting treatment with 
pembrolizumab. Central reading will be used to determine eligibility.
The first on-study imaging assessment should be performed at 12 weeks (84 days ± 7 days) 
after the restart of treatment. Subsequent tumor imaging should be performed every 12 weeks 
(84 days ± 7 days) or more frequently, if clinically indicated. Participants who remain on 
treatment will have imaging performed as determined by the treating physician per the local 
standard of care, but not less frequently than every 12 weeks (84 days ± 7 days).
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Per iRECIST (Section 8.2.1.6), if tumor imaging shows initial PD, tumor assessment should 
be repeated 4 to 8 weeks later in order to confirm PD with the option of continuing treatment 
while awaiting radiologic confirmation of progression. Participants who obtain confirmatory 
imaging do not need to undergo scheduled tumor imaging if it is <4 weeks later and may wait 
until the next scheduled imaging time point, if the participant is clinically stable.
Imaging should continue to be performed until locally verified disease progression, the start 
of a new anticancer treatment, withdrawal of consent, death, or notification by MSD, 
whichever occurs first. In clinically stable participants, disease progression may be 
confirmed by the investigator using iRECIST 4 to 8 weeks after the first tumor imaging 
indicating PD.
For participants who discontinue Second Course Phase study intervention, tumor imaging 
should be performed at the time of treatment discontinuation (± 4-week window). If previous 
imaging was obtained within 4 weeks prior to the date of discontinuation, then imaging at 
treatment discontinuation is not mandatory.
For participants who discontinue Second Course Phase study intervention without locally 
verified disease progression, every effort should be made to continue monitoring their 
disease status by radiologic imaging Q12W (84 days ± 7 days) from Second Course Phase 
Cycle 1, or more frequently, as clinically indicated thereafter, until the start of a new 
anticancer treatment, disease progression, death, withdrawal of consent, or the end of study, 
whichever occurs first.
8.2.1.4.1
Brain Imaging During Second Course Phase
A brain scan within 28 days of restarting pembrolizumab will only be performed in 
participants who have a history of protocol-eligible brain metastases or are clinically 
symptomatic. Subsequent brain scans in these participants will be performed Q12W 
(± 7 days), or as clinically indicated, after restarting pembrolizumab.
8.2.1.5
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
disease progression, and as a basis for all protocol guidelines related to disease status (eg, 
discontinuation of study intervention). Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
Upon investigator-assessed disease progression, the indicative scan(s) is/are to be submitted 
immediately to iCRO for BICR verification of progression. After submission of scan(s), the 
iCRO will email the assessment to the site and Sponsor.
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If disease progression is not verified, the process continues as follows:
•
If participant is clinically stable, continue study intervention per protocol
o
Resume imaging per protocol schedule (≥4 weeks to next scan)
o
Send scan(s) to iCRO
o
Continue local assessment
o
Do not change investigator assessment of progression
o
If subsequent scan(s) indicate progression, submit scan(s) to iCRO to request 
verification
•
If the participant is not clinically stable, the best medical practice is to be applied.
Before stopping study intervention or imaging or starting new anticancer therapy in a 
participant who is clinically stable, communication with the Sponsor is required.
If disease progression is centrally verified, the process continues as follows:
•
Investigator judgement will determine action
•
If participant is clinically stable and study intervention is to continue, communication 
with the Sponsor is required and a reconsent addendum must be signed
•
Obtain scan(s) locally per original protocol schedule
•
Do not send scan(s) to iCRO
Figure 2 illustrates the study intervention decision process involving verification of disease 
progression for participants.
For the purpose of this decision process, lack of clinical stability is defined as:
•
unacceptable toxicity
•
clinical signs or symptoms indicating clinically significant disease progression
•
decline in performance status
•
rapid disease progression or threat to vital organs or critical anatomical sites (eg, CNS 
metastasis, respiratory failure due to tumor compression, spinal cord compression) 
requiring urgent alternative medical intervention.
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Figure 2
Study Intervention Decision Making Process When Progression per RECIST 
1.1 is Observed by Investigator
8.2.1.6
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression and make treatment decisions [Seymour, L., et al 2017]. When 
clinically stable, participants may continue study intervention beyond RECIST 1.1 
progression with continued assessment of response according to the rules outlined in 
Appendix 8. iRECIST reflects that some participants can have a transient tumor flare after 
the start of immunotherapy then experience subsequent disease response. This data will be 
captured in the clinical database.
•
If participant is clinically stable and VOP is not centrally verified (refer to 
Section 8.2.1.5), continue study intervention per protocol
-
Perform scans 4 to 8 weeks after RECIST 1.1 progression
-
Continue investigator assessment per iRECIST
-
send scans to iCRO
-
If progression is BICR-verified, stop sending scans to iCRO
•
If the participant is not clinically stable, best medical practice is to be applied
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8.2.2
Patient-reported Outcomes
Note: As of Amendment 07, participants who are still on study treatment will no longer 
require ePRO assessments. Original protocol text has been retained for reference.
 
 
 
 
 
 
 
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. Clinically significant 
abnormal findings should be recorded as medical history. Height and weight will also be 
measured and recorded.
A brief directed physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) per institutional standard prior to 
study intervention administration and at other times according to the SoA (Section 1.3). New 
clinically significant abnormal findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
Temperature, pulse rate, respiratory rate, and blood pressure will be assessed.
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8.3.3
Electrocardiograms
A standard 12-lead ECG will be performed using local standard procedures. The timing of 
the ECG is specified in the SoA (Section 1.3). Clinically significant abnormal findings 
should be recorded as medical history. Additional ECGs may be performed, as clinically 
necessary.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation In the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.4.1
Bone Marrow or Blood Cytogenetic Samples
Bone marrow or blood cytogenetic samples may be collected for participants with prolonged 
hematological toxicities as defined in Section 6.6.2.2.
Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic 
analysis and flow cytometry, and a core biopsy for bone marrow cellularity. If it is not 
possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then 
attempts should be made to perform the tests on a blood sample.
8.3.5
Performance Assessments: Eastern Cooperative Oncology Group 
Performance Status
The ECOG Performance Status is standardized criteria to measure how cancer impacts level 
of functioning (performance status) in terms of ability to care for oneself, daily activity, and 
physical ability (walking, working, etc) with grades 0 to 5. The investigator or qualified 
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designee will assess the participant’s ECOG status at Screening Phase, prior to 
administration of each dose of study intervention, and during the follow-up phase, as 
specified in the SoA (Section 1.3).
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation/randomization, must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event cause the participant to be excluded from the study, or is the result of a 
protocol-specified intervention, including, but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.
•
All AEs from the time of intervention allocation/randomization through 30 days after 
cessation of study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation/randomization 
through 90 days after cessation of study intervention or 30 days after cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention 
allocation/randomization through the time required to eliminate systemic exposure after 
cessation of study intervention as described in Section 5.1, or 30 days after cessation of 
study intervention if the participant initiates new anticancer therapy must be reported by 
the investigator.
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•
Any SAE of MDS/AML or new primary malignancy should be reported regardless of the 
investigator’s assessment of causality or knowledge of the treatment arm.
•
Additionally, any SAE brought to the attention of an investigator at any time outside the 
time specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 14.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 14
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
NSAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE, including 
Cancer and Overdose
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
– drug/vaccine 
related.
(Follow 
ongoing to 
outcome)
Within 
24 hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
– due to intervention
– causes exclusion
Report all
Previously 
reported – Follow 
to completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
ECI (requiring 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– requiring 
regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
ECI (does not require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 
5 calendar days 
of learning of 
event (unless 
an SAE)
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious 
adverse event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. SAEs and other reportable safety events, including 
pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be followed 
until resolution, stabilization, until the event is otherwise explained, or the participant is lost 
to follow-up (as defined in Section 7.3). The investigator will also make every attempt to 
follow nonserious AEs that occur in randomized participants for outcome. Further 
information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Note: To meet EU CTR requirements, the Sponsor will report SUSARs to the Eudravigilance 
database via E2B(R3) electronic ICSR form in compliance with CTR 536/2014.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding (spontaneously reported to the 
investigator or their designee) that occurs in a participant during the study are reportable to 
the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
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Pregnancy outcomes of ectopic pregnancy, 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.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study.
8.4.7
Events of Clinical Interest
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 

An overdose of Sponsor's products, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.

