Conditions: Triple Negative Breast Cancer (TNBC)
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Cell Death 1 Ligand 1(PDL1, PD-L1) Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 882
Healthy volunteers: no

Brief summary:
The study will consist of two parts.

In Part 1, the safety of pembrolizumab (MK-3475) in combination with one of three different chemotherapies will be assessed in the treatment of locally recurrent inoperable or metastatic triple negative breast cancer (TNBC), which has not been previously treated with chemotherapy.

In Part 2, the safety and efficacy of pembrolizumab plus background chemotherapy will be assessed compared to the safety and efficacy of placebo plus background chemotherapy in the treatment of locally recurrent inoperable or metastatic TNBC, which has not been previously treated with chemotherapy.

The primary hypotheses are that:

1. the combination of pembrolizumab and chemotherapy prolongs Progression-Free Survival (PFS) compared to placebo and chemotherapy in:

   * all participants,
   * participants with programmed cell death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors, and
   * participants with PD-L1 CPS ≥10 tumors, and
2. the combination of pembrolizumab and chemotherapy prolongs Overall Survival (OS) compared to placebo and chemotherapy in:

   * all participants,
   * participants with PD-L1 CPS ≥1 tumors, and
   * participants with PD-L1 CPS ≥10 tumors.

Detailed description:

Arms:
arm 1: Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle PLUS nab-paclitaxel 100 mg/m\^2 IV on Days 1, 8 and 15 of each 28-day cycle. arm 2: Participants receive pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS paclitaxel 90 mg/m\^2 IV on Days 1, 8 and 15 of each 28-day cycle. arm 3: Participants receive pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS gemcitabine/carboplatin 1000 mg/m\^2 (gemcitabine) and an Area Under the Curve (AUC) 2 (carboplatin) on Days 1 and 8 of each 21-day cycle. arm 4: Participants receive pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS one of three background chemotherapy regimens at investigator's discretion: 1) nab-paclitaxel 100 mg/m\^2 IV on Days 1, 8 and 15 of each 28-day cycle, 2) paclitaxel 90 mg/m\^2 IV on Days 1, 8 and 15 of each 28-day cycle, OR 3) gemcitabine/carboplatin 1000 mg/m\^2 (gemcitabine) and an AUC 2 (carboplatin) on Days 1 and 8 of each 21-day cycle. arm 5: Participants receive placebo (normal saline) IV on Day 1 of each 21-day cycle PLUS one of three background chemotherapy regimens at investigator's discretion: 1) nab-paclitaxel 100 mg/m\^2 IV on Days 1, 8 and 15 of each 28-day cycle, 2) paclitaxel 90 mg/m\^2 IV on Days 1, 8 and 15 of each 28-day cycle, OR 3) gemcitabine/carboplatin 1000 mg/m\^2 (gemcitabine) and an AUC 2 (carboplatin) on Days 1 and 8 of each 21-day cycle.

Interventions: intervention 1: Pembrolizumab intervention 2: Nab-paclitaxel intervention 3: Paclitaxel intervention 4: Gemcitabine intervention 5: Carboplatin intervention 6: Normale Saline Solution
Intervention descriptions: intervention 1: IV infusion intervention 2: IV infusion intervention 3: IV infusion intervention 4: IV infusion intervention 5: IV infusion intervention 6: IV infusion

Protocol document:
Prot_002.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Randomized, Double-Blind, Phase III Study of 
Pembrolizumab (MK-3475) plus Chemotherapy vs 
Placebo plus Chemotherapy for Previously 
Untreated Locally Recurrent Inoperable or 
Metastatic Triple Negative Breast Cancer – 
(KEYNOTE-355)
NCT02819518
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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
SPONSOR:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Randomized, Double-Blind, Phase III Study of Pembrolizumab (MK-3475) plus 
Chemotherapy vs Placebo plus Chemotherapy for Previously Untreated Locally Recurrent 
Inoperable or Metastatic Triple Negative Breast Cancer – (KEYNOTE-355)
IND NUMBER:124,442
EudraCT NUMBER:  2016-001432-35
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 12
SUMMARY OF CHANGES................................................................................................ 14
1.0
TRIAL SUMMARY.................................................................................................. 15
2.0
TRIAL DESIGN........................................................................................................ 16
Trial Design ........................................................................................................... 16
Trial Diagram........................................................................................................ 18
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 19
Primary Objective(s) & Hypothesis(es).............................................................. 19
Secondary Objective(s) & Hypothesis(es)........................................................... 20
Exploratory Objectives......................................................................................... 21
4.0
BACKGROUND & RATIONALE.......................................................................... 21
Background ........................................................................................................... 21
Pharmaceutical and Therapeutic Background .................................................... 21
Pre-Clinical and Clinical Studies........................................................................ 24
Ongoing Clinical Studies .................................................................................... 26
Information on Other Study-Related Therapy .................................................... 26
Rationale................................................................................................................ 27
Rationale for the Trial and Selected Subject Population .................................... 27
4.2.1.1
Rationale for the Study ................................................................................ 27
4.2.1.2
Rationale for Selected Subject Population................................................... 29
Rationale for Dose Selection/Regimen/Modification......................................... 29
4.2.2.1
Rationale for Pembrolizumab Dose Selection ............................................. 29
4.2.2.2
Rationale for Chemotherapy Dose Selections ............................................. 30
4.2.2.3
Rationale for Dose Interval and Trial Design.............................................. 31
4.2.2.3.1
Rationale for Dose Interval................................................................... 31
4.2.2.3.2
Rationale for Study Design................................................................... 31
Rationale for Endpoints ...................................................................................... 32
4.2.3.1
Efficacy Endpoints....................................................................................... 32
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4.2.3.1.1
Primary.................................................................................................. 32
4.2.3.1.2
Secondary.............................................................................................. 32
4.2.3.1.3
Exploratory ........................................................................................... 32
4.2.3.2
Safety Endpoints.......................................................................................... 33
4.2.3.3
Planned Exploratory Biomarker Research................................................... 33
4.2.3.4
Future Biomedical Research........................................................................ 35
Benefit/Risk ........................................................................................................... 36
5.0
METHODOLOGY ................................................................................................... 36
Entry Criteria........................................................................................................ 36
Diagnosis/Condition for Entry into the Trial...................................................... 36
Subject Inclusion Criteria.................................................................................... 36
Subject Exclusion Criteria .................................................................................. 40
Trial Treatment(s) ................................................................................................ 43
Dose Selection/Modification .............................................................................. 43
5.2.1.1
Dose Selection (Preparation) ....................................................................... 43
5.2.1.2
Dose Modification ....................................................................................... 44
5.2.1.2.1
Dose Modification and Toxicity Management Guidelines for 
Pembrolizumab ..................................................................................... 45
5.2.1.2.2
Nab-Paclitaxel....................................................................................... 50
5.2.1.2.3
Paclitaxel............................................................................................... 50
5.2.1.2.4
Gemcitabine/Carboplatin...................................................................... 50
Timing of Dose Administration.......................................................................... 50
5.2.2.1
Pembrolizumab/Saline Placebo ................................................................... 51
5.2.2.2
Nab-Paclitaxel.............................................................................................. 51
5.2.2.3
Paclitaxel...................................................................................................... 51
5.2.2.4
Gemcitabine/Carboplatin ............................................................................. 51
Trial Blinding...................................................................................................... 51
Randomization or Treatment Allocation............................................................ 52
Stratification.......................................................................................................... 53
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 53
Acceptable Concomitant Medications ................................................................ 53
Prohibited Concomitant Medications.................................................................. 53
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Rescue Medications & Supportive Care............................................................. 54
Supportive Care Guidelines for Subjects Receiving Pembrolizumab/Placebo... 54
Supportive Care Guidelines for Chemotherapy-related Adverse Events ........... 55
Diet/Activity/Other Considerations..................................................................... 55
Diet...................................................................................................................... 55
Subject Withdrawal/Discontinuation Criteria................................................... 55
Subject Replacement Strategy............................................................................. 56
Beginning and End of the Trial ........................................................................... 56
Clinical Criteria for Early Trial Termination ................................................... 56
6.0
TRIAL FLOW CHART ........................................................................................... 58
First Course Treatment Phase............................................................................. 58
Screening and Treatment Periods (Parts 1 and 2)............................................... 58
6.1.1.1
Pembrolizumab/Placebo Plus Taxane (Paclitaxel or Nab-Paclitaxel) ......... 58
6.1.1.2
Pembrolizumab/Placebo Plus Gemcitabine/Carboplatin............................. 62
End of Treatment and After Treatment Discontinuation (Parts 1 and 2)............ 65
Second Course Phase (Retreatment Phase) for Part 1 Subjects or Part 2 
Subjects Randomized to Pembrolizumab Plus Chemotherapy........................ 67
Treatment Period................................................................................................. 67
6.2.1.1
Pembrolizumab ............................................................................................ 68
6.2.1.2
Pembrolizumab Plus Taxane (Paclitaxel or Nab-Paclitaxel)....................... 70
6.2.1.3
Pembrolizumab Plus Gemcitabine/Carboplatin........................................... 72
End of Treatment and After Treatment Discontinuation .................................... 74
7.0
TRIAL PROCEDURES ........................................................................................... 76
Trial Procedures ................................................................................................... 76
Administrative Procedures.................................................................................. 76
7.1.1.1
Informed Consent......................................................................................... 76
7.1.1.1.1
General Informed Consent.................................................................... 76
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 77
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 77
7.1.1.3
Subject Identification Card .......................................................................... 77
7.1.1.4
Medical History ........................................................................................... 77
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7.1.1.4.1
Other Than Breast Cancer..................................................................... 77
7.1.1.4.2
Breast Cancer Diagnosis Details........................................................... 77
7.1.1.4.3
Prior Treatments for Breast Cancer ...................................................... 77
7.1.1.5
Prior and Concomitant Medications Review............................................... 78
7.1.1.5.1
Prior Medications.................................................................................. 78
7.1.1.5.2
Concomitant Medications..................................................................... 78
7.1.1.5.3
Medications in Disease Status Follow-up Phase .................................. 78
7.1.1.6
Assignment of Screening Number............................................................... 78
7.1.1.7
Assignment of Treatment/Randomization Number..................................... 78
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)................................... 79
Clinical Procedures/Assessments........................................................................ 79
7.1.2.1
Adverse Event Monitoring........................................................................... 79
7.1.2.2
12-Lead Electrocardiogram ......................................................................... 79
7.1.2.3
Physical Examination................................................................................... 79
7.1.2.3.1
Full Physical Examination.................................................................... 79
7.1.2.3.2
Directed Physical Examination............................................................. 80
7.1.2.4
Vital Signs.................................................................................................... 80
7.1.2.5
Patient Reported Outcomes.......................................................................... 80
7.1.2.5.1
The Patient Reported Outcomes ........................................................... 80
7.1.2.6
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 80
7.1.2.7
Post-Treatment Disease Status..................................................................... 81
7.1.2.8
Menopausal Status ....................................................................................... 81
7.1.2.9
Tumor Imaging and Assessment of Disease Status ..................................... 81
7.1.2.9.1
Initial Tumor Imaging........................................................................... 82
7.1.2.9.2
Tumor Imaging During the Study......................................................... 82
7.1.2.9.3
End of Treatment and Follow-up Tumor Imaging................................ 83
7.1.2.9.4
RECIST 1.1 Assessment of Disease..................................................... 83
7.1.2.9.5
irRECIST Assessment of Disease......................................................... 84
7.1.2.10 Tumor Tissue Collection.............................................................................. 87
Laboratory Procedures/Assessments .................................................................. 88
7.1.3.1
Laboratory Safety Evaluations..................................................................... 88
7.1.3.2
Pharmacokinetic Evaluations....................................................................... 89
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7.1.3.3
Blood for Menopausal Status....................................................................... 89
7.1.3.4
Blood Collection for RNA Analysis and Plasma and Serum Biomarker 
Analyses....................................................................................................... 90
7.1.3.5
Planned Genetic Analysis Sample Collection.............................................. 90
7.1.3.6
Future Biomedical Research Sample Collection ......................................... 90
Other Procedures................................................................................................. 90
7.1.4.1
Withdrawal/Discontinuation........................................................................ 90
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 90
7.1.4.2
Blinding/Unblinding .................................................................................... 91
7.1.4.3
Calibration of Critical Equipment................................................................ 92
Visit Requirements.............................................................................................. 92
7.1.5.1
Screening...................................................................................................... 92
7.1.5.2
Treatment Period (Parts 1 and 2) ................................................................. 93
7.1.5.3
End of Treatment ......................................................................................... 93
7.1.5.4
After Treatment Discontinuation................................................................. 93
7.1.5.4.1
Safety Follow-up Visit.......................................................................... 93
7.1.5.4.2
Disease Status Follow-up Visit............................................................. 94
7.1.5.4.3
Survival Follow-up ............................................................................... 94
7.1.5.5
Survival Status ............................................................................................. 94
7.1.5.6
Second Course Phase (Retreatment Phase).................................................. 94
7.1.5.6.1
Conditions of Second Course Phase ..................................................... 94
7.1.5.6.2
Visit Requirements of Second Course Phase........................................ 95
Assessments/Procedures/Windows ................................................ 95
Discontinuation During the Second Course Phase......................... 96
Laboratory Tests During the Second Course Phase....................... 96
Concomitant Medications During the Second Course Phase......... 96
Vital Signs During the Second Course Phase ................................ 96
Pembrolizumab Retreatment During the Second Course Phase .... 96
Tumor Imaging During the Second Course Phase......................... 97
Assessing and Recording Adverse Events .......................................................... 97
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 98
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 99
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Immediate Reporting of Adverse Events to the Sponsor.................................... 99
7.2.3.1
Serious Adverse Events ............................................................................... 99
7.2.3.2
Events of Clinical Interest.......................................................................... 100
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting.......... 101
Evaluating Adverse Events............................................................................... 101
Sponsor Responsibility for Reporting Adverse Events .................................... 104
TRIAL GOVERNANCE AND OVERSIGHT................................................. 104
Scientific Advisory Committee......................................................................... 104
Executive Oversight Committee....................................................................... 104
Data Monitoring Committee............................................................................. 104
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 104
Statistical Analysis Plan Summary ................................................................... 105
Responsibility for Analyses/In-House Blinding ............................................... 107
Hypotheses/Estimation....................................................................................... 108
Analysis Endpoints ............................................................................................. 108
Efficacy Endpoints............................................................................................ 109
Safety Endpoints ............................................................................................... 109
Analysis Populations........................................................................................... 109
Efficacy Analysis Populations .......................................................................... 109
Safety Analysis Populations ............................................................................. 110
Statistical Methods.............................................................................................. 110
Statistical Methods for Efficacy Analyses........................................................ 110
8.6.1.1
Progression-Free Survival (PFS) ............................................................... 111
8.6.1.2
Overall Survival (OS) ................................................................................ 113
8.6.1.3
Objective Response Rate (ORR) ............................................................... 113
8.6.1.4
Disease Control Rate (DCR)...................................................................... 113
8.6.1.5
Duration of Response (DOR)..................................................................... 114
8.6.1.6
Summary of Statistical Methods for Efficacy............................................ 114
Statistical Methods for Safety Analyses ........................................................... 116
Summaries of Demographic and Baseline Characteristics ............................... 118
Interim Analyses ................................................................................................. 119
Part 1: Safety Interim Analysis......................................................................... 119
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Part 2: Efficacy Interim Analyses..................................................................... 119
Multiplicity .......................................................................................................... 123
Sample Size and Power Calculations ................................................................ 126
Subgroup Analyses and Effect of Baseline Factors ......................................... 130
Compliance (Medication Adherence)................................................................ 130
Extent of Exposure.............................................................................................. 130
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 131
Investigational Product ...................................................................................... 131
Packaging and Labeling Information ............................................................... 131
Clinical Supplies Disclosure............................................................................... 132
Storage and Handling Requirements................................................................ 132
Discard/Destruction/Returns and Reconciliation ............................................ 132
Standard Policies................................................................................................. 132
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 133
Confidentiality..................................................................................................... 133
Confidentiality of Data ..................................................................................... 133
Confidentiality of Subject Records................................................................... 133
Confidentiality of Investigator Information...................................................... 133
Confidentiality of IRB/IEC Information........................................................... 134
Compliance with Financial Disclosure Requirements..................................... 134
Compliance with Law, Audit and Debarment ................................................. 134
Compliance with Trial Registration and Results Posting Requirements...... 136
Quality Management System............................................................................. 136
Data Management............................................................................................... 137
Publications ......................................................................................................... 137
11.0
LIST OF REFERENCES....................................................................................... 139
12.0
APPENDICES......................................................................................................... 149
Code of Conduct for Clinical Trials.................................................................. 149
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 152
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Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 156
Abbreviations ...................................................................................................... 167
ECOG Performance Status................................................................................ 172
Contraceptive Guidance..................................................................................... 173
Definitions......................................................................................................... 173
Contraception Requirements............................................................................. 174
13.0
SIGNATURES......................................................................................................... 175
Sponsor's Representative ................................................................................... 175
Investigator.......................................................................................................... 175
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LIST OF TABLES
Table 1
Efficacy of Chemotherapy as 1L Treatment for mTNBC .................................. 29
Table 2
Adequate Organ Function Laboratory Values .................................................... 38
Table 3
Study Treatments ................................................................................................ 43
Table 4
Suggested Dose Modifications for Study Chemotherapies ................................ 45
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated With Pembrolizumab................................................... 46
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines .......................................................................................................... 49
Table 7
Subject Randomization/Allocation for Part 1..................................................... 52
Table 8
Imaging and Treatment After First Radiologic Evidence of PD ........................ 86
Table 9
Laboratory Tests ................................................................................................. 88
Table 10
Evaluating Adverse Events............................................................................... 102
Table 11
Censoring Rules for Primary and Sensitivity Analyses of PFS........................ 112
Table 12
Censoring Rules for DOR................................................................................. 114
Table 13
Analysis Strategy for Key Efficacy Endpoints (Part 2).................................... 115
Table 14
Analysis Strategy for Safety Parameters........................................................... 118
Table 15
Summary of Timing, Sample Size and Decision Guidance of Efficacy 
Interim Analyses and Final Analysis (Part 2, at Initial Alpha)........................ 121
Table 16
Summary of Efficacy Decision Guidance After Alpha Re-Allocation (Part 2, 
Selected Scenarios).......................................................................................... 123
Table 17
Initial Alpha Allocation .................................................................................... 124
Table 18
Power for ORR ................................................................................................. 129
Table 19
Product Descriptions......................................................................................... 131
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LIST OF FIGURES
Figure 1
Part 1 Study Design ............................................................................................ 18
Figure 2
Part 2 (Phase III) Study Design........................................................................... 19
Figure 3
Imaging and Treatment for Clinically Stable Subjects After First Radiologic 
Evidence of PD Based on RECIST 1.1 and as Assessed by Site/Investigator .. 84
Figure 4
Multiplicity Strategy ......................................................................................... 126
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
MK-3475-355-07
17-JUN-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.
MK-3475-355-06
01-SEP-2021
To include language pertaining to the KN587 extension trial, as 
the plan is to transition current subjects over to KN587.
MK-3475-355-05
04-OCT-2019
The objectives, hypotheses, and statistical analysis plan were 
changed to include subjects with PD-L1 positive tumors with a 
higher combined positive score (CPS) cutoff of ≥10 (CPS ≥10).
MK-3475-355-04
20-MAR-2019
The timing of the final analysis was changed from overall survival 
(OS) event driven to both OS event and follow-up time driven to 
ensure adequate follow-up duration at time of the final analysis.
MK-3475-355-03
31-AUG-2018
Allocation of alpha over the primary endpoints and key secondary 
endpoints has been adjusted to allocate initial alpha to objective 
response rate (ORR) hypotheses and will allow testing of ORR 
hypothesis at interim analysis 1 (IA1) independent of the outcome 
of the other hypotheses.
IA1 timing has been changed from progression-free survival (PFS)
event driven to “~ 9 months after 640 Part 2 subjects are 
randomized”. IA1 will now include the analysis of ORR, as well 
as interim analyses of PFS and OS. 
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Document
Date of Issue
Overall Rationale
MK-3475-355-02
05-FEB-2018
To align with the most current label and safety information for 
pembrolizumab, guidelines were added for dose modification in 
the event of myocarditis and updated guidelines for several other 
conditions. Additionally, reorganized this information under new 
headers and tables.
MK-3475-355-01
06-DEC-2016
Updates were made to harmonize the pneumonitis exclusion 
criterion throughout the pembrolizumab program. This change was 
not expected to result in a change in the study population.
MK-3475-355-00
21-APR-2016
Original protocol
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
Title Page
Section 12.1
Throughout
Title Page
Code of Conduct for Clinical 
Trials
Throughout
Sponsor entity name and 
address change.
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.
ADDITIONAL CHANGES FOR THIS AMENDMENT:
No additional changes.
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1.0 TRIAL SUMMARY
Abbreviated Title
A Randomized, Double-Blind, Phase III Study of Pembrolizumab (MK-
3475) plus Chemotherapy vs Placebo plus Chemotherapy for Previously 
Untreated Locally Recurrent Inoperable or Metastatic Triple Negative 
Breast Cancer – (KEYNOTE-355)
Sponsor Product Identifiers
MK-3475
Pembrolizumab
Trial Phase
Phase III
Clinical Indication
Locally recurrent inoperable or metastatic triple negative breast cancer 
(TNBC), which has not been previously treated with chemotherapy
Trial Type
Interventional
Type of control
Part 1: No treatment control
Part 2: Placebo-controlled trial on a background of chemotherapy
Route of administration
Intravenous
Trial Blinding
Double-blind
Treatment Groups
Part 1: There are 3 treatment arms (unblinded, open-label):

pembrolizumab + nab-paclitaxel

pembrolizumab + paclitaxel

pembrolizumab + gemcitabine/carboplatin
Part 2: There are 2 treatment arms (double-blind):

pembrolizumab + chemotherapy

placebo + chemotherapy
Pembrolizumab: 200 mg intravenously (IV) every 3 weeks (Q3W)
Placebo: Normal saline IV Q3W
Chemotherapy:

Nab-paclitaxel: 100 mg/m2 IV on Days 1, 8, and 15 every 
28 days or

Paclitaxel: 90 mg/m2 on Days 1, 8, and 15 every 28 days or

Gemcitabine and carboplatin:
1000 mg/m2 and AUC 2, 
respectively, on Days 1 and 8 every 21 days
Number of trial subjects
Approximately 30 subjects will be enrolled for Part 1; for Part 2, 
approximately 828 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 
65 months from the time the first subject signs the informed consent 
until the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the study from the time the subject signs 
the informed consent form through the final protocol-specified contact.  
After a screening phase of up to 28 days, eligible subjects will receive 
assigned treatment.  Study treatment will continue until any of the 
following occurs:
disease progression is verified using Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by a 
central imaging vendor (or progressive disease [PD] is locally 
confirmed, if subject is further followed by immune-related RECIST 
[irRECIST]); unacceptable toxicity; intercurrent illness that necessitates 
discontinuation of study treatment; Investigator’s decision to withdraw 
the subject; pregnancy; non-compliance with study treatment or 
procedure requirements; withdrawal of consent to treatment; death; end 
of the study; or other administrative reasons requiring cessation of study 
treatment.
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After discontinuation of all study treatments, each subject will be 
followed for 30 days for AE monitoring; serious adverse events (SAEs) 
will be collected for 90 days after the end of study treatment or until the 
subject starts a new anti-cancer treatment, but for at least 30 days after 
the last dose of study treatment, whichever occurs first.
Subjects who discontinue all study treatments for reasons other than PD 
will continue post-treatment imaging studies for disease status follow-up 
at the same frequency as already used, e.g., every 9 or 12 weeks (±7 
days) depending on time elapsed since randomization, until centrally 
verified disease progression, start of a non–study anti-cancer treatment, 
withdrawal of consent to study participation, death, or end of the study. 
All subjects will be followed by telephone every 12 weeks (±7 days), or 
more often as needed, for overall survival (OS) until death, withdrawal 
of consent to study participation, or end of the study.
A list of abbreviations used in this document can be found in Section 12.4 – Abbreviations.
2.0 TRIAL DESIGN
Trial Design
This is a randomized, placebo-controlled, double-blind, global
Phase III study
of 
pembrolizumab + chemotherapy vs. placebo + chemotherapy for subjects with locally 
recurrent inoperable or metastatic triple negative breast cancer (TNBC), which has not been 
previously treated with chemotherapy.  Prior treatment with chemotherapy in the 
(neo)adjuvant setting is allowed.  For such subjects, the period between completion of 
treatment with curative intent (e.g., date of primary breast tumor surgery or date of last 
adjuvant chemotherapy administration, whichever occurred last) and first documented local 
or distant disease recurrence must be ≥6 months.  Subjects who received taxane, gemcitabine,
or platinum agents in the (neo)adjuvant setting can be treated with same class anticancer drug
(taxane, gemcitabine, or carboplatin, respectively), if ≥12 months have elapsed between 
completion of treatment with curative intent and the first documented local or distant disease 
recurrence.
Part 1 will be an unblinded, open-label, safety run-in, in which approximately 30 subjects 
will be partially randomized with forced randomization depending on prior (neo)adjuvant 
treatment (as described in Section 5.3 – Randomization or Treatment Allocation), to ensure 
enrollment of at least 10 subjects to each treatment arm. Subjects will be closely followed
for unacceptable toxicities for 21 or 28 days after the first pembrolizumab +
gemcitabine/carboplatin or pembrolizumab + taxane administrations, respectively.
Since
pembrolizumab and chemotherapy have different mechanisms of action and non-overlapping 
toxicities, safety-compromising interactions between these 2 classes of anticancer regimens 
are not expected; thus, enrollment to Part 2 will continue while an external Data Monitoring
Committee (DMC) reviews the safety data from Part 1 (see Section 7.3.3 – Data Monitoring 
Committee).
Part 2 will be a Phase III, double-blind, placebo-controlled study on a background of 
chemotherapy, for which approximately 828 eligible subjects will be randomized 2:1 to 
receive pembrolizumab +
chemotherapy
or placebo +
chemotherapy, respectively. 
Randomization Ratio
Part 2: 2:1
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Pembrolizumab will be given at 200 mg intravenously (IV) every 3 weeks (Q3W) and 
normal saline will be used as a placebo. Nab-paclitaxel will be given at 100 mg/m2 IV on 
Days 1, 8, and 15 every 28 days; paclitaxel at 90 mg/m2 IV on Days 1, 8, and 15 of every 
28 days;
and IV gemcitabine/carboplatin at 1000 mg/m2
(gemcitabine) and an
AUC 2 (carboplatin) on Days 1 and 8 every 21 days.  Subject crossover between treatment 
arms is not permitted.  Pembrolizumab/placebo will be prepared in a blinded fashion by an 
assigned unblinded pharmacist. Subjects, Investigators, other study site staff (except for the 
unblinded pharmacist), and the Sponsor will be blinded to pembrolizumab/placebo 
administration but unblinded to chemotherapy administration.  Investigators, other study site 
staff, and subjects will be blinded to subject-level tumor programmed cell death ligand 1
(PD-L1) biomarker results.
Disease status will be followed by imaging studies at Weeks 8 (±7 days), 16 (±7 days), and
24 (–7 days) post randomization (allowing efficacy data to be captured as close to 24 weeks 
post randomization as possible for a more accurate evaluation of disease control rate [DCR]).  
Imaging will continue every 9 weeks (±7 days) thereafter during the first year, independent 
of any treatment delays. Imaging studies will be performed every 12 weeks (±7 days) after 
the first year.  Safety will be monitored according to National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 (v4.0).
Study treatment will continue until any of the following occurs:  disease progression is 
verified using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by a
central imaging vendor (CIV) (or progressive disease [PD] is locally confirmed if the subject 
is further followed by immune-related RECIST [irRECIST]) (see Section 7.1.2.9.5 –
irRECIST Assessment of Disease); unacceptable toxicity; intercurrent illness that 
necessitates discontinuation of study treatment; Investigator’s decision to withdraw the 
subject; pregnancy; subject noncompliance with study treatment or procedure requirements;
withdrawal of consent to treatment; death; end of the study; or other administrative reasons 
requiring cessation of study treatment.
See Section 5.8 – Subject Withdrawal/Discontinuation Criteria for information regarding 
discontinuation of pembrolizumab/placebo in subjects who attain an Investigator-determined 
confirmed complete response (CR) and in subjects who complete 35 administration of 
pembrolizumab/placebo.  See Section 7.1.5.6 – Second Course Phase (Retreatment Phase) 
for information regarding criteria for potential retreatment of
subjects who stop 
pembrolizumab with stable disease (SD) or better in the first course treatment of the trial.
After discontinuation of all study treatments, each subject will be followed for 30 days for 
AE monitoring; serious adverse events (SAEs) will be collected for 90 days after the end of 
study treatment or until the subject starts a new anti-cancer treatment, but for at least 30 days 
after the last dose of study treatment, whichever occurs first.
Subjects who discontinue all study treatments for reasons other than PD will continue
post-treatment imaging studies for disease status follow-up at the same frequency as already 
used, e.g., every 9 or 12 weeks (± 7 days) during the first year or second year, respectively, 
depending on time elapsed since randomization, until centrally verified disease progression, 
start of a non–study anti-cancer treatment, withdrawal of consent to study participation, 
death, or end of the study. 
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All subjects will be followed by telephone every 12 weeks (± 7 days), or more often as 
needed, for overall survival (OS) until withdrawal of consent to study participation, death, or 
end of the study.
The study will be conducted in conformance with Good Clinical Practices (GCPs).
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
This study will use a DMC to monitor safety and efficacy (see Section 8.1 – Statistical 
Analysis Plan Summary, Section 8.2 – Responsibility for Analyses/In-House Blinding, and 
Section 8.7 – Interim Analyses).
With the exception of the Part 1 safety interim analysis (see Section 8.7.1– Part 1: Safety 
Interim Analysis), safety monitoring will be performed at regular intervals.  Information 
regarding objectives and statistical design and analysis is provided in Section 3.0 –
Objective(s) & Hypothesis(es) and Section 8.0 – Statistical Analysis Plan.
Trial Diagram
The study design for Part 1 is depicted in Figure 1.
Figure 1
Part 1 Study Design
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The study design for Part 2 is depicted in Figure 2.
Figure 2
Part 2 (Phase III) Study Design
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
Part 1 (Safety Run-In):
(1) Objective:
To evaluate the safety and tolerability of 3 pembrolizumab +
chemotherapy combinations, namely, pembrolizumab + paclitaxel, pembrolizumab + 
nab-paclitaxel, and pembrolizumab + gemcitabine/carboplatin.
Part 2 (Phase III study):
The combination of pembrolizumab and chemotherapy will be compared to placebo and 
chemotherapy for the treatment of previously untreated locally recurrent inoperable or 
metastatic centrally confirmed triple negative breast cancer (TNBC):
(1) Objective:  To compare progression-free survival (PFS) based on Response 
Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by a 
blinded central imaging vendor (CIV) in all subjects.
Hypothesis:  The combination of pembrolizumab and chemotherapy prolongs PFS 
compared to placebo and chemotherapy in all subjects.
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(2) Objective: To compare PFS based on RECIST 1.1 as assessed by a blinded CIV in 
subjects with PD-L1 positive tumors (combined positive score [CPS] ≥1).
Hypothesis:  The combination of pembrolizumab and chemotherapy prolongs PFS 
compared to placebo and chemotherapy in subjects with PD-L1 positive tumors
(CPS ≥1).
(3) Objective: To compare PFS based on RECIST 1.1 as assessed by a blinded CIV in 
subjects with PD-L1 positive tumors (CPS ≥10).
Hypothesis:  The combination of pembrolizumab and chemotherapy prolongs PFS 
compared to placebo and chemotherapy in subjects with PD-L1 positive tumors
(CPS ≥10).
(4) Objective: To compare overall survival (OS) in all subjects.
Hypothesis:  The combination of pembrolizumab and chemotherapy prolongs OS 
compared to placebo and chemotherapy in all subjects.
(5) Objective: To compare OS in subjects with PD-L1 positive tumors (CPS ≥1).
Hypothesis:  The combination of pembrolizumab and chemotherapy prolongs OS 
compared to placebo and chemotherapy in subjects with PD-L1 positive tumors
(CPS ≥1).
(6) Objective: To compare OS in subjects with PD-L1 positive tumors (CPS ≥10).
Hypothesis:  The combination of pembrolizumab and chemotherapy prolongs OS 
compared to placebo and chemotherapy in subjects with PD-L1 positive tumors
(CPS ≥10).
The study is considered to have met its primary objective if the combination of 
pembrolizumab and chemotherapy is superior to placebo and chemotherapy in either PFS or 
OS in either all subjects or in subjects with PD-L1 positive tumors (CPS ≥1 or CPS ≥10) at 
either an interim analysis or the final analysis (OS only).
Secondary Objective(s) & Hypothesis(es)
Part 2 (Phase III study):
For comparisons, the combination of pembrolizumab and chemotherapy will be compared to 
placebo and chemotherapy for the treatment of previously untreated locally recurrent
inoperable or metastatic centrally confirmed TNBC:
(1) Objective:  To compare objective response rate (ORR) based on RECIST 1.1 as 
assessed by a blinded CIV in all subjects.
Hypothesis:  The combination of pembrolizumab and chemotherapy increases ORR 
compared to placebo and chemotherapy in all subjects.
(2) Objective:  To compare ORR based on RECIST 1.1 as assessed by a blinded CIV in 
subjects with PD-L1 positive tumors (CPS ≥1).
Hypothesis:  The combination of pembrolizumab and chemotherapy increases ORR 
compared to placebo and chemotherapy in subjects with PD-L1 positive tumors
(CPS ≥1).
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(3) Objective:  To compare ORR based on RECIST 1.1 as assessed by a blinded CIV in 
subjects with PD-L1 positive tumors (CPS ≥10).
(4) Objective:  To evaluate duration of response (DOR) based on RECIST 1.1 as 
assessed by a blinded CIV in all subjects and in subjects with PD-L1 positive tumors
(CPS ≥1 and CPS ≥10).
(5) Objective:  To compare DCR based on RECIST 1.1 as assessed by a blinded CIV in 
all subjects and in subjects with PD-L1 positive tumors (CPS ≥1 and CPS ≥10).
(6) Objective: 
To evaluate the safety and tolerability of 3 pembrolizumab +
chemotherapy combinations.
(7) Objective: To evaluate changes in health-related quality-of-life (QoL) assessments 
from baseline in all subjects and in subjects with PD-L1 positive tumors (CPS ≥1 and
CPS ≥10) using the European Organization for Research and Treatment of Cancer
(EORTC) Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC 
Breast Cancer–Specific Quality of Life Questionnaire (EORTC QLQ-BR23).
Exploratory Objectives
Part 2 (Phase III study):
For comparisons, the combination of pembrolizumab and chemotherapy will be compared to 
placebo and chemotherapy for the treatment of previously untreated locally recurrent
inoperable or metastatic centrally confirmed TNBC:
(1) Objective:
To characterize utilities in all subjects and in subjects with PD-L1 
positive tumors (CPS ≥1 and CPS ≥10) using EuroQol-5 Dimension Questionnaire 
(EQ-5D™).
(2) Objective:
To investigate association(s) between anti-tumor activity of study 
treatments and efficacy/resistance biomarkers, utilizing tumor and blood specimens 
obtained before randomization, during treatment, and at disease progression.
(3) Objective:
To identify molecular (genomic, metabolic,
and/or proteomic) 
determinants of response or resistance to pembrolizumab and other treatments in this 
study, so as to define novel predictive and pharmacodynamic biomarkers and 
understand the mechanism of action of pembrolizumab.
4.0 BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab (MK-3475).
Pharmaceutical and Therapeutic Background
Programmed cell death 1 (PD-1) checkpoint inhibition and cancer treatment.  The 
importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1]. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and prognosis in various 
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malignancies [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14].  In particular, the 
presence of cluster of differentiation (CD) 8–positive (CD8+) T cells and the ratio of CD8+ 
effector T cells/FoxP3+ regulatory T cells seem to correlate with improved prognosis and 
long-term survival in many solid tumors [7], [15], [16], [17], [18], [19], [20], [21].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control [22].
The normal function of PD-1, expressed on the cell surface of 
activated T cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions.  PD-1 (encoded by the gene 
Pdcd1) is an immunoglobulin (Ig)
superfamily member related to CD28 and 
cytotoxic T-Lymphocyte–associated antigen-4
(CTLA-4), which has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
programmed cell death ligand 2 [PD-L2]).  The structures of murine PD-1 alone [23], and in 
complex with its ligands, were first resolved [24], [25], and more recently the nuclear 
magnetic resonance–based (NMR-based) structure of the human PD-1 extracellular region 
and analyses of its interactions with its ligands were also reported [26]. PD-1 and family 
members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) 
domain responsible for ligand binding and a cytoplasmic tail which is responsible for the 
binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based 
signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an 
immunoreceptor tyrosine-based switch motif (ITSM).  Following T cell stimulation, PD-1 
recruits the tyrosine phosphatases Src homology phosphatase (SHP)-1 (SHP-1) and SHP-2 to 
the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector 
molecules, 
such 
as 
CD3 
zeta 
(CD3ζ), 
protein 
kinase 
C-theta 
(PKCθ),
and 
zeta-chain-associated protein kinase 70kDa (ZAP70), which are involved in the CD3 T cell 
signaling cascade [27].  The mechanism by which PD-1 down-modulates T cell responses is 
similar to, but distinct from, that of CTLA-4 [28].  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 (NKCs) [29]. Expression has also been shown during thymic development 
on CD4-CD8–double negative T cells [30] as well as subsets of macrophages [31] and 
dendritic cells [32]. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed 
or can be induced in a variety of cell types [33]. PD-L1 is expressed at low levels on various 
nonhematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is 
only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments [33].
Both ligands are type I transmembrane receptors 
containing both 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-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.  Although healthy organs express little (if any) PD-L1, 
a variety of cancers were demonstrated to express abundant levels of this T cell 
inhibitor [34], [35], which, via its interaction with the PD-1 receptor on tumor-specific 
T cells, plays a critical role in immune evasion by tumors [36].  As a consequence, the PD-
1/PD-L1 pathway is an attractive target for therapeutic intervention in cancer [37].
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Information on Disease to be Treated – TNBC. Excluding basal cell and squamous cell 
skin cancers, breast cancer is the most commonly diagnosed malignancy in women, 
accounting for 29% of all new cancers.  It is also the second leading cause of cancer death 
(after lung cancer) among women.  About 232,670 new cases of breast cancer and 
40,000 deaths due to breast cancer are expected in women in the United States (US) in 
2014 [38].  TNBC is phenotypically defined by a lack of estrogen receptor and progesterone 
receptor (EG/PGR) expression and the absence of human epidermal growth factor receptor-2 
(HER2) overexpression and/or amplification [39].  TNBC represents 15% to 20% of all 
breast cancers [40] and is overlapping, but not synonymous, with the basal-like subtype 
defined by gene expression, as about 70% of TNBCs have basal-like characteristics [41], 
[42].
TNBC is a molecularly heterogeneous disease and includes tumor subsets with different 
prognosis.  Recent gene expression profiling has identified up to 6 distinct TNBC subtypes 
(2 basal-like, an immunomodulatory, a mesenchymal, a mesenchymal stem-like, and a 
luminal androgen receptor [AR] subtype) [43].
TNBC is associated with younger age at diagnosis, premenopausal status, African American 
race, more advanced disease stage, higher grade, high mitotic indices, family history of 
breast cancer, breast cancer 1 (BRCA1) mutations, and more aggressive behavior than other 
breast cancer subtypes [40].  As reported in a seminal study on TNBC, 34% of all subjects 
with TNBC experience distant recurrence with a median distant recurrence-free survival 
(DRFS) of 2.6 years, compared to a distant recurrence rate of 20% and a median DRFS of 
5 years in other breast cancer subtypes; the peak of recurrence for TNBC is within 1 to 
3 years after initial diagnosis, and decreases significantly thereafter; subjects with TNBC also 
have shorter median OS compared to subjects with non-TNBC (4.2 vs 6.0 years) [39].  
Finally, subjects with TNBC tend to relapse with distant metastases rather than local 
recurrences and are more likely to develop visceral metastases, including central nervous 
system (CNS) involvement [44].
Treatment of TNBC is challenging and represents an area of unmet medical need, as these 
tumors lack therapeutic targets, such as ER and HER2, and become rapidly resistant to 
chemotherapy upon local recurrence and/or metastasis (even though they are often sensitive 
to cytotoxic drugs at initial presentation) [45].
The majority of subjects with metastatic 
TNBC (mTNBC) have experienced relapse after neoadjuvant or adjuvant therapy for early or 
locally advanced disease.  In a frequently referenced study, the median OS of all (at any line 
of therapy) subjects with mTNBC was 13.3 months [46].
Immune checkpoint inhibition for the treatment of TNBC. 
Several studies have 
demonstrated that presence of TILs is a prognostic factor in TNBC, thus implicating the 
immune system in the pathophysiology and potentially the treatment of such tumors.  Greater 
lymphocytic infiltration confers better prognosis in TNBC, independent of systemic therapy
[47], [48].  In addition, unsupervised gene expression profiling of TNBCs has identified a 
gene signature enriched for cytotoxic CD8+ T cell genes and NKC activity, which is 
predictive of good clinical outcome [49].  These findings suggest that inhibition of immune 
checkpoints has the potential to improve TNBC prognosis by increasing the efficacy of 
tumor-associated immune response in eliminating breast cancer cells [50].
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Targeting the PD-1 immune checkpoint for the treatment of TNBC. The PD-1 ligand, 
PD-L1, is not detected in normal breast tissue, but has been reported to be expressed in about 
half of all breast cancers, particularly in hormone receptor–negative and high grade, 
proliferative tumors [51].  In addition, the presence of regulatory T cells, tumor PD-L1 
expression, and PD-1–positive TILs has been associated with high histologic grade, 
ER negativity, and prominent tumor lymphocytic infiltration [52]. In an independent study, 
PD-L1 was found expressed in 23% of breast cancer specimens and it was again associated 
with age, tumor size, American Joint Committee on Cancer (AJCC) primary tumor 
classification, tumor grade, lymph node status, absence of ER expression, and high Ki-67 
expression [53].  A recent publication reported that PD-L1 messenger ribonucleic acid 
(mRNA) is expressed in nearly 60% of breast tumors, independently of hormone receptor
status, and is positively correlated with PD-L1 protein expression and increased TILs [54].  
Another study mining The Cancer Genome Atlas (TCGA) ribonucleic acid (RNA)
sequencing data showed that PD-L1 gene expression is significantly higher in TNBCs 
compared to non-TNBCs, and is associated with phosphatase and tensin homolog (PTEN)
loss; in the same study, PD-L1 was found expressed in 20% of TNBCs [55].  Finally, in an 
abstract presented in the 2014 American Society of Clinical Oncology (ASCO) Annual 
meeting, it was reported that PD-L1 protein levels are positively correlated with expression 
of other immune regulators, such as CTLA-4 and indoleamine 2,3-dioxygenase 1 (IDO1), 
and with AR-negative and BRCA1-mutant TNBC [56].  Despite their discordance in the 
reported absolute PD-L1 levels in breast tumors, the aforementioned studies clearly 
demonstrate that TNBCs are characterized by PD-L1 positivity and presence of TILs, and
thus suggest that PD-1 immune checkpoint inhibition is a therapeutic strategy worthy of 
further investigation for the treatment of this aggressive breast cancer subtype.
Pre-Clinical and Clinical Studies
PD-1 immune checkpoint inhibition – Preclinical studies. Therapeutic studies in mouse 
models have shown that administration of antibodies blocking PD-1/PD-L1 interaction 
enhances infiltration of tumor-specific CD8+ T cells
and ultimately leads to 
tumor rejection, either as a monotherapy or in combination with other treatment 
modalities [57], [58], [59], [60], [61], [62], [63].  Anti–mouse PD-1 or anti–mouse PD-L1 
antibodies have demonstrated anti-tumor responses in models of squamous cell carcinoma, 
pancreatic carcinoma, melanoma, acute myeloid leukemia and colorectal carcinoma [58],
[60], [62], [64], [65].  In such studies, tumor infiltration by CD8+ T cells and increased
interferon gamma (IFN-γ), granzyme B and perforin expression were observed, indicating 
that the mechanism underlying the anti-tumor activity of PD-1 checkpoint inhibition
involved local infiltration and activation of effector T cell function in vivo [58]. Experiments 
have confirmed the in vivo efficacy of anti–mouse PD-1 antibody as a monotherapy, as well 
as in combination with chemotherapy, in syngeneic mouse tumor models (see the IB).
Pembrolizumab – Clinical studies. Pembrolizumab [Keytruda® (US); previously known as 
lambrolizumab, MK-3475 and SCH 9000475] is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab was the first 
anti–PD-1 therapy to receive regulatory approval in the US (September 2014).
Pembrolizumab is approved in the US at a dose of 2 mg/kg administered as an intravenous 
infusion over 30 minutes Q3W for the treatment of patients with unresectable or metastatic 
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melanoma with disease progression following ipilimumab and, if BRAF V600 mutation 
positive, a BRAF inhibitor
(see also prescribing information for KEYTRUDA®
(pembrolizumab) for injection, for intravenous use) [66].
It is approved in EU for both 
first-line (1L) and previously treated subjects with unresectable or metastatic melanoma.
Pembrolizumab is also approved in the US (at the same dose as in melanoma) for the 
treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors 
express PD-L1 as determined by an FDA-approved test with disease progression on or after 
platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations 
should have disease progression on FDA-approved therapy for these aberrations prior to 
receiving pembrolizumab.  (See also prescribing information for KEYTRUDA®
(pembrolizumab) for injection, for intravenous use.)
KEYNOTE-012 (KN012) – Clinical data supporting pembrolizumab use for the 
treatment of mTNBC.  In the first report of clinical activity of an immune checkpoint 
inhibitor in TNBC, an MSD-sponsored multi-center, nonrandomized Phase Ib study (KN012) 
showed that single agent pembrolizumab given at 10 mg/kg every 2 weeks (Q2W) is a
well-tolerated and effective treatment with significant anticancer activity in a subset of 
heavily pre-treated subjects with mTNBC [67].
Methods: PD-L1 expression in ≥1% tumor cells or in stroma (i.e., PD-L1 positive mTNBC) 
was required for study entry.  Tumor PD-L1 status was determined by immunohistochemical 
analysis of archival tumor specimens using the MSD proprietary 22C3 antibody.  Primary 
objectives of this study were to determine the safety, tolerability, and anti-tumor activity of 
pembrolizumab in subjects with PD-L1 positive mTNBC. Secondary objectives included
assessments of PFS, OS, and DOR.  Adverse events reported in any subject receiving at least 
1 dose of study treatment were monitored and graded using NCI CTCAE v4.0.  Radiographic
imaging was obtained every 8 weeks and evaluated by both investigator and an independent 
radiologist to assess clinical responses as defined by RECIST 1.1.
Results: Of the 111 subjects whose tumor samples were screened for PD-L1 expression, 
58% had PD-L1 positive tumors.
A total of 32 female subjects with a median age of
50.5 years (range 29 to 72 years) and PD-L1 positive mTNBC were enrolled in the study. 
Most of these subjects had received and progressed on multiple lines of therapy for advanced 
disease. The median number of prior lines of systemic therapy for metastatic disease was 2,
with 46.9% of subjects having received ≥3 lines. Overall, 56% of subjects experienced one 
or more treatment-related toxicities, including 16% who experienced one or more Grade 3-5
events. The most common treatment-related AEs of any grade included arthralgia (18.8%), 
fatigue (18.8%), myalgia (18.8%), and nausea (15.6%). As of the data cutoff date of 
23-Mar-2015, 5 subjects (15.6%) experienced at least one drug-related SAE; each of 
4 subjects experienced one of the following: Grade 3 anemia, headache, aseptic meningitis or 
pyrexia, and a fifth subject with rapidly progressing metastatic disease experienced Grade 5 
disseminated intravascular coagulation (DIC) with thrombocytopenia and decreased blood 
fibrinogen. Of the 27 subjects with centrally confirmed measurable disease, 1 subject (3.7%) 
had a CR, 4 subjects (14.8%) had a confirmed partial response (PR), 25.9% had SD, and 
44.4% had PD, as assessed by central radiology review. The median time to response was 
18 weeks (range 7 to 32). As of 23-Mar-2015, the median DOR had not been reached (range 
15.0 to 47.3+ weeks), and 3 subjects (1 CR; 2 PR) were still on treatment after at least 
15 months.
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Conclusions: This was the first report of clinical activity of an immune checkpoint inhibitor 
in TNBC.  The preliminary results from this study suggest that single agent pembrolizumab 
is a well-tolerated and effective treatment with significant anticancer activity in a subset of 
heavily pre-treated subjects with recurrent/metastatic TNBC.
Ongoing Clinical Studies
Two clinical studies are currently investigating the efficacy of single agent pembrolizumab as 
later line of treatment for mTNBC, namely KEYNOTE-086 (KN86) and KEYNOTE-119 
(KN119).