An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).

Any event of MDS/AML, new primary malignancy, or pneumonitis should be reported 
whether it is considered a non-serious AE (eg, non-melanoma skin cancer) or SAE and 
regardless of investigator’s assessment of causality.
8.5
Treatment of Overdose
Olaparib must only be used in accordance with the dosing recommendations in this protocol. 
Any dose or frequency of dosing that exceeds the dosing regimen specified in this protocol 
should be reported as an overdose.
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For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater.
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
8.6
Pharmacokinetics
Pharmacokinetic parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants as specified in the SoA:
•
Archival or newly obtained tumor tissue
•
Blood for genetic analysis
•
Blood for RNA analyses
•
Blood for circulating tumor DNA
•
Blood for serum and plasma biomarker analyses
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the laboratory manual.
8.8.1
Planned Genetic Analysis Sample Collection
The genetic analysis specimen should be collected for the analysis of the association between 
genetic variants in DNA and drug response. This specimen will not be collected at the site if 
the IRB/IEC does not approve the collection based on a local law or regulation. If the 
specimen is collected, leftover extracted DNA will be stored for FBR if the participant 
provides documented informed consent for this research. 
The genetic analysis specimen should be obtained pre-dose on Day 1 but may be collected at 
the next scheduled visit, if needed. Specimen collection, storage, and shipment instructions 
for genetic analysis specimens will be in the Central Laboratory Manual.
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8.9
Future Biomedical Research Sample Collection
All specimen collections for study-specific assessments shown in the SoA are described 
within the full Informed Consent. 
If the participant has provided documented informed consent for FBR, leftover specimens 
will be used for FBR. The following specimens will be included for FBR:
•
Leftover specimens listed in Sections 8.8.
8.10
Health Economics Medical Resource Utilization and Health Economics
Medical resource utilization and health economics data associated with medical encounters 
will be collected in the CRF by the investigator and study-site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded.
The collected data may be used to conduct exploratory economic analyses and will include:
All-cause hospitalizations and emergency department visits must be reported in the eCRF. 
See Section 8.4.1 for reporting requirements.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Approximately 28 days before intervention allocation/randomization, potential participants 
will be evaluated to determine that they fulfill the entry requirements as set forth in Section 
5. Screening procedures are to be completed within 28 days before the first dose of study 
intervention.
A test performed, as part of routine clinical management prior to the participant signing 
consent, is not to be repeated if performed within the specified time frame and the results are 
acceptable.
Screening procedures may be repeated after consultation with the Sponsor. If a study 
assessment needs to be repeated, the investigator may perform a retest of screening 
procedures to assess the eligibility of a participant as noted in Sections 5.1 and 5.2. 
Participants who are retested will retain their original screening number.
8.11.2
Pre-Randomization Visit
All participants will be evaluated at a Pre-Randomization Visit, which will occur 4 weeks 
(± 7 days) after Cycle 4 Day 1 of treatment in the Induction Phase and prior to study 
procedures/intervention in the Maintenance Phase. Investigators will review the 
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inclusion/exclusion criteria to ensure eligibility. A checklist will be completed and must be 
reviewed and approved by the Sponsor.
Participants with PD must be excluded from the Maintenance Phase and should enter EOT 
(refer to Section 1.3.3).
8.11.3
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1. Assessments/procedures should be performed, prior to the 
administration of study intervention.
8.11.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
Randomized participants who discontinue study treatment for reasons other than PD will 
move into the follow-up phase (Section 8.12.6).
8.11.5
Second Course Phase (Retreatment Period)
Note: Participants are allowed to start Second Course Treatment with locally verified PD. 
Original protocol text has been retained for reference.
All participants who receive 35 cycles of pembrolizumab with SD, PR, or CR in either arm 
may be eligible for up to 1 additional year (17 cycles) of treatment with pembrolizumab if 
they progress after stopping study treatment from the Maintenance Phase. This retreatment is 
termed the Second Course Phase, and it is only available if the study remains open and the 
participant meets the following conditions:
•
Experienced radiographic disease progression by RECIST 1.1 after stopping initial 
treatment with pembrolizumab
•
No new anticancer treatment was administered after the last dose of study intervention
•
The participant meets all of the safety parameters listed in the inclusion criteria and none 
of the safety parameters listed in the exclusion criteria
•
The study is ongoing
•
Had SD, PR, or CR, and stopped pembrolizumab treatment after completion of 
35 administrations (approximately 2 years) of study intervention for reasons other than 
disease progression or intolerability.
An objective response or disease progression that occurs during the Second Course Phase for 
a participant will not be counted as an event for the primary analysis of either endpoint in this 
study.
Procedures and visit requirements for the Second Course Phase are outlined in Section 1.3.4.
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8.11.6
Posttreatment Visit
8.11.6.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before initiation of a new anticancer treatment, whichever 
comes first.
Participants who are eligible for retreatment with pembrolizumab may have up to 2 safety 
follow-up visits: 1 after the Initial Treatment or First Course and 1 after the Second Course.
8.11.6.2
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than disease progression will begin Efficacy 
Follow-up and should be assessed Q6W (42 days ± 7 days) during the 60 weeks following 
randomization and thereafter approximately Q9W (63 days ± 7 days) to monitor disease 
status. Every effort should be made to collect information regarding disease status until the 
start of new anticancer therapy, disease progression, death, end of study. or withdrawal of 
consent, whichever occurs first. Information regarding poststudy anticancer treatment will be 
collected if new treatment is initiated. Participants who completed all efficacy assessments 
and/or will not have further efficacy assessments must enter Survival Follow-up.
8.11.6.3
Survival Follow-up Contacts
Participant survival follow-up status will be assessed approximately every 12 weeks to assess 
for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first.
The first survival follow-up assessment should be scheduled as described below:
•
For participants who discontinue treatment intervention and who will not enter Efficacy 
Follow-up, the first survival follow-up contact will be scheduled 12 weeks after the 
Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).
•
For participants who complete assessments in Efficacy Follow-up, the first survival 
follow-up contact will be scheduled 12 weeks after the last efficacy assessment follow-up 
visit has been performed.
8.11.7
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, an 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 period will be 
contacted for their vital status.
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If a participant withdraws consent or is lost to follow-up, vital status (survival information) 
can be conducted by review of medical records or public records when vital status is in 
question in accordance with local regulations, unless the participant has specifically 
withdrawn consent for collection of vital status data.
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If changes 
are made to primary and/or key secondary hypotheses or the statistical methods related to 
those hypotheses after the study has begun, but prior to any unblinding/final database lock, 
then the protocol will be amended (consistent with International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use [ICH] Guideline E9). 
Changes to exploratory or other non-confirmatory analyses made after the protocol has been 
finalized, but prior to unblinding/final database lock, will be documented in a supplemental 
statistical analysis plan (sSAP) and referenced in the clinical study report (CSR) for the 
study. Post hoc exploratory analyses will be clearly identified in the CSR. Separate analysis 
plans (ie, separate documents from the sSAP) will be developed to detail biomarker analyses. 
The PRO analysis plan will be included in the sSAP.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below. The comprehensive plan 
is provided in Section 9.2 through Section 9.12.
Study Design 
Overview
A Phase 3 Study of Pembrolizumab in Combination with 
Pemetrexed/Platinum (Carboplatin or Cisplatin) Followed by 
Pembrolizumab and Maintenance Olaparib vs Maintenance Pemetrexed 
in the First-Line Treatment of Participants with Metastatic Nonsquamous 
Non-Small-Cell Lung Cancer
Treatment 
Assignment
After the Induction Phase treatment with pembrolizumab in combination 
with pemetrexed and platinum, approximately 672 eligible participants 
will be randomized in a 1:1 ratio to one of 2 treatment arms:
1. Pembrolizumab + olaparib
2. Pembrolizumab + pemetrexed
Stratification factors are as follows:

ECOG PS of 0 vs. 1

PD-L1 TPS: <50% vs. ≥50%

CR/PR vs. SD at Randomization
Analysis Populations
Efficacy: Intent-to-Treat (ITT)
Safety: All Participants as Treated (APaT)
PROs: Full Analysis Set (FAS)
Primary Endpoints

PFS per RECIST 1.1 (Section 4.2.1.1) by BICR

OS
Secondary Endpoints

Safety and tolerability

PROs
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Statistical Methods 
for Key Efficacy 
Analyses
The dual primary hypotheses of PFS and OS will be evaluated by 
comparing pembrolizumab plus maintenance olaparib to pembrolizumab 
plus maintenance pemetrexed using a stratified log-rank test. The hazard 
ratio (HR) will be estimated using a stratified Cox regression model. 
Event rates over time will be estimated within each treatment arm using 
the Kaplan-Meier method.
Statistical Methods 
for Key Safety 
Analyses
The analysis of safety results in APaT will follow a tiered approach. The 
tiers differ with respect to the analyses that will be performed. There are 
no events of interest that warrant elevation to Tier 1 events in this study. 
Tier 2 safety parameters will be assessed via point estimates with 95% 
confidence intervals (CIs) provided for between-treatment comparisons; 
only point estimates by treatment group are provided for Tier 3 safety 
parameters. The 95% CIs for the between-treatment differences in 
percentages will be provided using the Miettinen and Nurminen method.
Interim Analyses
Multiplicity
The overall Type I error rate over the multiple endpoints will be strongly 
controlled at 2.5% (one-sided). 
 
 
 
 
 
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Sample Size and 
Power
Assumes that approximately 33% of patients progress or drop out during 
the Induction Phase, approximately 1005 participants will need to be 
enrolled into Induction Phase. The randomized sample size is 
approximately 672 participants. 
 
 
 