KN-086 (NCT02447003):
A Phase II Clinical Trial of Pembrolizumab 
(MK-3475) as Monotherapy for
Metastatic Triple Negative Breast Cancer 
(mTNBC) – (KEYNOTE-086), and

KN-119 (NCT02555657): A Randomized, Open-Label Phase III Clinical Trial of 
Single Agent Pembrolizumab vs Single Agent Chemotherapy per Physician’s 
Choice for Metastatic Triple Negative Breast Cancer (mTNBC) – (KEYNOTE-119)
Ongoing clinical studies are also being conducted in melanoma, NSCLC, head and neck 
cancer, breast cancer, gastric cancer, colorectal cancer, a number of other advanced solid 
tumor indications, and hematologic malignancies.
For further details, please refer to the IB.
Information on Other Study-Related Therapy
Taxanes are among the most effective and commonly used therapies for the treatment of
breast cancer, particularly in the adjuvant setting. Accordingly, the role of taxanes in the 
metastatic setting continues to evolve as new strategies to optimize taxane use and clinical 
outcomes are actively investigated [68].
Paclitaxel is a natural product (obtained via a semi-synthetic process from the Pacific yew 
tree [Taxus brevifolia]) with anti-tumor activity. It promotes the assembly and stabilization 
of microtubules, while inhibiting their depolymerization, and thus results in inhibition of
mitosis and cell death. In the US, paclitaxel is approved for the adjuvant treatment of 
node-positive breast cancer administered sequentially to standard doxorubicin-containing 
combination chemotherapy; it is also approved as single agent for the treatment of metastatic 
breast cancer (mBC) after failure of combination chemotherapy for metastatic disease or 
relapse within 6 months of adjuvant chemotherapy. Approval was based on a Phase III study
of 2 different doses (175 mg/m2 vs 135 mg/m2) of Cremofor EL (CrEL)-dissolved paclitaxel 
given Q3W in subjects with mBC whose disease had progressed on or after previous 
chemotherapy [69].
Compared to the lower dose, the higher dose was associated with a 
longer median time to disease progression (TTP) (4.2 vs 3.0 months, respectively; P = 0.027) 
and a longer median OS (11.7 vs 10.5 months, respectively; P = 0.321).  In the European 
Union (EU), paclitaxel is approved as monotherapy for late mBC and in combination with 
bevacizumab as 1L treatment.
Nab-paclitaxel is a combination of albumin and paclitaxel that forms particles of a mean 
130 nm in diameter. Unlike previous taxanes, the nab-paclitaxel formulation is solvent-free 
and does not require premedication to prevent solvent-related hypersensitivity reactions. It 
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received US Food and Drug Administration (FDA) approval in 2005 for the treatment of 
breast cancer after failure of combination chemotherapy for metastatic disease or relapse 
within 6 months of adjuvant chemotherapy (prior therapy should have included an 
anthracycline, unless clinically contraindicated). Nab-paclitaxel is also approved in the EU 
as second-line (2L) monotherapy for mBC. These approvals were based on a randomized 
phase III study, which compared nab-paclitaxel 260 mg/m2 Q3W to paclitaxel 175 mg/m2
Q3W with corticosteroid or antihistamine premedication [70]. Treatment with nab-paclitaxel 
led to a significantly higher ORR compared with paclitaxel based on the intention-to-treat 
(ITT) population (33% vs 19%, respectively; P = 0.001). The ORR was also significantly 
higher in subjects who received nab-paclitaxel as 1L therapy (42% vs 27%; P = 0.029) or 
2L and above (2L+) therapy (27% vs 13%; P = 0.006). Subjects who received nab-paclitaxel 
had a 25% lower risk of progression compared with those receiving paclitaxel (hazard ratio 
[HR] 0.75; P = 0.006). The incidence of Grade 4 neutropenia was significantly lower with 
nab-paclitaxel treatment (9% vs 22%, respectively; P = 0.001). Nab-paclitaxel was associated 
with higher incidence of Grade 3 sensory neuropathy (10% vs 2%; P = 0.001), which 
improved to ≤Grade 2 in about 3 weeks. 
Nab-paclitaxel demonstrated a statistically 
significant improvement in OS in subjects who received it as 2L+ therapy (56.4 vs 
46.7 weeks; P = 0.024), but only a modest, nonsignificant OS difference in the
ITT population (65 vs 56 weeks; P = 0.374).
Gemcitabine/carboplatin was the first chemotherapy regimen investigated in a randomized,
double-blind, Phase III study for the treatment of mTNBC [71]. In this Sanofi-sponsored 
study,
the combination of iniparib and gemcitabine/carboplatin was compared to 
gemcitabine/carboplatin for the treatment of mTNBC [71]; gemcitabine/carboplatin were 
used at 1000 mg/m2 and AUC 2, respectively, on Days 1 and 8 of a 3-week cycle and 
resulted in a median PFS of 4.6 months and a median OS of 12.6 months as 1L therapy. 
Although not formally approved for the treatment of metastatic breast cancer,
the combination of gemcitabine and carboplatin
is included in oncology society 
guidelines [72], [73] and used as 1L combination treatment for mTNBC worldwide.
Rationale
Rationale for the Trial and Selected Subject Population
4.2.1.1
Rationale for the Study
Rationale for combining pembrolizumab with chemotherapy. This study will investigate 
whether the combination of pembrolizumab and chemotherapy (nab-paclitaxel, paclitaxel or 
gemcitabine/carboplatin) improves the PFS and OS of subjects with previously untreated 
locally recurrent inoperable or metastatic TNBC compared to placebo and chemotherapy. 
The rationale behind combining pembrolizumab with chemotherapy is based on the 
immunomodulatory effects of the latter [74], which may in turn increase the anti-tumor
activity of PD-1 pathway inhibition. Even though cytotoxic drugs, including taxanes and 
gemcitabine/carboplatin, have historically been considered immunosuppressive, they can 
also have immunopotentiating roles by 1) depleting immuno-suppressive cells, such as 
regulatory T cells and myeloid-derived suppressor cells, to enhance a latent anti-tumor
immune response, 2) inducing an immunogenic cell death, 3) enhancing tumor antigen 
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presentation by upregulating the expression of tumor antigens themselves, or of the major 
histocompatibility complex (MHC) class I molecules to which the antigens bind, 
4) upregulating co-stimulatory molecules (B7-1) or down regulating co-inhibitory molecules 
(PD-L1/B7-H1 or B7-H4) expressed on the tumor cell surface, thus enhancing the strength of 
effector T cell activity, and 5) rendering tumor cells more sensitive to T cell–mediated lysis 
through fas-, perforin-, and granzyme B–dependent mechanisms [75].
Rationale for chemotherapy choices. No standard of care (SOC) currently exists for the 
treatment for TNBC in any setting. Similar to any advanced breast cancer, the recommended 
initial treatment for subjects with locally recurrent inoperable or metastatic TNBC includes 
anthracyclines and taxanes. For subjects previously treated with an anthracycline, or for 
whom anthracyclines are contraindicated or not considered the best treatment option, taxanes 
are most commonly used as 1L treatment, when the time interval between completion of 
taxane-based (neo)adjuvant therapy and recurrence is at least 12 months [76]. Subjects with 
earlier (<12 months) local or distant disease recurrence are treated with chemotherapies not 
previously used in the (neo)adjuvant setting; in the case of aggressive disease and/or visceral 
crisis, combination, rather than single agent, chemotherapy is indicated and may include any 
one of different regimens, such as gemcitabine/carboplatin, capecitabine/vinorelbine, 
gemcitabine/cisplatin, etc.
In KEYNOTE-355 (KN355), 3 such combination regimens will be investigated, namely 
pembrolizumab + nab-paclitaxel, pembrolizumab + paclitaxel, and pembrolizumab +
gemcitabine/carboplatin. This design ensures inclusion of the most commonly used single 
agent chemotherapy class (taxanes) and a combination regimen frequently used as 
1L treatment for locally recurrent inoperable or metastatic TNBC.  
The rationale for including both nab-paclitaxel and paclitaxel as the taxane options in this 
multicenter, international study is based on their:

Differential availability and clinical use worldwide

Similar efficacies in terms of OS in mBC
Docetaxel was not included as a taxane option in KN355, as it is associated with a more 
severe toxicity profile than paclitaxel or nab-paclitaxel, as well as a strict requirement for 
steroid premedication that cannot be tapered during the entire length of its administration.
In regard to efficacy, although in earlier studies nab-paclitaxel showed higher anti-tumor
activity than paclitaxel in mBC, results from a recent study indicated that paclitaxel and
nab-paclitaxel resulted in similar PFS when given on a weekly basis (in combination with 
bevacizumab) as 1L treatment for mBC and mTNBC [77].
Comparison of paclitaxel or 
nab-paclitaxel to gemcitabine/carboplatin also reveals similar efficacies, in terms of PFS and 
OS, as 1L treatment for mTNBC (Table 1), and further supports use of these 3 regimens as 
chemotherapy choices in KN355.
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Table 1
Efficacy of Chemotherapy as 1L Treatment for mTNBC
Study/Breast Cancer 
Subtype/Reference
Line
Drug
ORR%/PFSmo/OSmo
Meta-analysis of 3 Phase III trials: 
E2100, AVADO, RIBBON 1 – MBC
TNBC subgroup analysis
Miles et al. 2013 [78]
1L
Paclitaxel or docetaxel or 
capecitabine or (A/EC, FA/EC)
23/5.4/17.5
E2100-Phase III – MBC
TNBC subgroup analysis
Gray et al. 2009 [79]
1L
Paclitaxel
22/5.3/16.3
Phase III – TNBC
1L subgroup analysis
O’Shaughnessy et al. 2014 [71]
1L
Gemcitabine + carboplatin
NR/4.6/13.9
Phase III – MBC
TNBC subgroup analysis
Rugo et al. 2015 [77]
1L
Paclitaxel + bevacizumab
NR/6.5/NR
Nab-paclitaxel + bevacizumab
NR/7.4/NR
1L=first line; MBC=metastatic breast cancer; mTNBC=metastatic triple negative breast cancer; NR=not 
reached; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; TNBC=triple 
negative breast cancer.
Note: In all studies included in Table 1, paclitaxel and nab-paclitaxel were both given on Days 1, 8, and 15 
every 28 days.
4.2.1.2
Rationale for Selected Subject Population
Adults with locally recurrent inoperable or metastatic TNBC, which has not been 
previously treated with chemotherapy. As mentioned in Section 4.1.1 – Pharmaceutical 
and Therapeutic Background, treatment of advanced TNBC is challenging and represents an 
area of high unmet medical need. Triple negative breast tumors lack therapeutic targets, such 
as ER and HER2, become rapidly resistant to chemotherapy, and are associated with poor 
clinical outcomes. Locally recurrent inoperable breast cancer is considered clinically similar 
to previously untreated metastatic disease [80], and thus the KN355 study population 
includes subjects with “early” advanced disease, requiring 1L treatment for locally recurrent 
inoperable or metastatic TNBC.
Rationale for Dose Selection/Regimen/Modification
4.2.2.1
Rationale for Pembrolizumab Dose Selection
The planned dose of pembrolizumab for this trial 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 across all indications and regardless of tumor type. As outlined below, this 
dose is justified by: 
•
Clinical data from eight randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every two weeks (Q2W)
•
Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and
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•
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically 
based pharmacokinetic [PBPK] analysis) at 200 mg Q3W
Among the eight randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and non-small cell lung cancer, covering different disease settings (treatment 
naïve, previously treated, PD-L1 enriched and all-comers) and different treatment settings 
(monotherapy and in combination with chemotherapy). Five studies compared 2 mg/kg Q3W 
vs. 10 mg/kg Q3W (KN001 B2, KN001 D, KN002, KN010 and KN021), and three studies 
compared 10 mg/kg Q3W vs. 10 mg/kg Q2W (KN001 B3, KN001 F2 and KN006). All of 
these studies demonstrated flat dose- and exposure-response relationships across the doses 
studied representing an approximate 5 to 7.5 fold difference in exposure. The 2 mg/kg (or 
200 mg fixed-dose) Q3W provided similar responses to the highest doses studied. 
Subsequently, flat dose-/exposure-response relationships were also observed in other tumor 
types including head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin 
Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the tumor type. 
These findings are consistent with the mechanism of action of pembrolizumab, which acts by 
interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Secondly, a PBPK analysis was conducted to predict tumor PD-1 saturation over a 
wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other subject covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
4.2.2.2
Rationale for Chemotherapy Dose Selections
Taxanes will be used at the following doses and schedules: paclitaxel 90 mg/m2 on Days 1, 
8, and 15 every 28 days and nab-paclitaxel 100 mg/m2 on Days 1, 8, and 15 every 28 days.
Although approved for metastatic breast cancer on a tri-weekly basis, paclitaxel at 80 mg/m2
weekly was better tolerated and superior in efficacy compared to 175 mg/m2 Q3W [81], and 
in clinical practice both paclitaxel and nab-paclitaxel are most commonly used on a 3-week 
on (Days 1, 8, and 15)/1-week off schedule every 28 days (Table 1). Furthermore, in data 
presented at the 2015 San Antonio Breast Cancer Symposium (SABCS), nab-paclitaxel at 
100 mg/m2 on Days 1, 8, 15 every 28 days was overall tolerated, when given in combination 
with the PD-L1 inhibitor atezolizumab [82], [83].
Gemcitabine/carboplatin will be used at the following doses and schedules: gemcitabine at
1000 mg/m2 + carboplatin at a dose equivalent to an AUC of 2, on Days 1 and 8 every 
21 days [71].
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Normal saline infusion Q3W will be used as placebo for pembrolizumab. The use of saline 
placebo in combination with chemotherapy will ensure the objectivity of investigator- and 
centrally assessed disease progression.
4.2.2.3
Rationale for Dose Interval and Trial Design
4.2.2.3.1
Rationale for Dose Interval
As explained in Section 4.2.2.1 – Rationale for Pembrolizumab Dose Selection and 
Section 4.2.2.2 – Rationale for Chemotherapy Dose Selections, pembrolizumab will be given 
Q3W, paclitaxel and nab-paclitaxel will be given on a 3-week on (Days 1, 8, and 15)/1-week 
off schedule every 28 days, and gemcitabine/carboplatin will be given on Days 1 and 8 every 
21 days, according to most common clinical practice.
4.2.2.3.2
Rationale for Study Design
KN355 is a randomized, double-blind, Phase III clinical study, as this is the gold standard for 
demonstrating superiority of a therapeutic regimen compared to another.
Rationale for Central Confirmation of TNBC Status. Several studies have reported 
discordance in evaluation of ER, PGR, and HER2 status between local and central 
laboratories, due to both technical issues in immunohistochemistry (IHC) testing and 
interpretation issues in fluorescence in situ hybridization (FISH) testing [84], [85], [86]. It is, 
thus, recommended that central testing should be performed to determine study eligibility, 
particularly in large studies involving multiple collaborating institutions in several 
countries [85].
Rationale for Selection of Stratification Factors. 
1. Chemotherapy
on 
study 
(taxane
[i.e., 
paclitaxel 
or 
nab-paclitaxel] 
vs 
gemcitabine/carboplatin).  The efficacy of pembrolizumab/placebo + taxane may be 
different from that of pembrolizumab/placebo + gemcitabine/carboplatin combination 
therapy.  Stratification for chemotherapy on study will ensure similar distribution of 
subjects receiving taxane and gemcitabine/carboplatin in the 2 study arms, which 
allows efficient subgroup analysis by chemotherapy on study.
Taxane options, 
e.g., nab-paclitaxel and paclitaxel, are grouped in one stratum given that both are used 
as 
monotherapy 
and 
are 
microtubule 
disassembly 
inhibitors, 
whereas 
gemcitabine/carboplatin is a combination of 2 chemotherapies with different 
mechanisms of action, e.g., antimetabolite (gemcitabine) and DNA damaging agent 
(carboplatin).  Furthermore, given 1) the higher (almost universal) use of taxanes in 
the (neo)adjuvant setting, 2) the restriction in rechallenge with taxanes to subjects 
whose disease recurrence occurred ≥12 months since completion of treatment, and 
3) the more frequent use of gemcitabine/carboplatin in subjects with more aggressive 
disease, about equal distribution of subjects to the taxane and gemcitabine/carboplatin 
strata is expected.
2. Tumor PD-L1 status (positive [i.e., CPS ≥1]; vs negative [CPS <1]).  Given that the 
dual primary objectives of this study are PFS and OS in all subjects and in subjects 
with PD-L1 positive tumors (CPS ≥1 and CPS ≥10), stratification for tumor PD-L1 
status will be applied to ensure similar distribution of subjects with PD-L1 CPS ≥1
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and PD-L1 CPS <1 in the 2 study arms. Efficacy will also be analyzed in patients 
with PD-L1 CPS ≥10.
3. Prior treatment with same class of chemotherapy in the (neo)adjuvant setting (yes vs 
no).
Use of taxane, gemcitabine, and/or platinum agents for initially diagnosed 
Stage I-III breast cancer may differentially impact tumor responsiveness to the same 
vs different class of chemotherapy in the metastatic setting. Furthermore, in clinical 
trials evaluating taxane use for metastatic breast cancer, prior treatment with taxanes 
is a commonly used stratification factor.
Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
4.2.3.1.1
Primary
OS and PFS were selected as the dual primary endpoints for KN355, because OS has been 
recognized as the gold standard for demonstration of superiority of a new anti-neoplastic 
therapy in a randomized Phase III study, whereas PFS based on RECIST 1.1 has been an 
acceptable endpoint and has been used as a primary efficacy endpoint in a number of 
randomized Phase III studies in metastatic breast cancer. Drugs approved in the recent years 
for the treatment of mBC based on PFS data include: 1) pertuzumab in combination with 
trastuzumab and docetaxel for HER2-positive mBC (2012), 2) everolimus in combination 
with exemestane for hormone receptor–positive, HER2-negative mBC (2012), 3) lapatinib 
for HER2-positive mBC (2007), 3) ixabepilone for mBC (2007).
RECIST 1.1 will be used to determine the dates of progression as this methodology is 
accepted by regulatory authorities. In addition, final determination of radiographic PD will 
be based on the CIV assessment of progression rather than local site investigator/radiology 
assessment.  Expedited assessment by the CIV in instances of suspected radiologic 
progression identified at the site (verification of PD) will be communicated to the site study 
team.
4.2.3.1.2
Secondary
ORR, DOR, and DCR based on RECIST 1.1 and assessed by blinded CIV are commonly 
used efficacy endpoints in Phase III clinical studies.
4.2.3.1.3
Exploratory
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with treatment of pembrolizumab.  Immunotherapeutic agents such as pembrolizumab may 
produce anti-tumor 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 can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions. Standard RECIST 1.1 may, 
thus, not provide an accurate response assessment of immunotherapeutic agents such as 
pembrolizumab.  Based on an analysis of subjects with melanoma enrolled in Keynote-001, 
7% of evaluable subjects experienced delayed or early tumor pseudo-progression.  Of note, 
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subjects who had PD by RECIST 1.1, but not by immune-related Response Criteria, had 
longer OS than subjects with PD by both criteria.  Additionally, the data suggest that 
RECIST 1.1 may underestimate the benefit of pembrolizumab in approximately 15% of 
subjects.  These findings support the need to apply a modification to RECIST 1.1 that takes 
into account the unique patterns of atypical response in immunotherapy and enable treatment 
beyond initial radiographic progression. 
4.2.3.2
Safety Endpoints
Commonly used safety parameters for evaluating investigational systemic anti-cancer
treatments are included as safety endpoints for the study including rate of AE/SAEs and fatal 
SAEs, causality and outcome of AE/SAEs, rate of treatment discontinuations and reasons, 
changes in vital signs, laboratory values etc. Grading of AE/SAEs will be based on 
NCI CTCAE v4.0.
4.2.3.3
Planned Exploratory Biomarker Research
Introduction:  Cancer immunotherapies are an important novel class of anti-tumor agents.  
However, much remains to be learned about how cancer immunotherapies work and 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 
as well as determinants of AEs in the course of our clinical trials.  To that end we seek to 
define novel predictive/pharmacodynamic biomarkers and the best strategies of combination 
therapy with immuno-oncology drugs. To fully leverage the clinical data collected in this 
trial, we will also collect biospecimens (blood components, tumor material, etc.) to support 
biomarker analyses of cellular components (e.g., protein, deoxyribonucleic acid [DNA], 
RNA, metabolites) and other blood soluble molecules.  A recently or newly obtained core or 
excisional biopsy from a locally recurrent inoperable or metastatic tumor site should be 
submitted, unless contraindicated due to site inaccessibility and/or subject safety concerns. 
An archival tumor specimen obtained before the diagnosis of locally recurrent inoperable or 
metastatic breast cancer may be submitted after consultation with the Sponsor, if neither a 
recently nor a newly obtained biopsy from a locally recurrent inoperable or a metastatic site 
is available.
Investigations may include, but are not limited to, the following:
Germline (blood) for Genetic Analyses (e.g., single nucleotide polymorphism [SNP]
analyses, whole exome sequencing, whole genome sequencing):  This research will evaluate 
whether genetic variation within a clinical trial 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 in order to interpret tumor-
specific DNA mutations. 
Although its prevalence is low and its significance in TNBC has not yet been determined, 
microsatellite instability (MSI) may be evaluated as this is an important biomarker for 
response to pembrolizumab in some cancers, such as colorectal carcinoma
[87].
Microsatellite instability is a form of genomic instability, through the insertion or deletion of 
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repeating units during DNA replication and failure of the mismatch repair system to correct 
DNA replication errors.
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 (i.e., mutations, methylation status, MSI, etc.).  Key molecular changes of 
interest to immune-oncology drug development are the mutational burden of tumors and the 
clonality of T cells in the tumor microenvironment.  Increased mutational burden (sometimes 
referred to as a ‘hyper-mutated’ state) is one of the major mechanisms of neo-antigen 
presentation in the context of a tumor.  The increased presence of foreign-like peptides on the 
cell surface due to somatic mutations in the DNA of the tumor increases the chances that the 
tumor will be ‘visible’ to the adaptive immune system through the Class I MHC (MHC-I)
antigen presentation mechanism. There are a number of mechanisms by which a tumor can 
have increased mutational burden, such as defects in key genes related to DNA mismatch 
repair mechanisms or environmental induced factors such as smoking or ultraviolet (UV)
light exposure.  Additionally, a DNA tetrapeptide neo-antigen mutational signature can also 
be obtained by use of bioinformatic prediction tools of human leukocyte antigen–restricted
(HLA-restricted) mutated peptide binding to MHC-I and to the T cell. There is a potential 
that in the hyper-mutated state, the presence of neo-antigen mutational patterns and the 
detection of increased T cell clonality, both of which can be determined by use of next-
generation sequencing methods, may correlate with response to pembrolizumab therapy 
and/or that the converse, the ‘hypomutated’ state (the absence of neo-antigens) may correlate 
with nonresponse.  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, in order to understand tumor-specific mutations, it is 
necessary to compare the tumor genome with the germline genome.  Particular emphasis will 
be placed on the following biological determinants/pathways: BRCA1/2, PI3K, PTEN, 
epidermal growth factor receptor (EGFR), MEK, fibroblast growth factor receptor (FGFR), 
MET, and Notch signaling [88], [89], [90], [91].  Microsatellite instability may also be 
evaluated in the tumor.
Hereditary and somatic defects in genes that support homologous recombination have been 
implicated in predisposition to a variety of cancers and in their responsiveness to therapy.
TNBC is such a cancer, as BRCA1/2 mutations and other homologous recombination defects 
play an important role in the pathophysiology of this tumor type and the degree of 
homologous recombination defect (HRD) (low vs high HRD score) may predict efficacy of 
anti-cancer regimens [92].  An HRD assay may be used in this study.
Tumor and blood RNA analyses: Both genome-wide and targeted mRNA expression 
profiling and sequencing in tumor tissue and 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 (such as 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 
(e.g., interleukin 10 [IL-10]).  MicroRNA profiling may also be pursued.
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Proteomics and Immunohistochemistry (IHC) using Blood or Tumor:  Tumor and blood 
samples from this study may undergo proteomic analyses (e.g., PD-L1 IHC).  Triple negative 
tumor status will be assessed according to the most recent ASCO/College of American 
Pathologists (CAP) guidelines. PD-L1 protein level, as assessed by IHC in tumor sections, 
has been shown to correlate with response to pembrolizumab in patients with NSCLC, and a 
PD-L1 IHC diagnostic is marketed for use with pembrolizumab in NSCLC.  Preliminary data 
indicate that this association may also be true in additional cancer types (i.e., TNBC, head 
and neck squamous cell carcinoma [HNSCC], and gastric).  Additional tumor or 
blood-derived proteins may also correlate with response to pembrolizumab.  Therefore, 
tumor tissue may be subjected to proteomic profiling using a variety of platforms that could 
include but are not limited to immunoassay, liquid chromatography/mass spectrometry.  This 
approach could identify novel protein biomarkers that could aid in patient selection for 
pembrolizumab therapy.
Other Biomarkers in Tumor Specimens:  TILs have been shown to provide prognostic and
potentially 
predictive 
value, 
particularly 
in TNBC
[54], 
[93], 
[94], 
[95]
and 
HER2-overexpressing breast cancer [95], [96], [97].  Hematoxylin and eosin–stained
(H&E-stained) breast tumor sections will be evaluated for TILs, according to a recently 
published standardized methodology [9].
Other blood-derived Biomarkers:  In addition to expression on the tumor tissue, PD-L1 
and other tumor derived proteins can be shed from tumors and released into the blood.  
Enzyme-linked immunoassay can measure such proteins in serum and correlate this 
expression with response to pembrolizumab therapy, as well as levels of PD-L1 IHC or 
protein in the tumor.  Advantages to this method are that blood is an easily accessed 
compartment from which tumor- derived protein biomarkers may be measured.  This 
research would serve to develop such assays for clinical use.
4.2.3.4
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research 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 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of this Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
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Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical studies are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Additional potential benefits are addressed in Section 4.1.3 – Ongoing Clinical Studies, 
which details responses to pembrolizumab in the TNBC cohort of the multi-cohort Phase Ib
study, KEYNOTE-012, which enrolled subjects with PD-L1 positive (in ≥1% of tumor cells 
or in stroma, by IHC) tumors.  A total of 32 female subjects with a median age of 50.5 years 
(range 29 to 72 years) and PD-L1 positive mTNBC were enrolled in the study.  Most of these 
subjects had received and progressed on multiple lines of therapy for advanced disease. The 
median number of prior lines of systemic therapy for metastatic disease was 2, with 46.9% of 
subjects having received ≥3 lines.  Of the 27 subjects with centrally confirmed measurable 
disease, one subject (3.7%) had a CR, 4 subjects (14.8%) had a confirmed PR, 25.9% had 
SD, and 44.4% had PD based on RECIST 1.1 as assessed by CIV. As of 23 Mar 2015, the 
median DOR had not been reached (range 15.0 to 47.3+ weeks), and 3 subjects (1 CR; 2 PR) 
were still on treatment after at least 15 months.  Similar to pembrolizumab studies in other 
tumor types, the most common AEs included fatigue (17.9%), decreased appetite (12.8%), 
hypothyroidism (12.8%), and arthralgia (10.3%).  Five subjects (15.6%) experienced at least 
one drug-related SAE; each of 4 subjects experienced one of the following:  Grade 3 anemia, 
headache, aseptic meningitis or pyrexia, and a fifth subject experienced Grade 5 DIC with 
thrombocytopenia and decreased blood fibrinogen in the setting of rapidly progressive 
disease.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical study may be found in the accompanying IB and Informed Consent documents.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male and female subjects with locally recurrent inoperable or metastatic TNBC, which has 
not been previously treated with chemotherapy, and who are at least 18 years of age will be 
enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Have signed informed consent to study participation. The subject may also provide 
consent for Future Biomedical Research (FBR). 
However, the subject may 
participate in the main trial without participating in FBR.
2. Be at least 18 years of age on the day of signing informed consent.
3. Have locally recurrent inoperable breast cancer not previously treated with 
chemotherapy and which cannot be treated with curative intent.
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OR
Have metastatic breast cancer not previously treated with chemotherapy.
Note: Subjects with a history of locally recurrent breast cancer, which was previously 
treated with curative intent, may be eligible.
4. Have centrally confirmed TNBC, as defined by the most recent ASCO/CAP 
guidelines.
Note: 
Subjects initially diagnosed with hormone receptor–positive and/or 
HER2-positive breast cancer must have central confirmation of TNBC in a tumor 
biopsy obtained from a local recurrence or distant metastasis site.
5. Have completed treatment for Stage I-III breast cancer, if indicated, and ≥6 months 
elapsed between the completion of treatment with curative intent (e.g., date of 
primary breast tumor surgery or date of last adjuvant chemotherapy administration, 
whichever occurred last) and first documented local or distant disease recurrence.
Note: Adjuvant radiation therapy is not considered treatment with curative intent for 
the purpose of calculating the ≥6 month interval requirement described above. 
Note: First documentation of local or distant disease recurrence must be in the form 
of a dated biopsy, pathology, or imaging study report. A laboratory report indicating 
tumor marker elevation cannot be used as documentation of local or distant disease 
recurrence, unless accompanied by dated biopsy, pathology, or imaging study report.
Note: Subjects who received taxane, gemcitabine, or platinum agents in the 
(neo)adjuvant setting can be treated with same class of chemotherapy (taxane or 
gemcitabine/carboplatin), if ≥12 months have elapsed between the completion of 
treatment with curative intent (e.g., date of primary breast tumor surgery or date of 
last adjuvant chemotherapy administration, whichever occurred last) and first 
documented local or distant disease recurrence.
6. Have been treated with (neo)adjuvant anthracycline, if they received systemic 
treatment in the (neo)adjuvant setting, unless anthracycline was contraindicated or not 
considered the best treatment option for the subject in the opinion of the treating 
physician.
Note: Subjects presenting with de novo metastatic TNBC are eligible for the study, if 
anthracycline is contraindicated or not considered the best treatment option for the 
subject in the opinion of the treating physician. 
7.
Have measurable disease based on RECIST 1.1 as determined by local radiology 
review. 
Note:
Target lesions situated in a previously irradiated area are considered 
measurable, only if they have shown unequivocal progression based on RECIST 1.1 
after radiation therapy.
Note: Chest wall recurrence can be used as a target lesion, only if measurable by 
diagnostic quality imaging modality (digital photography alone is not adequate).
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8. Have provided recently or newly obtained core or excisional biopsy from a locally 
recurrent inoperable or metastatic tumor lesion for central determination of TNBC
status and PD-L1 expression, unless contraindicated due to site inaccessibility and/or 
subject safety concerns.
Note: Adequacy of biopsy specimen for the above analyses must be confirmed by the 
central laboratory.  Submission of another tumor specimen may be required, if 
adequate tumor tissue was not provided the first time.
Note: An archival tumor specimen obtained before the diagnosis of locally recurrent 
inoperable or metastatic breast cancer may be submitted after consultation with the 
Sponsor, if neither a recently nor a newly obtained biopsy from a locally recurrent 
inoperable or a metastatic site is available.
9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 
as assessed within 10 days prior to the start of study treatment.
10. Have life expectancy ≥12 weeks from randomization.
11. Demonstrate adequate organ function, within 10 days prior to the start of study 
treatment, as defined in the following table (Table 2).
Table 2
Adequate Organ Function Laboratory Values
System
Laboratory value
Hematological
Absolute neutrophil count (ANC)
≥1,500/µL
Platelets
≥100,000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Creatinine OR
Measured or calculatedb creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥30 mL/min for subject with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR Direct bilirubin ≤ULN for subjects 
with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for subjects with liver 
metastases)
Albumin
≥3.0 g/dL
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System
Laboratory value
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time (aPTT)
≤1.5 × ULN 
unless 
subject 
is 
receiving 
anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of 
anticoagulants
≤1.5 × ULN 
unless 
subject 
is 
receiving 
anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of 
anticoagulants
ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) = aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR = glomerular filtration rate; ULN = upper 
limit of normal.
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
b Creatinine clearance (CrCl) should be calculated per institutional standard.
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.
12. This inclusion criterion was removed during amendment 06 as a result of updates to 
the contraception and pregnancy criteria. The updated information has been added to 
inclusion criterion #13.
13. A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies:
•
Is not a WOCBP
OR
•
Is a WOCBP and:
-
Uses a contraceptive method that is highly effective (with a failure rate of 
<1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in Appendix 6 during the intervention period 
and for at least the time needed to eliminate each study intervention after the 
last dose of study intervention and agrees not to donate eggs (ova, oocytes) to 
others or freeze/store for her own use for the purpose of reproduction during 
this period. The length of time required to continue contraception for each 
study intervention is as follows:
◦
pembrolizumab: 120 days
◦
chemotherapy: 180 days
The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention. 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 
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study interventions is more stringent than the requirements above, the local label 
requirements are to be followed. 
-
Has a negative highly-sensitive pregnancy test ([urine or serum] as required by 
local regulations) within 24 hours (urine) or 72 hours (serum) before the first dose 
of study intervention. (If a urine test cannot be confirmed as negative [eg, an 
ambiguous result], a serum pregnancy test is required. In such cases, the 
participant must be excluded from participation if the serum pregnancy result is 
positive). Additional requirements for pregnancy testing during and after study 
intervention are in Appendix 6.
-
Has had her medical history, menstrual history, and recent sexual activity 
reviewed by the investigator to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.
14. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least the time needed to eliminate each study 
intervention after the last dose of study intervention. The length of time required to 
continue contraception for each study intervention is as follows:
-
chemotherapy: 95 days
•
Refrain from donating sperm
PLUS either:
•
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
•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized 
or secondary to medical cause [Appendix 6]) as detailed below:
-
Agree to 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. 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.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating in a clinical study and receiving an investigational agent
and/or using an investigational device, or has participated in a clinical study and 
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received an investigational agent and/or used an investigational device within
4 weeks prior to randomization.
Note: Subjects who have entered the follow-up phase of a clinical study may 
participate as long as 4 weeks have elapsed since the last dose of the investigational 
agent and/or removal of the device.
Note: Subjects who were treated with radiation therapy may participate as long as at 
least 2 weeks have elapsed since the last dose of radiation therapy was administered.
2. Has not recovered (e.g., to ≤Grade 1 or to baseline) from AEs due to a previously 
administered therapy.
Note:  Alopecia of any grade is an exception to this criterion.
Note: Prior to randomization, the subject must have recovered adequately from any 
toxicity and/or complications associated with any recent procedure.
3. Has neuropathy ≥Grade 2.
4. Has an active autoimmune disease that has required systemic treatment in the past 
2 years (e.g., with use of disease modifying agents, corticosteroids,
or 
immunosuppressive drugs).  Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency)
is not considered a form of systemic treatment.
5. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to randomization.
6. Has a known additional malignancy that progressed or required active treatment 
within the last 5 years. 
Exceptions include basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin that has undergone potentially curative therapy,
and in situ cervical cancer.
7. Has known active CNS metastases and/or carcinomatous meningitis.  Subjects with 
known brain metastases may participate provided that the brain metastases have been 
previously treated (except with chemotherapy) and are radiographically stable.  To 
demonstrate radiographic stability of previously treated brain metastases, a minimum 
of 2 post-treatment brain imaging assessments are required: 1) The first brain imaging
must be acquired after treatment of brain metastases has been completed 2) The 
second brain imaging must be obtained during screening (i.e., within 28 days of 
randomization) and 4 weeks after the previous post-treatment brain imaging.
Note: Known brain metastases are considered active, if any of the following criteria 
are applicable:
a.
Brain imaging during screening demonstrates progression of existing 
metastases and/or appearance of new lesions compared to brain imaging 
performed at least 4 weeks earlier. 
Radiographic stability of previously treated brain metastases is based on 
local radiology/investigator review, but dated reports of 2 imaging studies
(the most recent performed during screening) documenting stability of 
brain metastasis(es) over ≥4 weeks must be submitted to the Sponsor.
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Such brain imaging studies should be available at the site for submission 
to CIV, if later needed.
b. Neurological symptoms attributed to brain metastases have not returned to 
baseline 
c.
Steroids were used for management of symptoms related to brain metastases 
within 28 days of randomization
8. Has history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis
9. Has active, or a history of, interstitial lung disease.
10. Has a known history of active TB (Bacillus Tuberculosis)
11. Has an active infection requiring systemic therapy.
12. Has a history of class II-IV congestive heart failure or myocardial infarction within 
6 months of randomization.
13. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with subject participation for 
the full duration of the study, or render study participation not compatible with the
subject’s best interest, in the opinion of the treating Investigator.  
14. Has a known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the study.
15. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days (or 
longer as specified by local institutional guidelines) after the last dose of study 
treatment.
16. Has received prior therapy with an anti–PD-1, anti–PD-L1, or anti–PD-L2 agent or 
with an agent directed to another co-inhibitory T cell receptor (such as CTLA-4, 
OX-40, CD137) or has previously participated in MSD pembrolizumab (MK-3475)
clinical studies.
17. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
18. Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or 
hepatitis C (e.g., HCV RNA [qualitative] is detected).
19. Has received a live vaccine within 30 days prior to randomization.
20. Has a known history of hypersensitivity or allergy to pembrolizumab and any of its 
components and/or to any of the study chemotherapies (e.g., nab-paclitaxel,
paclitaxel, gemcitabine, or carboplatin) and any of their components.
21. Is receiving any medication prohibited in combination with study chemotherapies as 
described in the respective product labels, unless medication was stopped within 
7 days prior to randomization.
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Trial Treatment(s)
The treatments to be used in this trial are outlined below in Table 3. If a particular taxane is 
not approved in a participating country, this agent cannot be used and selected via the
Interactive Voice Response System (IVRS)/Integrated Web Response System (IWRS) during 
randomization.
Table 3
Study Treatments
Drug
Dose/
Potency
Dose Frequency
Route of 
Administration
Treatment 
Period
Use
Pembrolizumab
200 mg
Day 1
IV infusion
Every 21 days
Experimental
Nab-paclitaxel
100 mg/m2
Days 1, 8, and 15
IV infusion
Every 28 days
Chemotherapy 
background 
treatment
Paclitaxel
90 mg/m2
Days 1, 8, and 15
IV infusion
Every 28 days
Gemcitabine 
Carboplatin
1000 mg/m2
AUC 2
Days 1 and 8
IV infusion
Every 21 days
Placebo (Normal 
Saline)
NA
Day 1
IV infusion
Every 21 days
Placebo for 
Pembrolizumab
Study treatment should begin on the day of randomization or within 3 days after the 
randomization date.
All supplies indicated in Table 3 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial 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.
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of doses to be used in this study
is provided in 
Section 4.2.2 – Rationale for Dose Selection/Regimen/Modification.
The dose amount required to prepare the pembrolizumab infusion solution will be based on a 
fixed dose of 200 mg. Details on dose calculation, preparation, and administration of 
pembrolizumab are provided in the Pharmacy Manual.
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Taxanes will be prepared and administered per local guidelines and practices at the doses 
indicated below:

nab-paclitaxel:  100 mg/m2

paclitaxel:  90 mg/m2
Gemcitabine will be prepared and administered per local guidelines and practices at
1000 mg/m2.
Carboplatin will be prepared and administered per local guidelines and practices at AUC 2.
5.2.1.2
Dose Modification
The NCI CTCAE v4.0 must be used to grade the severity of AEs. If appropriate, the 
Investigator may attribute each toxicity event to an immunologic etiology and/or 
chemotherapy. If the dose of one drug in the regimen is delayed, treatment with the other 
drug(s) may continue as scheduled.  Missed doses in chemotherapy treatment periods should 
be skipped, if not given within the allowed window of ±3 days. 
Dose modifications for individual study treatment(s) must be based on the maximum toxicity 
experienced during the previous treatment period with this(these) drug(s) and must be 
performed in a stepwise manner, as described in Table 4 and Table 5. Toxicity (except for 
alopecia) needs to resolve to ≤Grade 1 or baseline prior to resuming treatment with the same 
drug(s).  For subjects requiring a study treatment dose modification, the next treatment 
period with this(these) drug(s) may be delayed, if the scheduled off-drug periods are not 
adequate to allow for recovery to ≤Grade 1 or the baseline status of the subject.
Pembrolizumab dose reductions are not permitted.  Pembrolizumab/placebo treatment 
may be interrupted or discontinued due to an adverse event. If a dose reduction for toxicity 
occurs with chemotherapy, the dose(s) may not be re-escalated. Subjects may have a 
maximum of 2 dose modifications per chemotherapy (if applicable) for toxicities throughout 
the course of the study.  If a subject experiences several toxicities and there are conflicting 
recommendations, the most conservative dose adjustment recommended should be followed 
(dose reduction appropriate to the most severe toxicity).  
If the toxicity may be attributed to both an immunologic etiology (pembrolizumab/placebo-
related) and chemotherapy, pembrolizumab/placebo should be interrupted or discontinued 
and chemotherapy should be reduced (if applicable), interrupted, or discontinued, according 
to local guidelines and practices.
Subjects may have chemotherapy discontinued and
continue on pembrolizumab/placebo.  Any requests for unblinding will be considered on an 
individual subject basis and only after consultation with the Sponsor. Should an Investigator 
discontinue treatment with chemotherapy and continue the subject on treatment with 
pembrolizumab/placebo the subject does not need to come to the clinic on dates when only 
the chemotherapy would have been administered. Similarly, subjects may discontinue 
pembrolizumab/placebo and continue on chemotherapy alone, if appropriate.
Chemotherapy administration may be interrupted due to AEs for a maximum of 4 weeks; 
pembrolizumab/placebo may be interrupted due to AEs for a maximum of 12 weeks.
Note: Pembrolizumab/placebo and chemotherapy dosing interruptions are permitted in the 
case of medical/surgical events or logistical reasons not related to study therapy 
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(e.g., elective surgery, unrelated medical events, subject vacation, and/or holidays).  Subjects 
should be placed back on study treatment within 3 weeks of the scheduled interruption, 
unless otherwise discussed with the Sponsor.  The reason for interruption should be 
documented in the subject’s study record.
Suggested dose modifications for chemotherapy are detailed in Table 4 (local guidelines and 
practices should be followed, if different than below recommendations).
Table 4
Suggested Dose Modifications for Study Chemotherapies
Dose level 0
Dose level -1
Dose level -2
Dose level -3
Nab-paclitaxel
100 mg/m2
~ 20% reduction
~ 20% reduction
Discontinue
Paclitaxel
90 mg/m2
~ 20% reduction
~ 20% reduction
Discontinue
Gemcitabine 
1000 mg/m2
~ 20% reduction
~ 20% reduction
Discontinue
Carboplatin
AUC 2
AUC 1.5
AUC 1
Discontinue
5.2.1.2.1
Dose Modification and Toxicity Management Guidelines for Pembrolizumab
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
AEs (both serious and non-serious) associated with pembrolizumab exposure may represent 
an immunologic etiology. These immune-related AEs (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 trial 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. Based on 
the severity of irAEs, withhold or permanently discontinue pembrolizumab/placebo and 
administer corticosteroids. Dose modification and toxicity management guidelines for irAEs 
associated with pembrolizumab are provided in Table 5.
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Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated With Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects for signs and symptoms of 
pneumonitis

Evaluate subjects with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment

Add prophylactic antibiotics for opportunistic 
infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects 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).