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
Although the study is open-label, analyses or summaries generated by randomized treatment 
assignment, and/or actual treatment received will be limited and documented. In addition, the 
independent radiologist(s) will perform the central imaging review without knowledge of 
treatment group assignment.
The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IRT.
Planned interim analyses are described in Section 9.7.
The members of the Data Monitoring Committee (DMC) must not be involved with the study 
in any other way (eg, they cannot be study investigators) and must have no competing 
interests that could affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to trial participants (see Section 9.7) and 
recommend to the EOC if the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC Charter that is 
reviewed and approved by all the DMC members.
In addition, an unblinding plan will be developed to maintain information about unblinding 
of Sponsor personnel prior to full unblinding at Sponsor. The personnel who have access to 
allocation schedules at what times will be documented in Appendix 4 (Interim Analysis Data 
Sources Memo) in the DMC Charter.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are provided in Section 3.
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9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below. Exploratory endpoints will be described in the sSAP.
9.4.1
Efficacy Endpoints
Dual Primary
Progression-free Survival
Progression-free survival is defined as the time from randomization to the first documented 
disease progression per RECIST 1.1 (Section 4.2.1.1) based on BICR or death due to any 
cause, whichever occurs first.
Overall Survival
Overall survival is defined as the time from randomization to death due to any cause.
9.4.2
Safety Endpoints
Safety measurements are described in Section 4.2.1.1.1, Section 8.3, and Section 8.4.
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9.4.3
Patient-reported Outcome Endpoints
The following secondary PRO endpoints will be evaluated as described in Section 4.2.1.3:
•
Global Health Status/QoL scale (EORTC QLQ-C30 Items 29 and 30)
•
Single-item symptom scales: cough (EORTC QLQ-LC13 Item 1), chest pain (EORTC 
QLQ-LC13 Item 10), and dyspnea (EORTC QLQ-C30 Item 8)
•
Composite-symptom endpoints: cough (QLQ-LC13 Item 1), chest pain (QLQ-LC13 
Item 10), and dyspnea (QLQ-C30 Item 8)
•
Physical functioning scale (EORTC QLQ-C30 Items 1 through 5)
Exploratory PRO endpoints include:
•
EQ-5D-5L health-state dimensions (Items 1 through 5)
•
EQ-5D-5L VAS (Item 6)
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The intent-to-treat (ITT) population will serve as the population for primary efficacy 
analysis. All randomized participants will be included in this population. Participants will be 
included in the treatment group to which they are randomized.
Details on the approach to handling missing data are provided in Section 9.6.
9.5.1.1
Safety Analysis Populations
The All Participants as Treated (APaT) population will be used for the analysis of safety data 
in this study. The APaT population consists of all randomized participants who received at 
least 1 dose of study intervention. Participants will be included in the treatment group 
corresponding to the study intervention they actually received for the analysis of safety data 
using the APaT population. For most participants, this will be the intervention group to 
which they are randomized. Participants who take incorrect study intervention for the entire 
treatment period will be included in the intervention group corresponding to the study 
intervention actually received. Any participant who receives the incorrect study intervention 
for 1 cycle, but receives the correct intervention for all other cycles, will be analyzed 
according to the correct intervention group, and a narrative will be provided for any events 
that occur during the cycle for which the participant is incorrectly dosed.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study intervention is required for inclusion in the analysis of each specific parameter. To 
assess change from baseline, a baseline measurement is also required. The baseline value is 
defined as the last available measurement on or before the participant’s first study 
intervention during Maintenance Phase.
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Details on the approach to handling safety analyses are provided in Section 9.6.
9.5.2
Patient-reported Outcomes Analysis Population
The PRO analyses are based on the PRO Full Analysis Set population, defined as 
randomized participants who have at least 1 PRO assessment available and have received at 
least 1 dose of study intervention.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
9.6.1
Statistical Methods for Efficacy Analyses
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 9.8. Nominal p-values will be computed 
for other efficacy analyses, but these values should be interpreted with caution due to 
potential issues of multiplicity. Response or progression in the Second Course Phase will not 
count toward the PFS endpoint in this study.
9.6.1.1
Progression-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
intervention group. The treatment difference in PFS will be assessed by the stratified log-
rank test. A stratified Cox proportional hazard model with Efron’s method of tie handling 
will be used to assess the magnitude of the treatment difference (ie, the HR) between the 
treatment arms. The HR and its 95% CI from the stratified Cox model with Efron’s method 
of tie handling and with a single treatment covariate will be reported. The stratification 
factors used for randomization (Section 6.3.2) will be applied to both the stratified log-rank 
test and the stratified Cox model.
Since PD is assessed periodically, PD can occur any time in the time interval between the last 
assessment when PD was not documented and the assessment when PD is documented. The 
true date of PD will be approximated by the date of the first assessment when PD is 
objectively documented per RECIST 1.1 by BICR. Death is always considered a confirmed 
PD event. Participants who do not experience a PFS event will be censored at the last disease 
assessment. Sensitivity analyses will be performed for comparison of PFS based on the 
investigator’s assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by BICR, 1 primary 
and 2 sensitivity analyses with a different set of censoring rules will be performed. For the 
primary analysis, if the events (PD or death) are immediately after more than one missed 
disease assessment, the data are censored at the last disease assessment prior to missing 
visits. Also, data after new anticancer therapy are censored at the last disease assessment 
prior to the initiation of new anticancer therapy. The first sensitivity analysis follows the 
intent-to-treat principle. That is, PDs/deaths are counted as events, regardless of missed study 
visits or initiation of new anticancer therapy. The second sensitivity analysis considers 
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initiation of new anticancer treatment or discontinuation of treatment due to reasons other 
than complete response to be a PD event for participants without documented PD or death. If 
a participant meets multiple criteria for censoring, the censoring criterion that occurs earliest 
will be applied.
The censoring rules for primary and sensitivity analyses are summarized in Table 15.
Table 15
Censoring Rules for Primary and Secondary Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
PD or death 
documented after ≤1 
missed disease 
assessment, and before 
new anticancer 
intervention, if any
Progressed at date of 
documented PD or 
death 
Progressed at date of 
documented PD or 
death
Progressed at date 
of documented PD 
or death
PD or death 
documented 
immediately after ≥2 
consecutive missed 
disease assessments or 
after new anticancer 
intervention, if any
Censored at last disease 
assessment prior to 
the earlier date of ≥2 
consecutive missed 
disease assessment and 
new anticancer 
intervention, if any
Progressed at date of 
documented PD or 
death
Progressed at date 
of documented PD 
or death
No PD and no death; 
new anticancer 
intervention is not 
initiated
Censored at last disease 
assessment 
Censored at last 
disease assessment 
Progressed at 
treatment 
discontinuation due 
to reasons other 
than complete 
response; otherwise 
censored at last 
disease assessment 
if still on study 
intervention or 
completed study 
intervention.
No PD and no death;
new anticancer 
intervention is initiated
Censored at last disease 
assessment before new 
anticancer intervention
Censored at last 
disease assessment
Progressed at date 
of new anticancer 
intervention
Abbreviations: PD = progressive disease; PFS = progression-free survival.
In case the proportional hazards assumption is not valid, supportive analyses using the 
restricted mean survival time (RMST) method may be conducted for PFS to account for the 
possible non-proportional hazards effect.
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Further details of sensitivity analyses will be described in sSAP as needed.
9.6.1.2
Overall Survival (OS)
The nonparametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test. A stratified 
Cox proportional hazard model with Efron’s method of tie handling will be used to assess the 
magnitude of the treatment difference (ie, the HR) between the treatment arms. The HR and 
its 95% CI from the stratified Cox model with a single treatment covariate will be reported. 
The stratification factors used for randomization (Section 6.3.2) will be applied to both the 