Subjects with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Subjects 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.
Grade 4
Permanently 
discontinue
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
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
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement therapy 
for subjects with T1DM 

Administer anti-hyperglycemic in 
subjects with hyperglycemia 

Monitor subjects for hyperglycemia or other 
signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers (e.g., propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (e.g., 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
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE administer 
corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All other immune-
related AEs
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of event.  
Events that require 
discontinuation 
include and not 
limited to:  Guillain-
Barre Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE 
resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
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Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab 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 associated 
infusion reaction are provided in Table 6. 
Table 6
Pembrolizumab 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 subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject 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 (e.g., from 
100 mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab
with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 
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 (i.e., not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (e.g.,
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further study drug treatment.
No subsequent dosing
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 Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
at http://ctep.cancer.gov
5.2.1.2.2
Nab-Paclitaxel
Dose modifications for nab-paclitaxel will be implemented according to local guidelines and 
practices. 
5.2.1.2.3
Paclitaxel
Dose modifications for paclitaxel will be implemented according to local guidelines and 
practices. 
5.2.1.2.4
Gemcitabine/Carboplatin
Dose modifications for gemcitabine and/or carboplatin will be implemented according to 
local guidelines and practices.
Timing of Dose Administration
Study treatment will be administered on an outpatient basis after all procedures/assessments 
have been completed, and in the following order: pembrolizumab or saline placebo infusion 
will be administered first, followed by premedication for the assigned chemotherapy (if 
applicable; see Section 5.6.2 – Supportive Care Guidelines for Chemotherapy-related
Adverse Events) and then administration of chemotherapy, according to local guidelines and 
practices.
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5.2.2.1
Pembrolizumab/Saline Placebo
Pembrolizumab or saline placebo will be administered as a 30-minute IV infusion Q3W. 
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  A window of –5 minutes/+10 minutes is permitted. The reason for any delay in 
infusion outside of the protocol specified window should be documented in the subject’s 
chart and recorded on the electronic Case Report Forms (eCRFs).
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution.
5.2.2.2
Nab-Paclitaxel
Nab-paclitaxel will be administered as IV infusion on Days 1, 8, and 15 every 28 days
according to local guidelines and practices. 
5.2.2.3
Paclitaxel
Paclitaxel will be administered as IV infusion on Days 1, 8, and 15 every 28 days according 
to local guidelines and practices. 
5.2.2.4
Gemcitabine/Carboplatin
Gemcitabine and carboplatin will be administered as IV infusions on Days 1 and 8 every 
21 days according to local guidelines and practices.
Trial Blinding 
Part 1 (Safety Run-In):
Both pembrolizumab and chemotherapy administration will be 
open-label.
Part 2 (Phase III Study): Chemotherapy administration will be open-label.  Because this is 
a double-blind study for pembrolizumab, the Sponsor, investigators, other study site staff 
(except for the unblinded pharmacist), and subjects will be blinded to pembrolizumab vs
saline placebo administration.  The study site’s unblinded pharmacist will obtain each 
subject’s study identification number and study drug assignment from the IVRS/IWRS and 
prepare study treatment solutions for infusion.  The unblinded pharmacist will provide the 
blinded study site staff with ready-to-use blinded identically packaged pembrolizumab/saline 
infusion solutions for administration at scheduled infusion visits. In addition to emergent 
unblinding for severe or life-threatening AEs with potential immunologic etiology, non-
emergent unblinding to pembrolizumab versus placebo administration may occur on an 
individual subject basis and only after consultation with the Sponsor at the time of (1) 
centrally verified disease progression and subject has discontinued all study treatments or,
(2) when the subject has discontinued all study treatments and a new anti-cancer treatment is 
going to be started. Non-emergent unblinding only after consultation and approval from the 
Sponsor is implemented through IRT by following the instructions in the IRT site user 
manual.  Investigators, other study site staff, and subjects will be blinded to subject-level 
tumor PD-L1 biomarker results.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
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Randomization or Treatment Allocation
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS). There are 2 main treatment arms.  
Subjects will be assigned randomly in a 2:1 ratio to pembrolizumab + chemotherapy or 
placebo + chemotherapy, respectively, in Part 2 (Phase III study), after stratification as 
described in Section 5.4 – Stratification. The chemotherapy that each subject is eligible for
will be determined according to Inclusion Criterion #5 in Section 5.1.2 – Subject Inclusion 
Criteria.
If chemotherapy options include more than one regimen, choice of study 
chemotherapy will be at physician’s discretion. The distribution of the subjects among the 
3 chemotherapy options (paclitaxel, nab-paclitaxel, or gemcitabine/carboplatin) will be 
monitored closely.
For Part 1 (Safety Run-In), there are 3 treatment arms:
pembrolizumab + paclitaxel, 
pembrolizumab + nab-paclitaxel, or pembrolizumab + gemcitabine/carboplatin.  Enrollment 
in Part 1 will stop once ≥10 subjects are enrolled in each arm.
To ensure approximately 
synchronous enrollment to all 3 treatment arms in Part 1, subject randomization/allocation 
will be performed as summarized in Table 7. Forced randomization will be applied to stop 
enrollment into a specific treatment once ≥10 subjects are enrolled in that treatment.  
Approximately 30 subjects are expected to enroll in total in Part 1.  
Table 7
Subject Randomization/Allocation for Part 1
Group
Subject Breast Cancer History
Subject Randomization/Allocation
1

No prior (neo)adjuvant chemotherapy 
treatment (including subjects with 
de novo mTNBC), or

Local or distant disease recurrence
≥12 months 
after 
completion 
of 
treatment 
with 
curative 
intent 
(e.g., date of primary breast tumor 
surgery or date of last adjuvant 
chemotherapy 
administration, 
whichever occurred last), or

Interval 
between 
completion 
of 
treatment with curative intent and 
disease recurrence of 6 to 12 months, 
and no prior treatment with either 
platinum or gemcitabine or taxane in 
the (neo)adjuvant setting.
Subjects will be randomized in a 1:1:1 ratio 
among

pembrolizumab + nab-paclitaxel 

pembrolizumab + paclitaxel 

pembrolizumab +
gemcitabine/carboplatin
2
Interval between completion of treatment
with curative intent and disease recurrence 
of 6 to 12 months, and prior platinum or 
gemcitabine treatment in the (neo)adjuvant 
setting, and no prior taxane treatment in the
(neo)adjuvant setting.
Subjects will be randomized in a 1:1 ratio 
between

pembrolizumab + nab-paclitaxel 

pembrolizumab + paclitaxel 
3
Interval between completion of treatment
with curative intent and disease recurrence 
of 6 to 12 months, and prior taxane 
treatment in the (neo)adjuvant setting, and
no prior platinum or gemcitabine treatment 
in the (neo)adjuvant setting.
Subjects will be allocated to

pembrolizumab +
gemcitabine/carboplatin
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Stratification
Treatment allocation/randomization will be stratified according to the following factors:
Part 1 (Safety Run-In): 
There is no stratification factor for Part 1.
Part 2 (Phase III Study):
1. Chemotherapy 
on 
study 
(taxane 
[i.e., 
paclitaxel 
or 
nab-paclitaxel] 
vs 
gemcitabine/carboplatin).
2. Tumor PD-L1 status (CPS ≥1 vs CPS <1).
3. Prior treatment with same class of chemotherapy in the (neo)adjuvant setting
(yes vs no).
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
All treatments that the Investigator considers necessary for a subject’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 
prescription, over-the-counter (OTC), 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.
All concomitant medications received within 30 days before randomization, while on study 
treatment, and up to 30 days after the last dose of study treatment should be recorded.
Concomitant medications administered beyond 30 days after the last dose of study treatment
should be recorded when prescribed for SAEs (see Section 7.2 – Assessing and Recording 
Adverse Events).
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening, 
Treatment, and Retreatment Phase of this study:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol
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
Investigational agents other than pembrolizumab

Radiation therapy
o
Radiation therapy is prohibited within 2 weeks prior to randomization
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed after consultation with Sponsor (except during screening).

Herbal supplements

Live vaccines within 30 days prior to randomization and while participating in the 
study.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella, herpes zoster, yellow fever, rabies, Bacillus 
Calmette–Guérin (BCG), and typhoid (oral) vaccines. Seasonal influenza vaccines 
for injection are generally killed virus vaccines and are allowed. However, intranasal 
influenza vaccines (e.g., Flu - Mist®) are live attenuated vaccines, and are not 
allowed.

Glucocorticoids for any purpose other than the following:

To modulate symptoms from an AE of suspected immunologic etiology.  

Inhaled steroids for management of asthma.

Physiologic doses of prednisone 10 mg (or equivalent) per day

Use of prophylactic corticosteroids to avoid allergic reactions (e.g., to 
paclitaxel and/or IV contrast dye) is permitted.

Any medication prohibited in combination with chemotherapy as described in the 
respective product labels for nab-paclitaxel, paclitaxel, gemcitabine, and carboplatin.
The Exclusion Criteria describe other medications that are prohibited in this study.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Rescue Medications & Supportive Care
Supportive Care Guidelines for Subjects Receiving Pembrolizumab/Placebo
Subjects 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 
Section 5.2.1, Table 5. 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.
Note:  If, after evaluation, the event is determined not to be related to pembrolizumab/placebo, 
the investigator does not need to follow the treatment guidance.  Refer to Section 5.2.1 – Dose 
Selection/Modification and Table 5 for pembrolizumab/placebo dose modifications.
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It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
Supportive Care Guidelines for Chemotherapy-related Adverse Events
Paclitaxel-, nab-paclitaxel-, or gemcitabine/carboplatin-related AEs should be managed 
according to local guidelines and practices.
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
A subject must be discontinued from the trial if:
○
The subject or legal representative (such as parent or legal representative) withdraws 
consent.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
o
The subject or legal representative (such as parent or legal guardian) withdraws consent 
for study treatment.
o
The subject has confirmed radiographic disease progression, with the exception as 
outlined in Section 7.1.2.9.5 – irRECIST Assessment of Disease.
o
The subject has unacceptable toxicity, as described in Section 7.2 – Assessing and 
Recording Adverse Events.
o
The subject has an intercurrent illness that prevents further administration of treatment.
o
The Investigator made a decision to discontinue subject’s treatment on study.
o
The subject is noncompliant with study treatment or procedural requirements.
o
The subject has a confirmed positive serum pregnancy test.
o
Administrative reasons.
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In addition, if a subject completes 35 administrations of pembrolizumab/placebo, the subject 
must be discontinued from pembrolizumab/placebo study treatment but may continue 
chemotherapy treatment at the investigator’s discretion.  The subject should continue to be 
monitored in the trial.  
Subjects who attain an
investigator-determined confirmed CR may discontinue 
pembrolizumab/placebo 
after 
receiving
at 
least 
2 additional 
administrations 
of 
pembrolizumab/placebo beyond the date when the initial CR was declared and at least 
8 administrations of pembrolizumab/placebo in total. (Dis)continuation of chemotherapy
after confirmed CR is at the Investigator’s discretion.
Subjects who are discontinued from all study treatments should continue to be monitored in 
the trial, as outlined in Sections 7.1.5.3 – End of Treatment and 7.1.5.4 – After Treatment 
Discontinuation.
Subjects who stop pembrolizumab/placebo with SD or better may be eligible for up to 
17 additional treatments with pembrolizumab if they meet eligibility criteria for retreatment 
phase as specified in Section 7.1.5.6 – Second Course Phase (Retreatment Phase).
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit, 
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. The study may be stopped early for futility or safety at the recommendation of the DMC.
2. Quality of quantity of data recording is inaccurate or incomplete as assessed by the 
Sponsor.
3. Poor adherence to protocol and regulatory requirements.
4. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects from study drugs/drug combinations under investigation.
5. Plans to modify or discontinue the development of study drugs/drug combinations.
Statistical criteria for stopping the study are provided in Section 8.0– Statistical Analysis 
Plan.
Enrollment will not be halted during the planned safety interim and efficacy interim analyses.
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Further recruitment in the study or at (a) particular study site(s) may be stopped due to 
insufficient compliance with the protocol, GCP, and/or other applicable regulatory 
requirements or procedure-related problems or if the number of discontinuations for 
administrative reasons is too high.
In the event of Sponsor decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made.
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6.0 TRIAL FLOW CHART
First Course Treatment Phase
Screening and Treatment Periods (Parts 1 and 2)
6.1.1.1
Pembrolizumab/Placebo Plus Taxane (Paclitaxel or Nab-Paclitaxel)
Study Period
Screening 
Period
Treatment Period (3-Week Cycles)
Treatment Cycle/Title:
Screeningb
1
2
3
4
5 and 
Beyonda
Scheduled Day:
–28 to –1
1c
8
15
1
8
15
1
8
15
1
8
15
1/8/15a
Scheduling Window (Days):
N/A
N/A
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Informed Consent
X
Informed Consent for Future Biomedical Research
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication Reviewd
X
X
X
X
X
X
X
X
X
X
X
X
Survival Statust
Clinical Procedures/Assessments
Full Physical Examinatione
X
X
Directed Physical Examinatione
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
Vital Signs and Weightf
X
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab/Placebo Administration (Placebo 
given only in Part 2)g, h
X
X
X
X
X
Taxane Administrationg, h
X
X
X
X
X
X
X
X
X
X
ePROsi
X
X
X
X
ECOG Performance Statusj
X
X
X
X
X
X
Adverse Events Monitoringk
X
X
X
X
X
X
X
X
X
X
X
X
Menopausal Status
X
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Study Period
Screening 
Period
Treatment Period (3-Week Cycles)
Treatment Cycle/Title:
Screeningb
1
2
3
4
5 and 
Beyonda
Scheduled Day:
–28 to –1
1c
8
15
1
8
15
1
8
15
1
8
15
1/8/15a
Scheduling Window (Days):
N/A
N/A
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Laboratory Procedures/Assessments:  Analysis performed by local laboratories
CBC with Differentialj
X
Xl
X
X
X
X
X
X
X
X
X
Xl
Chemistryj
X
Xl
X
X
X
Xl
Urinalysisj
X
PT/INR and aPTTj
X
T3 (or Free T3), Free T4, and TSH
X
Xm
Xm
Serum vitamin Dj
X
Serum FSH and estradiolj
X
Tumor markers (CA15-3, CEA, and CA27.29)
X
Xn
X
Pregnancy Test – Serum or Urine β-Human 
Chorionic Gonadotropin (β-hCG)
Xo
X
X
X
X
X
Laboratory Procedures/Assessments:  Analysis performed by central laboratory
Blood for Genetic Analysesp
X
Blood for RNA Analysesq
X
X
X
Blood for Plasma Biomarker Analysesq
X
X
X
Blood for Serum Biomarker Analysesq
X
X
X
Efficacy Assessments
Tumor Imagingr
X
Xr
X
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Study Period
Screening 
Period
Treatment Period (3-Week Cycles)
Treatment Cycle/Title:
Screeningb
1
2
3
4
5 and 
Beyonda
Scheduled Day:
–28 to –1
1c
8
15
1
8
15
1
8
15
1
8
15
1/8/15a
Scheduling Window (Days):
N/A
N/A
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Tumor Tissue Collection
Recently or Newly Obtained Tumor Collection
Xs
a.
Starting with Cycle 5, the pattern of study treatment administration and assessments and procedures performed in Cycles 1 through 4 will be repeated, unless stated
otherwise.
b.
Relative to day of randomization.
c.
Cycle 1, Day 1, may be on the same day as randomization or at most 3 days post randomization.
d.
Record all medications taken within 30 days prior to randomization and all medications taken during treatment period of the study.
e.
Full physical examination and directed physical examination will include neurologic examination to be performed by the treating physician or designee.
f.
Vital signs measurements include temperature, pulse, blood pressure, respiratory rate, and weight.  Height is measured only at 1st clinic visit.
g.
In Part 1, for subjects receiving pembrolizumab + taxane (paclitaxel or nab-paclitaxel), pembrolizumab will be administered every 3 weeks (Q3W) on Day 1 of each 3-week 
cycle.  Paclitaxel or nab-paclitaxel will be administered on a 3-week on (Days 1, 8, and 15)/1-week off schedule every 28 days. Should an Investigator discontinue treatment 
with chemotherapy but continue treatment with pembrolizumab, the subject does not need to come to the clinic on dates when only the chemotherapy would have been 
administered. The subject should still follow the treatment and procedure schedule for pembrolizumab visits.
h.
In Part 2, for subjects randomly assigned to pembrolizumab/placebo + taxane (paclitaxel or nab-paclitaxel), pembrolizumab/placebo will be administered Q3W on Day 1 of 
each 3-week cycle.  Paclitaxel or nab-paclitaxel will be administered on a 3-week on (Days 1, 8, and 15)/1-week off schedule every 28 days. Visit schedule for subjects who 
discontinued treatment with chemotherapy, but continued pembrolizumab/placebo treatment remains as described above in “g”.
i.
The electronic Patient Reported Outcomes (ePROs) include EORTC QLQ-C30, EORTC QLQ-BR23, and EQ-5D™. Refer to Section 7.1.2.5 – Patient-Reported Outcomes 
for details on timing for ePROs.
j.
Screening laboratory tests and ECOG must be performed within 10 days prior to the start of study treatment (serum FSH and estradiol will only be measured, if clinically 
indicated for determination of menopausal status). Thereafter, laboratory samples can be collected up to 72 hours prior to scheduled administration of study treatment.
k.
Record all AEs occurring through the end of treatment and as described in Section 6.1.2 – End of Treatment and After Treatment Discontinuation (Parts 1 and 2).
l.
The CBC and chemistry laboratory tests do not need to be performed on Cycle 1, Day 1, if obtained within 10 days prior to the start of study treatment. However, they will 
be performed on Day 1 of each subsequent cycle.  Note:  CBC will also be performed on additional days, as described in the table above.
m.
Post randomization, thyroid function tests should be collected every 2 cycles. 
n.
CA15-3, CEA, and CA27.29 should be collected during screening and then according to the imaging schedule (can be conducted at corresponding study visit) until study 
treatment discontinuation (see also Section 6.1.2 – End of Treatment and After Treatment Discontinuation (Parts 1 and 2).
o.
For women of reproductive potential, a urine pregnancy test will be performed within 24 hours or serum pregnancy test should be performed within 72 hours prior to the first 
dose of study treatment.  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. While the subject is on study, pregnancy 
testing should be conducted as per local regulations where applicable.
p.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at that site if 
there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent.  If the planned genetic analyses are not approved, but FBR is 
approved and consent is given, this sample will be collected for the purpose of FBR.
q.
Blood should be collected at pre-dose on Cycles 1, 2, and 5 or at time of discontinuation as described in Section 6.1.2 – End of Treatment and After Treatment 
Discontinuation (Parts 1 and 2).  Leftover RNA, plasma, and serum will be stored at the end of the study for future biomedical research if the subject has consented.
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r.
Post-baseline imaging studies will be performed at Weeks 8 (±7 days), 16 (±7 days), and 24 (–7 days) post randomization, every 9 weeks (±7 days) thereafter during the first 
year, and every 12 weeks (±7 days) after the first year. Imaging at Week 24 should be performed within 24 weeks post randomization. Refer to Section 7.1.2.9 – Tumor 
Imaging and Assessment of Disease Status for details on tumor imaging and assessment of disease.
s.
All subjects must have central confirmation of TNBC status and determination of tumor PD-L1 status prior to randomization (see Section 5.1.2 – Subject Inclusion Criteria).  
The same, recently or newly obtained, core or excisional tumor biopsy (fine needle aspiration [FNA] not adequate) from a locally recurrent inoperable or metastatic tumor 
lesion can be used for both investigations.  Additional information is provided in Section 7.1.2.10 – Tumor Tissue Collection.
t.
During the Survival Follow-up phase, contacts are approximately every 12 weeks by telephone (or more often as needed). Updated survival status may be requested by the 
Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the 
Sponsor defined time period will be contacted for their survival status (excluding subjects that have a death event previously recorded).
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6.1.1.2
Pembrolizumab/Placebo Plus Gemcitabine/Carboplatin
Study Period:
Screening 
Period
Treatment Period (3-Week Cycles)
Treatment Cycle/Title:
Screeningb
1
2
3
4
5 and Beyonda
Scheduled Day:
–28 to –1
1c
8
1
8
1
8
1
8
1/8a
Scheduling Window (Days):
N/A
N/A
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Informed Consent
X
Informed Consent for Future Biomedical Research
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication Reviewd
X
X
X
X
X
X
X
X
X
X
Survival Statust
Clinical Procedures/Assessments
Full Physical Examinatione
X
X
Directed Physical Examinatione
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
Vital Signs and Weightf
X
X
X
X
X
X
X
X
X
X
Pembrolizumab/Placebo Administration (Placebo given 
only in Part 2)g, h
X
X
X
X
X
Gemcitabine/Carboplatin Administrationg, h
X
X
X
X
X
X
X
X
X
ePROsi
X
X
X
X
ECOG Performance Statusj
X
X
X
X
X
X
Adverse Events Monitoringk
X
X
X
X
X
X
X
X
X
X
Menopausal Status
X
Laboratory Procedures/Assessments:  Analysis performed by local laboratories
CBC with Differentialj
X
Xl
X
X
X
X
X
X
X
Xl
Chemistryj
X
Xl
X
X
X
Xl
Urinalysisj
X
PT/INR and aPTTj
X
T3 (or Free T3), Free T4, and TSH
X
Xm
Xm
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Study Period:
Screening 
Period
Treatment Period (3-Week Cycles)
Treatment Cycle/Title:
Screeningb
1
2
3
4
5 and Beyonda
Scheduled Day:
–28 to –1
1c
8
1
8
1
8
1
8
1/8a
Scheduling Window (Days):
N/A
N/A
±3
±3
±3
±3
±3
±3
±3
±3
Serum vitamin Dj
X
Serum FSH and estradiolj
X
Tumor markers (CA15-3, CEA, and CA27.29)
X
Xn
Xn
Pregnancy Test – Serum or Urine β-Human Chorionic 
Gonadotropin (β-hCG)
Xo
X
X
X
X
X
Laboratory Procedures/Assessments:  Analysis performed by central laboratory
Blood for Genetic Analysesp
X
Blood for RNA Analysesq
X
X
X
Blood for Plasma Biomarker Analysesq
X
X
X
Blood for Serum Biomarker Analysesq
X
X
X
Efficacy Assessments
Tumor Imagingr
X
Xr
Xr
Tumor Tissue Collection
Recently or Newly Obtained Tumor Collection
Xs
a.
Starting with Cycle 5, the pattern of study treatment administration and assessments and procedures performed in Cycles 1 through 4 will be repeated, unless stated 
otherwise.
b.
Relative to day of randomization.
c.
Cycle 1, Day 1, may be on the same day as randomization or at most 3 days post randomization.
d.
Record all medications taken within 30 days prior to randomization and all medications taken during treatment period of the study.
e.
Full physical examination and directed physical examination will include neurologic examination to be performed by the treating physician or designee.
f.
Vital signs measurements include temperature, pulse, blood pressure, respiratory rate, and weight.  Height is measured only at 1st clinic visit.
g.
In Part 1, for subjects receiving pembrolizumab + gemcitabine/carboplatin, pembrolizumab will be administered every 3 weeks (Q3W) on Day 1 of each 3-week cycle.  
Gemcitabine/carboplatin will be administered on Days 1 and 8 every 21 days. Should an Investigator discontinue treatment with chemotherapy, but continue treatment with 
pembrolizumab, the subject does not need to come to the clinic on dates when only the chemotherapy would have been administered The subject should still follow the 
treatment and procedure schedule for pembrolizumab visits.
h.
In Part 2, for subjects randomly assigned to pembrolizumab/placebo + gemcitabine/carboplatin, pembrolizumab/placebo will be administered Q3W on Day 1 of each 3-week 
cycle.  Gemcitabine/carboplatin will be administered on Days 1 and 8 every 21 days. Visit schedule for subjects who discontinued treatment with chemotherapy, but 
continued pembrolizumab/placebo treatment remains as described above in “g”.
i.
The electronic Patient Reported Outcomes (ePROs) include EORTC QLQ-C30, EORTC QLQ-BR23, and EQ-5D™.  Refer to Section 7.1.2.5 – Patient-Reported Outcomes 
for details on timing for ePROs.
j.
Screening laboratory tests and ECOG must be performed within 10 days prior to the start of study treatment (serum FSH and estradiol will only be measured, if clinically 
indicated for determination of menopausal status).  Thereafter, laboratory samples can be collected up to 72 hours prior to scheduled administration of study treatment.
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k.
Record all AEs occurring through the end of treatment and as described in Section 6.1.2 – End of Treatment and After Treatment Discontinuation (Parts 1 and 2).
l.
The CBC and chemistry laboratory tests do not need to be performed on Cycle 1, Day 1, if obtained within 10 days prior to the start of study treatment.  However, they will 
be performed on Day 1 of each subsequent cycle.  Note:  CBC will also be performed on additional days, as described in the table above.
m.
Post randomization, thyroid function tests should be collected every 2 cycles.  
n.
CA15-3, CEA, and CA27.29 should be collected during screening and then according to the imaging schedule (can be conducted at corresponding study visit) until study 
treatment discontinuation (see also Section 6.1.2 – End of Treatment and After Treatment Discontinuation (Parts 1 and 2).
o.
For women of reproductive potential, a urine pregnancy test will be performed within 24 hours or serum pregnancy test should be performed within 72 hours prior to the first 
dose of study treatment.  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. While the subject is on study, pregnancy 
testing should be conducted as per local regulations where applicable.
p.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at that site if 
there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent.  If the planned genetic analyses are not approved, but FBR is 
approved and consent is given, this sample will be collected for the purpose of FBR.
q.
Blood should be collected at pre-dose on Cycles 1, 2, and 5 or at time of discontinuation as described in Section 6.1.2 – End of Treatment and After Treatment 
Discontinuation (Parts 1 and 2).  Leftover RNA, plasma, and serum will be stored at the end of the study for future biomedical research if the subject has consented.
r.
Post baseline imaging studies will be performed at Weeks 8 (±7 days), 16 (±7 days), and 24 (–7 days) post randomization, every 9 weeks (±7 days) thereafter during the first 
year, and every 12 weeks (±7 days) after the first year.  Imaging at Week 24 should be performed within 24 weeks post randomization.  Refer to Section 7.1.2.9 – Tumor 
Imaging and Assessment of Disease Status for details on tumor imaging and assessment of disease.
s.
All subjects must have central confirmation of TNBC status and determination of tumor PD-L1 status prior to randomization (see Section 5.1.2 – Subject Inclusion Criteria).  
The same, recently or newly obtained, core or excisional tumor biopsy (fine needle aspiration [FNA] not adequate) from a locally recurrent inoperable or metastatic tumor 
lesion can be used for both investigations.  Additional information is provided in Section 7.1.2.10– Tumor Tissue Collection.
t.
During the Survival Follow-up phase, contacts are approximately every 12 weeks by telephone (or more often as needed). Updated survival status may be requested by the 
Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the 
Sponsor defined time period will be contacted for their survival status (excluding subjects that have a death event previously recorded).
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End of Treatment and After Treatment Discontinuation (Parts 1 and 2)
End of Treatment
After Treatment Discontinuation
Treatment Cycle/Title
Last Dosea
Safety Follow-up
Disease Status Follow-upa
Survival 
Follow-upb
At Time of Treatment 
Discontinuation
30 Days Post Last Dose
Every 9 or 12 Weeks Post Last dose
Every 
12 Weeksb
Scheduled Day
N/A
N/A
N/A
N/A
Scheduling Window (Days):
N/A
±3
±7
±7
Administrative Procedures
Prior and Concomitant Medication Reviewc
X
X
Clinical Procedures/Assessments
Full Physical Examinationd
X
X
Vital Signs and Weighte
X
X
ePROsf
X
X
ECOG Performance Status
X
X
Post-treatment Disease Status
X
Survival Statusb
X
Adverse Events Monitoringg
X
X
Laboratory Procedures/Assessments:  Analysis performed by local laboratories
CBC with Differential
X
X
Chemistry
X
X
T3 (or Free T3), Free T4, and TSH
X
X
Tumor markers (CA15-3, CEA, and CA27.29)
X
X
X
Pregnancy Test – Serum or Urine β-Human Chorionic 
Gonadotropin (β-hCG)h
Laboratory Procedures/Assessments:  Analysis performed by central laboratory
Blood for RNA Analysesj
X
Blood for Plasma Biomarker Analysesj
X
Blood for Serum Biomarker Analysesj
X
Efficacy Assessments
Tumor Imagingi
X
X
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End of Treatment
After Treatment Discontinuation
Treatment Cycle/Title
Last Dosea
Safety Follow-up
Disease Status Follow-upa
Survival 
Follow-upb
At Time of Treatment 
Discontinuation
30 Days Post Last Dose
Every 9 or 12 Weeks Post Last dose
Every 
12 Weeksb
Scheduled Day
N/A
N/A
N/A
N/A
Scheduling Window (Days):
N/A
±3
±7
±7
Tumor Tissue Collection
Optional Tumor Collection
X
a.
For subjects who discontinue study treatment without centrally verified disease progression, please see Section 7.1.4.1 – Withdrawal/Discontinuation for guidance.
b.
During the Survival Follow-up phase, contacts are approximately every 12 weeks by telephone (or more often as needed). Updated survival status may be requested by the 
Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the 
Sponsor defined time period will be contacted for their survival status (excluding subjects that have a death event previously recorded).
c.
Record all medications taken at time of and after treatment discontinuation.
d.
Full physical examination and directed physical examination will include neurologic examination to be performed by the treating physician or designee.
e.
Vital signs measurements include temperature, pulse, blood pressure, respiratory rate, and weight.  
f.
The electronic Patient Reported Outcomes (ePROs) include EORTC QLQ-C30, EORTC QLQ-BR23, and EQ-5D™.  Refer to Section 7.1.2.5 –Patient-Reported Outcomes 
for details on timing for ePROs.
g.
Record all AEs occurring within 30 days post treatment end.  Report all SAEs occurring up to 90 days post treatment end or until subject initiates new anti-cancer therapy, 
but for at least 30 days post treatment end, whichever occurs first.  Afterwards, report only drug-related SAEs.
h.
For women of reproductive potential, while the subject is on study, pregnancy testing should be conducted as per local regulations where applicable.
i.
Refer to Section 7.1.2.9 – Tumor Imaging and Assessment of Disease Status for details on tumor imaging and assessment of disease.
j.
Blood should be collected at time of discontinuation.  Leftover RNA, plasma, and serum will be stored at the end of the study for future biomedical research if the subject 
has consented.
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Second Course Phase (Retreatment Phase) for Part 1 Subjects or Part 2 Subjects 
Randomized to Pembrolizumab Plus Chemotherapy 
Treatment Period
For subjects assigned to treatment with pembrolizumab + chemotherapy, continuation or 
resumption of the same chemotherapy received in the First Course Treatment Phase may be 
administered in the Second Course Phase at the discretion of the Investigator. Note that 
chemotherapy different from that received in the First Course Treatment Phase is not 
permitted.  The Trial Flow Charts for subjects who will be administered retreatment in the 
Second Course Phase are provided below for subjects receiving pembrolizumab alone 
(Section 6.2.1.1 – Pembrolizumab), pembrolizumab + taxane (paclitaxel or nab-paclitaxel)
(Section 6.2.1.2 – Pembrolizumab Plus Taxane [Paclitaxel or Nab-Paclitaxel]), or 
pembrolizumab 
+ 
gemcitabine/carboplatin 
(Section 6.2.1.3 – Pembrolizumab 
Plus 
Gemcitabine/Carboplatin).  Complete details regarding retreatment are provided in Section 
7.1.5.6 – Second Course Phase (Retreatment Phase).
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6.2.1.1
Pembrolizumab
Study Period:
Treatment Period (3-Week Cycles)a
Treatment Cycle/Title:
1
2
3
4
5 and Beyondb
Scheduled Day:
1
1
1
1
1
Scheduling Window (Days):a
N/A
±3
±3
±3
±3
Administrative Procedures
Eligibility Criteriaa
X
Concomitant Medication Review
X
X
X
X
X
Survival Statusk,l
Clinical Procedures/Assessments
Full Physical Examination
X
Directed Physical Examination
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
Pembrolizumab Administrationc
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
Review Adverse Eventsd
X
X
X
X
X
Laboratory Procedures/Assessments:  Analysis performed by local laboratories
CBC with Differential
Xe
X
X
X
Xe
Chemistry
Xe
X
X
X
Xe
Urinalysis
X
PT/INR and aPTTf
X
T3 (or Free T3), Free T4, and TSHg
Xg
Xg
Xg
Tumor markers (CA15-3, CEA, and CA27.29)h
X
X
X
Pregnancy Test – Serum or Urine β-Human Chorionic Gonadotropin (β-hCG)
Xi
X
X
X
X
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Study Period:
Treatment Period (3-Week Cycles)a
Treatment Cycle/Title:
1
2
3
4
5 and Beyondb
Scheduled Day:
1
1
1
1
1
Scheduling Window (Days):a
N/A
±3
±3
±3
±3
Efficacy Assessments
Tumor Imagingj,k
X
X
X
a.
For assessment/procedure details, see Section 7.0 – Trial Procedures.  For information regarding eligibility criteria for retreatment, see Section 7.1.5.6.1 – Conditions of 
Second Course Phase.  For specific timings and windows, see Section 7.1.5.6.2 – Visit Requirements of Second Course Phase.
b.
Starting with Cycle 5, the pattern of retreatment administration and assessments and procedures performed in Cycles 1 through 4 will be repeated, unless stated otherwise.
c.
For retreatment, pembrolizumab will be administered every 3 weeks (Q3W) on Day 1 of each 3-week cycle.  
d.
Guidance on recording AEs and ECIs can be found Section 7.1.2.1 – Adverse Event Monitoring.
e.
The CBC and chemistry laboratory tests do not need to be performed on Cycle 1, Day 1, if obtained within 10 days prior to the first retreatment dose of pembrolizumab.  
However, they will be performed on Day 1 of each subsequent cycle.
f.
Any subject receiving anticoagulant therapy should have coagulation factors monitored closely throughout the study.
g.
T3 or FT3 can be assayed based on local guidelines and practices.  To be repeated every 2 cycles after Cycle 5. 
h.
Tumor markers (CA15-3, CEA, and CA27.29) should be collected according to the imaging schedule (can be conducted at corresponding study visit) until retreatment
discontinuation.
i.
For women of reproductive potential, a urine pregnancy test will be performed within 24 hours or serum pregnancy test should be performed within 72 hours prior to the first 
retreatment dose of pembrolizumab.  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.  While the subject is on study, 
pregnancy testing should be conducted as per local regulations where applicable.
j.
Tumor imaging (including brain imaging in subjects with known brain metastases) must be performed within 28 days prior to starting retreatment with pembrolizumab.  
Tumor imaging should continue to be performed every 9 weeks (±7 days) after start of Second Course Phase or more frequently if clinically indicated, regardless of any 
treatment delays.  Tumor imaging timing should follow calendar days and should not be adjusted for any dose modifications.  The same image modality acquisition and 
technical parameters should be used throughout the study.
k.
If a subject is discontinued from retreatment with documented PD, imaging is not performed.  The subject will then enter survival follow-up.
l.
During the Survival Follow-up phase, contacts are approximately every 12 weeks by telephone (or more often as needed). Updated survival status may be requested by the 
Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the 
Sponsor defined time period will be contacted for their survival status (excluding subjects that have a death event previously recorded).
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6.2.1.2
Pembrolizumab Plus Taxane (Paclitaxel or Nab-Paclitaxel)
Study Period:
Treatment Period (3-Week Cycles)a
Treatment Cycle/Title:
1
2
3
4
5 and 
Beyondb
Scheduled Day:
1
8
15
1
8
15
1
8
15
1
8
15
1/8/15b
Scheduling Window (Days):a
N/A
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Eligibility Criteriaa
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
Survival Statusk,l
Clinical Procedures/Assessments
Full Physical Examination
X
Directed Physical Examination
X
X
X
X
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab Administrationc
X
X
X
X
X
Taxane Administrationc
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
Review Adverse Eventsd
X
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments:  Analysis performed by local laboratories
CBC with Differential
Xe
X
X
X
X
X
X
X
X
X
Xe
Chemistry
Xe
X
X
X
Xe
Urinalysis
X
PT/INR and aPTTf
X
T3 (or Free T3), Free T4, and TSHg
Xg
Xg
Xg
Tumor markers (CA15-3, CEA, and CA27.29)h
X
-
Xh
X
Pregnancy Test – Serum or Urine β-Human Chorionic 
Gonadotropin (β-hCG)
Xi
X
X
X
X
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Study Period:
Treatment Period (3-Week Cycles)a
Treatment Cycle/Title:
1
2
3
4
5 and 
Beyondb
Scheduled Day:
1
8
15
1
8
15
1
8
15
1
8
15
1/8/15b
Scheduling Window (Days):a
N/A
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Efficacy Assessments
Tumor Imagingj
X
-
Xk
X
a.
For assessment/procedure details, see Section 7.0 – Trial Procedures.  For information regarding eligibility criteria for retreatment, see Section 7.1.5.6.1 – Conditions of 
Second Course Phase.  For specific timings and windows, see Section 7.1.5.6.2 – Visit Requirements of Second Course Phase.
b.
Starting with Cycle 5, the pattern of retreatment administration and assessments and procedures performed in Cycles 1 through 4 will be repeated, unless stated otherwise.
c.
Continuation or resumption of same chemotherapy as received in the First Course Treatment Phase may be administered in the Second Course Phase at the discretion of the 
investigator.  Note that chemotherapy different from that received in the First Course Treatment Phase is not permitted.  For subjects receiving pembrolizumab + taxane 
(paclitaxel or nab-paclitaxel), pembrolizumab will be administered every 3 weeks (Q3W) on Day 1 of each 3-week cycle.  Paclitaxel or nab-paclitaxel will be administered 
on a 3-week on (Days 1, 8, and 15)/1-week off schedule every 28 days. Should an Investigator discontinue treatment with chemotherapy, but continue treatment with 
pembrolizumab, the subject does not need to come to the clinic on dates when only the chemotherapy would have been administered. The subject should still follow the 
treatment and procedure schedule for pembrolizumab visits.
d.
Guidance on recording AEs and ECIs can be found Section 7.1.2.1 – Adverse Event Monitoring.
e.
The CBC and chemistry laboratory tests do not need to be performed on Cycle 1, Day 1, if obtained within 10 days prior to the first retreatment dose.  However, they will be 
performed on Day 1 of each subsequent cycle.  Note:  CBC will also be performed on additional days, as described in the table above.
f.
Any subject receiving anticoagulant therapy should have coagulation factors monitored closely throughout the study.
g.
T3 or FT3 can be assayed based on local guidelines and practices.  To be repeated every 2 cycles after Cycle 5. 
h.
Tumor markers (CA15-3, CEA, and CA27.29) should be collected according to the imaging schedule (can be conducted at corresponding study visit) until retreatment
discontinuation.
i.
For women of reproductive potential, a urine pregnancy test will be performed within 24 hours or serum pregnancy test should be performed within 72 hours prior to the first 
retreatment dose.  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.  While the subject is on study, pregnancy testing 
should be conducted as per local regulations where applicable.
j.
Tumor imaging (including brain imaging in subjects with known brain metastases) must be performed within 28 days prior to starting retreatment.  Tumor imaging should 
continue to be performed every 9 weeks (±7 days) after start of Second Course Phase or more frequently if clinically indicated, regardless of any treatment delays.  Tumor 
imaging timing should follow calendar days and should not be adjusted for any dose modifications.  The same image modality acquisition and technical parameters should 
be used throughout the study.
k.
If a subject is discontinued from retreatment with documented PD, imaging is not performed.  The subject will then enter survival follow-up.
l.
During the Survival Follow-up phase, contacts are approximately every 12 weeks by telephone (or more often as needed). Updated survival status may be requested by the 
Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the 
Sponsor defined time period will be contacted for their survival status (excluding subjects that have a death event previously recorded).
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6.2.1.3
Pembrolizumab Plus Gemcitabine/Carboplatin
Study Period:
Treatment Period (3-Week Cycles)a
Treatment Cycle/Title:
1
2
3
4
5 and Beyondb
Scheduled Day:
1
8
1
8
1
8
1
8
1/8b
Scheduling Window (Days):a
N/A
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Eligibility Criteriaa
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
Survival Statusk,l
Clinical Procedures/Assessments
Full Physical Examination
X
Directed Physical Examination
X
X
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
Pembrolizumab Administrationc
X
X
X
X
X
Gemcitabine/Carboplatin Administrationc
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
Review Adverse Eventsd
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments:  Analysis performed by local laboratories
CBC with Differential
Xe
X
X
X
X
X
X
X
Xe
Chemistry
Xe
X
X
X
Xe
Urinalysis
X
PT/INR and aPTTf
X
T3 (or Free T3), Free T4, and TSHg
X
X
X
Tumor markers (CA15-3, CEA, and CA27.29)h
X
X
X
Pregnancy Test – Serum or Urine β-Human Chorionic 
Gonadotropin (β-hCG)i
X
X
X
X
X
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Study Period:
Treatment Period (3-Week Cycles)a
Treatment Cycle/Title:
1
2
3
4
5 and Beyondb
Scheduled Day:
1
8
1
8
1
8
1
8
1/8b
Scheduling Window (Days):a
N/A
±3
±3
±3
±3
±3
±3
±3
±3
Efficacy Assessments
Tumor Imagingj
X
X
Xk
a.
For assessment/procedure details, see Section 7.0 – Trial Procedures.  For information regarding eligibility criteria for retreatment, see Section 7.1.5.6.1 – Conditions of 
Second Course Phase.  For specific timings and windows, see Section 7.1.5.6.2 – Visit Requirements of Second Course Phase.
b.
Starting with Cycle 5, the pattern of retreatment administration and assessments and procedures performed in Cycles 1 through 4 will be repeated, unless stated otherwise.
c.
Continuation or resumption of same chemotherapy as received in the First Course Treatment Phase may be administered in the Second Course Phase at the discretion of the 
investigator. Note that chemotherapy different from that received in the First Course Treatment Phase is not permitted.  For subjects receiving pembrolizumab + 
gemcitabine/carboplatin, pembrolizumab will be administered every 3 weeks (Q3W) on Day 1 of each 3-week cycle.  Gemcitabine/carboplatin will be administered on Days 
1 and 8 every 21 days. Should an Investigator discontinue treatment with chemotherapy, but continue treatment with pembrolizumab, the subject does not need to come to 
the clinic on dates when only the chemotherapy would have been administered. The subject should still follow the treatment and procedure schedule for pembrolizumab 
visits.
d.
Guidance on recording AEs and ECIs can be found Section 7.1.2.1 – Adverse Event Monitoring.
e.
The CBC and chemistry laboratory tests do not need to be performed on Cycle 1, Day 1, if obtained within 10 days prior to the first retreatment dose.  However, they will be 
performed on Day 1 of each subsequent cycle.  Note:  CBC will also be performed on Day 8 of each cycle, as described in the table above.
f.
Any subject receiving anticoagulant therapy should have coagulation factors monitored closely throughout the study.
g.
T3 or FT3 can be assayed based on local guidelines and practices.  To be repeated every 2 cycles after Cycle 5. 
h.
Tumor markers (CA15-3, CEA, and CA27.29) should be collected according to the imaging schedule (can be conducted at corresponding study visit) until retreatment
discontinuation.
i.
For women of reproductive potential, a urine pregnancy test will be performed within 24 hours or serum pregnancy test should be performed within 72 hours prior to the first 
retreatment dose.  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.  While the subject is on study, pregnancy testing 
should be conducted as per local regulations where applicable.
j.
Tumor imaging (including brain imaging in subjects with known brain metastases) must be performed within 28 days prior to starting retreatment.  Tumor imaging should 
continue to be performed every 9 weeks (±7 days) after start of Second Course Phase or more frequently if clinically indicated, regardless of any treatment delays.  Tumor 
imaging timing should follow calendar days and should not be adjusted for any dose modifications.  The same image modality acquisition and technical parameters should 
be used throughout the study.
k.
If a subject is discontinued from retreatment with documented PD, imaging is not performed.  The subject will then enter survival follow-up.
l.
During the Survival Follow-up phase, contacts are approximately every 12 weeks by telephone (or more often as needed). Updated survival status may be requested by the 
Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the 
Sponsor defined time period will be contacted for their survival status (excluding subjects that have a death event previously recorded).
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End of Treatment and After Treatment Discontinuation
Study Period:
End of Treatment
After Treatment Discontinuation
Last Dosea
Safety Follow-up
Disease Status Follow-upa
Survival Follow-upb
Treatment Cycle/Title:
At Time of Treatment 
Discontinuation
30 Days Post Last Dose
Every 9 or 12 Weeks Post 
Last Dose
Every 12 Weeksb
Scheduled Day:
N/A
N/A
N/A
N/A
Scheduling Window (Days):c
N/A
±3
±7
±7
Administrative Procedures
Concomitant Medication Review
X
X
Clinical Procedures/Assessments
Full Physical Examination
X
Vital Signs and Weight
X
ECOG Performance Status
X
Review Adverse Eventsd
X
X
X
Post-study Anti-Cancer Therapy Status
X
X
Survival Statusb
X
Laboratory Procedures/Assessments:  Analysis performed by local laboratories
CBC with Differential
X
Chemistry
X
T3 (or Free T3), Free T4, and TSHe
Xf
Tumor markers (CA15-3, CEA, and CA27.29)f
X
Xf
Pregnancy Test – Serum or Urine β-Human Chorionic 
Gonadotropin (β-hCG)g
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Study Period:
End of Treatment
After Treatment Discontinuation
Last Dosea
Safety Follow-up
Disease Status Follow-upa
Survival Follow-upb
Treatment Cycle/Title:
At Time of Treatment 
Discontinuation
30 Days Post Last Dose
Every 9 or 12 Weeks Post 
Last Dose
Every 12 Weeksb
Scheduled Day:
N/A
N/A
N/A
N/A
Scheduling Window (Days):c
N/A
±3
±7
±7
Efficacy Assessments
Tumor Imagingh
X
Xi
a.
For subjects who discontinue retreatment without centrally verified disease progression, please see Section 7.1.4.1 – Withdrawal/Discontinuation for guidance.
b.
During the Survival Follow-up phase, contacts are approximately every 12 weeks by telephone (or more often as needed). Updated survival status may be requested by 
the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during 
the Sponsor defined time period will be contacted for their survival status (excluding subjects that have a death event previously recorded).
c.
For assessment/procedure details, see Section 7.0 – Trial Procedures.  For specific timings and windows, see Section 7.1.5.6.2 – Visit Requirements of Second Course 
Phase.
d.
Record all AEs occurring within 30 days post retreatment end.  Report all SAEs occurring up to 90 days post retreatment end or until subject initiates new anti-cancer
therapy, but for at least 30 days post retreatment end, whichever occurs first.  Afterwards, report only drug-related SAEs.
e.
T3 or FT3 can be assayed based on local guidelines and practices.  
f.
Tumor markers (CA15-3, CEA, and CA27.29) should be collected according to the imaging schedule (can be conducted at corresponding study visit) until retreatment
discontinuation.
g.
For women of reproductive potential, while the subject is on study, pregnancy testing should be conducted as per local regulations where applicable.
h.
Tumor imaging (including brain imaging in subjects with known brain metastases) must be performed within 28 days prior to starting retreatment.  Tumor imaging 
should continue to be performed every 9 weeks (±7 days) after start of Second Course Phase or more frequently if clinically indicated.  Tumor imaging timing should 
follow calendar days and should not be adjusted for any dose modifications. The same image modality acquisition and technical parameters should be used throughout 
the study.
i.
If a subject is discontinued from retreatment with documented PD, imaging is not performed.  The subject will then enter survival follow-up, in which the subject will be 
contacted via a telephone call every 12 weeks (or more often as needed).
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
7.1.1.1.1
General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  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 subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
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7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the study.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
7.1.1.4.1
Other Than Breast Cancer
Demographic information and medical history will be obtained by the investigator or 
qualified designee.  Medical history will include all active conditions and any conditions 
diagnosed within the prior 10 years that are considered by the Investigator to be clinically 
significant.  Any autoimmune disorders should be recorded regardless of onset date. 
Details regarding the subject’s breast cancer history will be recorded separately and should 
not be listed as medical history.
7.1.1.4.2
Breast Cancer Diagnosis Details
The Investigator or qualified designee will obtain details regarding the subject’s breast cancer 
initial diagnosis and current disease status.
7.1.1.4.3
Prior Treatments for Breast Cancer
The investigator or qualified designee will review all prior treatments for subject’s breast 
cancer diagnosis, including systemic treatments, radiation and surgeries.
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7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1
Prior Medications
The investigator or qualified designee will review and record prior medication use, including 
any protocol-specified washout requirement(s), within 30 days prior to randomization.
7.1.1.5.2
Concomitant Medications
The investigator or qualified designee will record all medications taken by the subject during 
study.  All medications related to reportable SAEs and events of clinical interest (ECIs)
should be recorded as defined in Section 7.2 – Assessing and Recording Adverse Events.
7.1.1.5.3
Medications in Disease Status Follow-up Phase
The investigator or qualified designee will review all new anti-cancer therapies initiated after 
the last dose of study treatment.  If a subject initiates a new anti-cancer therapy within 
30 days after the last dose of study treatment, the 30-day Safety Follow-up visit must occur 
before the first dose of the new therapy.  Once new anti-cancer therapy has been initiated, the 
subject will move into the survival follow-up (SFU) phase.  
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements are provided in Section 7.1.5.1 –
Screening.
7.1.1.7
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Study treatment should begin on the day of randomization or at most within 3 days post 
randomization.
In a situation where rerandomization of the participants is planned (eg, study extension 
periods), the rerandomization will be based on a new randomization schedule; however, each 
participant will retain his/her original treatment/randomization number. Only the study 
intervention regimen associated with the rerandomization period or phase may change.
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7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified pembrolizumab/placebo administration
for 
>12 weeks and chemotherapy administration for >4 weeks require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
subject management.
Administration of study treatments will be witnessed by the investigator and/or study staff.
The total volume of pembrolizumab/placebo and chemotherapy infused will be compared to 
the total volume prepared to determine compliance in each dose of pembrolizumab/placebo 
and chemotherapy administered.
The instructions for preparing and administering pembrolizumab will be provided in the 
Pharmacy Manual. Chemotherapy(ies) will be prepared and administered according to local 
guidelines and practices.
Please refer to Section 5.2 – Trial Treatments for instructions on pembrolizumab and 
chemotherapy.
Clinical Procedures/Assessments
7.1.2.1
Adverse Event Monitoring
The investigator or qualified designee will assess each subject for potential new or worsening 
AEs at scheduled clinic visits or more frequently if clinically indicated.  AEs will 
be graded according to NCI CTCAE
v4.0
and recorded during study treatment
and protocol-specified
follow-up 
period 
post discontinuation 
of 
study 
treatment 
(Section 7.2.4 – Evaluating Adverse Events).  Toxicities will be characterized in terms of 
seriousness, causality, toxicity grading, and action taken with regard to study treatment(s).  
AEs associated with pembrolizumab/placebo exposure should be evaluated for possible 
immune etiology; see Section 7.2.3.2 – Events of Clinical Interest regarding the 
identification, evaluation, and management of AEs with potential immunologic etiology.
Please refer to Section 7.2 – Assessing and Recording Adverse Events for detailed 
information regarding the assessment and recording of AEs.  
7.1.2.2
12-Lead Electrocardiogram
A standard 12-lead electrocardiogram (ECG) will be performed using local procedures 
during screening.  Clinically significant abnormal findings should be recorded as medical 
history. Additional ECG evaluations may be performed as clinically necessary.
7.1.2.3
Physical Examination
7.1.2.3.1
Full Physical Examination
The investigator or clinical designee will perform a complete physical examination during 
screening.  Clinically significant abnormal findings should be recorded as medical history.  
Post randomization, full physical examinations should be performed as specified in the Trial 
Flow Chart – Section 6.0, and new clinically significant abnormal findings should be 
recorded as AEs.
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7.1.2.3.2
Directed Physical Examination
The investigator or clinical designee will perform directed physical examinations as specified 
in the Trial Flow Chart – Section 6.0 and, as needed, according to subject’s signs and 
symptoms.  New clinically significant abnormal findings should be recorded as AEs.
7.1.2.4
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of study treatment, at treatment discontinuation, and at the safety 
follow-up, as specified in the Trial Flow Chart – Section 6.0.  Vital signs should include 
temperature, pulse, blood pressure respiratory rate, and weight.  Height will be measured in 
the first course treatment phase at the 1st clinic visit only.
7.1.2.5
Patient Reported Outcomes
The electronic Patient Reported Outcomes (ePROs; EORTC QLQ-C30, EORTC QLQ-BR23, 
and EQ-5D™) questionnaires will be administered by trained study site personnel and 
completed electronically by the subjects themselves.
It is strongly recommended that ePROs are administered prior to administration of study 
treatment, AE evaluation, and disease status notification.  The ePROs are completed in the 
following order: EQ-5D™, then EORTC QLQ-C30, and last the EORTC QLQ-BR23 at the 
time points specified in the Trial Flow Chart – Section 6.0 and briefly summarized below.
7.1.2.5.1
The Patient Reported Outcomes
The Patient Reported Outcomes (PROs) are assessed as follows:

On Day 1 of each of the first 3 cycles 

After the 3rd cycle and until the end of Year 1, they will occur every 3rd cycle (every 
9 weeks) until PD, while the subject is receiving study treatment

During Year 2, they will occur every 4th cycle (every 12 weeks) until PD, while the 
subject is receiving study treatment

At the Treatment Discontinuation Visita

At 30-day Safety Follow-up Visita
a If the Treatment Discontinuation Visit occurs 30 days from the last dose of study treatment, 
at the time of the mandatory Safety Follow up Visit, ePROs do not need to be repeated.
7.1.2.6
Eastern Cooperative Oncology Group (ECOG) Performance Status
The investigator or qualified designee will assess ECOG performance status 
(Section 12.5 – ECOG Performance Status) at screening, prior to administration of study 
treatment on Day 1 of each treatment cycle, at treatment discontinuation, and at the safety 
follow-up, as specified in Section 6.0 – Trial Flow Chart.
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7.1.2.7
Post-Treatment Disease Status
After discontinuation of all study treatments for reasons other than PD, disease status will be 
followed as specified in Section 6.0 – Trial Flow Chart.
7.1.2.8
Menopausal Status
The menopausal status (pre-menopausal or post-menopausal) for all female subjects less than 
age 60 years must be determined at screening according to the definitions below. The date of 
the subject’s last menstrual period (LMP) and, when indicated, serum FSH and estradiol 
levels must be assessed and recorded in the eCRFs.
Pre-menopausal

≤12 months since LMP 
OR

Biochemical evidence of premenopausal status according to serum FSH and estradiol 
levels and local institutional guidelines
Post-menopausal

Subject has undergone prior bilateral ovariectomy/oophorectomy 
OR

>12 months since LMP and no hysterectomy, hormone replacement, ER antagonist, 
chemotherapy, or ovarian suppression at any time since LMP 
OR

Biochemical evidence of post-menopausal status according to serum FSH and 
estradiol levels and local institutional guidelines.
7.1.2.9
Tumor Imaging and Assessment of Disease Status
The process for image collection and transmission to the CIV can be found in the Site 
Imaging Manual (SIM).  Tumor imaging should be acquired by computed tomography (CT, 
strongly preferred).  Magnetic resonance imaging (MRI) should be used when CT is 
contraindicated and for brain imaging. For each subject, the same imaging modality and 
consistent use of contrast should be used throughout the study to optimize assessment of 
existing and new tumor burden.
Brain imaging (MRI is preferred) is required at screening and during the study (at the same 
schedule as other imaging for evaluation of disease status) for subjects with known brain 
metastases and those with worsening and/or new neurological symptoms. CT imaging will 
be acceptable, if MRI is medically contraindicated.  (See also Section 7.1.2.9.1 – Initial 
Tumor Imaging.)
If a subject has a history of bone metastases and/or has new bone pain or other 
symptoms/signs suggestive of bone metastases during screening, a bone scan (and plain 
X-ray, if bone scan is negative) is required prior to study entry.  During the study, a bone 
scan (and plain X-ray, if bone scan is negative) will be performed as needed for evaluation of 
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worsening and/or new bone pain or other symptoms/signs suggestive of bone metastases OR
if the site believes a subject has attained a CR.  Any supplemental imaging done to support a 
positive or negative bone scan should be submitted to the CIV.
Measurable disease for subject eligibility will be determined based on RECIST 1.1 as 
accessed by local radiology review. Although RECIST 1.1 references a maximum of 5 target 
lesions in total and 2 per organ, MSD allows a maximum of 10 target lesions in total and 
5 per organ. While on study, scheduled imaging studies should be submitted to the CIV.
Unscheduled imaging studies obtained for assessment of disease progression or other reason,
but capturing radiologic progression, should also be submitted to the CIV.
Site/investigator-assessed first radiologic evidence of PD will also be evaluated by the CIV 
in real time, and the results of central imaging review will be expeditiously communicated to 
the study site and the Sponsor (See Section 7.1.2.9.4 – RECIST 1.1 Assessment of Disease).
7.1.2.9.1
Initial Tumor Imaging
Baseline tumor imaging must be performed during the 28-day screening window prior to 
randomization to confirm measurable disease based on RECIST 1.1 as assessed by local 
radiology review. The screening images must be submitted to the CIV for retrospective 
review.
Scans performed as part of routine clinical management are acceptable for use as screening 
tumor imaging studies, if they are of diagnostic quality, were performed within 28 days prior 
to randomization and were submitted to the CIV for review.
Subjects with previously treated brain metastasis(es) may be eligible for study participation 
provided metastatic disease to the brain is radiographically stable, i.e., without 
site/investigator-assessed radiologic evidence of progression for ≥4 weeks prior to the 
screening brain imaging study. To demonstrate radiographic stability of previously treated 
brain metastases, a minimum of 2 post-treatment brain imaging assessments are required: 1) 
The first brain imaging must be acquired after treatment of brain metastases has been 
completed 2) The second brain imaging must be obtained during screening (i.e., within 
28 days of randomization) and 4 weeks after the previous post-treatment brain imaging.  
Any neurologic symptoms must have returned to baseline and steroids must not have been
used for management of symptoms related to brain metastases for at least 28 days prior to 
randomization.  Subjects with carcinomatous meningitis are excluded regardless of clinical 
stability.
7.1.2.9.2
Tumor Imaging During the Study
Post-baseline imaging assessments should be performed at 8 weeks (±7 days), 16 weeks 
(±7 days), and 24 weeks (– 7 days) post randomization, and then every 9 weeks (±7 days) 
during the first year (or more frequently if clinically indicated). Imaging at Week 24 should 
be performed within 24 weeks post randomization. After 1 year, subjects who remain on 
treatment will have imaging performed every 12 weeks (±7 days).  Imaging timing should 
follow calendar days and should not be adjusted for delays in cycle starts.  Imaging should 
not be discontinued until disease progression is verified by CIV or the start of new 
anti-cancer treatment, withdrawal of consent, death, or end of the study, whichever occurs 
first. 
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Based on RECIST 1.1, PRs and CRs should be confirmed by repeat tumor imaging studies at 
≥4 weeks from the date response was first documented.  Subjects will then return to regularly
scheduled imaging, starting with the next scheduled imaging time point. Subjects who obtain 
a confirmation scan do not need to undergo the next scheduled tumor imaging, if this is 
<4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point.
Based on irRECIST, for clinically stable subjects meeting the conditions detailed in 
Section 7.1.2.9.5 – irRECIST Assessment of Disease, study treatment may be continued until 
PD is locally confirmed by imaging studies performed at least 4 weeks after initial local PD
by imaging.  If disease progression is not confirmed and subjects remain clinically stable, 
they may continue study treatment and resume tumor imaging at the next scheduled imaging 
time point. Subjects with confirmed PD per irRECIST should discontinue study treatment
and regularly scheduled imaging studies, unless PD has not been verified by CIV, in which 
case regularly scheduled imaging studies should continue until central verification of PD. 
Study treatment may continue after locally confirmed PD according to an exception detailed 
in Section 7.1.2.9.5 – irRECIST Assessment of Disease.
7.1.2.9.3
End of Treatment and Follow-up Tumor Imaging
In subjects who discontinue all study treatments, tumor imaging should be performed at the 
time of treatment discontinuation (±4-week window).  If a previous scan was obtained within 
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not
mandatory.  In subjects who discontinue all study treatments after central verification of 
disease progression, no further tumor imaging studies are required.
In subjects who discontinue all study treatments without central verification of disease 
progression, every effort should be made to continue monitoring of disease status by imaging 
performed at the same schedule as before treatment discontinuation (e.g., every 9 or 
12 weeks [±7 days] during the first or second year of study, respectively, depending on time 
elapsed since randomization) and until (1) the start of new anti-cancer treatment, (2) disease 
progression verified by CIV, (3) death, (4), withdrawal of consent to study participation, or 
(5) the end of the study, whichever occurs first.
7.1.2.9.4
RECIST 1.1 Assessment of Disease
RECIST 1.1 [98] will be applied by local radiology review for assessing subject eligibility 
and by CIV as the primary measure for assessing efficacy parameters (other than OS), as 
described in the primary and secondary study objectives. Imaging studies showing first 
radiologic evidence of PD as assessed by site/investigator should be immediately submitted 
to the CIV, which will then notify the site and the Sponsor whether PD based on RECIST 1.1
is centrally verified or not. Figure 3 illustrates the imaging flow algorithm for verification of 
PD by CIV for clinically stable subjects.
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Note:  Verified refers to centrally verified.
Figure 3
Imaging and Treatment for Clinically Stable Subjects After First Radiologic 
Evidence of PD Based on RECIST 1.1 and as Assessed by Site/Investigator
7.1.2.9.5
irRECIST Assessment of Disease
Immune-related RECIST is RECIST 1.1 adapted as described below to account for the 
unique tumor response seen with immunotherapeutic drugs. irRECIST will be used by 
site/investigator to assess tumor response and make treatment decisions both before and after 
PD is verified by CIV (Table 8).
Related imaging data will be collected in the clinical 
database. Treatment efficacy based on irRECIST as assessed by CIV will be evaluated 
retrospectively.
When feasible, study treatment should be continued
until PD
is confirmed by 
site/investigator at least 4 weeks after initial local PD.
The possibility to continue study 
treatment past centrally verified PD takes into account the observation that subjects with a 
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transient tumor flare in the first few months after the start of immunotherapy may experience 
response at subsequent time points.
Subjects who are deemed clinically unstable are not 
required to have repeat tumor imaging for confirmation of PD. Tumor flare includes any of 
the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing non-target lesion(s)

Development of new lesion(s)
Continuing study treatment past centrally verified PD is at the discretion of the treating 
physician and should be based on the subject’s overall clinical condition, including 
performance status, clinical symptoms, and laboratory data.  Clinical stability is defined by
the following criteria:
1) Absence of symptoms and signs indicating clinically significant progression of 
disease, including worsening of laboratory values, and
2) No decline in ECOG performance status, and
3) Absence of rapid progression of disease, and
4) Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent medical and/or surgical intervention  
In determining whether tumor burden has increased, decreased or remained stable per 
irRECIST, the site/investigator should consider all target and non-target lesions as well as 
any incremental new lesion(s).
PD is not confirmed based on irRECIST at repeat imaging, if ALL of the following criteria 
are met:

Sum of target lesion diameters is <20% or <5 mm absolute increase compared to 
nadir, and

Non-target disease resulting in initial PD is stable or qualitatively improved, and

New lesion resulting in initial PD is stable or qualitatively improved, and

No incremental new lesion(s) since last evaluation, and

No incremental new non-target lesion progression since last evaluation
If PD is not confirmed based on irRECIST as assessed by site/investigator and the subject 
continues to be clinically stable, treatment may continue and follow the regular imaging 
schedule. 
PD is confirmed based on irRECIST at repeat imaging, if ANY of the following occur:

Sum of target lesion diameters remains ≥20% and at least 5 mm absolute increase 
compared to nadir, or

Non-target disease resulting in initial PD is qualitatively worse, or

New lesion resulting in initial PD is qualitatively worse, or
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
Additional new lesion(s) since last evaluation, or

Additional new non-target lesion progression since last evaluation
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be 
discontinued from study therapy.
Note:  If a subject has confirmed radiographic progression based on irRECIST (i.e., 2 scans 
at least 4 weeks apart demonstrating PD), but he/she is still deriving clinically meaningful 
benefit, and there is no further increase in the tumor burden at the confirmatory tumor 
imaging, an exception to treatment discontinuation may be considered following consultation 
with the Sponsor. If study treatment is continued, tumor imaging should also continue to be 
performed, as outlined in the Trial Flow Chart – Section 6.0, and submitted to the CIV for 
review.
Additional details are referenced in MSD TIP Sheet for RECIST 1.1 and irRECIST.
Table 8
Imaging and Treatment After First Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD 
based on
RECIST 1.1 as 
assessed by 
site/investigator
has been verified 
by the central 
imaging vendor
Repeat imaging 
at ≥4 weeks at 
site to confirm 
PD
May continue 
study treatment at 
site/Investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging based on 
irRECIST as 
assessed by 
site/investigator
No additional 
imaging required
Discontinue treatment
Repeat tumor 
imaging confirms 
PD based on
irRECIST as 
assessed by
site/investigator
No additional 
imaging required
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
Sponsor)
No additional 
imaging required
Treatment already 
discontinued
Repeat tumor 
imaging shows 
SD, PR or CR 
based on 
irRECIST as 
assessed by 
site/investigator
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue study 
treatment at site/
Investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments 
May restart study 
treatment if condition 
has improved and/or 
subject is clinically 
stable at
site/Investigator’s 
discretion. Next tumor 
imaging should occur 
according to the regular 
imaging schedule 
outlined in the protocol
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7.1.2.10 Tumor Tissue Collection 
All subjects must have central confirmation of TNBC status and determination of tumor 
PD-L1 status prior to randomization (Section 5.1.2 – Subject Inclusion Criteria). The same, 
recently or newly obtained, core or excisional tumor biopsy ([FNA not adequate) from a 
locally recurrent inoperable or metastatic tumor lesion can be used for both investigations. 
Note: For a newly obtained tumor biopsy, tissue from 3 to 4 passes of an 18-gauge 
needle should be submitted as one specimen.
Note: Adequacy of biopsy specimen for the above analyses must be confirmed by the 
central laboratory.  Submission of another tumor specimen may be required, if adequate 
tumor tissue was not provided the first time.
Note: An archival tumor specimen obtained before the diagnosis of locally recurrent 
inoperable or metastatic breast cancer may be submitted after consultation with the 
Sponsor, if neither a recently nor a newly obtained biopsy from a locally recurrent 
inoperable or a metastatic site is available.
Testing will be performed by a central vendor using commercially validated assays, and 
tumor status for hormone receptor and HER2 expression will be determined according to the 
most recent ASCO/CAP guidelines:
a.
ER negative status is defined as <1% tumor cells positive for ER by IHC, irrespective 
of staining intensity 
b. PGR negative status is defined as <1% tumor cells positive for PGR by IHC, 
irrespective of staining intensity
c.
HER2 negative status is determined by: 

IHC 1+, as defined by incomplete membrane staining that is faint/barely 
perceptible and within >10% of invasive tumor cells, OR

IHC 0, as defined by no staining observed or membrane staining that is 
incomplete and is faint/barely perceptible and within ≤10% of the invasive tumor 
cells, OR

FISH 
negative 
based 
on 
single-probe 
average 
HER2 
copy 
number 
<4.0 signals/cell, or Dual-probe HER2/centromeric probe for chromosome 17 
(CEP17) ratio <2.0 with an average HER2 copy number <4.0 signals/cell
Newly obtained tumor tissue should be submitted in formalin (preferred) or as formalin-fixed 
paraffin embedded (FFPE) tumor tissue blocks.  If after agreement with the Sponsor 
unstained slides are submitted, the slides should be freshly cut and submitted to the testing 
laboratory within 14 days from site slide sectioning date; otherwise, a new specimen will be 
requested.  A recently obtained or archival tumor specimen should be submitted as an FFPE 
block or unstained slides as described above.
Optional core or excisional biopsy is recommended to be obtained at disease progression.
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Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this study
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from screening to post-treatment-discontinuation visits), including approximate 
blood/tissue volumes drawn/collected by visit and by sample type per subject can be found in 
the Procedures Manual.
7.1.3.1
Laboratory Safety Evaluations
Laboratory tests to be performed in this study are specified in Table 9.
Table 9
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin (β-hCG)a
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR)b
Platelet count
Alanine aminotransferase (ALT) Protein
aPTTb
WBC (total and 
differential)
Aspartate aminotransferase 
(AST)
Specific gravity 
Total triiodothyronine (T3) 
or Free T3c
Red Blood Cell 
Count
Bicarbonate or carbon dioxide 
(CO2)d
Microscopic exam, if 
abnormal results noted
Free thyroxine (T4)
Absolute 
Neutrophil Counte
Calcium
Thyroid stimulating 
hormone (TSH)
Absolute 
Lymphocyte 
Count
Chloride
Blood for Genetic Analysisf
Creatinine
Blood for RNA Analysis, 
Plasma and Serum 
Biomarker Analyses
Glucose
Blood for PK studies
Phosphorus
Anti-pembrolizumab 
Antibodies
Potassium
FSH, estradiolg
Sodium
Vitamin D levels
Total Bilirubin  
Tumor markers (CA15-3, 
CEA, and CA27.29)
Direct Bilirubin, if total 
bilirubin is elevated above the 
upper limit of normal
Total protein
Blood Urea Nitrogen or Ureah
Lactate dehydrogenase (LDH)
Uric acid
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Hematology
Chemistry
Urinalysis
Other
a.
A urine pregnancy test should be performed within 24 hours or serum pregnancy test should be performed 
within 72 hours prior to the first dose of study treatment in women of childbearing potential. If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.  While the 
subject is on study, pregnancy testing should be conducted as per local regulations where applicable.
b.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all 
subjects.  Any subject receiving anticoagulant therapy should have coagulation factors monitored closely 
throughout the study.
c.
Total T3 is preferred; if not available, free T3 may be tested.
d.
Depending on local standard of care.
e.
Either absolute number or % of WBC is acceptable as per institutional standards.
f.
Blood for Genetic Analysis as described in Section 7.1.3.5 Planned Genetic Analysis Sample Collection 
and in Section 7.1.3.6 – Future Biomedical Research Sample Collection.
g.
Blood for menopausal status is required only for some subjects, as described in Section 7.1.3.3 – Blood for 
Menopausal Status.
h.
Blood Urea Nitrogen is preferred; if not available urea may be tested.
Screening laboratory tests must be performed within 10 days prior to the start of study 
treatment.  Predose laboratory procedures can be conducted up to 72 hours prior to dosing.  
Please note that only safety labs affecting potential treatment need to be reviewed prior to 
study therapy administration following the Screening Visit. 
Vitamin D, tumor markers, and other labs which would not affect potential treatment of the 
subject can be reviewed, in a timely manner, by an Investigator after the date of study 
therapy administration. Similarly, in cases in which a site is not able to obtain the thyroid 
function testing (total triiodothyronine [T3], free thyroxine [free T4], and thyroid stimulating 
hormone [TSH]) results prior to scheduled dosing, review of the thyroid function test results 
after dosing is acceptable and poses no additional immediate safety risk to subjects.
7.1.3.2
Pharmacokinetic Evaluations
The accumulation of robust PK and ADA data has allowed for the adequate characterization 
of the clinical pharmacology of pembrolizumab across indications. Therefore, upon approval 
of Amendment 02 each site is to stop the collection of PK and ADA samples for all subjects. 
Blood samples for PK and ADA collected prior to Amendment 02 may be stored. Analysis 
will be performed only if required.
7.1.3.3
Blood for Menopausal Status
Blood collection at screening for biochemical evidence of menopausal status (FSH and 
estradiol) will be needed if subject:
1) Is ≤60 years old, and
2) Has not had a bilateral oophorectomy, and
3) Has not had a menstrual period for at least 12 months, and
4) Has had a hysterectomy or was on hormone replacement, ER antagonist, 
chemotherapy or ovarian suppression at any time since LMP.
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7.1.3.4
Blood Collection for RNA Analysis and Plasma and Serum Biomarker 
Analyses
Blood should be collected at pre-dose on Cycles 1, 2, and 5 or at time of discontinuation.
Leftover RNA, plasma, and serum will be stored at the end of the study for FBR if the 
subject has consented (see Section 7.1.3.6 – Future Biomedical Research Sample Collection).
Further details are provided in the Procedures Manual.
7.1.3.5
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual. Samples should be collected for planned analysis
of associations between genetic variants in germline/tumor DNA and drug response.  If a
documented law or regulation prohibits (or local IRB/IEC does not approve) sample
collection for these purposes, then such samples should not be collected at the corresponding
sites.  Leftover DNA extracted from planned genetic analysis samples will be stored for
future biomedical research only if subject signs the FBR consent.
7.1.3.6
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of FBR:

DNA for future research

Leftover plasma and serum from biomarker analyses

Leftover RNA

Leftover main study tumor tissue
Other Procedures
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from all study treatments prior to completion of the study
should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the end-of-treatment visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.  As noted above, subjects who are discontinued from all study 
treatment should continue to be monitored in the trial, as outlined in Sections 7.1.5.3 – End 
of Treatment and 7.1.5.4 – After Treatment Discontinuation.
7.1.4.1.1
Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed. Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
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are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens. In this situation, the request for specimen 
destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
TRIAL TREATMENT IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE SUBJECT. EVERY EFFORT 
SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or sub-investigator needs to identify the drug 
used by a subject and/or the dosage administered, he/she will contact the emergency 
unblinding call center by telephone and make a request for emergency unblinding.  As 
requested by the investigator or sub-investigator the emergency unblinding call center will 
provide the information to him/her promptly and report unblinding to the sponsor.  The 
emergency unblinding call center will make a record promptly however, the investigator or 
sub-investigator must enter the toxicity grade of the adverse experiences observed, their 
relation to study drug, the reason thereof, etc., in the medical chart etc., before unblinding is 
performed.
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
Trial treatment identification information is to be unmasked ONLY if necessary for the 
welfare of the subject. Every effort should be made not to unblind. 
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible. Once an emergency unblinding or a 
non-emergency unblinding has taken place, the principal investigator, site personnel, and 
Sponsor personnel may be unblinded so that the appropriate follow-up medical care can be 
provided to the subject.  Subjects whose treatment assignment has been unblinded (by the 
investigator or through the emergency unblinding call center) must be discontinued from 
study drug that was blinded.
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Section 5.8 outlines the criteria for allowing subjects who are discontinued from treatment to 
continue to be monitored in the trial.
7.1.4.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Laboratory equipment – as required for eligibility and safety assessment laboratory 
tests

Imaging equipment – as required for study objectives

Drug administration equipment –
as required for storage, preparation,
and 
administration (infusion) of study treatments.
See protocol-specified guidance in the Administrative Binder, Procedures Manual, and SIM.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame.  
Screening procedures are to be completed within 28 days prior to randomization except for 
the following:

Laboratory tests and ECOG performance status are to be performed within 10 days 
prior to the start of study treatment.

For women of reproductive potential, a urine pregnancy test will be performed within 
24 hours or serum pregnancy test will be performed within 72 hours prior to the 
subject receiving the first dose of study treatment.  If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.  
Subjects may be rescreened once after initially failing to meet the inclusion/exclusion 
criteria.  Results from assessments performed during the initial screening period are 
acceptable in lieu of a repeat screening test, if performed within the specified time frame and 
the corresponding inclusion criterion is met.
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7.1.5.2
Treatment Period (Parts 1 and 2)
Visit timing requirements during the treatment period are as follows:

Assessments/procedures should be performed prior to randomization and on Day 1 of
each cycle unless otherwise specified in the flow chart.

Treatment cycles are 3 weeks (starting with Day 1 of pembrolizumab administration).  

The window for each visit is ±3 days unless otherwise noted.  Cycle 1 treatment 
should be no more than 3 days after randomization.  

Optional core or excisional biopsy is recommended to be obtained at disease 
progression.
In Part 1 (safety run-in; open-label) of the study, there are 3 treatment arms 
(pembrolizumab + nab-paclitaxel, pembrolizumab + paclitaxel, and pembrolizumab +
gemcitabine/carboplatin).  In Part 2 (Phase III; double-blind), there are 2 treatment arms 
(pembrolizumab + chemotherapy and placebo + chemotherapy).
For the full list of all visit assessments/procedures please see Section 6.0 – Trial Flow Chart.  
Specific procedure-related details are provided above in Section 7.1 – Trial Procedures.
7.1.5.3
End of Treatment
The End of Treatment Visit should occur at the time all study treatments are discontinued for 
any reason.  If the End of Treatment Visit occurs 30 days from the last dose of 
study treatment, at the time of the mandatory Safety Follow up Visit, procedures do not 
need to be repeated.  Visit requirements are outlined in Section 6.0 – Trial Flow Chart.  
Specific procedure-related details are provided above in Section 7.1 – Trial Procedures.  
Additional details regarding subject withdrawal and discontinuation are presented in 
Section 5.8 – Subject Withdrawal/Discontinuation Criteria.
7.1.5.4
After Treatment Discontinuation
7.1.5.4.1
Safety Follow-up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of all study treatments or before the initiation of a new anti-cancer treatment, 
whichever comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded. Subjects with an AE of Grade >1 will be followed until resolution of the AE to 
Grade 0–1 (or to subject’s baseline) or until the beginning of a new anti-cancer therapy, 
whichever occurs first.  SAEs that occur within 90 days, and ECIs that occur within 30 days,
of the end of treatment or before initiation of a new anti-cancer treatment should also be 
followed and recorded for a minimum of 30 days.
Subjects 
who 
are 
eligible 
for 
retreatment 
with 
pembrolizumab 
(see 
Section 7.1.5.6.1 – Conditions of Second Course Phase) may have up to 2 safety follow-up 
visits, one after the Treatment Period and one after the Second Course Phase.
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7.1.5.4.2
Disease Status Follow-up Visit
Subjects who discontinue all study treatments for a reason other than disease progression will 
move into the Disease Status Follow-Up phase and should be assessed according to the 
already followed tumor imaging schedule.
Every effort should be made to collect information regarding disease status until the start of 
new anti-cancer therapy, centrally verified disease progression, death, or end of study.  
Information regarding post-study anti-cancer treatment will be collected if new treatment is 
initiated.
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.5.6.1 – Conditions of Second Course Phase will move from the Follow-Up 
Phase to the Second Course Phase when they experience disease progression.  Details are 
provided in Section 7.1.5.6 – Second Course Phase (Retreatment Phase).
7.1.5.4.3
Survival Follow-up
Subjects who experience centrally verified disease progression (or locally confirmed disease 
progression, if subject is further followed by irRECIST after centrally verified PD) or start a 
new anti-cancer therapy move into the Survival Follow-Up phase and should be contacted by 
telephone approximately every 12 weeks (or more often as needed) to assess for survival 
status until death, withdrawal of consent, or the end of the trial, whichever occurs first.
7.1.5.5
Survival Status
To ensure current and complete survival data is available at the time of database locks,
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (eDMC) review, interim and/or final analysis.
Upon Sponsor 
notification, all subjects who do not/will not have a scheduled study visit or study contact 
during the Sponsor defined time period will be contacted for their survival status (excluding 
subjects that have a previously recorded death event in the collection tool).
7.1.5.6
Second Course Phase (Retreatment Phase)
7.1.5.6.1
Conditions of Second Course Phase
Subjects who stop pembrolizumab/placebo with SD or better may be eligible for up to 
17 additional administrations of pembrolizumab,
if they progress after stopping 
pembrolizumab/placebo and are found to have received pembrolizumab upon unblinding to 
pembrolizumab vs placebo administration on an individual subject basis and only after 
consultation with the Sponsor.  Retreatment with pembrolizumab is termed the Second 
Course Phase of this study and is only available if the study remains open and the subject 
meets the following conditions:
Either 

Stopped 
initial treatment 
with 
pembrolizumab/placebo
after 
attaining 
an 
investigator-determined confirmed CR based on RECIST 1.1, and
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Was treated with at least 8 cycles of pembrolizumab/placebo before 
discontinuing study treatment, and
Received at least 2 cycles of pembrolizumab/placebo beyond the date when 
the initial CR was declared
OR

Had SD, PR,
or CR and stopped pembrolizumab/placebo
treatment after 
35 administrations
of pembrolizumab/placebo for reasons other than disease 
progression or intolerability
AND

Experienced an investigator-determined and centrally verified radiographic disease 
progression 
by 
RECIST 
1.1 
after 
stopping 
initial 
treatment 
with 
pembrolizumab/placebo, and
Upon unblinding at the time of centrally verified disease progression were 
found to have received pembrolizumab, and
No new anti-cancer treatment was administered since the last dose of 
pembrolizumab, and
The subject meets the safety parameters listed in the Inclusion/Exclusion 
criteria, and
The study is ongoing
An objective response or disease progression that occurs during the Second Course Phase for 
a subject will not be counted as an event for the primary analysis of either endpoint in this 
trial.
7.1.5.6.2
Visit Requirements of Second Course Phase
Assessments/Procedures/Windows
Assessments and procedures during the Second Course Phase will be performed
as specified in 
the 
Trial 
Flow 
Charts
in 
Section 6.2.1.1 – Pembrolizumab,
Section 6.2.1.2 – Pembrolizumab 
Plus 
Taxane 
(Paclitaxel 
or 
Nab-Paclitaxel), 
and 
Section 6.2.1.3 – Pembrolizumab Plus Gemcitabine/Carboplatin.  Treatment cycles are 
3 weeks (starting with the first pembrolizumab retreatment) and visit windows are ±3 days 
unless otherwise noted.
For subjects assigned to treatment with pembrolizumab + chemotherapy, continuation or 
resumption of the same chemotherapy received in the First Course Treatment Phase may be 
administered during the Second Course Phase at the discretion of the investigator.  Note that 
chemotherapy different from that received in the First Course Treatment Phase is not 
permitted.  If toxicity occurs, refer to the dose modification guidelines provided in 
Section 5.6.1 – Supportive Care Guidelines for Subjects Receiving Pembrolizumab/Placebo.  
Imaging should always be performed every 9 weeks (±7 days), or more frequently if 
clinically indicated, regardless of any treatment delays.
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Discontinuation During the Second Course Phase
For reasons for retreatment discontinuation during the Second Course Phase, see 
Section 5.8 – Subject Withdrawal/Discontinuation Criteria; subjects must discontinue 
pembrolizumab after 17 administrations.  Imaging requirements for these subjects are 
described in Section 7.1.5.6.2.7 – Tumor Imaging During the Second Course Phase.
Laboratory Tests During the Second Course Phase
Laboratory tests for determining eligibility for retreatment are to be performed within 
10 days prior to the first retreatment dose.  See Section 7.1.3 – Laboratory 
Procedures/Assessments for details regarding laboratory tests.
For women of reproductive potential, a urine pregnancy test should be performed within 24 
hours or serum pregnancy test should be performed within 72 hours prior to receiving the 
first retreatment dose. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required.  While the subject is on study, pregnancy testing 
should be conducted as per local regulations where applicable.
After Cycle 1, laboratory samples can be collected up to 72 hours prior to the scheduled time 
point.  See Section 7.1.3 – Laboratory Procedures/Assessments for details regarding 
laboratory tests. T3 or FT3 can be assayed based on local standards.
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the Second 
Course Phase for any subject receiving anticoagulant therapy.
Clinically significant abnormal laboratory test results that are drug-related AEs should be 
followed until return to within the normal range or baseline.  Laboratory tests do not need to 
be repeated after the end of retreatment if values are within normal range.
Laboratory safety measurements will be graded per NCI CTCAE v4.0.  
Concomitant Medications During the Second Course Phase
Enter new medications started during the Second Course Phase through the Safety Follow-up 
visit.  Record all medications taken for AEs as defined in Section 7.2 – Assessing and 
Recording Adverse Events.
Vital Signs During the Second Course Phase
Vital signs will include temperature, pulse, respiratory rate, weight, and blood pressure.  
Height will not be measured in the Second Course Phase (see Section 7.1.2.4 – Vital Signs).  
Vitals should be taken prior to retreatment administration.
Pembrolizumab Retreatment During the Second Course Phase
Subjects who start retreatment should resume pembrolizumab at 200 mg IV Q3W.  If 
chemotherapy is also given at physician’s discretion, subjects must receive the same 
chemotherapy agent(s) as used in the First Course Phase (see Section 6.2 – Second Course 
Phase [Retreatment Phase] for Part 1 Subjects or Part 2 Subjects Randomized to 
Pembrolizumab Plus Chemotherapy).
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Tumor Imaging During the Second Course Phase
Tumor imaging scans must be performed within 28 days prior to starting retreatment. Local 
readings (investigator assessment with site radiology readings) will be used to determine 
eligibility.  Imaging should be submitted to the CIV for retrospective review.
The first on-study imaging assessment should be performed at 9 weeks (±7 days) after the 
start of retreatment.  Subsequent tumor imaging should be performed every 9 weeks 
(±7 days) or more frequently if clinically indicated.
Per irRECIST (Section 7.1.2.9.5 – irRECIST Assessment of Disease), if tumor imaging 
shows initial PD, tumor assessment should be repeated ≥4 weeks later in order to confirm PD 
with the option of continuing retreatment while awaiting radiologic confirmation of 
progression.  Subjects who obtain a confirmation scan 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 clinically stable.
Imaging should continue to be performed until disease progression, the start of new 
anti-cancer treatment, withdrawal of consent, death, or notification by the Sponsor, 
whichever occurs first.  Disease progression may be confirmed at least 4 weeks after the first 
tumor imaging indicating PD in clinically stable subjects.
In subjects who discontinue retreatment, tumor imaging should be performed at the time of 
retreatment discontinuation (±4-week window).  If a previous scan was obtained within 
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not
mandatory. In subjects who discontinue retreatment due to confirmed disease progression, 
this is the final required tumor imaging.
In subjects who discontinue retreatment without further documented disease progression, 
every effort should be made to continue monitoring their disease status by radiologic imaging 
every 9 weeks (±7 days) until (1) the start of new anti-cancer treatment, (2) disease 
progression verified by CIV, (3) death, or (4) the end of the study, whichever occurs first.
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
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Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.  
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For purposes of this study, an overdose will be defined as ≥1000 mg (5 times the dose) of 
pembrolizumab and as any dose ≥20% over the prescribed dose for chemotherapies included 
in KN355. No specific information is available on the treatment of pembrolizumab or 
chemotherapy overdose. In the event of an overdose, study treatment should be discontinued 
and the subject should be observed closely for signs of toxicity. Appropriate supportive 
treatment should be provided, if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
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Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  All reported pregnancies  must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
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.
Refer to Table 10 for additional details regarding each of the above criteria.
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For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 
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2. 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 trial site guidance for assessment and 
follow up of these criteria can be found in the Investigator Trial File Binder (or equivalent).
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3 – Immediate Reporting of Adverse Events to the Sponsor. 
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 blinded efficacy endpoint events and safety data to ensure the 
safety of the subjects in the study.  Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., 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 adverse experience to the single agent.
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Table 10
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid 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 or hospitalization indicated; disabling; 
limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient 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 pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of an MSD product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship 
to Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event 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 drug and the adverse event based upon the 
available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product 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 
Sponsor’s 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
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
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. 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 Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or (3) 
Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR CLINICAL 
DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology or 
toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
DMC regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial. The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.7 - Interim 
Analyses) and recommend to the EOC if the trial 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 trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in a separate charter that is 
reviewed and approved by the DMC.  The DMC will monitor the trial at an appropriate 
frequency, as described in the detailed DMC charter.  The DMC will also make 
recommendations to the Sponsor protocol team regarding steps to ensure both subject safety 
and the continued ethical integrity of the trial.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to analysis unblinding, changes are made to primary and/or 
key secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9).  Changes to exploratory or 
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other non-confirmatory analyses made after the protocol has been finalized, but prior to the 
conduct of analysis, will be documented in a supplemental statistical analysis plan (sSAP) 
and referenced in the Clinical Study Report (CSR) for the study.  A separate PK analysis plan 
as well as biomarker analysis plan may be provided as appropriate.  Post-hoc exploratory 
analyses will be clearly identified in the CSR.  The PRO analysis plan will also be included 
in the sSAP.  
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan (SAP) are summarized below; the 
comprehensive plan is provided in Sections 8.2 – Responsibility for Analyses/In-House 
Blinding through 8.12 – Extent of Exposure.
Study Design 
Overview
A Randomized, Double-Blind, Phase III Study of Pembrolizumab (MK-3475) plus 
Chemotherapy vs Placebo plus Chemotherapy for Previously Untreated Locally 
Recurrent Inoperable or Metastatic Triple Negative Breast Cancer
Treatment 
Assignment
Part 1:
Approximately 30 subjects will be partially-randomized (unblinded open-label)
among 3 treatment arms: (1) pembrolizumab + nab-paclitaxel, (2) pembrolizumab +
paclitaxel and (3) pembrolizumab + gemcitabine/carboplatin.
Part 2:
Approximately 828 subjects will be randomized (double-blind) in a 2:1 ratio between 
2 treatment arms: (1) pembrolizumab + chemotherapy and (2) placebo +
chemotherapy. Stratification factors are as follows:
1.
Chemotherapy on study (taxane [i.e., paclitaxel or nab-paclitaxel] vs 
gemcitabine/carboplatin).
2.
Tumor PD-L1 status (CPS ≥1 vs CPS <1).
3.
Prior treatment with same class of chemotherapy in the (neo)adjuvant setting (yes 
vs no).
Analysis 
Populations
Part 1 and Part 2 subjects will be analyzed separately.
Part 1 Efficacy: All Subjects as Treated (ASaT)
Part 2 Efficacy: Intention-to-Treat Population (ITT)
Safety: All Subjects as Treated (ASaT)
Primary 
Endpoint(s)
Part 1:  Safety and tolerability.
Part 2:
1.
Progression-free survival (PFS) based on Response Evaluation Criteria in Solid 
Tumors Version 1.1 (RECIST 1.1) as assessed by a blinded central imaging 
vendor (CIV) in all subjects.
2.
PFS based on RECIST 1.1 as assessed by a blinded CIV in subjects with PD-L1 
positive tumors (CPS ≥1).
3.
PFS based on RECIST 1.1 as assessed by a blinded CIV in subjects with PD-L1 
positive tumors (CPS ≥10).
4.
Overall survival (OS) in all subjects.
5.
OS in subjects with PD-L1 positive tumors (CPS ≥1).
6.
OS in subjects with PD-L1 positive tumors (CPS ≥10).
Key Secondary
Endpoint(s)
Part 2: Objective response rate (ORR) based on RECIST 1.1 as assessed by a blinded
CIV in all subjects and in subjects with PD-L1 positive tumors (CPS ≥1).
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Statistical 
Methods for 
Key Efficacy 
Analyses
Part 2: The primary hypotheses will be evaluated by comparing pembrolizumab +
chemotherapy vs placebo + chemotherapy in PFS and OS using a stratified log-rank 
test. The hazard ratio (HR) will be estimated using a stratified Cox model.
The key secondary hypotheses of ORR will be evaluated by comparing 
pembrolizumab + chemotherapy vs placebo + chemotherapy in ORR using a 
stratified Miettinen and Nurminen method.
Statistical 
Methods for 
Key Safety 
Analyses
Part 1: Descriptive summary statistics will be provided for safety endpoints by 
treatment as appropriate.
Part 2: The analysis of safety will follow a tiered approach.  There is no Tier 1 safety 
endpoint for this trial. Point estimates and 95% confidence intervals (CIs) for 
between-treatment comparisons via the Miettinen and Nurminen method will be 
provided for Tier 2 safety endpoints; only point estimates by treatment group will be 
provided for Tier 3 safety endpoints. 
Interim 
Analyses
One safety interim analysis for Part 1 and 3 efficacy interim analyses for Part 2 will 
be performed.  Results will be reviewed by an external DMC. Details are provided in 
Section 8.7 – Interim Analyses.
Part 1 – Safety Interim Analysis: ~ 3 months after first subject randomized.
o
Timing: after all Part 1 subjects have completed the first 21 or 28 days 
(depending on chemotherapy treatment) of study treatment. 
o
Primary purpose: interim safety evaluation.
Part 2 – Efficacy Interim and Final Analyses
Interim analysis 1 (IA1): ~ 9 months after first 640 Part 2 subjects are randomized.
o Primary purpose: final ORR analysis, interim PFS and interim OS analysis.
Interim analysis 2 (IA2): after ~ 185 OS events among subjects with CPS ≥10 have 
been observed.
o Primary purpose: interim OS analysis and final PFS analysis.
Interim analysis 3 (IA3): after ~ 210 OS events among subjects with CPS ≥10 have 
been observed.
o Primary purpose: interim OS analysis.
Final analysis (FA): after ~ 664 OS events among all subjects, ~ 482 OS events 
among subjects with CPS ≥1, and ~ 240 OS events among subjects with CPS ≥10 
have been observed.
o Primary purpose: final OS analysis.
Multiplicity
Part 1: Multiplicity adjustment not applicable.
Part 2: The family-wise type-I error rate over the 6 primary hypotheses and the 2
secondary hypotheses will be strongly controlled at 2.5% (one-sided) with 0.5% 
allocated to PFS, 1.8% allocated to OS, and 0.2% allocated to ORR hypotheses.  An 
extension [99] of the graphical approach of Maurer and Bretz [100] will be applied to 
re-allocate alpha between PFS, OS and ORR hypotheses. The Spiessens and Debois
method [101] will be used to adjust the nominal alphas in ORR between all subjects 
and subjects with CPS ≥1. Group sequential methods will be used to allocate alpha 
between the interim and final analyses for OS endpoints.
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Sample Size 
and Power 
Part 1: Approximately 30 subjects will be enrolled.
Part 2: It is expected that ~ 664 OS events among all subjects, ~ 482 OS events 
among subjects with CPS ≥1, and ~ 240 OS events among subjects with CPS ≥10
have been observed at the FA. The planned sample size is approximately 
828 subjects. 
(1) PFS in all subjects: at IA2 the analysis has ~ 89% power at a one-sided 0.111% 
alpha level, if the true HR is 0.70. At IA2, with ~ 634 events the HR at boundary 
for success is ~ 0.77 (~ 1.6 months improvement over control median PFS of 
5.5 months). At IA2, PFS in all subjects can only be tested if both hypotheses of 
PFS in subjects with CPS ≥10 and PFS in subjects with CPS ≥1 are supported.
(2) PFS in subjects with CPS ≥1: at IA2 the analysis has ~ 97% power at a one-sided 
0.111% alpha level, if the true HR is 0.62. At IA2, with ~ 463 events the HR at 
boundary for success is ~ 0.74 (~ 1.9 months improvement over control median 
PFS of 5.5 months). At IA2, PFS in all subjects with CPS ≥1 can only be tested if 
the hypothesis of PFS in subjects with CPS ≥10 is supported.
(3) PFS in subjects with CPS ≥10: at IA2 the analysis has ~ 86% power at a 
one-sided 0.411% alpha level, if the true HR is 0.60. At IA2, with ~ 235 events 
the HR at boundary for success is ~ 0.69 (~ 2.4 months improvement over control 
median PFS of 5.5 months).
(4) OS in all subjects: the trial has ~ 60% power at a one-sided 0.75% alpha level, if 
the true HR is 0.80. With ~ 664 events, the HR at boundary for success at FA is
~ 0.81 (~ 4.0 months improvement over control median OS of 17.5 months).  
After IA1, OS in all subjects can be tested if hypothesis of OS in subjects with 
CPS ≥1 is supported.
(5) OS in subjects with CPS ≥1: the trial has ~ 87% power at a one-sided 0.75% 
alpha level, if the true HR is 0.71. With ~ 482 events, the HR at boundary for 
success at FA is ~ 0.78 (~ 4.8 months improvement over control median OS of 
17.5 months).
(6) OS in subjects with CPS ≥10: the trial has ~ 79% power at a one-sided 1.011% 
alpha level, if the true HR is 0.65. With ~ 240 events, the HR at boundary for 
success at FA is ~ 0.72 (~ 6.8 months improvement over control median OS of 
17.5 months).
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.
The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IVRS.
Part 1:
Part 1 of this study is being conducted as a partially randomized, open-label study, 
i.e., subjects, investigators, and Sponsor personnel will be aware of subject treatment 
assignments after each subject is enrolled and treatment is assigned. 
Planned safety interim analysis is described in Section 8.7 – Interim Analyses.  Study 
enrollment is likely to be ongoing at the time of the safety interim analysis (i.e., no planned 
enrollment pause between Part 1 and Part 2).  
The external DMC will serve as the primary reviewer of the results of the safety interim 
analysis and will make recommendations for discontinuation of the study or modification to 
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an EOC of the Sponsor. Additional logistical details, revisions to the above plan and data 
monitoring guidance will be provided in the DMC Charter.  Key aspects of the interim 
analysis are described in Section 8.7 – Interim Analyses.
Part 2:
Part 2 of this study will be conducted as a double-blind, Phase III study part under in-house 
blinding procedures.  The official, final database of Part 2 will not be unblinded until 
medical/scientific review has been performed, protocol deviations have been identified, and 
data have been declared final and complete. In addition, the independent radiologist(s) will 
perform the central imaging review without knowledge of treatment group assignment. The 
Investigators, other study site staff, and subjects will be blinded to subject-level PD-L1 
biomarker results. Analysis or summaries generated by PD-L1 status will be limited and 
documented. Additional details regarding trial blinding/unblinding including unblinding 
required for operational purposes (e.g., unblinded pharmacist) are described in Section 5.2.3 
– Trial Blinding.
Planned efficacy interim analyses are described in Section 8.7 – Interim Analyses.  Study 
enrollment is likely to be ongoing at the time of any efficacy interim analyses.  Blinding to 
treatment assignment will be maintained at all investigational sites.
Treatment-level results of the efficacy interim analyses will be provided by an external
unblinded statistician to the external DMC.  The external DMC will serve as the primary 
reviewer of the results of the interim analyses and will make recommendations for 
discontinuation of the study or modification to an EOC of the Sponsor. Depending on the 
recommendation of the DMC, the Sponsor may prepare a regulatory submission. If the DMC 
recommends modifications to the design of the protocol or discontinuation of the study, this 
EOC may be unblinded to results at the treatment level in order to act on these 
recommendations or facilitate regulatory filing.  Limited additional Sponsor personnel may 
be unblinded to the treatment level results of the interim analysis (analyses), if required, in 
order to act on the recommendations of the DMC or facilitate regulatory filing. The extent to 
which individuals are unblinded with respect to results of interim analyses will be 
documented.  Additional logistical details, revisions to the above plan and data monitoring 
guidance will be provided in the DMC Charter.  Key aspects of the interim analyses are 
described in Section 8.7 – Interim Analyses.
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.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0 – Objective(s) &
Hypothesis(es).
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
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Efficacy Endpoints
Primary
Progression-free survival (PFS) – based on RECIST 1.1 as assessed by a CIV
Progression-free survival is defined as the time from randomization to the first documented 
disease progression per RECIST 1.1 based on assessments by a CIV or death due to any 
cause, whichever occurs first.  See Section 8.6.1 – Statistical Methods for Efficacy Analyses
for the definition of censoring.
Overall Survival (OS)
Overall survival is defined as the time from randomization to death due to any cause. 
Subjects without documented death at the time of the analysis will be censored at the date of 
the last follow-up.
Secondary
Objective Response Rate (ORR) – based on RECIST 1.1 as assessed by a CIV
Objective response rate is defined as the proportion of the subjects in the analysis population 
who have a CR or PR. Responses are based on assessments by a CIV per RECIST 1.1.
Duration of Overall Response (DOR) – based on RECIST 1.1 as assessed by a CIV
For subjects who demonstrate CR or PR, duration of response is defined as the time from 
first documented evidence of CR or PR until disease progression or death due to any cause, 
whichever occurs first, based on assessments by a CIV per RECIST 1.1. See Section 8.6.1 –
Statistical Methods for Efficacy Analyses for the definition of censoring.
Disease Control Rate (DCR) – based on RECIST 1.1 as assessed by a CIV
Disease control rate is defined as the percentage of subjects who have achieved CR or PR or 
have demonstrated SD for at least 24 weeks, based on assessments by a CIV per RECIST 1.1. 
Safety Endpoints
Safety measurements are described in Section 4.2.3 – Rationale for Endpoints and 
Section 7.0 – Trial Procedures.
Analysis Populations
Efficacy Analysis Populations
The ITT population will serve as the population for primary efficacy analysis of Part 2. All 
randomized subjects will be included in this population. Subjects will be included in the 
treatment group to which they are randomized.
Part 1 subjects will be excluded from all Part 2 efficacy analyses and therefore will not 
contribute to the analyses to address the primary/secondary objectives of Part 2. The All 
Subjects as Treated (ASaT) population will be used for the analysis of Part 1 efficacy in this 
study.  The ASaT population consists of all randomized subjects who received at least one 
dose of study treatment. Subjects will be included in the treatment group corresponding to 
the study treatment they actually received for the analysis of Part 1 efficacy data using the 
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ASaT population.  For most subjects this will be the treatment group to which they are 
randomized.  Subjects who take incorrect study treatment for the entire treatment period will 
be included in the treatment group corresponding to the study treatment actually received. 
Any subject who receives the incorrect study treatment for one cycle, but receives the correct 
treatment for all other cycles, will be analyzed according to the correct treatment group.
Details on the approach to handling missing data are provided in Section 8.6 – Statistical 
Methods.
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all randomized subjects who received at least 
one dose of study treatment. Subjects will be included in the treatment group corresponding 
to the study treatment they actually received for the analysis of safety data using the ASaT 
population.  For most subjects this will be the treatment group to which they are randomized.  
Subjects who take incorrect study treatment for the entire treatment period will be included in 
the treatment group corresponding to the study treatment actually received. Any subject who 
receives the incorrect study treatment for one cycle, but receives the correct treatment for all 
other cycles, will be analyzed according to the correct treatment group and a narrative will be 
provided for any events that occur during the cycle for which the subject is incorrectly dosed.
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Part 1 and Part 2 subjects will be analyzed separately.
Details on the approach to handling missing data for safety analyses are provided in 
Section 8.6 – Statistical Methods.
Statistical Methods
This section describes the statistical methods that address the primary and secondary efficacy 
and safety objectives.  Methods related to PRO objectives and exploratory objectives will be 
described in the sSAP(s).
Statistical Methods for Efficacy Analyses
For Part 1, descriptive summaries will be provided for efficacy endpoints (e.g., PFS, OS, 
ORR, DOR, DCR) as appropriate. 
The efficacy analysis methods specified in this section apply to Part 2.  Part 1 subjects will be 
excluded from all Part 2 efficacy analyses and therefore will not contribute to the analyses to 
address the primary/secondary objectives of Part 2.
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 8.8 – Multiplicity. Nominal p-values 
will be computed for other efficacy analyses, but should be interpreted with caution due to 
potential issues of multiplicity.
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8.6.1.1
Progression-Free Survival (PFS)
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment 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 (i.e., HR) between the treatment 
arms. The HR and its 95% confidence interval (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 (see Section 5.4 – Stratification) will be applied, 
as stratification factors used for analysis, to both the stratified log-rank test and the stratified 
Cox model. 
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment in which PD was not documented and the assessment when PD 
is documented. For subjects who have PD, the true date of disease progression will be 
approximated by the date of the first assessment at which PD is objectively documented 
based on RECIST 1.1 as assessed by a CIV. Death is always considered as a confirmed PD 
event. Subjects who do not experience a PFS event will be censored at the last disease 
assessment.
In order to evaluate the robustness of the PFS endpoint based on RECIST 1.1 as assessed by 
a CIV, one primary and two 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 anti-cancer therapy are censored at the last disease 
assessment prior to the initiation of new anti-cancer therapy. The first sensitivity analysis 
follows the intention-to-treat principle. That is, PDs/deaths are counted as events regardless 
of missed study visits or initiation of new anti-cancer therapy. The second sensitivity 
analysis considers initiation of new anticancer treatment or discontinuation of treatment due 
to reasons other than complete response to be a PD event for subjects without documented 
PD or death. The censoring rules for primary and sensitivity analyses are summarized in 
Table 11.
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Table 11
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and no death; 
and new anticancer 
treatment 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 treatment or completed 
study treatment.
No PD and no death; 
new anticancer 
treatment is initiated
Censored at last disease 
assessment before new 
anticancer treatment 
Censored at last 
disease assessment
Progressed at date of new 
anticancer treatment
PD or death 
documented after ≤1 
missed disease 
assessment, and before 
new anti-cancer 
therapy, 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 anti-cancer 
therapy, if any
Censored at last disease 
assessment prior to 
the earlier date of ≥2 
consecutive missed 
disease assessment and 
new anti-cancer therapy, 
if any
Progressed at date 
of documented PD 
or death
Progressed at date of 
documented PD or death
The proportional hazards assumption on PFS will be examined using both graphical and 
analytical methods if warranted. The log[-log] of the survival function vs time for PFS may
be plotted for the comparison between the pembrolizumab + chemotherapy and placebo +
chemotherapy arms. 
If the curves are not parallel, indicating that hazards are not 
proportional, supportive analyses may be conducted to account for the possible 
non-proportional hazards effect associated with immunotherapies; for example, using 
Restricted Mean Survival Time (RMST) method [102] and parametric method [103].
One assumption for stratified Cox proportional hazard model is that the treatment HR is 
constant across the strata. If strong departures from the assumption of the HR being the same 
for all the strata observed (which can result in a notably biased and/or less powerful 
analysis), a sensitivity analysis may be performed based on a two-step weighted Cox model 
approach by Mehrotra et al., 2012 [104], in which the treatment effect is first estimated for 
each stratum, and then the stratum specific estimates are combined for overall inference 
using sample size weights.
Sensitivity analyses will be performed for PFS based on site investigator/local radiology 
review. Additional supportive unstratified analyses may also be provided. Further details of 
sensitivity analyses will be described in the sSAP.
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8.6.1.2
Overall Survival (OS)
The non-parametric 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 (i.e., the HR). 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 (see Section 5.4 – Stratification) will be applied, as 
stratification factors used for analysis, to both the stratified log-rank test and the stratified 
Cox model.
Subjects in the placebo + chemotherapy arm are expected to discontinue treatment earlier 
compared to subjects in the pembrolizumab + chemotherapy arm and are not allowed to 
crossover to the pembrolizumab + chemotherapy arm; however, they may be treated with 
another anti–PD-1 drug following the verification of PD by a blinded CIV. 
As an 
exploratory analysis, adjustment for the effect of crossover on OS may be performed based 
on recognized methods (e.g., the Rank Preserving Structural Failure Time (RPSFT) model 
proposed by Robins and Tsiatis [105], two-stage model), based on an examination of the 
appropriateness of the data to the assumptions required by the methods.
Additional supportive unstratified analyses may also be provided.  Further details of 
sensitivity analyses will be described in the sSAP as needed.
8.6.1.3
Objective Response Rate (ORR) 
The stratified Miettinen and Nurminen method will be used for the comparison of ORR 
between 2 treatment arms. The difference in ORR and its 95% CI from the stratified 
Miettinen and Nurminen method with strata weighting by sample size will be reported.  The 
stratification factors used for randomization (see Section 5.4 – Stratification) will be applied
to the analysis.
The ORR hypotheses will be tested according to the hypotheses testing plan as described in 
Section 8.8 – Multiplicity.
Sensitivity analyses will be performed for ORR based on site investigator/local radiology 
review.  Additional supportive unstratified analyses may also be provided.  Further details of 
sensitivity analyses will be described in the sSAP as needed.
8.6.1.4
Disease Control Rate (DCR)
The stratified Miettinen and Nurminen method will be used for the comparison of DCR 
between 2 treatment arms. The difference in DCR and its 95% CI from the stratified 
Miettinen and Nurminen method with strata weighting by sample size will be reported. The 
stratification factors used for randomization (see Section 5.4 – Stratification) will be applied 
to the analysis.
Sensitivity analyses will be performed for DCR based on site investigator/local radiology 
review.  Further details of sensitivity analyses will be described in the sSAP as needed.
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8.6.1.5
Duration of Response (DOR)
If sample size permits, DOR will be summarized descriptively using the non-parametric 
Kaplan-Meier method.  Only the subset of subjects who achieved CR or PR will be included 
in this analysis.  
Censoring rules for DOR are summarized in Table 12. 
Sensitivity analyses will be performed for DOR based on site investigator/local radiology 
review. Further details of sensitivity analyses will be described in the sSAP as needed.
Table 12
Censoring Rules for DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anti-cancer therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new anti-
cancer therapy initiated
Last adequate disease assessment 
before 
new 
anti-cancer 
therapy 
initiated
Censor
(non-event)
Death or progression immediately 
after ≥2 consecutive missed disease 
assessments or after new anti-cancer 
therapy, if any
Earlier date of last adequate disease 
assessment prior to ≥2 missed 
adequate disease assessments and 
new anti-cancer therapy, if any
Censor
(non-event)
Death or progression after ≤1 missed 
disease assessments and before new 
anti-cancer therapy, if any
PD or death
End of response
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
8.6.1.6
Summary of Statistical Methods for Efficacy
Table 13 summarizes the primary analysis approach for primary and secondary efficacy 
endpoints of Part 2.  Sensitivity analysis methods are described above for each endpoint as 
applicable.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, 
multiple populations, and interim analyses is described in Section 8.7 – Interim Analyses and 
in Section 8.8 – Multiplicity.
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Table 13
Analysis Strategy for Key Efficacy Endpoints (Part 2)
Endpoint/Variable
(Description, Time Point)
Statistical Methoda
Analysis 
Population
Missing Data Approach
Primary Hypothesis 1
PFS based on RECIST 1.1 assessed 
by a blinded CIV in all subjects
Test: Stratified log-rank test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT

Primary censoring rule

Sensitivity analysis 1

Sensitivity analysis 2
(More details are in Table 11)
Primary Hypothesis 2
PFS based on RECIST 1.1 assessed 
by a blinded CIV in subjects with 
PD-L1 positive tumors (CPS ≥1)
Test: Stratified log-rank test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT

Primary censoring rule

Sensitivity analysis 1

Sensitivity analysis 2
(More details are in Table 11)
Primary Hypothesis 3
PFS based on RECIST 1.1 assessed 
by a blinded CIV in subjects with 
PD-L1 positive tumors (CPS ≥10)
Test: Stratified log-rank test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT

Primary censoring rule

Sensitivity analysis 1

Sensitivity analysis 2
(More details are in Table 11)
Primary Hypothesis 4
OS in all subjects
Test: Stratified log-rank test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
Censored at last known alive 
date
Primary Hypothesis 5
OS in subjects with PD-L1 positive 
tumors (CPS ≥1)
Test: Stratified log-rank test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
Censored at last known alive 
date
Primary Hypothesis 6
OS in subjects with PD-L1 positive 
tumors (CPS ≥10)
Test: Stratified log-rank test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
Censored at last known alive 
date
Key Secondary Hypothesis 1 (Hypothesis 7)
ORR based on RECIST 1.1 assessed 
by a blinded CIV in all subjects
Stratified M & N methodb
The first 
~ 640 
subjects 
randomized 
in Part 2 (a 
subset of 
ITT)
Subjects with relevant data 
missing are considered 
non-responders
Key Secondary Hypothesis 2 (Hypothesis 8)
ORR based on RECIST 1.1 assessed 
by a blinded CIV in subjects with 
PD-L1 positive tumors (CPS ≥1)
Stratified M & N methodb
The first 
~ 640 
subjects 
randomized 
in Part 2 (a 
subset of 
ITT)
Subjects with relevant data 
missing are considered 
non-responders
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Endpoint/Variable
(Description, Time Point)
Statistical Methoda
Analysis 
Population
Missing Data Approach
Other Secondary Endpoints
ORR based on RECIST 1.1 assessed 
by a blinded CIV in subjects with 
PD-L1 positive tumors (CPS ≥10)
Stratified M & N methodb
ITT
Subjects with relevant data 
missing are considered 
non-responders
DCR based on RECIST 1.1 assessed 
by a blinded CIV in all subjects and 
in subjects with PD-L1 positive 
tumors (CPS ≥1 and CPS ≥10)
Stratified M & N methodb
ITT
Subjects with relevant data 
missing are considered 
non-responders
DOR based on RECIST 1.1 assessed 
by a blinded CIV in all subjects and 
in subjects with PD-L1 positive 
tumors (CPS ≥1 and CPS ≥10)
Summary statistics using 
Kaplan-Meier method
All 
responders 
in ITT
See Table 12
CIV=central imaging vendor; CPS=combined positive score; DCR=disease control rate; DOR=duration of response; 
ITT=intention-to-treat; M & N=Miettinen and Nurminen; ORR=objective response rate; OS=overall survival; 
PD-L1=programmed cell death ligand 1; PFS=progression-free survival; RECIST 1.1= Response Evaluation Criteria 
in Solid Tumors version 1.1.
a Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used for 
randomization will be used as stratification factors for analysis.
b Miettinen and Nurminen method.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences, laboratory tests, vital signs, etc. 
Part 1
Descriptive summary statistics (e.g., counts, percentage, mean, standard deviation) will be 
provided for safety endpoints by treatment for Part 1 as appropriate.  
Part 2
The analysis of safety results will follow a tiered approach [Table 14].  The tiers differ with 
respect to the analyses that will be performed.  For this protocol, there are no Tier 1 safety 
endpoints. Tier 2 parameters will be assessed via point estimates with 95% CIs provided for 
between-group comparisons; only point estimates by treatment group will be provided for 
Tier 3 safety parameters.
Adverse experiences (specific terms as well as system organ class terms) will be classified as 
belonging to “Tier 2” or “Tier 3”, based on the number or percent of subjects with events 
observed.  Specific AEs occurring in ≥5% of subjects in one or more treatment groups will 
be considered Tier 2 endpoints.  Specific Serious and Grade 3-5 AEs occurring in at least 8
subjects in the pembrolizumab + chemotherapy group, or at least 2 subjects in the placebo + 
chemotherapy group will also be considered Tier 2 endpoints.  All other adverse experiences 
and predefined limits of change will belong to Tier 3.
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The threshold of at least 5% of subjects with events in one or more treatment groups was 
chosen for specific AEs as Tier 2 endpoints because this incidence rate would allow 
meaningful statistical assessments for AEs in general.  The threshold of at least 8 subjects in 
the pembrolizumab + chemotherapy group, or at least 2 subjects in the placebo + 
chemotherapy group was chosen for specific Serious and Grade 3-5 AEs because the 95% CI 
for the between-group difference in percent incidence will always include zero with 2 to 1 
randomization ratio if there are less than 8 subjects with events in the treatment group and 
less than 2 subjects with events in the control group, and thus would add little to the 
interpretation of potentially meaningful differences. Serious and Grade 3-5 AEs are expected 
to occur less frequently but important for the overall safety assessment, as such the threshold 
to classify these AEs as Tier 2 endpoints are lower than that for general specific AEs. 
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 review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse experiences 
and predefined limits of change.
Continuous measures such as changes from baseline in laboratory and vital signs will be 
considered Tier 3 safety parameters.  Summary statistics for baseline, on-treatment, and 
change from baseline values will be provided by treatment group.
The broad clinical and laboratory AE categories consisting of the percentage of subjects with 
any AE, any drug related AE, any Grade 3-5 AE, any serious AE, any AE which is both 
drug-related and Grade 3-5, any AE which is both serious and drug-related, dose 
modification due to AE, and who discontinued due to an AE, and death will be considered 
Tier 2 endpoints.  For Tier 2 endpoints, point estimates and 95% CIs will be provided for 
between-treatment differences in the percentage of subjects with events; these analyses will 
be performed using the Miettinen and Nurminen method.
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Table 14
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive Statistics
Tier 2
Any AE
X
X
Any Serious AE 
X
X
Any Grade 3-5 AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade 3-5 and Drug-Related AE
X
X 
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
X
X
Specific AEs, SOCs (incidence ≥5% of subjects in one or 
more treatment groups)
X
X
Specific Serious AEs, SOCs (incidence ≥8 subjects in the 
pembrolizumab + chemotherapy group, or ≥2 subjects in 
the placebo + chemotherapy group)
X
X
Specific Grade 3-5 AEs, SOCs (incidence ≥8 subjects in the 
pembrolizumab + chemotherapy group, or ≥2 subjects in 
the placebo + chemotherapy group)
X
X
Tier 3
Specific AEs, SOCs (incidence <5% of subjects in both 
treatment groups) or PDLCs
X
Specific Serious AEs, SOCs (incidence <8 subjects in the 
pembrolizumab + chemotherapy group and <2 subjects in 
the placebo + chemotherapy group)
X
Specific Grade 3-5 AEs, SOCs (incidence <8 subjects in the 
pembrolizumab + chemotherapy group and <2 subjects in 
the placebo + chemotherapy group)
X
Change from Baseline Results (Labs, Vital Signs)
X
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X = results will be provided.
Summaries of Demographic and Baseline Characteristics
Part 1 and Part 2
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis testing will be performed on these 
characteristics.  The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed.  
Demographic variables (e.g., age) and baseline characteristics will be summarized by 
treatment either by descriptive statistics or categorical tables.
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Interim Analyses
The study has 1 planned safety interim analysis for Part 1 and 3 planned efficacy interim 
analyses for Part 2. Results will be reviewed by the external DMC.
Part 1: Safety Interim Analysis
A safety interim analysis will be performed after all Part 1 subjects have completed the first 
21 or 28 days (depending on chemotherapy treatment) of study treatment (unless early 
discontinued), i.e., 21 days after the first study treatment administration if the subject is in the 
pembrolizumab + gemcitabine/carboplatin arm or 28 days after the first study treatment 
administration if the subject is in either of the pembrolizumab + taxane arms. Interim safety 
data will be reviewed by the DMC.  It is estimated that the safety interim analysis will occur 
approximately 3 months after the first subject is randomized (depending on enrollment rate).
In addition, continuous safety monitoring will be performed for Part 1 prior to the safety 
interim analysis by the study team. If a potential safety issue signal is observed before 
10 subjects are enrolled in a treatment arm, the DMC will be notified to review data prior to 
the pre-specified safety interim analysis.
Part 2: Efficacy Interim Analyses
There are 3 planned efficacy interim analyses for Part 2 in this trial. Results will be 
reviewed by the DMC. Of note, the boundaries for the analyses in this section may be 
adjusted, as appropriate, using the graphical approach discussed in Section 8.8 – Multiplicity.
The boundaries provided in this section are calculated based on the estimated number of 
events at each analysis, and the actual interim boundaries will be determined using the actual 
observed and the planned numbers of events at the time of interim analyses with the rules and 
spending functions specified in Section 8.8 – Multiplicity. The actual final boundaries will be 
adjusted accordingly. Any changes to the timing of the analyses, along with its rationale, will 
be documented in the sSAP or a memo to the study file before the database lock.
Of note, Amendment 05 occurred after the conduct of efficacy interim analysis 1 (IA1), and 
the following information regarding IA1 is based on the planned number of events and 
original multiplicity strategy specified in the protocol prior to Amendment 05.
Interim Analysis 1 (Final ORR, Interim PFS and Interim OS Analysis)
The primary purpose of efficacy IA1 is to perform the final ORR, interim PFS and interim 
OS analysis. The ORR analysis at IA1 is considered the final ORR analysis of the study. IA1
will be performed after: (1) enrollment is completed, and (2) ~ 9 months after the first 640 
subjects randomized to Part 2.
At IA1, ORR analyses will be based on data from the first ~ 640 subjects randomized to Part 
2 and be tested in 1) all subjects and, 2) subjects with CPS ≥1. All subjects randomized on or 
prior to the date the 640th Part 2 subject is randomized will be included in the ORR analysis. 
The success boundary to demonstrate ORR superiority at IA1 approximately corresponds to 
an observed ORR difference of ~ 12.6 percentage points at α = 0.1% (one-sided) for all 
subjects, and an observed ORR difference of ~ 14.1 percentage points at nominal 
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α = ~ 0.145% (one-sided) for subjects with CPS ≥1, if there are 640 subjects in all subjects 
and 480 subjects in subjects with CPS ≥1 available for analysis (assuming PD-L1 positivity 
prevalence CPS ≥1 of 75%), respectively.
The estimated boundaries for PFS and OS endpoints at IA1 are provided in Table 15, 
assuming the planned numbers of events are analyzed.
Interim Analysis 2 (Interim OS Analysis and Final PFS Analysis)
The primary purpose of efficacy interim analysis 2 (IA2) is to evaluate superiority of 
pembrolizumab + chemotherapy vs placebo + chemotherapy in OS, and to perform final PFS 
analysis.
The analysis will be performed after ~ 185 OS events among subjects with 
CPS ≥10 have been observed. It is estimated that at IA2 ~ 523 OS events among all subjects 
and ~ 375 OS events among subjects with CPS ≥1 have been observed. The analysis may be 
delayed for up to 4 months if the planned number of OS events has not been reached in all 
subjects or in subjects with CPS ≥1. It is estimated that IA2 is expected to occur ~ 22 months 
after last subject randomized.
The estimated boundaries for PFS and OS endpoints at IA2 are provided in Table 15 and 
Table 16, assuming the planned numbers of events are analyzed.
Interim Analysis 3 (Interim OS Analysis)
The primary purpose of efficacy interim analysis 3 (IA3) is to evaluate superiority of 
pembrolizumab + chemotherapy vs placebo + chemotherapy in OS.  The analysis will be 
performed after ~ 210 OS events among subjects with CPS ≥10 have been observed. It is 
estimated at IA3 ~ 589 OS events among all subjects and ~ 424 OS events among subjects 
with CPS ≥1 have been observed. The analysis may be delayed for up to 4 months if the 
planned number of OS events has not been reached in all subjects or in subjects with CPS ≥1. 
It is estimated that IA3 is expected to occur ~ 30 months after last subject randomized.
The estimated boundaries for OS endpoints at IA3 are provided in Table 15 and Table 16, 
assuming the planned numbers of events are analyzed.
Final Analysis (Final OS Analysis)
The final analysis (FA) of the study is event driven and will be conducted after
approximately ~ 664 OS events among all subjects, ~ 482 OS events among subjects with 
CPS ≥1, and ~ 240 OS events among subjects with CPS ≥10 have been observed. It is 
estimated that FA is expected to occur ~ 43 months after last subject randomized. If after 
43 months after last subject randomized, the planned numbers of OS events still have not 
been observed, then the final OS analysis may be conducted at that time regardless. The 
success boundaries to demonstrate OS superiority at FA are presented in Table 15 and Table 
16, if the planned numbers of OS events are analyzed.
Table 15 summarizes the timing, sample size and decision guidance of the 3 efficacy interim 
analyses and FA, assuming there is no alpha re-allocation among hypotheses. 
ORR 
boundaries are based on the assumptions of 640 randomized subjects and 75% PD-L1
CPS ≥1 prevalence, and may be updated at time of the analyses using the actual observed 
numbers. PFS and OS boundaries are based on planned number of events and may be 
updated at times of the analyses according to the actual observed number of events, spending 
functions, and the spending time approach as specified in Section 8.8 – Multiplicity.
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Table 15
Summary of Timing, Sample Size and Decision Guidance of Efficacy Interim 
Analyses and Final Analysis (Part 2, at Initial Alpha)
Analysis
Criteria for Conduct of Analysis
Endpoint
and Testing 
Population
Parameter
Efficacy Bara, b
Interim Analysis 1:
Final ORR, Interim 
PFS and Interim OS 
Analysis
IA1 occurred ~ 4 months after last 
subject randomized.
IA1 was to be conducted when:
(1) enrollment is completed, and
(2) ~ 9 months after first 640 
subjects are randomized in Part 2
It was estimated that at IA1:
~ 500 PFS events among all 
subjects, ~ 360 PFS events among 
subjects with CPS ≥1, ~ 260 OS 
events among all subjects, and 
~ 185 OS events among subjects 
with CPS ≥1 have been observed.
ORR in all 
subjects
p-value (1-sided) at 
boundary
~ ORR difference at 
boundary
0.001
~ 12.6 percentage 
points
ORR in 
subjects with 
CPS ≥1
p-value (1-sided) at 
boundary
~ ORR difference at 
boundary
~ 0.00145c
~ 14.1 percentage 
points
PFS in all 
subjects
p-value (1-sided) at 
boundary
~ HR at boundary
0.0005
~ 0.73
PFS in 
subjects with 
CPS ≥1
p-value (1-sided) at 
boundary
~ HR at boundary
0.0005
~ 0.69
OS in all 
subjects
p-value (1-sided) at 
boundary
~ HR at boundary
0.0004
~ 0.64
OS in subjects 
with CPS ≥1
p-value (1-sided) at 
boundary
~ HR at boundary
0.0004
~ 0.59
Interim Analysis 2: 
Interim OS 
Analysis/Final PFS 
Analysis
IA2 will be conducted after
~ 185 OS events among subjects 
with CPS ≥10 have been observed d.
It is estimated that at IA2:
~ 523 OS events among all subjects, 
~ 375 OS events among subjects 
with CPS ≥1, ~ 634 PFS events 
among all subjects, ~ 463 PFS 
events among subjects with CPS ≥1,
and ~ 235 PFS events among 
subjects with CPS ≥10 have been 
observed.
PFS in 
subjects with 
CPS ≥10
p-value (1-sided) at 
boundary
~ HR at boundary
0.00411
~ 0.69
OS in subjects 
with CPS ≥1
p-value (1-sided) at 
boundary
~ HR at boundary
0.0022
~ 0.73
OS in subjects 
with CPS ≥10
p-value (1-sided) at 
boundary
~ HR at boundary
0.0034
~ 0.66
Interim Analysis 3: 
Interim OS Analysis
IA3 will be conducted after 
~ 210 OS events among subjects 
with CPS ≥10 have been observed d.
It is estimated that at IA3:
~ 589 OS events among all subjects, 
~ 424 OS events among subjects 
with CPS ≥1 have been observed.
OS in subjects 
with CPS ≥1
p-value (1-sided) at 
boundary
~ HR at boundary
0.0036
~ 0.76
OS in subjects 
with CPS ≥10
p-value (1-sided) at 
boundary
~ HR at boundary
0.0050
~ 0.69
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Analysis
Criteria for Conduct of Analysis
Endpoint
and Testing 
Population
Parameter
Efficacy Bara, b
Final Analysis (FA): 
Final OS Analysis
FA will be conducted after e:
~ 664 OS events among all subjects, 
~ 482 OS events among subjects 
with CPS ≥1, and ~ 240 OS events 
among subjects with CPS ≥10 have 
been observed.
OS in subjects 
with CPS ≥1
p-value (1-sided) at 
boundary
~ HR at boundary
0.0060
~ 0.78
OS in subjects 
with CPS ≥10
p-value (1-sided) at 
boundary
~ HR at boundary
0.0082
~ 0.72
a. Efficacy bar represents boundary at which statistical significance supporting pembrolizumab + chemotherapy is 
superior to placebo + chemotherapy can be claimed.
b. Efficacy bars at IA1 are based on planned number of events and original multiplicity strategy specified in the protocol 
prior to Amendment 05. Efficacy bars at IA2/IA3/FA for OS in subjects with CPS ≥1 are based on the actual number of 
events at IA1 and planned numbers of events at IA2/IA3/FA.
c. Approximate nominal alpha based on the Spiessens and Debois method accounting for correlation between ORR in all
subjects and ORR in subjects with CPS ≥1. The actual nominal alpha will be calculated based on the actual correlation 
between these two populations for testing.
d. IA2 and IA3 may be delayed for up to 4 months if the planned number of OS events in all subjects or in subjects with 
CPS ≥1 has not yet been reached.
e. FA may be conducted after 43 months post last patient randomized even if the planned numbers of events are not 
reached at that time.
If a hypothesis is supported, the alpha can be re-allocated to another hypothesis following the 
pre-specified rules in Section 8.8 – Multiplicity.  The hypotheses of PFS in all subjects, PFS 
in subjects with CPS ≥1, and OS in all subjects have initial alpha of 0% at IA2 (PFS) or 
IA2/IA3/FA (OS). As such, after IA1 they can only be tested after alpha re-allocation if 
relevant hypothesis(es) is supported. The efficacy decision guidance for these endpoints with 
respect to the re-allocated alpha from the support of other hypothesis(es) is summarized in 
Table 16 below (selected scenarios), assuming the planned numbers of events specified in 
Table 15 are available for analyses at each time point.
If an efficacy boundary is crossed at IA1 or IA2 for PFS, or at an interim analysis or the 
FA for OS, in either all subjects or subjects with CPS ≥1 or CPS ≥10, the study will be 
declared to have met its primary objective. The study may continue till completion regardless 
of the results of the interim analyses to obtain mature OS data.
Of note, an assumption of 75% prevalence of PD-L1 CPS ≥1, and 38% prevalence of PD-L1 
CPS ≥10 in mTNBC subjects were made in above calculations. The above timing, estimated 
event count, and criteria for interim and final analyses are subject to modification in the 
sSAP as needed based on emerging data on PD-L1 prevalence in mTNBC.
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Table 16
Summary of Efficacy Decision Guidance After Alpha Re-Allocation (Part 2, 
Selected Scenarios)
Endpoint
Scenario
Total 
Alpha 
Allocated
Analysis
Efficacy Boundary (After Alpha 
Re-Allocation)
p-value (1-sided) 
at Boundary
Approx. HR at 
Boundary
H1: PFS in all subjects
(IA2)
H2 and H3 
supported
0.00111
IA2
0.00111
0.77
H2: PFS in subjects
with CPS ≥1 (IA2)
H3
supported
0.00111
IA2
0.00111
0.74
H4: OS in all subjects 
(IA2/IA3/FA)
H5 
supported
0.0075
IA2
0.0026
0.77
IA3
0.0038
0.79
FA
0.0060
0.81
Multiplicity
Part 1
Multiplicity adjustment is not applicable.
Part 2
The multiplicity strategy specified in this section will be applied to the 6 primary hypotheses
and the 2 secondary hypotheses of Part 2: 
primary hypotheses of superiority of 
pembrolizumab + chemotherapy compared to placebo + chemotherapy in PFS and OS in all 
subjects and in subjects with PD-L1 positive tumors (CPS ≥1 and CPS ≥10), and secondary 
hypotheses of superiority of pembrolizumab + chemotherapy compared to placebo +
chemotherapy in ORR in all subjects and in subjects with PD-L1 positive tumors (CPS ≥1).
Based on emerging biomarker data external to this study, the initial alpha allocation among 
the 6 primary hypotheses and 2 secondary hypotheses is revised in Amendment 05. The 
revision of the alpha allocation occurs after the conduct of efficacy IA1. The family-wise 
Type-I error rate for this study is strongly controlled at 2.5% (one-sided) across all 6 primary 
hypotheses on PFS and OS as well as 2 secondary hypotheses on ORR. 
Figure 4 displays the revised multiplicity strategy diagram of the study. The initial one-sided 
alpha allocation for each hypothesis is shown in the rectangle representing the hypothesis. 
The weights for re-allocation from each hypothesis to the others are represented in the 
numbers along the lines connecting hypotheses. Overall, a total of 0.5% alpha is allocated to 
PFS endpoints, a total of 1.8% alpha is allocated to OS endpoints, and a total of 0.2% alpha is 
allocated to ORR endpoints. 
Table 17 also summarizes the revised initial alpha allocation before any alpha re-allocation.
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Table 17
Initial Alpha Allocation
Hypothesis
Initial Alpha Allocation
H1: PFS in all subjects

0.043% allocated at IA1 (already spent at IA1).