stratified log-rank test and the stratified Cox model. Participants without documented death 
at the time of analysis will be censored at the date of last known to be alive.
In case the proportional hazards assumption is not valid, the RMST method may be 
conducted for OS to account for the possible nonproportional hazards effect as a sensitivity 
analysis.
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9.6.1.3
Analysis Strategy for Key Efficacy Endpoints
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 16.
Table 16
Efficacy Analysis Methods for Key Efficacy Endpoints
Endpoint/
Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses:
PFS (RECIST 1.1) 
by BICR
Testing: Stratified log-rank test
To assess treatment difference
Estimation: Stratified Cox model 
with Efron’s tie handling method 
to assess the magnitude of 
treatment difference
ITT
1. Primary censoring rule
2. Sensitivity analysis 1
3. Sensitivity analysis 2
More details are in Table 14
OS
Testing: Stratified log-rank test
To assess treatment difference
Estimation: Stratified Cox model 
with Efron’s tie handling method 
to assess the magnitude of 
treatment difference
ITT
Censored at last known alive date
Abbreviations: BICR = blinded independent central review; ITT = intention to treat; OS = overall survival; PFS = 
progression-free survival; RECIST 1.1 = response evaluation criteria in solid tumors version 1.1.
9.6.2
Statistical Methods for Safety Analyses
Adverse events occurring in participants treated during the Induction Phase will be collected 
and reported, which will be detailed in the sSAP.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements after randomization.
The analysis of safety results in the APaT will follow a tiered approach (Table 17).
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Table 17
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Intervention 
Comparison
Descriptive 
Statistics
Tier 2
Any AE (≥10% of participants in either of the 
intervention arms)
X
X
Any serious AE (≥5% of participants in either of the 
intervention arms)
X
X
Any Grade 3 to 5 AE (≥5% of participants in either 
of the intervention arms)
X
X
Tier 3
AEs, Specific AEs, SOCs
X
Discontinuation due to AE
X
Dose interruption due to AE
X
Change from Baseline Results (Laboratories, ECGs, 
Vital Signs)a
X
Abbreviations: AE = adverse event; ECG = electrocardiogram; PDLC = pre-defined limit of change; SOC = system 
organ class. 
a The baseline value is defined as last available measurement on or before the first study intervention during 
Maintenance Phase.
The tiers differ with respect to the analyses that will be performed. Adverse events (specific 
terms and system organ class terms) and events that meet predefined limits of change in 
laboratory, vital signs, and ECG parameters are either prespecified as Tier 1 endpoints, or 
they will be classified as belonging to Tier 2 or Tier 3, based on the number of observed 
events.
Tier 1 Events
Safety parameters or adverse events of special interest (AEOSIs) that are identified a priori 
constitute Tier 1 safety endpoints that will be subject to inferential testing for statistical 
significance with p-values and 95% CIs provided for between-group comparisons. Those 
AEOSIs that are immune-mediated or potentially immune-mediated are well documented and 
will be separately evaluated; however, these events have been consistently characterized 
throughout the pembrolizumab clinical development program, and determination of statistical 
significance is not expected to add value to the safety evaluation. In addition, there are no 
known AEs associated with participants with NSCLC for which determination of a p-value is 
expected to impact the safety assessment. Thus, there are no AEs that warrant elevation to 
Tier 1 in this study.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method 
[Miettinen, O. and Nurminen, M. 1985], an unconditional, asymptotic method.
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Membership in Tier 2 requires that at least 10% of participants in any treatment group show 
the event. The threshold of at least 10% of participants was chosen for Tier 2 events, because 
the population enrolled in this study is in critical condition and usually experiences various 
AEs of similar types, regardless of treatment; events reported less frequently than 10% of 
participants would obscure the assessment of overall safety profile and add little to the 
interpretation of potentially meaningful treatment differences. In addition, Grade 3 to 5 AEs 
(≥5% of participants in one of the intervention groups) and SAEs (≥5% of participants in one 
of the intervention groups) will be considered Tier 2 endpoints. Because many 95% CIs may 
be provided without adjustment for multiplicity, the CIs should be regarded as a helpful 
descriptive measure to be used in safety review, not a formal method for assessing the 
statistical significance of the between-group differences.
Tier 3 Events
Safety parameters that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures
Continuous measures, such as changes from baseline (ie, the last available measurement on 
or before the first study intervention during Maintenance Phase) in laboratory, vital signs, 
and ECG parameters that are not pre-specified as Tier 1 endpoints, will be considered Tier 3 
safety parameters. Summary statistics for baseline, on-treatment, and change from baseline 
values will be provided by intervention group in tabular format.
9.6.3
Statistical Methods for PRO Analyses
Changes from baseline (at randomization) in the following secondary PRO endpoints from 
the EORTC QLQ-C30 and QLQ-LC13 questionnaires will be assessed:
•
Global health status/QoL score (QLQ-C30 Items 29 and 30)
•
Cough score (QLQ-LC13 Item 1)
•
Chest pain score (QLQ-LC13 Item 10)
•
Dyspnea score (QLQ-LC13 Item 8)
•
Physical functioning score (QLQ-C30 Items 1 through 5)
A constrained longitudinal data analysis model will be applied for each endpoint, with the 
PRO score as the response variable, and treatment, time, treatment by time interaction, and 
clinical study stratification factors as covariates. Least-square mean change from baseline (at 
randomization) will be summarized for each outcome. Treatment effect on PRO score change 
from baseline will primarily be evaluated at Week 18 post-randomization. If the overall PRO 
completion or compliance rates at Week 18 are less than 60% or 80%, respectively, then the 
primary analysis time point will be moved to the next earliest time point in which the rates 
are at least 60% for completion and at least 80% for compliance. The difference in the least-
square mean change from baseline will be reported at the primary analysis time point.
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Descriptive analyses will assess the empirical mean change (with 95% CIs) from baseline 
across all time points for each endpoint.
TTD is defined as the time from baseline (at randomization) to the first onset of a ≥10-point 
decrease in PRO score with confirmation by the subsequent visit of a ≥10-point deterioration 
from randomization. The Kaplan-Meier method will be used to estimate the TTD survival 
curves for global health status/QoL (QLQ-C30 Items 29 and 30), cough (QLQ-LC13 Item 1), 
chest pain (QLQ-LC13 Item 10), dyspnea (QLQ-C30 Item 8), and physical functioning 
(QLQ-C30 Items 1 through 5), separately, in each intervention arm. In addition, TTD 
survival curves will be estimated for the composite endpoint of cough, chest pain, or dyspnea 
by intervention arm. Stratified Cox proportional hazards models with Efron’s method of tie 
handling will be used to assess the magnitude of the intervention difference for 
pembrolizumab plus olaparib compared with pembrolizumab plus pemetrexed. Stratification 
factors used for randomization will be used in the stratified Cox proportional hazards models. 
The hazard ratio, 95% CI, and nominal p-value will be reported.
Details of additional PRO analyses will be included in the sSAP.
9.6.4
Summaries of Baseline Characteristics and Demographics
The comparability of the 2 intervention arms for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs (ie, baseline values will be 
the last available measurement on or before randomization). No statistical hypothesis tests 
will be performed on these characteristics. The number and percentage of participants 
randomized, and the primary reason for screening failure and discontinuation will be 
displayed. Demographic variables (such as age, gender), baseline characteristics will be 
summarized by intervention either by descriptive statistics or categorical tables. The reasons 
for exclusion from the ITT population (if any) will be summarized.
9.7
Interim Analyses
An eDMC will serve as the primary reviewer of the results of the interim analysis (analyses) 
of the study and will make recommendations for discontinuation of the study or protocol 
modifications to the EOC of the Sponsor (Appendix 1). If the DMC recommends 
modifications to the protocol design or study discontinuation, this executive committee (and 
potentially other limited Sponsor personnel) may be unblinded to results at the treatment 
level in order to act on these recommendations. The extent to which individuals are 
unblinded with respect to results of interim analyses will be documented. Additional 
logistical details will be provided in the DMC Charter.
Treatment-level results from the interim analysis will be provided to the DMC by the 
external unblinded statistician. Prior to final study unblinding, the unblinded statistician will 
not be involved in any discussions regarding modifications to the protocol, statistical 
methods, identification of protocol deviations, or data validation efforts after the interim 
analyses
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9.7.1
9.7.2
 