0% allocated at IA2.
H2: PFS in subjects with CPS ≥1

0.046% allocated at IA1 (already spent at IA1).

0% allocated at IA2.
H3: PFS in subjects with CPS ≥10

0.411% allocated at IA2 only.
H4: OS in all subjects

0.039% allocated at IA1 (already spent at IA1).

0% allocated at IA2/IA3/FA (group sequential).
H5: OS in subjects with CPS ≥1

0.75% allocated to IA1/IA2/IA3/FA (group sequential), which 
includes 0.036% spent at IA1.
H6: OS in subjects with CPS ≥10

1.011% allocated to IA2/IA3/FA (group sequential).
H7: ORR in all subjects

0.1% allocated at IA1 only (already spent at IA1).
H8: ORR in subjects with CPS ≥1

0.1% allocated at IA1 only (already spent at IA1).
An extension [99] of the graphical approach of Maurer and Bretz [100] will be used with 
Figure 4 to allocate and re-allocate alpha between hypotheses. 
Testing will first be 
performed in subjects with CPS ≥1 for a treatment effect on ORR (H8). If H8 is supported 
(ie, the null hypothesis is rejected), then the corresponding alpha can be added to that 
allocated for evaluating the treatment effect on ORR in all subjects (H7). If H7 is supported,
then the corresponding alpha can be re-allocated to PFS in subjects with CPS ≥10 (H3). If H3
is supported, then the corresponding alpha can be re-allocated, 27% to PFS in subjects with 
CPS ≥1 (H2 at IA2 only), and 73% to OS in subjects with CPS ≥10 (H6). If H2 is supported, 
the alpha for that hypothesis can be re-allocated to PFS in all subjects (H1 at IA2 only). If 
H1 is supported, the alpha for that hypothesis can be re-allocated to OS in subjects with 
CPS ≥10 (H6). If H6 is supported, the alpha for that hypothesis can then be re-allocated to 
OS in subjects with CPS ≥1 (H5). If H5 is supported, the alpha for that hypothesis can then 
be re-allocated to OS in all subjects (H4 at IA2/IA3/FA). If H4 is supported, at IA2/IA3/FA, 
the alpha for that hypothesis can be re-allocated back to H7.
In the above multiplicity strategy, actual alpha spent at IA1 was calculated based on the 
original pre-specified alpha allocation strategy prior to Amendment 05 by the pre-specified 
alpha spending functions, using the actual spending time calculated from the planned and 
observed information fractions at IA1. Under the revised alpha allocation, actual alpha spent 
at IA1 for PFS in all subjects (H1), PFS in subjects with CPS ≥1 (H2), and OS in all subjects 
(H4) will be kept intact by a Bonferroni approach to strongly control the family-wise Type-I 
error rate at one-sided 2.5%. After IA1, these alphas will no longer be re-allocated to other 
hypotheses under the graphical approach, nor can they be used to account for correlation 
among group sequential tests within each endpoint across different time points. As such, the 
revised total alpha after IA1 is now 2.5% - 0.043% (alpha spent at IA1 for H1) - 0.046%
(alpha spent at IA1 for H2) - 0.039% (alpha spent at IA1 for H4) ~ = 2.37% for all 
hypotheses (all numbers rounded, the actual alpha for testing will be calculated based on the 
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actual alpha spent for H1, H2 and H4 at IA1 with high precision). The 0.036% alpha spent at 
IA1 for H5 will be part of the new initial alpha of 0.75% for H5. Of note, a 0% initial alpha is 
now assigned to PFS in all subjects at IA2, PFS in subjects with CPS ≥1 at IA2, and OS in all 
subjects at IA2/IA3/FA. These endpoints at these specific timepoints are now part of the 
graphical approach and can still be tested if a positive alpha can be re-allocated to them after 
the success of testing relevant hypothesis(es). For example, if PFS in CPS ≥10 is supported at 
IA2, a one-sided alpha of 0.111% (0.411% × 0.27) will be re-allocated to PFS in CPS ≥1 at 
IA2 for testing. In addition, if a positive alpha can be re-allocated to OS in all subjects (H4) 
at either IA2, IA3 or FA, then a Lan-DeMets O'Brien-Fleming alpha-spending function will 
be used to distribute the alpha among IA2, IA3, and FA for appropriate testing at each time 
point, respectively.
For OS endpoints, a Lan-DeMets O'Brien-Fleming approximation alpha-spending function is
constructed to implement group sequential boundaries that control the Type-I error. Spending 
time will be plugged into the pre-specified spending function to calculate alpha spending. At 
the time of IA1 (as applicable), IA2, and IA3 for OS, the spending time will be the minimum 
of the actual observed information fraction and the planned information fraction for each 
endpoint, respectively (with the exception of OS in subjects with CPS ≥1 at IA1, please see 
next paragraph). At the time of FA for OS endpoints, the spending time will be 1. Of note, 
while the spending time used for alpha-spending calculation will be the minimum of the 
actual observed information fraction and the planned information fraction, the correlations 
used for computing bounds for each endpoint will still be from that endpoint depending on 
the actual event counts. The rationale for the above strategy is to ensure that full Type-I error 
is spent at the final analysis without overspending at the interim. Justification for the 
spending time approach can be found in Anderson et.al. [99]. Of note, prior to Amendment
05, a Hwang-Shih-DeCani alpha-spending function with gamma parameter (-4) was 
constructed to implement group sequential boundaries that control the Type-I error for PFS 
endpoints, and it is no longer applicable under Amendment 05.
For OS in subjects with CPS ≥1 (H5), the revised initial alpha is 0.75% which includes 
0.036% already spent at IA1. In order to account for the 0.036% alpha already spent at IA1 
for H5 under initial alpha allocation, the spending time at IA1 will be fixed at 56.1% such 
that the corresponding alpha distributed at IA1 using the Lan-DeMets O'Brien-Fleming 
spending function with a total initial alpha of 0.75% remains 0.036%.
The Spiessens and Debois method [101] will be used to calculate the nominal alpha of ORR 
in subjects with CPS ≥1 after accounting for the correlation between ORR endpoints in these 
2 populations, while fixing the nominal alpha at 0.001 for ORR in all subjects. The actual 
observed correlation will be used for this adjustment in the analysis. Of note, if at IA2, IA3
or FA, additional alpha can be reallocated to H7 (e.g., H4 is not successful at IA1 but 
successful at IA2), the p-value of ORR in all subjects obtained from IA1 will be re-evaluated 
using the updated alpha threshold at that time. Similarly, if at IA3 or FA additional alpha can 
be re-allocated to PFS endpoint(s), the p-value of PFS endpoint(s) obtained from IA2 will be 
re-evaluated using the updated alpha threshold at that time.
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a Nominal alpha for testing will be calculated based on Spiessens and Debois method accounting for correlation 
between ORR in all subjects and ORR in subjects with CPS ≥1. Of note, while the nominal alpha will be 
calculated and used for testing, the allocated alpha (0.001) will be passed to H7 when applicable.
b H5 α=0.0075 which includes 0.00036 already spent at IA1.
Note: The shaded boxes in this figure represent alpha that has already been spent at IA1 and will be considered 
lost for future analyses. These alphas will no longer be re-allocated to other hypotheses under the graphical 
approach, nor can they be used to account for correlation among group sequential tests within each endpoint 
across different time points.
Figure 4
Multiplicity Strategy
Sample Size and Power Calculations
Part 1
Part 1 of the study will enroll approximately 30 subjects. For each treatment with 10 subjects
available for analysis, if the underlying incidence rate of a given type of AE is 5% or 10%, 
there is 40% or 65% chance of observing at least one AE among the 10 subjects, respectively. 
If no AE of a given type is observed among the 10 subjects, this study part will provide 80%
confidence that the underlying percentage of subjects with the AE is <14.9% (90% 
confidence that the underlying rate of the AE is <20.6%) in the study population treated with 
the study treatment.
Part 2
Part 2 of the study will randomize approximately 828 subjects in a 2:1 ratio between the 
pembrolizumab + chemotherapy and the placebo + chemotherapy arms. 
Randomization will be implemented centrally using IVRS and will be monitored on a regular 
basis. When IVRS alerts study is approaching the desired enrollment, screening should be 
stopped in time. However, subjects already in screening phase may be enrolled even after 
the maximum sample size has been reached.
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Power considerations for each endpoint are described below.
PFS
The PFS power calculation is based on the following assumptions: 1) PFS follows an 
exponential distribution with a median of 5.5 months in the placebo + chemotherapy arm in 
all populations (all subjects, subjects with CPS ≥1, and subjects with CPS ≥10); 2) An 
enrollment period of 17 months for Part 2; 3) A yearly drop-out rate of 30%; 4) the true HR 
is 0.70, 0.62, and 0.60 for PFS in all subjects, subjects with CPS ≥1, and subjects with 
CPS ≥10, respectively. In addition, prior to Amendment 05, a Hwang-Shih-DeCani 
alpha-spending function with gamma parameter (-4) was constructed to implement group 
sequential boundaries that control the Type-I error for PFS endpoints.
Any change to the timing of the PFS analyses, along with its rationale, will be documented in 
the sSAP or a memo to the study file before the database lock.
PFS in all subjects
At IA1 it was expected that approximately 500 PFS events would have been accumulated 
among all subjects. An alpha of ~ 0.05% was to be allocated to PFS in all subjects at this 
analysis (subject to change according to the actual number of PFS events at IA1, based on the 
alpha-spending function with a total of 0.1% alpha originally allocated to PFS in all 
subjects). If the planned number of events of 500 was analyzed, this analysis had ~ 67%
power to demonstrate that pembrolizumab + chemotherapy is superior to placebo +
chemotherapy, if the underlying HR is 0.70.
At IA2 of the study, PFS in all subjects will only be tested if both hypotheses of PFS in 
subjects with CPS ≥1 and PFS in subjects with CPS ≥10 are supported. It is expected that 
approximately 634 PFS events will be observed among all subjects at IA2. A final PFS
analysis will be performed at IA2. This analysis has ~ 89% power to demonstrate that 
pembrolizumab + chemotherapy is superior to placebo + chemotherapy for PFS in all 
subjects at a one-sided 0.111% alpha level, if the underlying HR is 0.70.
PFS in subjects with CPS ≥1
At IA1 it was expected that approximately 360 PFS events would have been observed among
subjects with CPS ≥1. An alpha of ~ 0.05% was to be allocated to PFS in subjects with 
CPS ≥1 at this analysis (subject to change according to the actual number of PFS events at 
IA1, based on the alpha-spending function with a total of 0.1% alpha originally allocated to 
PFS in subjects with CPS ≥1). If the planned number of events of 360 was analyzed, this 
analysis had ~ 83% power to demonstrate that pembrolizumab + chemotherapy is superior to 
placebo + chemotherapy, if the underlying HR is 0.62.
At IA2 of the study, PFS in subjects with CPS ≥1 will only be tested if the hypothesis of PFS 
in subjects with CPS ≥10 is supported. It is expected that approximately 463 PFS events will 
be observed among subjects with CPS ≥1 at IA2. A final PFS analysis will be performed at 
IA2. This analysis has ~ 97% power to demonstrate that pembrolizumab + chemotherapy is 
superior to placebo + chemotherapy for PFS in subjects with CPS ≥1 at a one-sided 0.111% 
alpha level, if the underlying HR is 0.62.
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PFS in subjects with CPS ≥10
At IA2 of the study, it is expected that approximately 235 PFS events would have been 
observed among subjects with CPS ≥10.  The only PFS analysis in subjects with CPS ≥10 
will be performed at IA2.  The analysis has ~ 86% power to demonstrate that pembrolizumab 
+ chemotherapy is superior to placebo + chemotherapy for PFS in subjects with CPS ≥10 at a 
one-sided 0.411% alpha level, if the underlying HR is 0.60.
OS
The sample size and OS power calculation is based on the following assumptions: 1) OS 
follows an exponential distribution with a median of 17.5 months in the placebo +
chemotherapy arm in all populations (all subjects, subjects with CPS ≥1 and subjects with 
CPS ≥10); 2) An enrollment period of 17 months for Part 2 and a minimum of 43 months 
follow-up after enrollment completion; 3) A yearly dropout rate of 3%; 4) the true HR is 0.80, 
0.71, and 0.65 for OS in all subjects, subjects with CPS ≥1, and subjects with CPS ≥10, 
respectively.
In addition, a Lan-DeMets O'Brien-Fleming approximation alpha-spending 
function was constructed to implement group sequential boundaries that control the Type-I 
error for OS endpoints.
Any change to the timing of the OS analyses, along with its rationale, will be documented in 
the sSAP or a memo to the study file before the database lock.
OS in all subjects
After IA1, OS in all subjects can be tested if hypothesis of OS in subjects with CPS ≥1 is
supported. With ~ 664 OS events among all subjects at the final OS analysis, the trial has 
~ 60% power to demonstrate that pembrolizumab + chemotherapy is superior to placebo +
chemotherapy at a one-sided 0.75% alpha level, if the underlying HR is 0.80. If the planned 
numbers of events are analyzed, success boundary for OS in all subjects at FA approximately 
corresponds to an observed HR of ~ 0.81 (~ 4.0 months improvement over a control median 
OS of 17.5 months).
OS in subjects with CPS ≥1
It is expected that ~ 482 OS events will have occurred among subjects with CPS ≥1 at the 
final OS analysis. For OS in subjects with CPS ≥1, the trial has ~ 87% power to demonstrate 
that pembrolizumab + chemotherapy is superior to placebo + chemotherapy at a one-sided 
0.75% alpha-level, if the underlying HR is 0.71.
If the planned numbers of events are 
analyzed at IA2/IA3/FA, success boundary for OS in subjects with CPS ≥1 at FA
approximately corresponds to an observed HR of ~ 0.78 (~ 4.8 months improvement over a 
control median OS of 17.5 months).
OS in subjects with CPS ≥10
It is expected that ~ 240 OS events will have occurred among subjects with CPS ≥10 at the 
final OS analysis.  For OS in subjects with CPS ≥10, the trial has ~ 79% power to 
demonstrate that pembrolizumab + chemotherapy is superior to placebo + chemotherapy at a
one-sided 1.011% alpha-level, if the underlying HR is 0.65.  If the planned numbers of 
events are analyzed, success boundary for OS in subjects with CPS ≥10 at FA approximately 
corresponds to an observed HR of ~ 0.72 (~ 6.8 months improvement over a control median 
OS of 17.5 months).
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ORR
The ORR power calculation is based on the following assumptions: 1) under initial alpha 
allocated to ORR hypotheses; 2) the underlying ORR is 29% in the placebo + chemotherapy 
arm, and there is 15 or 18 percentage points increase in ORR in the pembrolizumab +
chemotherapy arm (ORR of 44% or 47%), in both all subjects and in subjects with CPS ≥1, 
respectively. The power for ORR endpoints is summarized in Table 18.
Table 18
Power for ORR
Population
N
Nominal 
Alpha
~ ORR Difference at 
Success Boundary
True ORR 
Difference
Power
All Subjects
640
0.001
12.6 percentage points
15 percentage points
72%
18 percentage points
91%
Subjects with CPS ≥1
480
0.00145a
14.1 percentage points
15 percentage points
58%
18 percentage points
80%
a Approximate nominal alpha based on the Spiessens and Debois method accounting for correlation between 
ORR in all subjects and ORR in subjects with CPS ≥1. The actual nominal alpha will be calculated based on 
the actual correlation between these two populations.
Assume 29% ORR in the placebo + chemotherapy arm
Assume 75% PD-L1 CPS ≥1 prevalence.
The assumptions for a median PFS of 5.5 months, median OS of 17.5 months, and 
an ORR of 29% in the placebo + chemotherapy arm are based on the estimates from 
Miles et al., 2013 [78], and the Phase III trial reported in O’Shaughnessy et al., 2014 [71].
The sample size and power calculations were performed in the software R (package 
“gsDesign”).
Of note, the assumptions of 75% prevalence of PD-L1 CPS ≥1, 38% prevalence of PD-L1 
CPS ≥10 in mTNBC subjects, and low discrepancy rate (e.g., <10%) between central and 
local determinations of baseline measurable disease were made in above calculations. The 
above assumptions and sample size calculations are subject to modification in the sSAP as 
needed based on emerging data on PD-L1 prevalence in mTNBC as well as correlation 
between PD-L1 expression and treatment effect, and/or emerging data on the discrepancy 
rate between central and local determinations of baseline measurable disease in mTNBC 
subjects.
Although safety issues are not expected for any of the pembrolizumab and chemotherapy 
combinations in this study, if one or more of the chemotherapy options (i.e., nab-paclitaxel, 
paclitaxel, or gemcitabine/carboplatin) is stopped because of a safety issue, then the Part 2 
primary analyses will be restricted to the remaining chemotherapy option(s) and the Part 2 
sample size will be based on only those remaining option(s).
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Subgroup Analyses and Effect of Baseline Factors
Part 1
There is no planned subgroup analysis for Part 1.
Part 2
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoints will be estimated and plotted within each category of the following classification 
variables: 

Chemotherapy on study (nab-paclitaxel vs paclitaxel vs gemcitabine/carboplatin; 
taxane vs gemcitabine/carboplatin).

Tumor PD-L1 status (CPS ≥1 vs CPS <1; CPS ≥5 vs CPS <5; CPS ≥10 vs CPS <10; 
CPS ≥15 vs CPS <15; CPS ≥20 vs CPS <20). Note: these subgroup analyses will 
only be conducted in the all subjects population.

Prior treatment with same class of chemotherapy in the (neo)adjuvant setting (yes vs 
no).

Prior (neo)adjuvant chemotherapy (yes vs no)

Prior (neo)adjuvant taxane treatment (yes vs no)

Prior (neo)adjuvant platinum treatment (yes vs no)

Menopausal status (for females only; pre- vs post-menopausal)

Age (<65 years vs ≥65 years)

Geographic region (Europe/Israel/North America/Australia vs Asia vs Rest of World) 

Ethnic origin (Hispanic vs Non-Hispanic)

ECOG status (0 vs 1)

HER2 status (2+ by IHC vs 0-1+ by IHC)

Disease-free interval (de novo metastasis vs <12 months vs ≥12 months)

Number of metastatic sites (<3 vs ≥3)

Visceral disease (yes vs no)

LDH (≥2.0 x Upper Limit of Normal [ULN] vs <2.0 x ULN)
Compliance (Medication Adherence)
Part 1 and Part 2
Drug accountability data for study treatment will be collected during the study. 
Any 
deviation from protocol-directed administration will be reported. 
Extent of Exposure
Part 1 and Part 2
The extent of exposure will be summarized as duration of treatment in number of cycles or 
administrations as appropriate.
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9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
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 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 19.
Table 19
Product Descriptions
Product Name & 
Potency
Dosage Form
Source/Additional Information
Pembrolizumab 
(MK-3475) 100 mg/4 mL
Solution for Infusion
Provided centrally by the Sponsor
Nab-paclitaxel 5 mg/mL
Powder for Infusion
Provided centrally by the Sponsor 
or locally by the trial site, 
subsidiary, or designee
Paclitaxel 6 mg/mL 
(potency may vary by 
country/source)
Solution for Infusion 
(dosage form may vary 
by country/source)
Provided centrally by the Sponsor 
or locally by the trial site, 
subsidiary, or designee
Gemcitabine (potency 
may vary by 
country/source)
Lyophilized powder for 
IV infusion (dosage form 
may vary by 
country/source)
Provided centrally by the Sponsor
or locally by the trial site, 
subsidiary, or designee
Carboplatin  10 mg/mL 
(potency may vary by 
country/source)
Solution for infusion
(dosage form may vary 
by country/source)
Provided centrally by the Sponsor
or locally by the trial site, 
subsidiary, or designee
All supplies indicated in Table 19 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 19 will be provided by the trial 
site, subsidiary or designee. Every attempt should be made to source these supplies from a 
single lot/batch number. The trial 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.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
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Clinical Supplies Disclosure
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind subjects and to unmask treatment for Part 2 of this trial.
The emergency 
unblinding call center should only be used in cases of emergency (see Section 7.1.4.2). In 
the event that the emergency unblinding call center is not available for a given site in this 
trial, the central electronic treatment allocation/randomization system (IVRS/IWRS) should 
be used in order to unblind subjects and to unmask treatment/vaccine identity. The Sponsor 
will not provide random code/disclosure envelopes or lists with the clinical supplies.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.  Once an emergency unblinding or a 
non-emergency unblinding has taken place, the principal investigator, site personnel, and 
Sponsor personnel may be unblinded so that the appropriate follow-up medical care can be 
provided to the subject.
Section 5.8 outlines the criteria for allowing subjects who are discontinued from treatment to 
continue to be monitored in the trial.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.  Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
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If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
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, commonly 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.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in Section 12.1 -
Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
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The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
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Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, MSD, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the Protocol/CSR 
CI during the anticipated review process, thorough understanding of clinical trial methods, 
appropriate enrollment of subject cohort, timely achievement of trial milestones).  The 
Protocol CI must be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  MSD, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  MSD entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
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Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. MSD will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
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Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
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Uno H, Claggett B, Tian L, Inoue E, Gallo P, Miyata T, et al. Moving beyond the 
hazard ratio in quantifying the between-group difference in survival analysis. J 
Clin Oncol. 2014 Aug 1;32(22):2380-5.
[103]
Odell PM, Anderson KM, Kannel WB. New models for predicting cardiovascular 
events. J Clin Epidemiol. 1994 Jun;47(6):583-92.
[104]
Mehrotra DV, Su SC, Li X. An efficient alternative to the stratified Cox model 
analysis. Stat Med. 2012 Jul 30;31(17):1849-56.
[105]
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using 
rank preserving structural failure time models. Commun Stat-Theor M 
1991;20(8):2609-31.
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12.0 APPENDICES
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I.
Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted in 
compliance with local and/or national regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or which 
are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the full control 
of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities and 
staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, sites are 
evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts to 
raise awareness of clinical trial opportunities in various communities. MSD will seek to engage underrepresented 
groups and those disproportionately impacted by the disease under study. MSD will support clinical trial 
investigators to enroll underrepresented groups and expand access to those who will ultimately use the products 
under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus source 
documentation according to standard operating procedures. Per MSD policies and procedures, if potential fraud, 
scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related Significant Quality Issues are 
reported, such matters are investigated. When necessary, appropriate corrective and/or preventative actions are 
defined and regulatory authorities and/or ethics review committees are notified.
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B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the extent 
scientifically appropriate, MSD seeks to publish the results of other analyses it conducts 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. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority acceptance/authorization 
prior to implementation of the trial or amendment, in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance with 
local and/or national regulations. Changes to the protocol that are required urgently to eliminate an immediate hazard 
and to protect participant safety may be enacted in anticipation of ethics committee approval. MSD will inform 
regulatory authorities of such new measures to protect participant safety, in compliance with local and/or national 
regulations.
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.
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, as well as all applicable 
data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on behalf of 
MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records that might 
identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an ethics 
committee.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to enroll 
participants in its trials. However, when enrollment is particularly challenging, additional payments may be made to 
compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent on 
chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may wish 
to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As noted
above, all publications resulting from MSD trials will indicate MSD as a source of funding.
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C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
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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 Research
The specimens collected in this trial as outlined in Section 7.1.3.6 – Future Biomedical 
Research Sample Collection7.1.3.6 – Future Biomedical Research Sample Collection will 
be used to study various causes for how subjects may respond to a drug/vaccine.  Future 
biomedical research specimen(s) will be stored to provide a resource for future trials 
conducted by the Sponsor focused on the study of biomarkers responsible for how a 
drug/vaccine enters and is removed by the body, how a drug/vaccine works, other 
pathways a drug/vaccine may interact with, or other aspects 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 Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are 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 trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the MSD Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., 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 this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed. Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated 
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mailbox (clinical.specimen.management@MSD.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main 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 trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial 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 Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial 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 (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
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through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects 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 Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address subject 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 e-mailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
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Abbreviations
Abbreviation/Term
Definition
1L
First Line
2L
Second Line
AE
Adverse Event
ADA
Anti-Drug Antibodies
AJCC
American Joint Committee on Cancer
ALK
Anaplastic Lymphoma Kinase
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
AR
Androgen Receptor
ASCO
American Society of Clinical Oncology
ASaT
All Subjects as Treated
AST
Aspartate Aminotransferase
AUC
Area Under the Concentration-Time Curve
ß-hCG
Beta Human Chorionic Gonadotropin
BCG
Bacillus Calmette–Guérin
BRAF
B-Raf proto-oncogene, serine-threonine kinase
BRCA1
Breast Cancer 1
BRCA2
Breast Cancer 2
CAP
College of American Pathologists
CBC
Complete Blood Count
CD
Cluster of Differentiation
CD8+
Cluster of Differentiation 8–positive
CEP17
centromeric probe for chromosome 17
CI
Confidence Interval
CIV
Central Imaging Vendor
CNS
Central Nervous System
CPS
Combined Positive Score
CR
Complete Response
CrEL
Cremofor EL
CSR
Clinical Study Report
CSR CI
Clinical Study Report Coordinating Investigator
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte–Associated Antigen-4
DCR
Disease control rate
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Abbreviation/Term
Definition
DIC
Disseminated Intravascular Coagulate
DKA
Diabetic Ketoacidosis
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DOR
Duration of Response
DRFS
Distant Recurrence-Free Survival
ECI
Events of Clinical Interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EGFR
Epidermal Growth Factor Receptor
EOC
Executive Oversight Committee
EORTC
European Organisation for Research and Treatment of Cancer
EORTC QLQ-BR23
European Organisation for Research and Treatment of Cancer
Breast Cancer–Specific Quality of Life Questionnaire
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer
Quality of Life Questionnaire Core 30
ePRO
Electronic Patient Reported Outcomes
EQ-5D™
EuroQol-5 Dimension Questionnaire
ER
Estrogen Receptor
ERC
Ethics Review Committee
EU
European Union
FA
Final Analysis
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FFPE
Formalin-Fixed Paraffin Embedded
FGFR
Fibroblast Growth Factor Receptor
FISH
Fluorescence In Situ Hybridization
FNA
Fine Needle Aspiration
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
HBsAg
Hepatitis B surface Antigen
HER2
Human Epidermal Growth Factor Receptor-2
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HLA
Human Leukocyte Antigen
HNSCC
Head and Neck Squamous Cell Carcinoma
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Abbreviation/Term
Definition
HPV
Human Papillomavirus
HR
Hazard Ratio
HRD
Homologous Recombination Defect
IA(1, 2, 3)
Interim Analysis (Interim Analysis 1, Interim Analysis 2, Interim 
Analysis 3)
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IDO1
indoleamine 2.3-dioxygenase 1
IEC
Independent Ethics Committee
IFN-γ
Interferon Gamma
Ig
Immunoglobulin
IHC
Immunohistochemistry
IL-10
Interleukin 10
INR
International Normalized Ratio
IRB
Institutional Review Board
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
ITIM
Immunoreceptor Tyrosine-based Inhibition Motif
ITSM
Immunoreceptor Tyrosine-based Switch Motif
ITT
Intention-To-Treat
IUD
Intrauterine Device
IV
Intravenous(ly)
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
LDH
Lactate Dehydrogenase
LMP
Last Menstrual Period
mAb
Monoclonal Antibody
mBC
Metastatic Breast Cancer
MHC
Major Histocompatibility Complex
mRNA
Messenger Ribonucleic Acid
MRI
Magnetic Resonance Imaging
MSI
Microsatellite Instability
MTD
Maximum Tolerated Dose
mTNBC
Metastatic Triple Negative Breast Cancer
NA or N/A
Not Applicable
NCI
National Cancer Institute
NKC
Natural Killer Cell
NMR
Nuclear Magnetic Resonance
NSAID
Nonsteroidal Anti-inflammatory Drug
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Abbreviation/Term
Definition
NSCLC
Non-Small Cell Lung Cancer
ORR
Objective Response Rate
OS
Overall Survival
OTC
Over-the-counter
Protocol CI
Protocol Coordinating Investigator
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
PGR
Progesterone Receptor
PIN
Personal Identification Number
PK
Pharmacokinetic
PKCθ
Protein kinase C-theta
PR
Partial Response
PT
Prothrombin Time
PTEN
Phosphatase and Tensin Homolog
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
QoL
Quality of Life
R/M
Recurrent or Metastatic
RECIST/RECIST 1.1
Response Evaluation Criteria in Solid Tumors/version 1.1
RMST
Restricted Mean Survival Time
RNA
Ribonucleic Acid
RPSFT
Rank Preserving Structural Failure Time
SABCS
San Antonio Breast Cancer Symposium
SAC
Scientific Advisory Committee
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SD
Stable Disease
SFU
Survival Follow-Up
SHP-1
Src Homology Phosphatase 1
SHP-2
Src Homology Phosphatase 2
SIM
Site Imaging Manual
SNP
Single Nucleotide Polymorphism
SOC
Standard of Care
SOP
Standard Operating Procedures
sSAP
Supplemental Statistical Analysis Plan
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Abbreviation/Term
Definition
T3
Triiodothyronine
T4
Thyroxine
TB
Bacillus Tuberculosis
TCGA
The Cancer Genome Atlas
TIL
Tumor Infiltrating Lymphocytes
TNBC
Triple Negative Breast Cancer
TSH
Thyroid Stimulating Hormone
TTP
Time to Disease Progression
ULN
Upper Limit of Normal
US
United States
UV
Ultraviolet
V-type
Variable Type
WBC
White Blood Cell
ZAP70
Zeta-Chain-Associated Protein Kinase 70kDa
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ECOG Performance Status
GRADE
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair
5
Dead
Source: Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5:649-655.
http://ecog-acrin.org/resources/ecog-performance-status
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Contraceptive Guidance
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 FSH level in the postmenopausal range may be used to confirm a postmenopausal 
state in women not using hormonal contraception or HRT. However, in the absence of 12 
months of amenorrhea, confirmation with two 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 non-hormonal 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.
08LQ5C


Product:  MK-3475 
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MK-3475-355-07 Final Protocol
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Confidential
Contraception Requirements
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,c
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).
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Confidential
13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
08LQ5C

SAP_001.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Randomized, Double-Blind, Phase III Study of Pembrolizumab 
(MK-3475) plus Chemotherapy vs Placebo plus Chemotherapy for 
Previously Untreated Locally Recurrent Inoperable or Metastatic 
Triple Negative Breast Cancer – (KEYNOTE-355)
14 Jan 2020
NCT02819518


MK-3475                                                                               PAGE 1
PROTOCOL NO. 355-05
Supplemental SAP
     14 Jan 2020 – sSAP Amendment 03
Supplemental Statistical Analysis Plan (sSAP)
 
 
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MK-3475                                                                               PAGE 2
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Supplemental SAP
     14 Jan 2020 – sSAP Amendment 03
TABLE OF CONTENTS
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES................................................................................................4
LIST OF FIGURES ..............................................................................................5
1. INTRODUCTION ..........................................................................................6
2. SUMMARY OF CHANGES..........................................................................6
3. ANALYTICAL AND METHODOLOGICAL DETAILS.............................6
3.1 Statistical Analysis Plan Summary...........................................................6
3.2 Responsibility for Analyses/In-House Blinding.......................................8
3.3 Hypotheses/Estimation .............................................................................9
3.3.1
Primary Objective(s) & Hypothesis(es)......................................10
3.3.2
Secondary Objective(s) & Hypothesis(es)..................................11
3.3.3
Exploratory Objectives ...............................................................11
3.4 Analysis Endpoints .................................................................................12
3.4.1
Efficacy Endpoints......................................................................12
3.4.2
Safety Endpoints.........................................................................13
3.5 Analysis Populations...............................................................................13
3.5.1
Efficacy Analysis Populations....................................................13
3.5.2
Safety Analysis Populations .......................................................13
3.6 Statistical Methods..................................................................................14
3.6.1
Statistical Methods for Efficacy Analyses..................................14
3.6.1.1
Progression-Free Survival (PFS) ....................................14
3.6.1.2
Overall Survival (OS).....................................................17
3.6.1.3
Objective Response Rate (ORR) ....................................19
3.6.1.4
Disease Control Rate (DCR)...........................................19
3.6.1.5
Duration of Response (DOR) .........................................19
3.6.1.6
Summary of Statistical Methods for Efficacy.................20
3.6.2
Statistical Considerations for Patient-Reported Outcomes 
(PRO)................................................................................................22
3.6.2.1
Patient Reported Outcome (PRO) Endpoints .................22
3.6.2.2
Patient Reported Outcome (PRO) Analysis 
Population...................................................................................23
3.6.2.3
Analysis Approaches ......................................................23
3.6.2.3.1
Scoring Algorithm ....................................................24
3.6.2.3.2
Patient Reported Outcome (PRO) Score 
Analysis ................................................................................25
3.6.2.3.3
Analysis of the Time to Deterioration (TTD)...........26
3.6.2.3.4
Summary of Completion and Compliance................26
3.6.3
Statistical Methods for Safety Analyses .....................................26
3.6.4
Summaries of Demographic and Baseline Characteristics.........29
3.6.5
Statistical Methods for Exploratory Analyses ............................29
3.7 Interim Analyses.....................................................................................29
3.7.1
Part 1: Safety Interim Analysis...................................................29
3.7.2
Part 2: Efficacy Interim Analyses...............................................29
3.8 Multiplicity .............................................................................................33
3.9 Sample Size and Power Calculations......................................................37
 
 
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MK-3475                                                                               PAGE 3
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Supplemental SAP
     14 Jan 2020 – sSAP Amendment 03
3.10
Subgroup Analyses and Effect of Baseline Factors..........................41
3.11
Compliance (Medication Adherence)...............................................41
3.12
Extent of Exposure............................................................................41
4. REFERENCES .............................................................................................42
 
 
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MK-3475                                                                               PAGE 4
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Supplemental SAP
     14 Jan 2020 – sSAP Amendment 03
LIST OF TABLES
Table 1
Censoring Rules for Primary and Sensitivity Analyses of PFS............................... 16
Table 2
Censoring Rules for DOR........................................................................................ 20
Table 3
Analysis Strategy for Key Efficacy Endpoints (Part 2)........................................... 20
Table 4
PRO Assessment Schedule...................................................................................... 22
Table 5
Analysis Strategy for Safety Parameters ................................................................. 28
Table 6
Summary of Timing, Sample Size and Decision Guidance of Efficacy Interim 
Analyses and Final Analysis (Part 2, at Initial Alpha).......................................................... 31
Table 7
Summary of Efficacy Decision Guidance after Alpha Re-Allocation (Part 2, Selected 
Scenarios).............................................................................................................................. 33
Table 8
Initial Alpha Allocation ........................................................................................... 34
Table 9
Power for ORR ........................................................................................................ 40
 
 
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MK-3475                                                                               PAGE 5
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Supplemental SAP
     14 Jan 2020 – sSAP Amendment 03
LIST OF FIGURES
Figure 1
Multiplicity Strategy................................................................................................ 36
 
 
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MK-3475                                                                               PAGE 6
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Supplemental SAP
     14 Jan 2020 – sSAP Amendment 03
1.
INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of confirmatory 
analyses for this trial, this supplemental SAP provides additional statistical analysis details/data 
derivations and documents modifications or additions to the analysis plan that are not “principal” 
in nature and result from information that was not available at the time of protocol finalization.     
2.
SUMMARY OF CHANGES
This sSAP aligns with the protocol amendment 05 (MK-3475-355-05) for the global study with 
regard to the statistical analysis plan.   In addition, the following changes were made to the sSAP 
which were not directly related to changes required due to this protocol amendment:
• Added max-combo test as a sensitivity analysis for overall survival (OS) (Section 3.6.1.2).
• Added sensitivity analysis to evaluate efficacy endpoints by PD-L1 cutoffs (Section 3.6.1).
3.
ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan is 
provided in Section 3.2– Responsibility for Analyses/In-House Blinding through Section 3.12–
Extent of Exposure.
Study Design 
Overview
A Randomized, Double-Blind, Phase III Study of Pembrolizumab (MK-3475) plus 
Chemotherapy vs Placebo plus Chemotherapy for Previously Untreated Locally 
Recurrent Inoperable or Metastatic Triple Negative Breast Cancer
Treatment 
Assignment
Part 1: 
Approximately 30 subjects will be partially-randomized (unblinded open-label) 
among 3 treatment arms: (1) pembrolizumab + nab-paclitaxel, (2) pembrolizumab + 
paclitaxel and (3) pembrolizumab + gemcitabine/carboplatin.
Part 2:
Approximately 828 subjects will be randomized (double-blind) in a 2:1 ratio between 
2 treatment arms: (1) pembrolizumab + chemotherapy and (2) placebo + 
chemotherapy.  Stratification factors are as follows:
1.
Chemotherapy on study (taxane [i.e., paclitaxel or nab-paclitaxel] vs 
gemcitabine/carboplatin).
2.
Tumor PD-L1 status (CPS ≥1 vs CPS <1).
3.
Prior treatment with same class of chemotherapy in the (neo)adjuvant setting 
(yes vs no).
Analysis 
Populations
Part 1 and Part 2 subjects will be analyzed separately.
Part 1 Efficacy: All Subjects as Treated (ASaT)
Part 2 Efficacy: Intention-to-Treat Population (ITT); ORR ITT Population for ORR 
endpoints.
Safety: All Subjects as Treated (ASaT) 
Primary 
Endpoint(s)
Part 1:  Safety and tolerability.
Part 2:
1.
Progression-free survival (PFS) based on Response Evaluation Criteria in Solid 
Tumors Version 1.1 (RECIST 1.1) as assessed by a blinded central imaging 
vendor (CIV) in all subjects.
2.
PFS based on RECIST 1.1 as assessed by a blinded CIV in subjects with PD-L1 
positive tumors. (CPS ≥1).
 