 
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9.8
Multiplicity
The overall Type I error rate is strongly controlled at a 0.025 (one-sided) α level. The study 
uses the graphical method of Maurer and Bretz [Anderson, K. M., et al 2017] to provide 
strong multiplicity control for multiple hypotheses as well as interim efficacy analyses; this 
method specifically extends previous graphical multiplicity methods to cases where 
individual hypotheses are tested in a group sequential fashion using an error spending 
approach.
 
 
 
9.8.1
 
 
 
 
 
 
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9.8.2
 
 
 
 
 
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9.8.3
Safety Analyses
The DMC has responsibility for assessment of the overall risk:benefit. When prompted by 
safety concerns, the DMC can request corresponding efficacy data. DMC review of efficacy 
data to assess the overall risk:benefit to study participants will not require a multiplicity 
adjustment typically associated with a planned efficacy interim analysis. However, to 
account for any multiplicity concerns raised by the DMC review of unplanned efficacy data 
prompted by safety concerns, a sensitivity analysis for PFS and OS adopting a conservative 
multiplicity adjustment may be prespecified in the sSAP. This analysis will be performed if 
requested by the DMC.
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9.9
Sample Size and Power Calculations
The study randomized approximately 672 participants in a 1:1 ratio into the 2 study 
interventions, pembrolizumab combined with maintenance olaparib and pembrolizumab 
combined with maintenance pemetrexed. PFS and OS are dual primary endpoints for the 
study.
9.10
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9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol directed administration will be reported.
9.12
Extent of Exposure
The extent of exposure for a participant is defined as the number of cycles in which the 
participant received study intervention. Summary statistics will be provided on extent of 
exposure for the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (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 of clinical trials. In all cases, MSD clinical trials will be 
conducted in compliance with local and/or national regulations (eg, International 
Council for Harmonisation Good Clinical Practice [ICH-GCP]) and 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 (eg, 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 (ie, participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial. Participants must meet 
protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate 
participants, adequacy of facilities and staff, previous performance in clinical 
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trials, as well as budgetary considerations. Prior to trial initiation, sites are 
evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and general principles of 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 fraud, scientific/research misconduct, or serious GCP-
noncompliance is suspected, the issues are investigated. When necessary, the 
clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results 
of its registered trials of marketed products in which treatment is assigned, according 
to the prespecified plans for data analysis. To the extent scientifically appropriate, 
MSD seeks to publish the results of other analyses it conducts that 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.Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated 
at each site. Significant changes or revisions to the protocol will be approved by the 
ethics committee prior to implementation, except changes required urgently to protect 
participant safety that may be enacted in anticipation of ethics committee approval. 
For each site, the ethics committee and MSD will approve the participant informed 
consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant 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.
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All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Participants may withdraw from an 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 participant confidentiality, to the greatest extent 
possible. Unless required by law, only the investigator, Sponsor (or representative), 
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 participant referrals. However, MSD may compensate 
referring physicians for time spent on chart review 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 (eg, 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.
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10.1.2
Financial Disclosure
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 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(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/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(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.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations. Participants will be assigned a unique identifier by the Sponsor. Any participant 
records or datasets that are transferred to the Sponsor will contain the identifier only; 
participant names or any information that would make the participant identifiable will not be 
transferred. The participant must be informed that their personal study-related data will be 
used by the Sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant. The participant must be informed that their medical 
records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the Sponsor, by appropriate IRB/IEC members, and by inspectors 
from regulatory authorities. The Sponsor has EU-approved Binding Corporate Rules since 
2017, covering all aspects of its Global Privacy Program (Corporate Policy 20), and is self-
certified pursuant to the EU-US Data Privacy Framework.
10.1.3.1
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 IRB, IEC, 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 study 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.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
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worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor. By signing this protocol, 
the investigator agrees to treat all participant data used and disclosed in connection with this 
study in accordance with all applicable privacy laws, rules, and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. 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.
10.1.4
Committees Structure
10.1.4.1
Steering Committee
This study will be conducted in consultation with a Steering Committee. The Steering 
Committee may be comprised of:
•
Sponsor personnel,
•
Investigators participating in the study, and
•
Consulting therapeutic-area experts and clinical trialists.
The Steering Committee will provide guidance on the operational aspects of the study, 
evaluate recommendations from the DMC, and make recommendations to the EOC.
Specific details regarding responsibilities and governance of the Steering Committee will be 
described in a separate charter.
10.1.4.2
Executive Oversight Committee
The EOC is composed of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC or Steering Committee regarding the 
study.
10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
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study results, consider the overall risk and benefit to study participants (Section 9.7) and 
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the eDMC charter that 
is reviewed and approved by all DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, https://euclinicaltrials.eu, or other local registries. MSD, as 
Sponsor of this study, will review this protocol and submit the information necessary to 
fulfill these requirements. MSD entries are not limited to FDAAA or the EMA clinical trials 
Regulation 536/2014 mandated trials. Information posted will allow participants to identify 
potentially appropriate studies for their disease conditions and pursue participation by calling 
a central contact number for further information on appropriate study locations and study-site 
contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials Regulation 536/2014, or other locally mandated registries 
are that of the Sponsor and agrees not to submit any information about this study or its results 
to those registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
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all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
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 this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. Detailed information regarding Data 
Management procedures for this protocol will be provided separately. The investigator must 
maintain accurate documentation (source data) that supports the information entered in the 
CRF. The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. Study 
documentation will be promptly and fully disclosed to the Sponsor by the investigator upon 
request and also shall be made available at the study 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 or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs. The Sponsor or designee 
is responsible for the data management of this study including quality checking of the data. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. Records and 
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documents, including participants’ documented informed consent, pertaining to the conduct 
of this study must be retained by the investigator for 15 years after study completion unless 
local regulations or institutional policies require a longer retention period (eg, EU CTR: 25 
years after the end of the study). No records may be destroyed during the retention period 
without the written approval of the Sponsor. No records may be transferred to another 
location or party without written notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
As of Amendment 07, at the final analysis, the pembrolizumab plus olaparib arm did not 
meet the primary endpoint of OS. In addition, at the protocol prespecified final PFS analysis 
at Interim Analysis 2 that occurred on PFS was not statistically significant compared with the 
control arm. The study will remain open so ongoing participants will have continued access 
to olaparib, pemetrexed and pembrolizumab if they qualify per protocol or until transferred to 
an extension study, if applicable. Given that the study did not meet primary endpoints, 
central imaging verification, ePRO data, and survival follow-up will no longer be collected.
Participants in survival follow-up will be discontinued from the study. Effective with 
Amendment 08, participants who are in follow-up and did not receive 35 doses of 
pembrolizumab during the initial treatment period and/or are not eligible for second course 