 
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3.
PFS based on RECIST 1.1 as assessed by a blinded CIV in subjects with PD-L1 
positive tumors (CPS ≥10).
4. Overall survival (OS) in all subjects.
5. OS in subjects with PD-L1 positive tumors (CPS ≥1).
6. OS in subjects with PD-L1 positive tumors (CPS ≥10).
Key Secondary 
Endpoint(s)
Part 2:  Objective response rate (ORR) based on RECIST 1.1 as assessed by a blinded 
CIV in all subjects and in subjects with PD-L1 positive tumors (CPS ≥1).
Statistical 
Methods for 
Key Efficacy 
Analyses
Part 2:  The primary hypotheses will be evaluated by comparing pembrolizumab + 
chemotherapy vs placebo + chemotherapy in PFS and OS using a stratified log-rank 
test. The hazard ratio (HR) will be estimated using a stratified Cox model.
The key secondary hypotheses of ORR will be evaluated by comparing 
pembrolizumab + chemotherapy vs placebo + chemotherapy in ORR using a 
stratified Miettinen and Nurminen method.
Statistical 
Methods for 
Key Safety 
Analyses
Part 1:  Descriptive summary statistics will be provided for safety endpoints by 
treatment as appropriate.
Part 2:  The analysis of safety will follow a tiered approach.  There is no Tier 1 safety 
endpoint for this trial. Point estimates and 95% confidence intervals (CIs) for 
between-treatment comparisons via the Miettinen and Nurminen method will be 
provided for Tier 2 safety endpoints; only point estimates by treatment group will be 
provided for Tier 3 safety endpoints. 
Interim 
Analyses
One safety interim analysis for Part 1 and 3 efficacy interim analyses for Part 2 will 
be performed.  Results will be reviewed by an external DMC.  Details are provided in 
Section 3.7– Interim Analyses. 
Part 1 – Safety Interim Analysis: ~ 3 months after first subject randomized.
o
Timing: after all Part 1 subjects have completed the first 21 or 28 days 
(depending on chemotherapy treatment) of study treatment. 
o
Primary purpose: interim safety evaluation.
Part 2 – Efficacy Interim and Final Analyses

Interim analysis 1 (IA1): ~ 9 months after first 640 Part 2 subjects are randomized.
o Primary purpose: final ORR analysis, interim PFS and interim OS analysis.

Interim analysis 2 (IA2): after ~ 185 OS events among subjects with CPS ≥10 have 
been observed.
o Primary purpose: interim OS analysis and final PFS analysis.

Interim analysis 3 (IA3): after ~ 210 OS events among subjects with CPS ≥10 have 
been observed.
o Primary purpose: interim OS analysis.

Final analysis (FA): after ~ 664 OS events among all subjects, ~ 482 OS events 
among subjects with CPS ≥1, and ~ 240 OS events among subjects with CPS ≥10 
have been observed.
o
Primary purpose: final OS analysis.
Multiplicity
Part 1: Multiplicity adjustment not applicable.
Part 2: The family-wise type-I error rate over the 6 primary hypotheses and the 2 
secondary hypotheses will be strongly controlled at 2.5% (one-sided) with 0.5% 
allocated to PFS, 1.8% allocated to OS, and 0.2% allocated to ORR hypotheses.  An 
extension [1] of the graphical approach of Maurer and Bretz [2] will be applied to re-
allocate alpha between PFS, OS and ORR hypotheses. The Spiessens and Debois 
method [3] will be used to adjust the nominal alphas in ORR between all subjects and 
subjects with CPS ≥1. Group sequential methods will be used to allocate alpha 
between the interim and final analyses for OS endpoints.
 
 
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Supplemental SAP
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Sample Size and 
Power 
Part 1:  Approximately 30 subjects will be enrolled.
Part 2: It is expected that ~ 664 OS events among all subjects, ~ 482 OS events among 
subjects with CPS ≥1, and ~ 240 OS events among subjects with CPS ≥10 have been 
observed at the FA. The planned sample size is approximately 828 subjects. 
(1) PFS in all subjects: at IA2 the analysis has ~ 89% power at a one-sided 0.111% 
alpha level, if the true HR is 0.70. At IA2, with ~ 634 events the HR at boundary 
for success is ~ 0.77 (~ 1.6 months improvement over control median PFS of 
5.5 months). At IA2, PFS in all subjects can only be tested if both hypotheses of 
PFS in subjects with CPS ≥10 and PFS in subjects with CPS ≥1 are supported.
(2) PFS in subjects with CPS ≥1: at IA2 the analysis has ~ 97% power at a one-sided 
0.111% alpha level, if the true HR is 0.62. At IA2, with ~ 463 events the HR at 
boundary for success is ~ 0.74 (~ 1.9 months improvement over control median 
PFS of 5.5 months). At IA2, PFS in all subjects with CPS ≥1 can only be tested if 
the hypothesis of PFS in subjects with CPS ≥10 is supported.
(3) PFS in subjects with CPS ≥10: at IA2 the analysis has ~ 86% power at a one-sided 
0.411% alpha level, if the true HR is 0.60. At IA2, with ~ 235 events the HR at 
boundary for success is ~ 0.69 (~ 2.4 months improvement over control median 
PFS of 5.5 months).
(4) OS in all subjects: the trial has ~ 60% power at a one-sided 0.75% alpha level, if 
the true HR is 0.80. With ~ 664 events, the HR at boundary for success at FA is
~ 0.81 (~ 4.0 months improvement over control median OS of 17.5 months).  After 
IA1, OS in all subjects can be tested if hypothesis of OS in subjects with CPS ≥1 
is supported.
(5) OS in subjects with CPS ≥1: the trial has ~ 87% power at a one-sided 0.75% alpha
level, if the true HR is 0.71. With ~ 482 events, the HR at boundary for success at 
FA is ~ 0.78 (~ 4.8 months improvement over control median OS of 17.5 months).
(6) OS in subjects with CPS ≥10: the trial has ~ 79% power at a one-sided 1.011% 
alpha level, if the true HR is 0.65. With ~ 240 events, the HR at boundary for 
success at FA is ~ 0.72 (~ 6.8 months improvement over control median OS of 
17.5 months).
3.2
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.
The Sponsor will generate the randomized allocation schedule(s) for study treatment assignment 
for this protocol, and the randomization will be implemented in IVRS.
The Investigators, other study site staff, and subjects will be blinded to subject-level PD-L1 
biomarker results.  Analysis or summaries generated by PD-L1 status will be limited and 
documented. 
Part 1:
Part 1 of this study is being conducted as a partially randomized, open-label study, i.e., subjects, 
investigators, and Sponsor personnel will be aware of subject treatment assignments after each 
subject is enrolled and treatment is assigned. 


'1*
=1<)


MK-3475                                                                               PAGE 9
PROTOCOL NO. 355-05
Supplemental SAP
     14 Jan 2020 – sSAP Amendment 03
Planned safety interim analysis is described in Section 3.7 – Interim Analyses.  Study enrollment 
is likely to be ongoing at the time of the safety interim analysis (i.e., no planned enrollment pause 
between Part 1 and Part 2).  
The external DMC will serve as the primary reviewer of the results of the safety interim analysis 
and will make recommendations for discontinuation of the study or modification to an EOC of the 
Sponsor.  Additional logistical details, revisions to the above plan and data monitoring guidance 
will be provided in the DMC Charter.  Key aspects of the interim analysis are described in 
Section 3.7– Interim Analyses.
Part 2:
Part 2 of this study will be conducted as a double-blind, Phase III study part under in-house 
blinding procedures. The official, final database of Part 2 will not be unblinded until 
medical/scientific review has been performed, protocol deviations have been identified, and data 
have been declared final and complete.  In addition, the independent radiologist(s) will perform 
the central imaging review without knowledge of treatment group assignment. Additional details 
regarding trial blinding/unblinding including unblinding required for operational purposes (e.g., 
unblinded pharmacist) are described in Protocol Section 5.2.3 – Trial Blinding.
Planned efficacy interim analyses are described in Section 3.7 – Interim Analyses.  Study 
enrollment is likely to be ongoing at the time of any efficacy interim analyses.  Blinding to 
treatment assignment will be maintained at all investigational sites.
Treatment-level results of the efficacy interim analyses will be provided by an external unblinded 
statistician to the external DMC.  The external DMC will serve as the primary reviewer of the 
results of the interim analyses and will make recommendations for discontinuation of the study or 
modification to an EOC of the Sponsor.  Depending on the recommendation of the DMC, the 
Sponsor may prepare a regulatory submission.  If the DMC recommends modifications to the 
design of the protocol or discontinuation of the study, this EOC may be unblinded to results at the 
treatment level in order to act on these recommendations or facilitate regulatory filing.  Limited 
additional Sponsor personnel may be unblinded to the treatment level results of the interim analysis 
(analyses), if required, in order to act on the recommendations of the DMC or facilitate regulatory 
filing.  The extent to which individuals are unblinded with respect to results of interim analyses 
will be documented.  Additional logistical details, revisions to the above plan and data monitoring 
guidance will be provided in the DMC Charter.  Key aspects of the interim analyses are described 
in Section 3.7 – Interim Analyses.
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.
3.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Protocol Section 3.0 – Objective(s) & 
Hypothesis(es) and are listed in this section.
 
 
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3.3.1
Primary Objective(s) & Hypothesis(es)
Part 1 (Safety Run-In):
(1)
Objective: To evaluate the safety and tolerability of 3 pembrolizumab + chemotherapy 
combinations, namely, pembrolizumab + paclitaxel, pembrolizumab + nab-paclitaxel, and 
pembrolizumab + gemcitabine/carboplatin.
Part 2 (Phase III study):
The combination of pembrolizumab and chemotherapy will be compared to placebo and 
chemotherapy for the treatment of previously untreated locally recurrent inoperable or metastatic 
centrally confirmed triple negative breast cancer (TNBC):
(1) Objective:  To compare progression-free survival (PFS) based on Response Evaluation 
Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by a blinded central 
imaging vendor (CIV) in all subjects.
Hypothesis:  The combination of pembrolizumab and chemotherapy prolongs PFS 
compared to placebo and chemotherapy in all subjects.
(2) Objective:  To compare PFS based on RECIST 1.1 as assessed by a blinded CIV in 
subjects with programmed cell death ligand 1 (PD-L1) positive tumors (combined positive 
score [CPS] ≥1).
Hypothesis:  The combination of pembrolizumab and chemotherapy prolongs PFS 
compared to placebo and chemotherapy in subjects with PD-L1 positive tumors (CPS ≥1).
(3) Objective:  To compare PFS based on RECIST 1.1 as assessed by a blinded CIV in 
subjects with PD-L1 positive tumors (CPS ≥10).
Hypothesis:  The combination of pembrolizumab and chemotherapy prolongs PFS 
compared to placebo and chemotherapy in subjects with PD-L1 positive tumors (CPS ≥10).
(4) Objective:  To compare overall survival (OS) in all subjects.
Hypothesis:  The combination of pembrolizumab and chemotherapy prolongs OS 
compared to placebo and chemotherapy in all subjects.
(5) Objective:  To compare OS in subjects with PD-L1 positive tumors (CPS ≥1).
Hypothesis:  The combination of pembrolizumab and chemotherapy prolongs OS 
compared to placebo and chemotherapy in subjects with PD-L1 positive tumors (CPS ≥1).
(6) Objective:  To compare OS in subjects with PD-L1 positive tumors (CPS ≥10).
Hypothesis:  The combination of pembrolizumab and chemotherapy prolongs OS 
compared to placebo and chemotherapy in subjects with PD-L1 positive tumors (CPS ≥10).
The study is considered to have met its primary objective if the combination of pembrolizumab 
and chemotherapy is superior to placebo and chemotherapy in either PFS or OS in either all 
subjects or in subjects with PD-L1 positive tumors (CPS ≥1 or CPS ≥10) at either an interim 
analysis or the final analysis (OS only).
 
 
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Supplemental SAP
     14 Jan 2020 – sSAP Amendment 03
3.3.2
Secondary Objective(s) & Hypothesis(es)
Part 2 (Phase III study):
For comparisons, the combination of pembrolizumab and chemotherapy will be compared to 
placebo and chemotherapy for the treatment of previously untreated locally recurrent inoperable 
or metastatic centrally confirmed TNBC:
(1) Objective:  To compare objective response rate (ORR) based on RECIST 1.1 as assessed 
by a blinded CIV in all subjects.
Hypothesis:  The combination of pembrolizumab and chemotherapy increases ORR 
compared to placebo and chemotherapy in all subjects.
(2) Objective:  To compare ORR based on RECIST 1.1 as assessed by a blinded CIV in 
subjects with PD-L1 positive tumors (CPS ≥1).
Hypothesis:  The combination of pembrolizumab and chemotherapy increases ORR 
compared to placebo and chemotherapy in subjects with PD-L1 positive tumors (CPS ≥1).
(3) Objective:  To compare ORR based on RECIST 1.1 as assessed by a blinded CIV in 
subjects with PD-L1 positive tumors (CPS ≥10).
(4) Objective:  To evaluate duration of response (DOR) based on RECIST 1.1 as assessed by 
a blinded CIV in all subjects and in subjects with PD-L1 positive tumors (CPS ≥1 and CPS 
≥10).
(5) Objective:  To compare disease control rate (DCR) based on RECIST 1.1 as assessed by 
a blinded CIV in all subjects and in subjects with PD-L1 positive tumors (CPS ≥1 and CPS 
≥10).
(6) Objective:  To evaluate the safety and tolerability of 3 pembrolizumab + chemotherapy 
combinations.
(7) Objective:  To evaluate changes in health-related quality-of-life (QoL) assessments from 
baseline in all subjects and in subjects with PD-L1 positive tumors (CPS ≥1 and CPS ≥10) 
using the European Organization for Research and Treatment of Cancer (EORTC) Quality 
of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC Breast Cancer–Specific 
Quality of Life Questionnaire (EORTC QLQ-BR23).
3.3.3
Exploratory Objectives 
Part 2 (Phase III study):
For comparisons, the combination of pembrolizumab and chemotherapy will be compared to 
placebo and chemotherapy for the treatment of previously untreated locally recurrent inoperable 
or metastatic centrally confirmed TNBC:
(1) Objective:  To characterize utilities in all subjects and in subjects with PD-L1 positive 
tumors (CPS ≥1 and CPS ≥10) using EuroQol-5 Dimension Questionnaire (EQ-5D™).
 
 
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(2) Objective:  To investigate association(s) between anti-tumor activity of study treatments 
and efficacy/resistance biomarkers, utilizing tumor and blood specimens obtained before 
randomization, during treatment, and at disease progression.
(3) Objective:  To identify molecular (genomic, metabolic, and/or proteomic) determinants of 
response or resistance to pembrolizumab and other treatments in this study, so as to define 
novel predictive and pharmacodynamic biomarkers and understand the mechanism of 
action of pembrolizumab.
3.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
3.4.1
Efficacy Endpoints
Primary
Progression-free survival (PFS) – based on RECIST 1.1 as assessed by a CIV
Progression-free survival is defined as the time from randomization to the first documented disease 
progression per RECIST 1.1 based on assessments by a CIV or death due to any cause, whichever 
occurs first.  See Section 3.6.1 – Statistical Methods for Efficacy Analyses for the definition of 
censoring.
Overall Survival (OS)
Overall survival is defined as the time from randomization to death due to any cause. Subjects 
without documented death at the time of the analysis will be censored at the date of the last follow-
up.
Secondary 
Objective Response Rate (ORR) – based on RECIST 1.1 as assessed by a CIV 
Objective response rate is defined as the proportion of the subjects in the analysis population who 
have a CR or PR. Responses are based on assessments by a CIV per RECIST 1.1.
Duration of Overall Response (DOR) – based on RECIST 1.1 as assessed by a CIV 
For subjects who demonstrate CR or PR, duration of response is defined as the time from first 
documented evidence of CR or PR until disease progression or death due to any cause, whichever 
occurs first, based on assessments by a CIV per RECIST 1.1.  See Section 3.6.1 – Statistical 
Methods for Efficacy Analyses for the definition of censoring.
Disease Control Rate (DCR) – based on RECIST 1.1 as assessed by a CIV 
Disease control rate is defined as the percentage of subjects who have achieved CR or PR or have 
demonstrated SD for at least 24 weeks, based on assessments by a CIV per RECIST 1.1. 
 
 
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3.4.2
Safety Endpoints
Safety measurements are described in Protocol Section 4.2.3 – Rationale for Endpoints and 
Protocol Section 7.0 – Trial Procedures.
3.5
Analysis Populations
3.5.1
Efficacy Analysis Populations
The ITT population will serve as the population for primary efficacy analysis of Part 2.  All 
randomized subjects will be included in this population.  Subjects will be included in the treatment 
group to which they are randomized. For the primary analysis of ORR endpoints, all subjects 
randomized on or prior to the date the 640th Part 2 subject is randomized will be included in the 
analysis, which is considered the ORR ITT population. The ORR endpoints will also be analyzed 
in the ITT population for estimation only. The analysis of DOR and DCR will be conducted in 
both the ORR ITT and the ITT population.
Part 1 subjects will be excluded from all Part 2 efficacy analyses and therefore will not contribute 
to the analyses to address the primary/secondary objectives of Part 2. The All Subjects as Treated 
(ASaT) population will be used for the analysis of Part 1 efficacy in this study.  The ASaT 
population consists of all randomized subjects who received at least one dose of study treatment. 
Subjects will be included in the treatment group corresponding to the study treatment they actually 
received for the analysis of Part 1 efficacy data using the ASaT population.  For most subjects this 
will be the treatment group to which they are randomized.  Subjects who take incorrect study 
treatment for the entire treatment period will be included in the treatment group corresponding to 
the study treatment actually received.  Any subject who receives the incorrect study treatment for 
one cycle, but receives the correct treatment for all other cycles, will be analyzed according to the
correct treatment group.
Details on the approach to handling missing data are provided in Section 3.6 – Statistical Methods.
3.5.2
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in this 
study.  The ASaT population consists of all randomized subjects who received at least one dose of 
study treatment. Subjects will be included in the treatment group corresponding to the study 
treatment they actually received for the analysis of safety data using the ASaT population.  For 
most subjects this will be the treatment group to which they are randomized.  Subjects who take 
incorrect study treatment for the entire treatment period will be included in the treatment group 
corresponding to the study treatment actually received.  Any subject who receives the incorrect 
study treatment for one cycle, but receives the correct treatment for all other cycles, will be 
analyzed according to the correct treatment group and a narrative will be provided for any events 
that occur during the cycle for which the subject is incorrectly dosed. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of study 
treatment is required for inclusion in the analysis of each specific parameter.  To assess change 
from baseline, a baseline measurement is also required.
 
 
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Part 1 and Part 2 subjects will be analyzed separately.
Details on the approach to handling missing data for safety analyses are provided in Section 3.6 –
Statistical Methods.
3.6
Statistical Methods
3.6.1
Statistical Methods for Efficacy Analyses
For Part 1, descriptive summaries will be provided for efficacy endpoints (e.g., PFS, OS, ORR, 
DOR, DCR) as appropriate. 
The efficacy analysis methods specified in this section apply to Part 2.  Part 1 subjects will be 
excluded from all Part 2 efficacy analyses and therefore will not contribute to the analyses to 
address the primary/secondary objectives of Part 2.
Efficacy results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 3.8 – Multiplicity.  Nominal p-values will be
computed for other efficacy analyses, but should be interpreted with caution due to potential issues 
of multiplicity.
Of note, for the stratified analyses performed in all subjects, all stratification factors [chemotherapy 
on study (taxane vs gemcitabine/carboplatin); tumor PD-L1 status (positive vs negative); prior 
treatment with same class of chemotherapy in the (neo)adjuvant setting (yes vs no)] will be 
included. For efficacy analyses performed in subjects with PD-L1 positive tumors, only the 
stratification factors of chemotherapy on study (taxane vs gemcitabine/carboplatin) and prior 
treatment with same class of chemotherapy in the (neo)adjuvant setting (yes vs no) will be 
considered in the analysis models, i.e., not considering the stratification factor of PD-L1 tumor 
status. If based on blinded data review, there is too small number (<10) of subjects in a specific 
stratum for analyses in all subjects or subjects with PD-L1 positive tumors, in the ITT or the ORR 
ITT population, that stratum will be combined with the neighboring stratum for the analysis. If the 
mis-stratification rate at randomization is greater than 10% based on review of blinded data, 
additional sensitivity analyses may be performed for primary efficacy and key secondary efficacy 
endpoints according to each subject’s stratum based on actual data collected. 
3.6.1.1
Progression-Free Survival (PFS)
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each treatment 
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 (i.e., HR) between the treatment arms.  The HR and its 95% 
confidence interval (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 
(see Protocol Section 5.4 – Stratification) will be applied, as stratification factors used for analysis, 
to both the stratified log-rank test and the stratified Cox model. 
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment in which PD was not documented and the assessment when PD is 
 
 
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documented.  For subjects who have PD, the true date of disease progression will be approximated 
by the date of the first assessment at which PD is objectively documented based on RECIST 1.1 
as assessed by a CIV.  Death is always considered as a confirmed PD event.  Subjects who do not 
experience a PFS event will be censored at the last disease assessment.   
In order to evaluate the robustness of the PFS endpoint based on RECIST 1.1 as assessed by a 
CIV, one primary and two 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 anti-cancer therapy are censored at the last disease assessment prior to 
the initiation of new anti-cancer therapy. The first sensitivity analysis follows the intention-to-treat 
principle. That is, PDs/deaths are counted as events regardless of missed study visits or initiation 
of new anti-cancer therapy.  The second sensitivity analysis considers initiation of new anticancer 
treatment or discontinuation of treatment due to reasons other than complete response to be a PD 
event for subjects without documented PD or death. The censoring rules for primary and sensitivity 
analyses are summarized in Table 1. If a subject meets multiple criteria for censoring, the censoring 
criterion that occurs earliest will be applied.  
 
 
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Table 1
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and no death; 
and new anticancer 
treatment 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 treatment or completed 
study treatment.
No PD and no death; 
new anticancer 
treatment is initiated
Censored at last disease 
assessment before new 
anticancer treatment 
Censored at last 
disease assessment
Progressed at date of new 
anticancer treatment
PD or death 
documented after ≤ 1 
missed disease 
assessment, and before 
new anti-cancer 
therapy, 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 anti-cancer 
therapy, if any
Censored at last disease 
assessment prior to 
the earlier date of ≥ 2 
consecutive missed 
disease assessment and 
new anti-cancer therapy, 
if any
Progressed at date 
of documented PD 
or death
Progressed at date of 
documented PD or death
The proportional hazards assumption on PFS will be examined using both graphical and analytical 
methods if warranted.  The log[-log] of the survival function vs time for PFS may be plotted for 
the comparison between the pembrolizumab + chemotherapy and placebo + chemotherapy arms.  
If the curves are not parallel, indicating that hazards are not proportional, supportive analyses may 
be conducted to account for the possible non-proportional hazards effect associated with 
immunotherapies; for example, using Restricted Mean Survival Time (RMST) method [4] and 
parametric method [5]. The RMST is simply the population average of the amount of event-free 
survival time experienced during a fixed study follow-up time. This quantity can be estimated by 
the area under the Kaplan-Meier curve up to the follow-up time.  The clinical relevance and 
feasibility should be taken into account in the choice of follow-up time to define RMST (e.g., near 
the last observed event time assuming that the period of clinical interest in the survival experience 
is the whole observed follow-up time for the trial, but avoiding the very end of the tail where 
variability may be high); a description of the RMST as a function of the cutoff time may be of 
interest. The difference between two RMSTs for the two treatment groups will be estimated and 
95% CI will be provided. 
One assumption for stratified Cox proportional hazard model is that the treatment HR is constant 
across the strata.  If strong departures from the assumption of the HR being the same for all the 
strata observed (which can result in a notably biased and/or less powerful analysis), a sensitivity 
 
 
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analysis may be performed based on a two-step weighted Cox model approach by Mehrotra et al., 
2012 [6], in which the treatment effect is first estimated for each stratum, and then the stratum 
specific estimates are combined for overall inference using sample size weights.
In case there is an imbalance between the treatment groups on disease assessment schedules or 
censoring patterns, we may also perform one additional PFS supportive analysis using Finkelstein 
(1986)’s likelihood-based score test [7] for interval-censored data, which modifies the Cox 
proportional hazard model for interval-censored data. The interval will be constructed so that the 
left endpoint is the date of the last disease assessment without documented PD and the right 
endpoint is the date of documented PD or death, whichever occurs earlier.
Sensitivity analyses will be performed for PFS based on site investigator/local radiology review.  
Additional PFS supportive analyses may be performed as appropriate, including a PFS analysis 
using time to scheduled tumor assessment visit from randomization as opposed to the actual tumor 
assessment time.  Additional supportive unstratified analyses may also be provided.  
Kaplan-Meier plots among different PD-L1 cutoff points may be provided for each treatment arm 
separately, in order to estimate the influence of patients’ CPS scores on PFS within each arm.
3.6.1.2
Overall Survival (OS)
The non-parametric 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 (i.e., the HR).  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 (see Protocol Section 5.4 – Stratification) will be applied, as stratification factors 
used for analysis, to both the stratified log-rank test and the stratified Cox model. The Kaplan-
Meier estimates of the OS rate at selected time points of interest (e.g., 6 months, 12 months, 18 
months etc.) will also be estimated.  
Subjects in the placebo + chemotherapy arm are expected to discontinue treatment earlier 
compared to subjects in the pembrolizumab + chemotherapy arm and are not allowed to crossover 
to the pembrolizumab + chemotherapy arm; however, they may be treated with another anti–PD-
1 drug following the verification of PD by a blinded CIV.  As an exploratory analysis, adjustment 
for the effect of crossover on OS may be performed based on recognized methods (e.g., the Rank 
Preserving Structural Failure Time (RPSFT) model proposed by Robins and Tsiatis [8], two-stage 
model [9]), based on an examination of the appropriateness of the data to the assumptions required 
by the methods.
The RPSFT model provides a randomization-based estimate of the treatment effect corrected for 
bias introduced by crossover from the control arm to the experimental treatment. This method is 
rank-preserving in the sense that it assumes that given two subjects i and j, if subject i failed before 
subject j when both were on one treatment, then subject i would also fail before subject j if both 
subjects took any other alternative treatment. The method is structural in the sense that it assumes 
a defined relationship between the observed survival time and the survival time that would have 
been observed if crossover had not occurred. It is also assumed that the treatment effect is the same 
 
 
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before and after progression. More specifically, the RPSFT method first relates the observed 
survival time to a latent survival time (experimental treatment-free survival time if the patient was 
never to receive the experimental treatment) through an accelerated failure time model. The 
treatment effect will then be estimated under the assumption that the latent survival curves are 
identical between the control and experimental treatment arms. Re-censoring of the latent survival 
time using the treatment effect will be applied in order to preserve the independent censoring 
assumption. The OS analysis will then be applied to the “corrected” survival dataset, which 
includes the adjusted survival time for subjects in the control arm so that it reflects the OS had 
they not received the experimental treatment as well as the observed survival time for subjects in 
the experimental treatment arm. The HR and the associated 95% CI for OS after adjustment of the 
crossover effect using the RPSFT method will be provided. 
Under the assumptions of no unmeasured confounders at the secondary baseline time-point 
(disease progression), treatment switching only happens after progression, and happens soon after 
progression, the “two-stage” approach may be appropriate. At Stage 1, the date of disease 
progression is used as a secondary baseline for subjects who have a documented progression in 
the control arm and data from these subjects beyond this time-point are considered as an 
observational dataset.  An accelerated failure time model including covariates for crossover and 
other prognostic covariates measured at the secondary baseline will be applied to this observational 
dataset to estimate an acceleration factor.  At Stage 2, a counterfactual survival dataset will be 
constructed such that survival time of subjects with treatment switching will be shrunk by the 
inverse of the acceleration factor, while no shrinkage is performed for the survival time of subjects 
in the control group without treatment switching or subjects in the experimental arm. The OS 
analysis will then be applied to this counterfactual survival dataset to estimate the HR from this 
two-stage method. 
It is very important to assess trial data, crossover mechanism, and treatment effect to determine 
which method is likely to be most appropriate to evaluate the crossover effect.  
Due to multiple occurrences of delayed separation phenomena observed in Immuno-Oncology 
randomized clinical trials, another sensitivity analysis, which evaluates the treatment difference 
for OS using the stratified max-combo test, may be conducted. The max-combo test statistic is the 
maximum of the log-rank test statistic and weighted log-rank variation of the Fleming-Harrington 
test statistics: Zm = max (Z1, Z2, Z3), where Z1, Z2 and Z3 are the test statistics from the FH (0, 0), 
FH (1, 1) and FH (0, 1) family of test statistics, respectively. FH (0, 0) corresponds to the log-rank 
test, while FH (1, 1) and FH (0, 1) are more sensitive to middle and late-difference alternatives, 
respectively. The adjusted nominal p-value, which can be derived by integrating under the 
multivariate normal density [10] will be reported. No formal hypothesis testing will be conducted.  
Kaplan-Meier plots among different PD-L1 cutoff points may be provided for each treatment arm 
separately, in order to estimate the influence of patients’ CPS scores on OS within each arm.
Additional supportive unstratified analyses may also be provided. Other sensitivity analyses 
described for the PFS endpoint may also be applied to the OS endpoint as appropriate.
 
 
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3.6.1.3
Objective Response Rate (ORR) 
The stratified Miettinen and Nurminen method will be used for the comparison of ORR between 
2 treatment arms. The difference in ORR and its 95% CI from the stratified Miettinen and 
Nurminen method with strata weighting by sample size will be reported.  The stratification factors 
used for randomization (see Protocol Section 5.4 – Stratification) will be applied to the analysis. 
The ORR hypotheses will be tested according to the hypotheses testing plan as described in Section 
3.8 – Multiplicity.
Sensitivity analyses will be performed for ORR based on site investigator/local radiology review.  
Sensitivity analyses using the Cochran–Mantel–Haenszel test (CMH) may also be performed. 
Additional supportive unstratified analyses may also be provided.   
3.6.1.4
Disease Control Rate (DCR)
The stratified Miettinen and Nurminen method will be used for the comparison of DCR between 
2 treatment arms.  The difference in DCR and its 95% CI from the stratified Miettinen and 
Nurminen method with strata weighting by sample size will be reported.   The stratification factors 
used for randomization (see Protocol Section 5.4 – Stratification) will be applied to the analysis. 
Sensitivity analyses will be performed for DCR based on site investigator/local radiology review.  
3.6.1.5
Duration of Response (DOR)
If sample size permits, DOR will be summarized descriptively using the non-parametric Kaplan-
Meier method.  Only the subset of subjects who achieved CR or PR will be included in this 
analysis.  
Censoring rules for DOR are summarized in Table 2. If a subject meets multiple criteria for 
censoring, the censoring criterion that occurs earliest will be applied.
For each DOR analysis, a corresponding summary of the reasons responding subjects are censored 
will also be provided. Responding subjects who are alive, have not progressed, have not initiated 
new anti-cancer treatment, have not been determined to be lost to follow-up, and have had a disease 
assessment within ~5 months of the data cutoff date are considered ongoing responders at the time 
of analysis.
A corresponding summary of the reasons for which the responding subjects are censored for the 
DOR analysis will also be provided. Sensitivity analyses will be performed for DOR based on site 
investigator/local radiology review.  
 
 
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Table 2
Censoring Rules for DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anti-cancer therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new anti-
cancer therapy initiated
Last adequate disease assessment 
before 
new 
anti-cancer 
therapy 
initiated
Censor
(non-event)
Death or progression immediately 
after ≥ 2 consecutive missed disease 
assessments or after new anti-cancer 
therapy, if any
Earlier date of last adequate disease 
assessment prior to ≥ 2 missed 
adequate disease assessments and 
new anti-cancer therapy, if any
Censor
(non-event)
Death or progression after ≤ 1 missed 
disease assessments and before new 
anti-cancer therapy, if any
PD or death
End of response
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for evaluation 
of response.  
3.6.1.6
Summary of Statistical Methods for Efficacy
Table 3 summarizes the primary analysis approach for primary and secondary efficacy endpoints 
of Part 2.  Sensitivity analysis methods are described above for each endpoint as applicable.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, multiple 
populations, and interim analyses is described in Section 3.7 – Interim Analyses and in Section 3.8
– Multiplicity.
Table 3
Analysis Strategy for Key Efficacy Endpoints (Part 2)
Endpoint/Variable
(Description, Time Point)
Statistical Methoda
Analysis 
Population
Missing Data Approach
Primary Hypothesis 1
PFS based on RECIST 1.1 assessed 
by a blinded CIV in all subjects
Test: Stratified log-rank test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
Primary censoring rule
Sensitivity analysis 1
Sensitivity analysis 2
(More details are in Table 1)
Primary Hypothesis 2
PFS based on RECIST 1.1 assessed 
by a blinded CIV in subjects with 
PD-L1 positive tumors (CPS ≥1)
Test: Stratified log-rank test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
Primary censoring rule
Sensitivity analysis 1
Sensitivity analysis 2
(More details are in Table 1)
Primary Hypothesis 3
PFS based on RECIST 1.1 assessed 
by a blinded CIV in subjects with 
PD-L1 positive tumors (CPS ≥10)
Test: Stratified log-rank test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
Primary censoring rule
Sensitivity analysis 1
Sensitivity analysis 2
(More details are in Table 1)
 
 
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Endpoint/Variable
(Description, Time Point)
Statistical Methoda
Analysis 
Population
Missing Data Approach
Primary Hypothesis 4
OS in all subjects
Test: Stratified log-rank test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
Censored at last known alive 
date
Primary Hypothesis 5
OS in subjects with PD-L1 positive 
tumors (CPS ≥1)
Test: Stratified log-rank test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
Censored at last known alive 
date
Primary Hypothesis 6
OS in subjects with PD-L1 positive 
tumors (CPS ≥10)
Test: Stratified log-rank test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
Censored at last known alive 
date
Key Secondary Hypothesis 1 (Hypothesis 7)
ORR based on RECIST 1.1 assessed 
by a blinded CIV in all subjects
Stratified M & N methodb
The first 
~ 640 
subjects 
randomized 
in Part 2 (a 
subset of 
ITT)
Subjects with relevant data 
missing are considered 
non-responders
Key Secondary Hypothesis 2 (Hypothesis 8)
ORR based on RECIST 1.1 assessed 
by a blinded CIV in subjects with 
PD-L1 positive tumors (CPS ≥1)
Stratified M & N methodb
The first 
~ 640 
subjects 
randomized 
in Part 2 (a 
subset of 
ITT)
Subjects with relevant data 
missing are considered 
non-responders
Other Secondary Endpoints
ORR based on RECIST 1.1 assessed 
by a blinded CIV in subjects with 
PD-L1 positive tumors (CPS ≥10)
Stratified M & N methodb
ITT
Subjects with relevant data 
missing are considered 
non-responders
DCR based on RECIST 1.1 assessed 
by a blinded CIV in all subjects and 
in subjects with PD-L1 positive 
tumors (CPS ≥1 and CPS ≥10)
Stratified M & N methodb
ITT
Subjects with relevant data 
missing are considered 
non-responders
DOR based on RECIST 1.1 assessed 
by a blinded CIV in all subjects and 
in subjects with PD-L1 positive 
tumors (CPS ≥1 and CPS ≥10)
Summary statistics using 
Kaplan-Meier method
All 
responders 
in ITT
See Table 2
CIV=central imaging vendor; CPS=combined positive score; DCR=disease control rate; DOR=duration of 
response; ITT=intention-to-treat; M & N=Miettinen and Nurminen; ORR=objective response rate; 
OS=overall survival; PD-L1=programmed cell death ligand 1; PFS=progression-free survival; RECIST 
1.1= Response Evaluation Criteria in Solid Tumors version 1.1.
a Statistical models are described in further detail in the text. For stratified analyses, the stratification factors 
used for randomization will be used as stratification factors for analysis.
b Miettinen and Nurminen method.
 
 
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3.6.2
Statistical Considerations for Patient-Reported Outcomes (PRO)
3.6.2.1 Patient Reported Outcome (PRO) Endpoints
The PRO endpoints include results from the EORTC QLQ-C30, EORTC QLQ-BR23, and EQ-
5D™ questionnaires.
The EORTC QLQ C30 is a self-reported 30-item cancer specific instrument that assesses 15 
domains: 5 functional scales (physical, role, emotional, cognitive and social functioning), 9 
symptom scales or single items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite 
loss, constipation, diarrhea and financial difficulties), and a global health status / QoL.  
The EORTC QLQ-BR23 is a breast-specific module of the EORTC QLQ. It includes 23 items 
composed of 4 functional scales (i.e., body image, sexual functioning, sexual enjoyment and future 
perspective) and 4 symptom scales (systemic therapy side effects, breast symptoms, arm symptoms 
and upset by hair loss).
EQ-5D is a standardized measure of health status developed by the EuroQol Group in order to 
provide a simple, generic measure of health for clinical and economic appraisal [11].  EQ-5D 
comprises two separate elements. Utility score (or descriptive system), the first of these captures 
health state across five dimensions: mobility, self-care, usual activities, pain / discomfort, anxiety 
/ depression. Unique health states are defined by combining response levels from each of the five 
dimensions. The second EQ-5D element is based on a vertical visual analogue scale (VAS).  The 
VAS records the respondent’s self-rated health on a vertical, visual analogue scale ranging from 0 
to 100 where the end points are labelled ‘Best imaginable health state’ (100) and ‘Worst 
imaginable health state’ (0).  This information can be used as a quantitative measure of health 
outcome as judged by the individual respondents. 
In this trial, the PROs will be assessed according to the following schedule (Table 4). For the 
analysis, PROs assessed at visits of “End of Treatment” and “Safety Follow-up” will be mapped 
into different time points according to the actual visit time.  If there are multiple PRO collections 
within the time window of a specific visit, the collection closest to the target day will be used in 
the analysis.
Table 4
PRO Assessment Schedule.
Week1
End of 
Treatment
Safety 
Follow-up3
Baseline (0)
3
6
15
24
33
42
512
Treatment 
Cycle (C)
C1 
C2
C3
C6
C9
C12
C15
C182
X
X
1PRO collections are scheduled on the 1st day of a cycle, and Week is counted as number of weeks elapsed since the start 
of treatment, e.g, the first day of C2 is mapped to Week 3.
2After the 3rd cycle and until the end of Year 1, PROs will be collected every 3rd cycle (every 9 weeks) until PD, while 
the subject is receiving study treatment. During Year 2, they will occur every 4th cycle (every 12 weeks) until PD, while 
the subject is receiving study treatment.
3If the End of Treatment Visit occurs 30 days from the last dose of study treatment, at the time of the mandatory Safety 
Follow up Visit, PROs do not need to be repeated.
 
 
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Key PRO Endpoint
Primary analysis time point:  the primary ePRO analysis time point is defined as the latest time 
point where the completion and compliance rates are still high enough based on blinded data 
review (~60% completion rate and ~80% compliance rate). The key PRO endpoint is:

The mean score changes from baseline to the primary analysis time point in EORTC QLQ-
C30 global health status / QoL score.
Supportive PRO Endpoints
The following are supportive PRO endpoints and may be analyzed as appropriate.
1. The mean score changes from baseline to the primary analysis time point in VAS as 
measured by EQ-5D.
2. The mean score changes from baseline to the primary analysis time point for:
o
The QLQ-C30 functional scale Physical Functioning.
o
The QLQ-C30 functional scale Emotional Functioning.
3. Time to deterioration (TTD), defined as time from start of treatment to first onset of 10 
points or more worsening from baseline, for 
o
The QLQ-C30 global health status/QoL score.
o
The QLQ-C30 functional scale Physical Functioning.
o
The QLQ-C30 functional scale Emotional Functioning.
4. The mean score changes from baseline to the primary analysis time point for other 
items/scales of QLQ-C30 and QLQ-BR23 as appropriate.
3.6.2.2 Patient Reported Outcome (PRO) Analysis Population
The PRO Full Analysis Set (FAS) population will be used for PRO analyses. The PRO FAS 
population consists of all randomized subjects who received at least one dose of study medication 
and completed at least one PRO assessment.
The PRO analysis will be conducted in Part 2 subjects only. The analysis will be conducted in all 
subjects in subjects with CPS≥1 and CPS≥10.
3.6.2.3 Analysis Approaches
The PROs are exploratory objectives in this study, thus no formal hypotheses are formulated. 
Nominal p-values without multiplicity adjustment will be provided and should be interpreted with 
caution. 
 
 
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3.6.2.3.1
Scoring Algorithm
QLQ-C30 Scoring 
The QLQ-C30 is composed of both multi-item scales and single-item measures. These include a 
global health status / QoL scale, five functional scales, three symptom scales, and six single items. 
Each of the multi-item scales includes a different set of items - no item occurs in more than one 
scale.
All of the scales and single-item measures will follow a standardization procedure prior to analysis 
so that scores range from 0 to 100. A high scale score represents a higher response level. Thus a 
high score for a functional scale represents a high / healthy level of functioning; a high score for 
the global health status / QoL represents a high QoL; but a high score for a symptom scale / item 
represents a high level of symptomatology / problems.
According to the EORTC QLQ-C30 Scoring Manual [12], the principle for scoring these scales is 
the same in all cases:
1. Estimate the average of the items that contribute to the scale; this is the raw score.
2. Use a linear transformation to standardize the raw score, so that scores range from 0 to 100; a 
higher score represents a higher ("better") level of functioning, or a higher ("worse") level of 
symptoms.
Specifically, if items I1, I2,…,In are included in a scale, the scoring procedure is as follows:
1. Compute the raw score:
2. Linear transformation to obtain the score S:
Function scales: 
Symptom scales / items: 
Global health status / QoL: 
100
1 

Range
RS
S
Range is the difference between the maximum possible value of RS and the minimum possible 
value. The QLQ-C30 has been designed so that all items in any scale take the same range of values. 
Therefore, the range of RS equals the range of the item values. If more than half of the items within 
one scale are missing, then the scale is considered missing, otherwise, the score will be calculated 
as the average score of those available items.
n
I
I
I
RS
n /)
...
(
2
1




100
1
1










Range
RS
S
100
1 

Range
RS
S
 
 
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MK-3475                                                                               PAGE 25
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QLQ-BR23 Scoring
The scoring approach for the QLQ-BR23 is identical in principle to that for the function and 
symptom scales / single items of the QLQ-C30. A linear transformation will be applied to 
standardize the scores between 0 and 100 as described above for the EORTC QLQ-C30 scoring.
EQ-5D Scoring
The EQ-5D utility score will be calculated based on the European algorithm [11] based on 
responses on the five health state dimensions, including mobility, self-care, usual activities, pain / 
discomfort, and anxiety / depression. 
3.6.2.3.2
Patient Reported Outcome (PRO) Score Analysis
To assess the treatment effect on the PROs, for each PRO endpoint defined, a constrained 
longitudinal data analysis (cLDA) model will be used as the primary analysis method, with the 
PRO score as the response variable [13].  Only PRO data up to the primary analysis time point 
will be included in this analysis model.
The cLDA model is specified as follows:
ܧ൫ܻ௜௝௧൯ൌߛ଴൅ߛ௝௧ܫሺݐ൐0ሻ൅ߚܺ௜,
݆ൌ1,2,   ݐൌ0,1, … ܶ
where Yijt is the PRO score for subject i, with treatment j, at visit t, 
0
γ
is the baseline mean for 
both treatment groups,
jt
γ
is the mean change from baseline for treatment group j at time t, 
i
X is
the stratification stratum value (Protocol Section 5.4) for subject i, and β is the corresponding 
coefficient for stratum. 
The treatment effect on PRO score change from baseline will be evaluated at the primary analysis 
time point. Between-group comparison will be performed and the differences in the least-squares 
mean change from baseline at the primary analysis time point will be reported, together with 95% 
CI and nominal p-value. In addition, model-based least-squares mean score with corresponding 
95% CI will be provided by treatment group at the primary analysis time point. 
Patients with disease progression confirmed or feeling worse due to drug-related AE may have 
missing PRO assessments. The missing data must be handled accordingly to obtain valid statistical 
analysis results. The cLDA model implicitly treats missing data as missing at random (MAR). 
Sensitivity analyses may be conducted in case the robustness of MAR assumption is questionable.
Descriptive statistics (e.g. mean and standard error) of change from baseline with no imputation 
for missing data of the following score/scales will also be plotted: QLQ-C30 global health 
status/QoL, QLQ-C30 physical functioning, QLQ-C30 emotional functioning, and EQ-5D VAS.


'1*
=1<)


MK-3475                                                                               PAGE 26
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Supplemental SAP
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3.6.2.3.3
Analysis of the Time to Deterioration (TTD)
The non-parametric Kaplan-Meier method will be used to estimate the deterioration curve in each 
group. The treatment difference in time-to-deterioration 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 (hazard ratio) between treatment arms. The 
stratification factors used for randomization (see Protocol Section 5.4 – Stratification) will be 
applied to the analysis.  This analysis will be conducted for QLQ-C30 global health status/QoL, 
QLQ-C30 functional scales physical functioning and emotional functioning.
Of note, for all above ePRO analysis (Section 3.6.2.3.2 to Section 3.6.2.3.3) in subjects with PD-
L1 positive tumors, only the stratification factors of chemotherapy on study (taxane vs 
gemcitabine/carboplatin) and prior treatment with same class of chemotherapy in the 
(neo)adjuvant setting (yes vs no) will be considered in the analysis models, i.e., not considering 
the stratification factor of PD-L1 tumor status. 
3.6.2.3.4
Summary of Completion and Compliance 
Completion and compliance of QLQ-C30, QLQ-BR23 and EQ-5D by treatment and visit will be 
described based on the PRO FAS population. 
Completion Rate is defined as the percentage of subjects who completes at least one score/item 
over the number of subjects in the PRO FAS population at each time point.
The completion rate is expected to shrink in the later visits during due to early discontinuations. 
Therefore, another measurement, Compliance Rate, defined as the percentage of subjects who 
completes at least one score/item over the number of eligible subjects who are expected to 
complete the PRO assessment (not including the subjects missing by design such as death, 
discontinuation, translation not available, etc.), will be employed as a supportive measure.
The reasons of non-completion and non-compliance will also be summarized. 
3.6.3
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences, laboratory tests, vital signs, etc. 
Part 1
Descriptive summary statistics (e.g., counts, percentage, mean, standard deviation) will be 
provided for safety endpoints by treatment for Part 1 as appropriate.  
Part 2
The analysis of safety results will follow a tiered approach (Table 5).  The tiers differ with respect 
to the analyses that will be performed.  For this protocol, there are no Tier 1 safety endpoints.  Tier 
2 parameters will be assessed via point estimates with 95% CIs provided for between-group 
 
 
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comparisons; only point estimates by treatment group will be provided for Tier 3 safety 
parameters.
Adverse experiences (specific terms as well as system organ class terms) will be classified as 
belonging to “Tier 2” or “Tier 3”, based on the number or percent of subjects with events observed.  
Specific AEs occurring in ≥ 5% of subjects in one or more treatment groups will be considered 
Tier 2 endpoints.  Specific Serious and Grade 3-5 AEs occurring in at least 8 subjects in the 
pembrolizumab + chemotherapy group, or at least 2 subjects in the placebo + chemotherapy group 
will also be considered Tier 2 endpoints.  All other adverse experiences and predefined limits of 
change will belong to Tier 3.
The threshold of at least 5% of subjects with events in one or more treatment groups was chosen 
for specific AEs as Tier 2 endpoints because this incidence rate would allow meaningful statistical 
assessments for AEs in general.  The threshold of at least 8 subjects in the pembrolizumab + 
chemotherapy group, or at least 2 subjects in the placebo + chemotherapy group was chosen for 
specific Serious and Grade 3-5 AEs because the 95% CI for the between-group difference in 
percent incidence will always include zero with 2 to 1 randomization ratio if  there are less than 8 
subjects with events in the treatment group and less than 2 subjects with events in the control 
group, and thus would add little to the interpretation of potentially meaningful differences. Serious 
and Grade 3-5 AEs are expected to occur less frequently but important for the overall safety 
assessment, as such the threshold to classify these AEs as Tier 2 endpoints are lower than that for 
general specific AEs. 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 review, not a formal 
method for assessing the statistical significance of the between-group differences in adverse 
experiences and predefined limits of change.
Continuous measures such as changes from baseline in laboratory and vital signs will be 
considered Tier 3 safety parameters.  Summary statistics for baseline, on-treatment, and change 
from baseline values will be provided by treatment group.    
The broad clinical and laboratory AE categories consisting of the percentage of subjects with any 
AE, any drug related AE, any Grade 3-5 AE, any serious AE, any AE which is both drug-related 
and Grade 3-5, any AE which is both serious and drug-related, dose modification due to AE, and 
who discontinued due to an AE, and death will be considered Tier 2 endpoints.  For Tier 2 
endpoints, point estimates and 95% CIs will be provided for between-treatment differences in the 
percentage of subjects with events; these analyses will be performed using the Miettinen and 
Nurminen method [14].
 
 
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MK-3475                                                                               PAGE 28
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Table 5
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any Serious AE 
X
X
Any Grade 3-5 AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade 3-5 and Drug-Related AE
X
X 
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
X
X
Specific AEs, SOCs (incidence ≥ 5% of subjects in 
one or more treatment groups)
X
X
Specific Serious AEs, SOCs (incidence ≥ 8 subjects 
in the pembrolizumab + chemotherapy group, or ≥ 2 
subjects in the placebo + chemotherapy group)
X
X
Specific Grade 3-5 AEs, SOCs (incidence ≥ 8 
subjects in the pembrolizumab + chemotherapy 
group, or ≥ 2 subjects in the placebo + 
chemotherapy group)
X
X
Tier 3
Specific AEs, SOCs (incidence < 5% of subjects in 
both treatment groups) or PDLCs
X
Specific Serious AEs, SOCs (incidence < 8 subjects 
in the pembrolizumab + chemotherapy group and < 
2 subjects in the placebo + chemotherapy group)
X
Specific Grade 3-5 AEs, SOCs (incidence <8 subjects 
in the pembrolizumab + chemotherapy group and < 
2 subjects in the placebo + chemotherapy group)
X
Change from Baseline Results (Labs, Vital Signs)
X
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X = results will be provided.
To properly account for the potential difference in follow-up time between treatment arms, which 
is expected to be longer in the pembrolizumab + chemotherapy arm, AE incidence density adjusted 
for treatment exposure analyses may be performed as appropriate.   
In addition to the tiered approach, exploratory analysis may be performed on time to first Grade 
3-5 AE. Time to first Grade 3-5 AE is defined as the time from the first day of study medication
to the first event of Grade 3-5 AE. The Kaplan-Meier method will be used to estimate the curve of 
time to first Grade 3-5 AE.  The treatment difference in time to first Grade 3-5 AE will be assessed 
by the log-rank test.  A Cox proportional hazard model with Efron's method of tie handling will 
be used to assess the magnitude of the treatment difference (i.e., the HR). The HR and its 95% CI 
from the Cox model with a single treatment covariate will be reported.  
 
 
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3.6.4
Summaries of Demographic and Baseline Characteristics
Part 1 and Part 2 
The comparability of the treatment groups for each relevant characteristic will be assessed by the 
use of tables and/or graphs.  No statistical hypothesis testing will be performed on these 
characteristics.  The number and percentage of subjects screened, randomized, the primary reasons 
for screening failure, and the primary reason for discontinuation will be displayed.  Demographic 
variables (e.g., age) and baseline characteristics will be summarized by treatment either by 
descriptive statistics or categorical tables.
3.6.5
Statistical Methods for Exploratory Analyses
The analyses plan for the exploratory objectives regarding biomarkers will be provided in separate 
SAP(s) as appropriate. 
An exploratory analysis of PFS2, defined as the time from randomization to subsequent disease 
progression after initiation of new anti-cancer therapy, or death from any cause, whichever occurs 
first, may be carried out. Subjects alive and for whom a PFS2 event has not been observed should 
be censored at the last time the subject was known alive and without disease progression.
3.7
Interim Analyses
The study has one planned safety interim analysis for Part 1 and 3 planned efficacy interim 
analyses for Part 2.   Results will be reviewed by the external DMC.
3.7.1
Part 1: Safety Interim Analysis
A safety interim analysis will be performed after all Part 1 subjects have completed the first 21 or 
28 days (depending on chemotherapy treatment) of study treatment (unless early discontinued), 
i.e., 21 days after the first study treatment administration if the subject is in the pembrolizumab + 
gemcitabine/carboplatin arm or 28 days after the first study treatment administration if the subject 
is in either of the pembrolizumab + taxane arms.  Interim safety data will be reviewed by the DMC.  
It is estimated that the safety interim analysis will occur approximately 3 months after the first 
subject is randomized (depending on enrollment rate). 
In addition, continuous safety monitoring will be performed for Part 1 prior to the safety interim 
analysis by the study team.  If a potential safety issue signal is observed before 10 subjects are 
enrolled in a treatment arm, the DMC will be notified to review data prior to the pre-specified 
safety interim analysis.
3.7.2
Part 2: Efficacy Interim Analyses
There are 3 planned efficacy interim analyses for Part 2 in this trial.  Results will be reviewed by 
the DMC.  Of note, the boundaries for the analyses in this section may be adjusted, as appropriate, 
using the graphical approach discussed in Section 3.8 – Multiplicity.  
The boundaries provided in this section are calculated based on the estimated number of events at 
each analysis, and the actual interim boundaries will be determined using the actual observed and 
 
 
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the planned numbers of events at the time of interim analyses with the rule and spending functions 
specified in Section 3.8 – Multiplicity. The actual final boundaries will be adjusted accordingly.
Any changes to the timing of the analyses, along with its rationale, will be documented in the sSAP 
or a memo to the study file before the database lock. 
Of note, Protocol Amendment 05 occurred after the conduct of efficacy interim analysis 1 (IA1), 
and the following information regarding IA1 is based on the planned number of events and original 
multiplicity strategy specified in the protocol prior to Protocol Amendment 05. 
Interim Analysis 1 (Final ORR, Interim PFS and Interim OS Analysis)
The primary purpose of efficacy IA1 is to perform the final ORR, interim PFS and interim OS 
analysis. The ORR analysis at IA1 is considered the final ORR analysis of the study.  IA1 will be 
performed after: (1) enrollment is completed, and (2) ~ 9 months after the first 640 subjects 
randomized to Part 2.  
At IA1, ORR analyses will be based on data from the first ~ 640 subjects randomized to Part 2 and 
be tested in 1) all subjects and, 2) subjects with CPS ≥1. All subjects randomized on or prior to the 
date the 640th Part 2 subject is randomized will be included in the ORR analysis. 
The success boundary to demonstrate ORR superiority at IA1 approximately corresponds to an 
observed ORR difference of ~ 12.6 percentage points at α = 0.1% (one-sided) for all subjects, and 
an observed ORR difference of ~ 14.1 percentage points at nominal α = ~ 0.145% (one-sided) for
subjects with CPS ≥1, if there are 640 subjects in all subjects and 480 subjects in subjects with 
CPS ≥1 available for analysis (assuming PD-L1 positivity prevalence CPS ≥1 of 75%), 
respectively.
The estimated boundaries for PFS and OS endpoints at IA1 are provided in Table 6, assuming the 
planned numbers of events are analyzed.
Interim Analysis 2 (Interim OS Analysis and Final PFS Analysis)
The primary purpose of efficacy interim analysis 2 (IA2) is to evaluate superiority of 
pembrolizumab + chemotherapy vs placebo + chemotherapy in OS, and to perform final PFS 
analysis.  The analysis will be performed after ~ 185 OS events among subjects with CPS ≥10 
have been observed. It is estimated that at IA2 ~ 523 OS events among all subjects and ~ 375 OS 
events among subjects with CPS ≥1 have been observed. The analysis may be delayed for up to 4 
months if the planned number of OS events has not been reached in all subjects or in subjects with 
CPS ≥1. It is estimated that IA2 is expected to occur ~ 22 months after last subject randomized.
The estimated boundaries for PFS and OS endpoints at IA2 are provided in Table 6 and Table 7, 
assuming the planned numbers of events are analyzed.
Interim Analysis 3 (Interim OS Analysis)
The primary purpose of efficacy interim analysis 3 (IA3) is to evaluate superiority of 
pembrolizumab + chemotherapy vs placebo + chemotherapy in OS.  The analysis will be 
performed after ~ 210 OS events among subjects with CPS ≥10 have been observed. It is estimated 
 
 
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at IA3 ~ 589 OS events among all subjects and ~ 424 OS events among subjects with CPS ≥1 have 
been observed. The analysis may be delayed for up to 4 months if the planned number of OS events 
has not been reached in all subjects or in subjects with CPS ≥1. It is estimated that IA3 is expected 
to occur ~ 30 months after last subject randomized.
The estimated boundaries for OS endpoints at IA3 are provided in Table 6 and Table 7, assuming 
the planned numbers of events are analyzed.
Final Analysis (Final OS Analysis)
The final analysis (FA) of the study is event driven and will be conducted after approximately ~
664 OS events among all subjects, ~ 482 OS events among subjects with CPS ≥1, and ~ 240 OS 
events among subjects with CPS ≥10 have been observed. It is estimated that FA is expected to 
occur ~ 43 months after last subject randomized. If after 43 months after last subject randomized, 
the planned numbers of OS events still have not been observed, then the final OS analysis may be 
conducted at that time regardless. The success boundaries to demonstrate OS superiority at FA are 
presented in Table 6 and Table 7, if the planned numbers of OS events are analyzed.
Table 6 summarizes the timing, sample size and decision guidance of the 3 efficacy interim 
analyses and FA, assuming there is no alpha re-allocation among hypotheses.  ORR boundaries 
are based on the assumptions of 640 randomized subjects and 75% PD-L1 CPS ≥1 prevalence, and 
may be updated at time of the analyses using the actual observed numbers. PFS and OS boundaries 
are based on planned number of events and may be updated at times of the analyses according to 
the actual observed number of events, spending functions, and the spending time approach as 
specified in Section 3.8 – Multiplicity.
Table 6
Summary of Timing, Sample Size and Decision Guidance of Efficacy Interim 
Analyses and Final Analysis (Part 2, at Initial Alpha)
Analysis
Criteria for Conduct of Analysis
Endpoint 
and Testing 
Population
Parameter
Efficacy Bara, b
Interim Analysis 1:
Final ORR, Interim 
PFS and Interim OS 
Analysis
IA1 occurred ~ 4 months after last 
subject randomized.
IA1 was to be conducted when:
(1) enrollment is completed, and
(2) ~ 9 months after first 640 
subjects are randomized in Part 2
It was estimated that at IA1:
~ 500 PFS events among all 
subjects, ~ 360 PFS events among 
subjects with CPS ≥1, ~ 260 OS 
events among all subjects, and 
~ 185 OS events among subjects 
with CPS ≥1 have been observed.
ORR in all 
subjects
p-value (1-sided) at 
boundary
~ ORR difference at 
boundary
0.001
~ 12.6 percentage 
points
ORR in 
subjects with 
CPS ≥1
p-value (1-sided) at 
boundary
~ ORR difference at 
boundary
~ 0.00145c
~ 14.1 percentage 
points
PFS in all 
subjects
p-value (1-sided) at 
boundary
~ HR at boundary
0.0005
~ 0.73
PFS in 
subjects with 
CPS ≥1
p-value (1-sided) at 
boundary
~ HR at boundary
0.0005
~ 0.69
 
 
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Analysis
Criteria for Conduct of Analysis
Endpoint 
and Testing 
Population
Parameter
Efficacy Bara, b
OS in all 
subjects
p-value (1-sided) at 
boundary
~ HR at boundary
0.0004
~ 0.64
OS in subjects 
with CPS ≥1
p-value (1-sided) at 
boundary
~ HR at boundary
0.0004
~ 0.59
Interim Analysis 2: 
Interim OS 
Analysis/Final PFS 
Analysis
IA2 will be conducted after 
~ 185 OS events among subjects 
with CPS ≥10 have been observed d.
It is estimated that at IA2:
~ 523 OS events among all subjects, 
~ 375 OS events among subjects 
with CPS ≥1, ~ 634 PFS events 
among all subjects, ~ 463 PFS 
events among subjects with CPS ≥1, 
and ~ 235 PFS events among 
subjects with CPS ≥10 have been 
observed.
PFS in 
subjects with 
CPS ≥10
p-value (1-sided) at 
boundary
~ HR at boundary
0.00411
~ 0.69
OS in subjects 
with CPS ≥1
p-value (1-sided) at 
boundary
~ HR at boundary
0.0022
~ 0.73
OS in subjects 
with CPS ≥10
p-value (1-sided) at 
boundary
~ HR at boundary
0.0034
~ 0.66
Interim Analysis 3: 
Interim OS Analysis
IA3 will be conducted after 
~ 210 OS events among subjects 
with CPS ≥10 have been observed d.
It is estimated that at IA3:
~ 589 OS events among all subjects, 
~ 424 OS events among subjects 
with CPS ≥1 have been observed.
OS in subjects 
with CPS ≥1
p-value (1-sided) at 
boundary
~ HR at boundary
0.0036
~ 0.76
OS in subjects 
with CPS ≥10
p-value (1-sided) at 
boundary
~ HR at boundary
0.0050
~ 0.69
Final Analysis (FA): 
Final OS Analysis
FA will be conducted after e:
~ 664 OS events among all subjects, 
~ 482 OS events among subjects 
with CPS ≥1, and ~ 240 OS events 
among subjects with CPS ≥10 have 
been observed.
OS in subjects 
with CPS ≥1
p-value (1-sided) at 
boundary
~ HR at boundary
0.0060
~ 0.78
OS in subjects 
with CPS ≥10
p-value (1-sided) at 
boundary
~ HR at boundary
0.0082
~ 0.72
a. Efficacy bar represents boundary at which statistical significance supporting pembrolizumab + chemotherapy is 
superior to placebo + chemotherapy can be claimed.
b. Efficacy bars at IA1 are based on planned number of events and original multiplicity strategy specified in the protocol 
prior to Protocol Amendment 05. Efficacy bars at IA2/IA3/FA for OS in subjects with CPS ≥1 are based on the actual 
number of events at IA1 and planned numbers of events at IA2/IA3/FA.
c. Approximate nominal alpha based on the Spiessens and Debois method accounting for correlation between ORR in all 
subjects and ORR in subjects with CPS ≥1. The actual nominal alpha will be calculated based on the actual correlation 
between these two populations for testing.
d. IA2 and IA3 may be delayed for up to 4 months if the planned number of OS events in all subjects or in subjects with 
CPS ≥1 has not yet been reached.
e. FA may be conducted after 43 months post last patient randomized even if the planned numbers of events are not 
reached at that time.
 
 
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If a hypothesis is supported, the alpha can be re-allocated to another hypothesis following the pre-
specified rules in Section 3.8 – Multiplicity.  The hypotheses of PFS in all subjects, PFS in subjects 
with CPS ≥1, and OS in all subjects have initial alpha of 0% at IA2 (PFS) or IA2/IA3/FA (OS). 
As such, after IA1 they can only be tested after alpha re-allocation if relevant hypothesis(es) is 
supported. The efficacy decision guidance for these endpoints with respect to the re-allocated alpha 
from the support of other hypothesis(es) is summarized in Table 7 below (selected scenarios), 
assuming the planned numbers of events specified in Table 6 are available for analyses at each 
time point.  
If an efficacy boundary is crossed at IA1 or IA2 for PFS, or at an interim analysis or the FA for 
OS, in either all subjects or subjects with CPS ≥1 or CPS ≥10, the study will be declared to have 
met its primary objective. The study may continue till completion regardless of the results of the 
interim analyses to obtain mature OS data.
Of note, an assumption of 75% prevalence of PD-L1 CPS ≥1, and 38% prevalence of PD-L1 CPS 
≥10 in mTNBC subjects were made in above calculations.  The above timing, estimated event 
count, and criteria for interim and final analyses are subject to modification in the sSAP as needed 
based on emerging data on PD-L1 prevalence in mTNBC.
Table 7
Summary of Efficacy Decision Guidance after Alpha Re-Allocation (Part 2, 
Selected Scenarios)
Endpoint
Scenario
Total 
Alpha 
Allocated
Analysis
Efficacy Boundary (After Alpha 
Re-Allocation)
p-value (1-sided) 
at Boundary
Approx. HR at 
Boundary
H1:  PFS in all subjects 
(IA2)
H2 and H3 
supported
0.00111
IA2
0.00111
0.77
H2:  PFS in subjects 
with CPS ≥1 (IA2)
H3 
supported
0.00111
IA2
0.00111
0.74
H4:  OS in all subjects 
(IA2/IA3/FA)
H5 
supported
0.0075
IA2
0.0026
0.77
IA3
0.0038
0.79
FA
0.0060
0.81
3.8
Multiplicity
Part 1
Multiplicity adjustment is not applicable.
Part 2
The multiplicity strategy specified in this section will be applied to the 6 primary hypotheses and 
the 2 secondary hypotheses of Part 2:  primary hypotheses of superiority of pembrolizumab + 
chemotherapy compared to placebo + chemotherapy in PFS and OS in all subjects and in subjects 
with PD-L1 positive tumors (CPS ≥1 and CPS ≥10), and secondary hypotheses of superiority of 
 
 
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pembrolizumab + chemotherapy compared to placebo + chemotherapy in ORR in all subjects and 
in subjects with PD-L1 positive tumors (CPS ≥1).  
Based on emerging biomarker data external to this study, the initial alpha allocation among the 6 
primary hypotheses and 2 secondary hypotheses is revised in Protocol Amendment 05. The 
revision of the alpha allocation occurs after the conduct of efficacy IA1. The family-wise Type-I 
error rate for this study is strongly controlled at 2.5% (one-sided) across all 6 primary hypotheses 
on PFS and OS as well as 2 secondary hypotheses on ORR. Figure 1 displays the revised 
multiplicity strategy diagram of the study.  The initial one-sided alpha allocation for each 
hypothesis is shown in the rectangle representing the hypothesis. The weights for re-allocation 
from each hypothesis to the others are represented in the numbers along the lines connecting 
hypotheses. Overall, a total of 0.5% alpha is allocated to PFS endpoints, a total of 1.8% alpha is 
allocated to OS endpoints, and a total of 0.2% alpha is allocated to ORR endpoints.   
Table 8 also summarizes the revised initial alpha allocation before any alpha re-allocation.
Table 8
Initial Alpha Allocation
Hypothesis
Initial Alpha Allocation
H1: PFS in all subjects

0.043% allocated at IA1 (already spent at IA1).

0% allocated at IA2.
H2: PFS in subjects with CPS ≥1

0.046% allocated at IA1 (already spent at IA1).

0% allocated at IA2.
H3: PFS in subjects with CPS ≥10

0.411% allocated at IA2 only
H4: OS in all subjects

0.039% allocated at IA1 (already spent at IA1).

0% allocated at IA2/IA3/FA (group sequential).
H5: OS in subjects with CPS ≥1

0.75% allocated to IA1/IA2/IA3/FA (group sequential), which 
includes 0.036% spent at IA1.
H6: OS in subjects with CPS ≥10

1.011% allocated to IA2/IA3/FA (group sequential).
H7: ORR in all subjects

0.1% allocated at IA1 only (already spent at IA1).
H8: ORR in subjects with CPS ≥1

0.1% allocated at IA1 only (already spent at IA1).
An extension [1] of the graphical approach of Maurer and Bretz [2] will be used with the following 
figure to allocate and re-allocate alpha between hypotheses.  Testing will first be performed in 
subjects with CPS ≥1 for a treatment effect on ORR (H8).  If H8 is supported (ie, the null 
hypothesis is rejected), then the corresponding alpha can be added to that allocated for evaluating 
the treatment effect on ORR in all subjects (H7).  If H7 is supported, then the corresponding alpha 
can be re-allocated to PFS in subjects with CPS ≥10 (H3). If H3 is supported, then the 
corresponding alpha can be re-allocated, 27% to PFS in subjects with CPS ≥1 (H2 at IA2 only), 
and 73% to OS in subjects with CPS ≥10 (H6).  If H2 is supported, the alpha for that hypothesis 
 
 
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can be re-allocated to PFS in all subjects (H1 at IA2 only).  If H1 is supported, the alpha for that 
hypothesis can be re-allocated to OS in subjects with CPS ≥10 (H6).  If H6 is supported, the alpha 
for that hypothesis can then be re-allocated to OS in subjects with CPS ≥1 (H5). If H5 is supported, 
the alpha for that hypothesis can then be re-allocated to OS in all subjects (H4 at IA2/IA3/FA). If 
H4 is supported, at IA2/IA3/FA, the alpha for that hypothesis can be re-allocated back to H7.
In the above multiplicity strategy, actual alpha spent at IA1 was calculated based on the original 
pre-specified alpha allocation strategy prior to Protocol Amendment 05 by the pre-specified alpha 
spending functions, using the actual spending time calculated from the planned and observed 
information fractions at IA1. Under the revised alpha allocation, actual alpha spent at IA1 for PFS 
in all subjects (H1), PFS in subjects with CPS ≥1 (H2), and OS in all subjects (H4) will be kept 
intact by a Bonferroni approach to strongly control the family-wise Type-I error rate at one-sided 
2.5%. After IA1, these alphas will no longer be re-allocated to other hypotheses under the graphical 
approach, nor can they be used to account for correlation among group sequential tests within each 
endpoint across different time points. As such, the revised total alpha after IA1 is now 2.5% -
0.043% (alpha spent at IA1 for H1) - 0.046% (alpha spent at IA1 for H2) - 0.039% (alpha spent at 
IA1 for H4) ~= 2.37% for all hypotheses (all numbers rounded, the actual alpha for testing will be 
calculated based on the actual alpha spent for H1, H2 and H4 at IA1 with high precision). The 
0.036% alpha spent at IA1 for H5 will be part of the new initial alpha of 0.75% for H5. Of note, a 
0% initial alpha is now assigned to PFS in all subjects at IA2, PFS in subjects with CPS ≥1 at IA2, 
and OS in all subjects at IA2/IA3/FA. These endpoints at these specific timepoints are now part of 
the graphical approach and can still be tested if a positive alpha can be re-allocated to them after 
the success of testing relevant hypothesis(es). For example, if PFS in CPS ≥10 is supported at IA2, 
a one-sided alpha of 0.111% (0.411% × 0.27) will be re-allocated to PFS in CPS ≥1 at IA2 for 
testing. In addition, if a positive alpha can be re-allocated to OS in all subjects (H4) at either IA2, 
IA3 or FA, then a Lan-DeMets O'Brien-Fleming alpha-spending function will be used to distribute 
the alpha among IA2, IA3, and FA for appropriate testing at each time point, respectively.
For OS endpoints, a Lan-DeMets O'Brien-Fleming approximation alpha-spending function is 
constructed to implement group sequential boundaries that control the Type-I error. Spending time 
will be plugged into the pre-specified spending function to calculate alpha spending. At the time 
of IA1(as applicable), IA2, and IA3 for OS, the spending time will be the minimum of the actual 
observed information fraction and the planned information fraction for each endpoint, respectively
(with the exception of OS in subjects with CPS ≥1 at IA1, please see next paragraph). At the time 
of FA for OS endpoints, the spending time will be 1. Of note, while the spending time used for 
alpha-spending calculation will be the minimum of the actual observed information fraction and 
the planned information fraction, the correlations used for computing bounds for each endpoint 
will still be from that endpoint depending on the actual event counts. The rationale for the above 
strategy is to ensure that full Type-I error is spent at the final analysis without overspending at the 
interim. Justification for the spending time approach can be found in Anderson et.al. [1]. Of note, 
prior to Protocol Amendment 05, a Hwang-Shih-DeCani alpha-spending function with gamma 
parameter (-4) was constructed to implement group sequential boundaries that control the Type-I 
error for PFS endpoints, and it is no longer applicable under Protocol Amendment 05.
For OS in subjects with CPS ≥1 (H5), the revised initial alpha is 0.75% which includes 0.036% 
already spent at IA1. In order to account for the 0.036% alpha already spent at IA1 for H5 under 
initial alpha allocation, the spending time at IA1 will be fixed at 56.1% such that the corresponding 
 
 
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alpha distributed at IA1 using the Lan-DeMets O'Brien-Fleming spending function with a total 
initial alpha of 0.75% remains 0.036%.
The Spiessens and Debois method [3] will be used to calculate the nominal alpha of ORR in 
subjects with CPS ≥1 after accounting for the correlation between ORR endpoints in these two 
populations, while fixing the nominal alpha at 0.001 for ORR in all subjects. The actual observed 
correlation will be used for this adjustment in the analysis. Of note, if at IA2, IA3 or FA, additional 
alpha can be reallocated to H7 (e.g., H4 is not successful at IA1 but successful at IA2), the p-value 
of ORR in all subjects obtained from IA1 will be re-evaluated using the updated alpha threshold 
at that time.  Similarly, if at IA3 or FA additional alpha can be re-allocated to PFS endpoint(s), the 
p-value of PFS endpoint(s) obtained from IA2 will be re-evaluated using the updated alpha 
threshold at that time.
Figure 1
Multiplicity Strategy
a
a Nominal alpha for testing will be calculated based on Spiessens and Debois method accounting for correlation 
between ORR in all subjects and ORR in subjects with CPS ≥1. Of note, while the nominal alpha will be calculated 
and used for testing, the allocated alpha (0.001) will be passed to H7 when applicable.
b H5 α=0.0075 which includes 0.00036 already spent at IA1.
Note: The shaded boxes in this figure represent alpha that has already been spent at IA1 and will be considered lost 
for future analyses. These alphas will no longer be re-allocated to other hypotheses under the graphical approach, nor 
can they be used to account for correlation among group sequential tests within each endpoint across different time 
points.
 
 
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3.9
Sample Size and Power Calculations
Part 1
Part 1 of the study will enroll approximately 30 subjects.  For each treatment with 10 subjects 
available for analysis, if the underlying incidence rate of a given type of AE is 5% or 10%, there 
is 40% or 65% chance of observing at least one AE among the 10 subjects, respectively.  If no AE 
of a given type is observed among the 10 subjects, this study part will provide 80% confidence 
that the underlying percentage of subjects with the AE is <14.9% (90% confidence that the 
underlying rate of the AE is <20.6%) in the study population treated with the study treatment.
Part 2
Part 2 of the study will randomize approximately 828 subjects in a 2:1 ratio between the 
pembrolizumab + chemotherapy and the placebo + chemotherapy arms. 
Randomization will be implemented centrally using IVRS and will be monitored on a regular basis.  
When IVRS alerts study is approaching the desired enrollment, screening should be stopped in 
time.  However, subjects already in screening phase may be enrolled even after the maximum 
sample size has been reached.
Power considerations for each endpoint are described below.
PFS 
The PFS power calculation is based on the following assumptions:  1) PFS follows an exponential 
distribution with a median of 5.5 months in the placebo + chemotherapy arm in all populations (all 
subjects, subjects with CPS ≥1, and subjects with CPS ≥10); 2) An enrollment period of 17 months 
for Part 2; 3) A yearly drop-out rate of 30%; 4) the true HR is 0.70, 0.62, and 0.60 for PFS in all 
subjects, subjects with CPS ≥1, and subjects with CPS ≥10, respectively.  In addition, prior to 
Protocol Amendment 05, a Hwang-Shih-DeCani alpha-spending function with gamma parameter 
(-4) was constructed to implement group sequential boundaries that control the Type-I error for 
PFS endpoints.
Any change to the timing of the PFS analyses, along with its rationale, will be documented in the 
sSAP or a memo to the study file before the database lock.
PFS in all subjects
At IA1 it was expected that approximately 500 PFS events would have been accumulated among 
all subjects.  An alpha of ~0.05% was to be allocated to PFS in all subjects at this analysis (subject 
to change according to the actual number of PFS events at IA1, based on the alpha-spending 
function with a total of 0.1% alpha originally allocated to PFS in all subjects).  If the planned 
number of events of 500 was analyzed, this analysis had ~ 67% power to demonstrate that 
pembrolizumab + chemotherapy is superior to placebo + chemotherapy, if the underlying HR is 
0.70.
 
 
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At IA2 of the study, PFS in all subjects will only be tested if both hypotheses of PFS in subjects 
with CPS ≥1 and PFS in subjects with CPS ≥10 are supported. It is expected that approximately 
634 PFS events will be observed among all subjects at IA2.  A final PFS analysis will be performed 
at IA2.  This analysis has ~ 89% power to demonstrate that pembrolizumab + chemotherapy is 
superior to placebo + chemotherapy for PFS in all subjects at a one-sided 0.111% alpha level, if 
the underlying HR is 0.70. 
PFS in subjects with CPS ≥1
At IA1 it was expected that approximately 360 PFS events would have been observed among 
subjects with CPS ≥1.  An alpha of ~0.05% was to be allocated to PFS in subjects with CPS ≥1 at 
this analysis (subject to change according to the actual number of PFS events at IA1, based on the 
alpha-spending function with a total of 0.1% alpha originally allocated to PFS in subjects with 
CPS ≥1).  If the planned number of events of 360 was analyzed, this analysis had ~ 83% power to 
demonstrate that pembrolizumab + chemotherapy is superior to placebo + chemotherapy, if the 
underlying HR is 0.62.
At IA2 of the study, PFS in subjects with CPS ≥1 will only be tested if the hypothesis of PFS in 
subjects with CPS ≥10 is supported. It is expected that approximately 463 PFS events will be 
observed among subjects with CPS ≥1 at IA2.  A final PFS analysis will be performed at IA2. This 
analysis has ~ 97% power to demonstrate that pembrolizumab + chemotherapy is superior to
placebo + chemotherapy for PFS in subjects with CPS ≥1 at a one-sided 0.111% alpha level, if the 
underlying HR is 0.62.
PFS in subjects with CPS ≥10
At IA2 of the study, it is expected that approximately 235 PFS events would have been observed 
among subjects with CPS ≥10.  The only PFS analysis in subjects with CPS ≥10 will be performed 
at IA2.  The analysis has ~ 86% power to demonstrate that pembrolizumab + chemotherapy is 
superior to placebo + chemotherapy for PFS in subjects with CPS ≥10 at a one-sided 0.411% alpha 
level, if the underlying HR is 0.60.
OS 
The sample size and OS power calculation is based on the following assumptions:  1) OS follows 
an exponential distribution with a median of 17.5 months in the placebo + chemotherapy arm in 
all populations (all subjects, subjects with CPS ≥1 and subjects with CPS ≥10); 2) An enrollment 
period of 17 months for Part 2 and a minimum of 43 months follow-up after enrollment completion; 
3) A yearly dropout rate of 3%; 4) the true HR is 0.80, 0.71, and 0.65 for OS in all subjects, subjects 
with CPS ≥1, and subjects with CPS ≥10, respectively.  In addition, a Lan-DeMets O'Brien-
Fleming approximation alpha-spending function was constructed to implement group sequential 
boundaries that control the Type-I error for OS endpoints.
Any change to the timing of the OS analyses, along with its rationale, will be documented in the 
sSAP or a memo to the study file before the database lock.
 
 
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OS in all subjects
After IA1, OS in all subjects can be tested if hypothesis of OS in subjects with CPS ≥1 is supported. 
With ~ 664 OS events among all subjects at the final OS analysis, the trial has ~ 60% power to 
demonstrate that pembrolizumab + chemotherapy is superior to placebo + chemotherapy at a one-
sided 0.75% alpha level, if the underlying HR is 0.80.
If the planned numbers of events are 
analyzed, success boundary for OS in all subjects at FA approximately corresponds to an observed 
HR of ~ 0.81 (~ 4.0 months improvement over a control median OS of 17.5 months).
OS in subjects with CPS ≥1
It is expected that ~ 482 OS events will have occurred among subjects with CPS ≥1 at the final OS 
analysis.  For OS in subjects with CPS ≥1, the trial has ~ 87% power to demonstrate that 
pembrolizumab + chemotherapy is superior to placebo + chemotherapy at a one-sided 0.75% 
alpha-level, if the underlying HR is 0.71.  If the planned numbers of events are analyzed at 
IA2/IA3/FA, success boundary for OS in subjects with CPS ≥1 at FA approximately corresponds 
to an observed HR of ~ 0.78 (~ 4.8 months improvement over a control median OS of 17.5 
months).
OS in subjects with CPS ≥10
It is expected that ~ 240 OS events will have occurred among subjects with CPS ≥10 at the final 
OS analysis.  For OS in subjects with CPS ≥10, the trial has ~ 79% power to demonstrate that 
pembrolizumab + chemotherapy is superior to placebo + chemotherapy at a one-sided 1.011% 
alpha-level, if the underlying HR is 0.65.  If the planned numbers of events are analyzed, success 
boundary for OS in subjects with CPS ≥10 at FA approximately corresponds to an observed HR 
of ~ 0.72 (~ 6.8 months improvement over a control median OS of 17.5 months).
ORR
The ORR power calculation is based on the following assumptions:  1) under initial alpha allocated 
to ORR hypotheses; 2) the underlying ORR is 29% in the placebo + chemotherapy arm, and there 
is 15 or 18 percentage points increase in ORR in the pembrolizumab + chemotherapy arm (ORR 
of 44% or 47%), in both all subjects and in subjects with CPS ≥1, respectively.  The power for
ORR endpoints is summarized in Table 9.
 
 
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Table 9
Power for ORR
Population
N
Nominal 
Alpha
~ ORR Difference at 
Success Boundary
True 
ORR 
Difference
Power
All Subjects
640
0.001
12.6 percentage points
15 percentage points
72%
18 percentage points
91%
Subjects with CPS ≥1
480
0.00145a
14.1 percentage points
15 percentage points
58%
18 percentage points
80%
a Approximate nominal alpha based on the Spiessens and Debois method accounting for correlation between 
ORR in all subjects and ORR in subjects with CPS ≥1. The actual nominal alpha will be calculated based on the 
actual correlation between these two populations.
Assume 29% ORR in the placebo + chemotherapy arm.
Assume 75% PD-L1 CPS ≥1 prevalence.
The assumptions for a median PFS of 5.5 months, median OS of 17.5 months, and an ORR of 29% 
in the placebo + chemotherapy arm are based on the estimates from Miles et al., 2013 [15], and 
the Phase III trial reported in O’Shaughnessy et al., 2014 [16].
The sample size and power calculations were performed in the software R (package “gsDesign”).
Of note, the assumptions of 75% prevalence of PD-L1 CPS ≥1, 38% prevalence of PD-L1 CPS 
≥10 in mTNBC subjects and low discrepancy rate (e.g., <10%) between central and local 
determinations of baseline measurable disease were made in above calculations. The above 
assumptions and sample size calculations are subject to modification as needed based on emerging 
data on PD-L1 prevalence in mTNBC as well as correlation between PD-L1 expression and 
treatment effect, and/or emerging data on the discrepancy rate between central and local 
determinations of baseline measurable disease in mTNBC subjects.
Although safety issues are not expected for any of the pembrolizumab and chemotherapy 
combinations in this study, if one or more of the chemotherapy options (i.e., nab-paclitaxel, 
paclitaxel, or gemcitabine/carboplatin) is stopped because of a safety issue, then the Part 2 primary 
analyses will be restricted to the remaining chemotherapy option(s) and the Part 2 sample size will 
be based on only those remaining option(s).
 
 
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3.10
Subgroup Analyses and Effect of Baseline Factors
Part 1
There is no planned subgroup analysis for Part 1.
Part 2
To determine whether the treatment effect is consistent across various subgroups, the estimate of 
the between-group treatment effect (with a nominal 95% CI) for the primary endpoints will be 
estimated and plotted within each category of the following classification variables: 

Chemotherapy on study (nab-paclitaxel vs paclitaxel vs gemcitabine/carboplatin; taxane 
vs gemcitabine/carboplatin).

Tumor PD-L1 status (CPS ≥1 vs CPS <1; CPS ≥5 vs CPS <5; CPS ≥10 vs CPS <10; CPS 
≥15 vs CPS <15; CPS ≥20 vs CPS <20). Note:  these subgroup analyses will only be 
conducted in the all subjects population.

Prior treatment with same class of chemotherapy in the (neo)adjuvant setting (yes vs no).

Prior (neo)adjuvant chemotherapy (yes vs no)

Prior (neo)adjuvant taxane treatment (yes vs no)

Prior (neo)adjuvant platinum treatment (yes vs no)

Menopausal status (for females only; pre- vs post-menopausal)

Age (<65 years vs ≥65 years)

Geographic region (Europe/Israel/North America/Australia vs Asia vs Rest of World) 

Ethnic origin (Hispanic vs Non-Hispanic)

ECOG status (0 vs 1)

HER2 status (2+ by IHC vs 0-1+ by IHC)

Disease-free interval (de novo metastasis vs <12 months vs ≥12 months)

Number of metastatic sites (<3 vs ≥3)

Visceral disease (yes vs no)

LDH (≥2.0 x Upper Limit of Normal [ULN] vs <2.0 x ULN)
3.11
Compliance (Medication Adherence)
Part 1 and Part 2
Drug accountability data for study treatment will be collected during the study.  Any deviation 
from protocol-directed administration will be reported. 
3.12
Extent of Exposure
Part 1 and Part 2 
The extent of exposure will be summarized as duration of treatment in number of cycles or 
administrations as appropriate.
 
 
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4.
REFERENCES
[1] K. Anderson, L. Wang and C. Gause, "Application of graphical multiplicity methods in 
complex group sequential trials," Merck & Co., Inc. (US), Kenilworth (NJ), 2017.
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Approaches," Statistics in Biopharmaceutical Research, vol. 5, no. 4, pp. 311-320, 2013. 
[3] B. Spiessens and M. Debois, "Adjusted significance levels for subgroup analyses in clinical 
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[4] H. Uno, B. Claggett, L. Tian, E. Inoue, P. Gallo and T. Miyata, "Moving beyond the hazard 
ratio in quantifying the between-group difference in survival analysis," Journal of Clinical 
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[5] P. Odell, K. Anderson and W. Kannel, "New models for predicting cardiovascular events," 
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[6] D. Mehrotra, S. Su and X. Li, "An efficient alternative to the stratified Cox model analysis," 
Statistics in Medicine, vol. 31, no. 17, pp. 1849-1856, 2012. 
[7] D. Finkelstein, "A proportional hazards model for interval-censored failure time data," 
Biometrics, vol. 42, pp. 845-854, 1986. 
[8] J. Robins and A. Tsiatis, "Correcting for non-compliance in randomized trials using rank 
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[9] N. R. Latimer and K. R. Abrams, "NICE DSU Technical Support Document 16: Adjusting 
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[10] T. G. Karrison, "Versatile tests for comparing survival curves based on weighted log-rank 
statistics," The Stata Journal, vol. 16, no. 3, p. 678–690, 2016. 
[11] M. van Reenen and M. Oppe, EQ-5D-3L User Guide V5.1, 2015. 
[12] P. Fayers, N. Aaronson, K. Bjordal, M. Groenvold, D. Curran and A. Bottomley, EORTC 
QLQ-C30 Scoring Manual (3rd edition), Brussels: EORTC, 2001. 
[13] K. Liang and S. Zeger, "Longitudinal data analysis of continuous and discrete responses for 
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2000. 
 
 
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[14] O. Miettinen and M. Nurminen, "Comparative analysis of two rates," Statistics in Medicine, 
no. 4, pp. 213-226, 1985. 
[15] D. Miles, V. Dieras, J. Cortes, A. Duenne, J. Yi and J. OShaughnessy, "First-line 
bevacizumab in combination with chemotherapy for HER2-negative metastatic breast 
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24, no. 11, pp. 2773-2780, 2013. 
[16] J. O'Shaughnessy, L. Schwartzberg, M. Danso, K. Miller, H. Rugo and M. Neubauer, "Phase 
III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in 
patients with metastatic triple-negative breast cancer," Journal of Clinical Oncology, vol. 32, 
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