treatment should be discontinued.
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 21 will be performed by the local laboratory.
•
All on-treatment samples will be collected prior to administration of study intervention.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 21
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count 
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC count
Hemoglobin
Hematocrit
Chemistry
Blood Urea Nitrogen 
(BUN) or ureaa
Potassium
Aspartate 
aminotransferase
(AST)/serum glutamic-
oxaloacetic transaminase 
(SGOT)
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Carbon dioxide (CO2
or bicarbonate)b
Chloride
Phosphorous
Creatinine or creatinine 
clearancec
Sodium
Alanine 
aminotransferase
(ALT)/serum glutamic-
pyruvic transaminase 
(SGPT)
Total protein
Glucose (nonfasting)
Calcium
Alkaline phosphatase
Lactate 
dehydrogenase
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone (as needed in WOCBP only)

Serum or urine human chorionic gonadotropin (hCG) pregnancy test (as needed for WOCBP).

Serology (HIV antibody, hepatitis B surface antigen, and hepatitis C virus antibody), as required 
by local health authority or institutional regulations. Refer to Appendix 7 for country-specific 
information.

Coagulation factors (PT or INR, and aPTT/PTT). Additional testing to be conducted as clinically 
indicated for participants taking anticoagulation therapy.

Thyroid-stimulating hormone (TSH), free thyroxine (FT4), triiodothyronine (T3)
Other Tests
Bone marrow or blood cytogenetic analysis for prolonged hematological toxicities (Section 6.6.2.2). 
This should include an aspirate for cellular morphology, cytogenetic analysis, and flow cytometry, and 
a core biopsy for bone marrow cellularity
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Laboratory 
Assessments
Parameters
Abbreviations: aPTT = activated partial thromboplastin time; FT4 = free thyroxine; HIV = human immunodeficiency 
virus; INR = international normalized ratio; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; 
PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cell; T3 = triiodothyronine; TSH = thyroid-
stimulating hormone; WBC = white blood cell; WOCBP = woman/women of childbearing potential.
Notes:
a.
BUN is preferred; if not available, urea may be tested.
b.
Performed only if considered the local standard of care.
c.
GFR (measured or calculated) or creatinine clearance can be used in place of creatinine. 
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
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d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, 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.
10.3.4
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes..
•
Is a new cancer (that is not a condition of the study)
•
Is associated with an overdose.
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
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•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 4.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life-threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Note: A semi-colon indicates ‘or’ within the description of the grade.
Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
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•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with IMP)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the study intervention discontinued or dose/exposure/frequency 
reduced?
o
If yes, did the AE resolve or improve?
o
If yes, this is a positive dechallenge.
o
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant reexposed to the study intervention in this study?
o
If yes, did the AE recur or worsen?
o
If yes, this is a positive rechallenge.
o
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose drug study; or (3) study 
intervention (s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
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•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
o
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
o
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
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10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A 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 postmenopausal state in women not using hormonal contraception or hormone 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with 2 FSH measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraceptive Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to 1 of the following during the protocol defined time frame in Section 5.1:
•
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
•
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant.
-
The following are not acceptable methods of contraception:
o
Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method (LAM).
o
Male condom with cap, diaphragm, or sponge with spermicide.
o
Male and female condom cannot be used together.
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration.
Note: Male participants must refrain from donating sperm during treatment and for at least 
180 days after the last dose of study intervention.
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
consistent and correct use of a highly effective method of contraception, as described in 
Table 22 during the protocol-defined time frame in Section 5.1.
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Table 22
Highly Effective Contraception Methods
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb
•
IUSc
•
Non-hormonal IUD
•
Bilateral tubal occlusion
• Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
•
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for participants of clinical studies.
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to those which 
inhibit ovulation.
c
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
-
Male condom with cap, diaphragm, or sponge with spermicide.
-
Male and female condom should not be used together (due to risk of failure with friction).
10.5.3
Pregnancy Testing
•
Pregnancy testing requirements for study inclusion are described in Section 5.1.
•
Pregnancy testing ([urine or serum] as required by local regulations) should be conducted 
at monthly intervals during intervention.
•
Pregnancy testing ([urine or serum] as required by local regulations) should be conducted 
30 days after the last dose of study intervention.
•
Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the participant’s participation in the study.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.
Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2.
Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3.
Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or their designate. Informed consent for future biomedical 
research should be presented to the participants on the visit designated in the SoA. If 
delayed, present consent at next possible Participant Visit. Consent forms signed by 
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the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
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6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
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9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
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4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
Information obtained from studying and testing clinical specimens offers unique 
opportunities to enhance our understanding of how individuals respond to drugs/vaccines, 
enhance our understanding of human disease, and ultimately improve public health through 
development of novel treatments targeted to populations with the greatest need. All 
specimens will be used by the Sponsor or those working for or with the Sponsor.  
Confidential Participant Information for Biomarker Research 1
To optimize the research, including exploratory research, that can be conducted with 
biomarker specimens, it is critical to link participants' clinical information with biomarker 
results. In fact, little or no research can be conducted without connecting the clinical study 
data to the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes are 
critical to understanding clinical context of analytical results. 
To maintain privacy of information collected from specimens obtained for research, the 
Sponsor has developed secure policies and procedures. All specimens will be single coded 
per ICH E15 guidelines, and as described in the following paragraph: 
At the clinical study site, unique codes will be placed on the biomarker specimens. This code 
is a random number which does not contain any personally identifying information 
embedded within it. The link (or key) between participant identifiers and this unique code 
will be held at the study site. No personal identifiers will appear on the specimen tube.  
Biorepository Specimen Usage 
Specimens obtained for the Sponsor will be used for analyses using good scientific practices. 
Analyses using biomarker specimens may be performed by the Sponsor, or an additional 
third party (eg, a university investigator) designated by the Sponsor. The investigator 
conducting the analysis will follow the Sponsor’s privacy and confidentiality requirements. 
Any contracted third-party analyses will conform to the specific scope of analysis outlined in 
the protocol and consent. Biomarker specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.   
Retention of Specimens 
Biomarker and other specimens will be stored in the biorepository for potential analysis for 
up to 15 years from the end of the study. If there are regulatory or governmental authority 
questions that are being answered, specimens may be stored for longer. In this special 
circumstance, specimens will be stored until these questions have been adequately addressed. 
The specimens will be stored in a limited access facility that operates to assure the integrity 
of the specimens and under strict supervision. Specimens will be destroyed according to 
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Sponsor policies and procedures and this destruction will be documented in the biorepository 
database.  
Data Security 
Databases containing specimen information and research results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research personnel 
and/or collaborators. Database user authentication is highly secure and is accomplished using 
network security policies and practices based on international standards to protect against 
unauthorized access.  
Reporting of Exploratory Research Data to Participants 
Results obtained from genetic and biomarker research will not be given to study participants 
or the trial doctor. 
If important research findings are discovered, the Sponsor may share this information by: 

publishing the results in peer-reviewed journals 

presenting the results at national meetings 

providing the results on a publicly accessible website that would be available to doctors 
and participants
Participants will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.  
Questions 
Any questions related to the exploratory biomarker research should be emailed directly to 
clinical.specimen.management@MSD.com. 
References 
1 International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers- pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html
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10.7
Appendix 7: Country-specific Requirements
10.7.1
France Country-specific Requirements
1. Section 1.3.1: Schedule of Activities for Screening and Induction Phases
Pregnancy testing is required at each cycle during treatment as well as at the end of study 
treatment.
2. Section 1.3.2: Schedule of Activities for Maintenance Phase
Pregnancy testing is required at each cycle during treatment as well as at the end of study 
treatment.
3. Section 1.3.4: Schedule of Activities for Second Course Phase
Pregnancy testing is required at each cycle during treatment as well as at the end of study 
treatment.
4. Section 10.5 Appendix 3: Contraceptive Guidance and Pregnancy Testing
Pregnancy testing is required at each cycle during treatment as well as at the end of study 
treatment.
10.7.2
Germany Country-specific Requirements
1. Section 5.2 Exclusion Criteria
•
Exclusion Criterion 10: HIV testing is required for participants who are residents of 
Germany.
•
Exclusion Criterion 11: Hepatitis B and C testing is required for participants who are 
residents of Germany.
•
Exclusion Criterion 12: TB testing is required for participants who are residents of 
Germany.
2. Section 1.3.1: Schedule of Activities for Screening and Induction Phases
Monthly urine pregnancy testing is required during treatment as well as at the end of 
study treatment.
3. Section 1.3.2: Schedule of Activities for Maintenance Phase
Monthly urine pregnancy testing is required during treatment as well as at the end of 
study treatment.
4. Section 1.3.4: Schedule of Activities for Second Course Phase
Pregnancy testing is required at each cycle during treatment as well as at the end of study 
treatment.
5. Section 6.5.1 (Prohibited Concomitant Medications): Live vaccines must not be 
administered for 90 days after the last dose of study intervention.
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6. Section 4.4: Legally Acceptable Representative
In order for a participant to be eligible to participate in Germany, they must be capable of 
providing documented informed consent; therefore, all references to a participant’s 
“legally acceptable representative” in the protocol are not applicable for participants in 
Germany.
7. Section 10.5 Appendix 3: Contraceptive Guidance and Pregnancy Testing
Monthly urine pregnancy testing after randomization is required during treatment as well 
as at the end of study treatment.
10.7.3
Japan Country-specific Requirements
For the assistance to early diagnosis of pneumonitis/interstitial lung disease (ILD) in study 
participants, the following items, such as pulse oximetry monitoring (peripheral capillary 
oxygen saturation [SpO2]), C-reactive protein (CRP), Krebs von den Lungen-6 (KL-6), and 
surfactant protein-D (SP-D), will be measured in this study. These items should be measured 
as follows:
•
SpO2 at the timing of vital sign assessment.
•
CRP, KL-6, and SP-D at screening*, predose on Day 1 of every cycle, end-of-treatment, 
and the Safety Follow-up Visit (30 days after last dose).
*Should be measured at the timing of clinical laboratory tests (such as 
hematology/chemistry).
If pneumonitis/ILD occurs regardless of causality with study intervention, an independent 
ILD evaluation committee will conduct adjudication of cases of the pneumonitis/ILD. For 
this purpose, relevant data, such as chest imaging (from the baseline to the recovery of 
pneumonitis/ILD) will be submitted to MSD K.K.
10.7.4
United Kingdom Country-specific Requirements
1. Section 6.5.1 (Prohibited Concomitant Medications): Live vaccines must not be 
administered for 90 days after the last dose of study intervention. Refer to Section 6.5 for 
information on COVID-19 vaccines.
2. Males are to be advised to seek counseling on sperm storage before starting pemetrexed 
and platinum-based therapy as per respective SmPCs.
3. Section 1.3.1: Schedule of Activities for Screening and Induction Phases
Monthly urine pregnancy testing is required during treatment as well as at the end of 
study treatment.
4. Section 1.3.2: Schedule of Activities for Maintenance Phase
Monthly urine pregnancy testing is required during treatment as well as at the end of 
study treatment.
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5. Section 1.3.4: Schedule of Activities for Second Course Phase
Monthly urine pregnancy testing is required during treatment as well as at the end of 
study treatment.
6. Section 10.5 Appendix 3: Contraceptive Guidance and Pregnancy Testing
Monthly urine pregnancy testing is required during treatment as well as at the end of 
study treatment.
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and to guide decisions about changes in management.
Assessment at screening and before RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show radiological disease progression by RECIST 1.1, the investigator 
will decide whether to continue a participant on study intervention until repeat scans 4 to 8 
weeks later are obtained, as described in Section 8.2.1.6.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:
•
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
Note: The iRECIST publication uses the terminology “sum of measurements,” but “sum 
of diameters” will be used in this protocol, consistent with the original RECIST 1.1 
terminology.
•
Unequivocal progression of nontarget lesion(s) identified at baseline
•
Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Nontarget.
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Assessment at the Confirmatory Scans
On the confirmatory scans, the participant will be classified as progression confirmed (with 
an overall response of iCPD), or as showing persistent unconfirmed progression (with an 
overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:
•
Any of the factors that were the basis for the iUPD at the previous visit show worsening
-
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared with any prior iUPD time point
-
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared with a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
-
For new lesions, worsening is any of these:
o
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time 
point
o
Visible growth of new nontarget lesions
o
The appearance of additional new lesions
•
Any new factor appears that would have triggered disease progression by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
•
None of the progression-confirming factors identified above occurs AND
•
The target lesion sum of diameters (initial target lesions) remains above the initial disease 
progression threshold (by RECIST 1.1)
Additional scans for confirmation are to be scheduled 4 to 8 weeks from the scans on which 
iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation scan proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
•
None of the progression-confirming factors identified above occurs, AND
•
The target lesion sum of diameters (initial target lesions) is not above the disease 
progression threshold.
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The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudoprogression, and the level of 
suspicion for progression is “reset.” This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Scan
If repeat scans do not confirm disease progression, and the participant continues to be 
clinically stable, study intervention is to continue. The regular scan schedule is to be 
followed. If disease progression is confirmed, participants may be discontinued from study 
intervention.
NOTE: If a participant has confirmed radiographic progression (iCPD) and clinically 
meaningful benefit, study intervention may be continued after consultation with the Sponsor. 
If study intervention is continued, tumor scans are to be performed after the intervals as 
outlined in Section 1.3.
Detection of Progression at Visits After Pseudoprogression Resolves
After resolution of pseudoprogression (ie, after iSD/iPR/iCR), another instance of 
progression (another iUPD) is indicated by any of the following events:
•
Target lesions
-
Sum of diameters reaches the disease progression threshold (≥20% and ≥5 mm 
increase from nadir) either for the first time, or after resolution of previous 
pseudoprogression. The nadir is always the smallest sum of diameters seen during the 
entire study, either before or after an instance of pseudoprogression.
•
Nontarget lesions
-
If nontarget lesions have never shown unequivocal progression, their doing so for the 
first-time results in iUPD.
-
If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
nontarget lesions, taken as a whole.
•
New lesions
-
New lesions appear for the first time
-
Additional new lesions appear
-
Previously identified new target lesions show an increase of ≥5 mm in the new lesion 
sum of diameters, from the nadir value of that sum
-
Previously identified nontarget lesions show any significant growth
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If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Scan above) is repeated. Progression 
must be confirmed before iCPD can occur.
The decision process on the subsequent iUPD is identical to the iUPD confirmation process 
for the initial disease progression, with one exception, which can occur if new lesions had 
occurred at a prior instance of iUPD, had not resolved, then worsened (increase in size or 
number) leading to the second iUPD. If new lesion worsening has not resolved at the 
confirmatory scan then iUPD cannot resolve to iSD or iPR. It will remain iUPD until either a 
decrease in the new lesion burden allows resolution to iSD or iPR, or until new or worsening 
cause of progression indicates iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
1L
first-line
AE
adverse event 
AEOSI
adverse events of special interest
ALK
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase
AML
acute myeloid leukemia 
ANC
absolute neutrophil count
APaT
all participants as treated
AST
aspartate aminotransferase
ATM
ataxia-telangiectasia mutated 
AUC
area under concentration-time curve
BCG
Bacillus Calmette–Guérin
BICR
blinded independent central review 
BID
twice daily
BRCA1/2
breast cancer susceptibility gene 1/2
BRCAm
breast cancer susceptibility gene mutation
C30
Core 30
CI
confidence interval
Cmax
maximum plasma concentration
CONSORT
Consolidated Standards of Reporting Trials 
COPD
chronic obstructive pulmonary disease
CR
complete response
CrCl
creatinine clearance
CRF
Case Report Form 
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trials Facilitation and Coordination Group
CTR
clinical trial regulation 
CYP
cytochrome P450
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Abbreviation
Expanded Term
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
duration of response 
DSB
double-strand breaks 
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Cancer Group
eCRF
electronic case report form
EDC
electronic data collection
eDMC
External Data Monitoring Committee 
EEA
European economic area
EGFR
epidermal growth factor receptor 
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EORTC
European Organization for Research and Treatment of Cancer 
EOS
end of study
EOT
end-of-treatment
ePRO
electronic patient-reported outcomes
EQ-5D-5L
European Quality of Life Five-dimension Five-level Scale 
Questionnaire
ESMO
European Society for Medical Oncology
EU
European Union
FAS
full analysis set
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone 
FSR
first site ready
FT4
free thyroxine
GCP
Good Clinical Practice 
G-CSF
granulocyte colony-stimulating factor 
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Abbreviation
Expanded Term
GFR
glomerular filtration rate
GM-CSF
granulocyte-macrophage colony-stimulating factor 
GMP
Good Manufacturing Practice
Hb
hemoglobin
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
heart rate
HRD
homologous recombination deficiency
HRD-LOH
homologous recombination deficiency loss of heterozygosity
HRQoL
health-related quality of life 
HRR
homologous recombination repair
HRRm
homologous recombination repair mutations
HRT
hormone replacement therapy
IB
investigator brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
iCPD
iRECIST confirmed progressive disease
iCR
iRECIST complete response
iCRO
imaging contract research organization
ICSR
Individual case study report
IEC
Independent Ethics Committee
Ig
immunoglobulin
IHC
immunohistochemistry
ILD
interstitial lung disease
IM
intramuscular
IND
Investigational New Drug 
IO
immuno-oncology
iPR
iRECIST partial response
irAE
immune-related adverse event 
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Abbreviation
Expanded Term
IRB
Institutional Review Board 
iRECIST
modified Response Evaluation Criteria in Solid Tumors 1.1 for 
immune-based therapeutics
IRT
interactive response system
iSD
iRECIST stable disease
ITT
intent-to-treat
IUD
intrauterine device
iUPD
iRECIST unconfirmed progressive disease
IV
intravenous 
LC13
Lung Cancer Module 13
LOH
loss of heterozygosity 
MASCC
Multinational Association of Supportive Care in Cancer
MDS
myelodysplastic syndrome 
MRI
magnetic resonance imaging 
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCT
National Clinical Trial
NHEJ
nonhomologous end-joining
NSCLC
non–small-cell lung cancer
ORR
objective response rate 
OS
overall survival
PARP
polyadenosine 5′ diphosphoribose polymerization
PBPK
Physiologically based PK
PD
progressive disease
PD-1
programmed cell death 1 
PD-L1
programmed cell death ligand 1 
PD-L2
programmed cell death ligand 2
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
PRO
patient reported outcome
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Abbreviation
Expanded Term
PT
prothrombin time
Q12W
every 12 weeks
Q2W
every 2 weeks 
Q3W
every 3 weeks
Q6W
every 6 weeks
Q9W
every 9 weeks
QLQ
Quality of Life Questionnaire
QoL
quality of life 
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RMST
restricted mean survival time
RNA
ribonucleic acid
SAE
serious adverse event 
SD
stable disease
SoA
schedule of activities
SOC
standard of care
SpO2
pulse oximetry monitoring
sSAP
supplemental statistical analysis plan
SSB
single strand break
SUSAR
suspected unexpected serious adverse reaction
t1/2
terminal half-life
TIL
tumor-infiltrating lymphocytes
Tmax
time to maximum plasma concentration
TPS
tumor proportion score
ULN
upper limit of normal
USPI
United States prescribing information
VOP
verification of progression
WOCBP
woman/women of childbearing potential 
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Bullinger M, Cull A, Duez NJ, et al. The 
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clinical trials in oncology. J Natl Cancer 
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[Ame, J. C., et al 2004]
Ame JC, Spenlehauer C, de Murcia G. The 
PARP superfamily. Bioessays. 2004 
Aug;26(8):882-93.
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[Anderson, K. M., et al 2017]
Anderson KM, Wang L, Gause CK. 
Application of graphical multiplicity 
methods in complex group sequential trials. 
Kenilworth (NJ): Merck & Co., Inc. (US); 
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08PHQG
08PWNL

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