Clinical trial NCT03715205
Conditions: Carcinoma, Non-Small-Cell Lung Melanoma
Keywords: programmed cell death 1 (PD-1, PD1) programmed cell death ligand 1 (PD-L1, PDL1) programmed cell death ligand 2 (PD-L2, PDL2)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2019-01-31; Completion date: 2024-08-21
Enrollment: 150 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study has been designed to evaluate the safety of pembrolizumab in participants in India with unresectable or metastatic melanoma and participants with non-small cell lung cancer (NSCLC) who are either untreated (programmed cell death ligand 1 \[PD-L1\] ≥50%) or have experienced disease progression after a platinum-containing systemic therapy (PD-L1 ≥1%).

Detailed description:

Arms: arm 1: Participants with melanoma or NSCLC receive 200 mg of pembrolizumab as an intravenous (IV) infusion every 3 weeks (Q3W) for up to 35 cycles.
Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: Administered as an intravenous (IV) infusion every 3 weeks (Q3W)

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Prospective, Open-label, Phase 4 Study to Evaluate 
the Safety of Pembrolizumab
(KEYTRUDA®) in Subjects with Unresectable or 
Metastatic Melanoma or PD-L1 positive Non-small 
Cell Lung Cancer (NSCLC) in India (Keynote-593)
NCT03715205
28-Jun-2022


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28-Jun-2022
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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 Prospective, Open-label, Phase 4 Study to Evaluate the Safety of Pembrolizumab 
(KEYTRUDA®) in Subjects with Unresectable or Metastatic Melanoma or PD-L1 positive 
Non-small Cell Lung Cancer (NSCLC) in India (Keynote-593)
EudraCT NUMBER:  Not Applicable
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 10
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 12
2.0
TRIAL DESIGN........................................................................................................ 13
Trial Design ........................................................................................................... 13
Trial Diagram........................................................................................................ 13
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 14
Primary Objective(s) & Hypothesis(es).............................................................. 14
Secondary Objective(s) & Hypothesis(es)........................................................... 14
4.0
BACKGROUND & RATIONALE.......................................................................... 14
Background ........................................................................................................... 14
Pharmaceutical and Therapeutic Background .................................................... 14
Programmed Cell Death 1 as a Target in Cancer Treatment: ...................... 14
Melanoma Background................................................................................ 15
Therapies in Melanoma................................................................................ 15
Pembrolizumab in Treatment of Metastatic Melanoma............................... 18
Lung Cancer Background ............................................................................ 18
Therapies in Non-Small Cell Lung Cancer.................................................. 19
Pembrolizumab in Treatment of Non-Small Cell Lung Cancer .................. 20
Rationale................................................................................................................ 21
Rationale for the Trial and Selected Subject Population .................................... 21
Rationale for Dose Selection/Regimen/Modification......................................... 21
Rationale for the Use of Comparator/Placebo ............................................. 22
Rationale for Endpoints ...................................................................................... 22
Efficacy Endpoints....................................................................................... 22
Safety Endpoints.......................................................................................... 22
Planned Exploratory Biomarker Research................................................... 22
Future Biomedical Research........................................................................ 22
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Benefit/Risk ........................................................................................................... 22
5.0
METHODOLOGY ................................................................................................... 23
Entry Criteria........................................................................................................ 23
Diagnosis/Condition for Entry into the Trial...................................................... 23
Subject Inclusion Criteria.................................................................................... 23
Subject Exclusion Criteria .................................................................................. 27
Trial Treatment(s) ................................................................................................ 29
Dose Selection/Modification .............................................................................. 29
Dose Selection (Preparation) ....................................................................... 29
Dose Modification (Escalation/Titration/Other).......................................... 30
5.2.1.2.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).......................................................................................... 30
Timing of Dose Administration.......................................................................... 37
Trial Blinding...................................................................................................... 37
Randomization or Treatment Allocation............................................................ 37
Stratification.......................................................................................................... 37
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 37
Acceptable Concomitant Medications ................................................................ 38
Prohibited Concomitant Medications.................................................................. 38
Rescue Medications & Supportive Care............................................................. 39
Supportive Care Guidelines ................................................................................ 39
Diet/Activity/Other Considerations..................................................................... 39
Diet...................................................................................................................... 39
Contraception...................................................................................................... 39
Pregnancy............................................................................................................ 41
Use in Nursing Women....................................................................................... 41
Subject Withdrawal/Discontinuation Criteria................................................... 41
Discontinuation of Treatment ............................................................................. 41
Withdrawal from the Trial .................................................................................. 42
Subject Replacement Strategy............................................................................. 43
Beginning and End of the Trial ........................................................................... 43
Clinical Criteria for Early Trial Termination ................................................... 43
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6.0
TRIAL FLOW CHART ........................................................................................... 44
7.0
TRIAL PROCEDURES ........................................................................................... 48
Trial Procedures ................................................................................................... 48
Administrative Procedures.................................................................................. 48
Informed Consent......................................................................................... 48
7.1.1.1.1
General Informed Consent.................................................................... 48
Inclusion/Exclusion Criteria ........................................................................ 49
Subject Identification Card .......................................................................... 49
Medical History ........................................................................................... 49
7.1.1.4.1
Subsequent Antineoplastic Therapy Status........................................... 49
Prior and Concomitant Medications Review ............................................... 49
7.1.1.5.1
Prior Medications.................................................................................. 49
7.1.1.5.2
Concomitant Medications..................................................................... 49
Assignment of Screening Number............................................................... 50
Assignment of Treatment/Randomization Number..................................... 50
Trial Compliance (Medication/Diet/Activity/Other)................................... 50
Clinical Procedures/Assessments........................................................................ 50
Review Adverse Events ............................................................................... 50
Eastern Cooperative Oncology Group Performance Status......................... 51
Physical Examination................................................................................... 51
Vital Signs and Weight................................................................................ 51
12-Lead Electrocardiograms........................................................................ 51
Administration of Pembrolizumab (30-minute Infusion) ............................ 51
Laboratory Procedures/Assessments .................................................................. 51
Laboratory 
Safety 
Evaluations 
(Hematology, 
Chemistry, 
and 
Urinalysis).................................................................................................... 51
Pregnancy Test............................................................................................. 53
Other Procedures................................................................................................. 53
Withdrawal/Discontinuation........................................................................ 53
7.1.4.1.1
Lost to Follow-up.................................................................................. 53
Subject Blinding/Unblinding ....................................................................... 53
Calibration of Equipment............................................................................. 54
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Tumor and Brain Imaging............................................................................ 54
Tumor Biopsy/Archival Tissue Collection, NSCLC Subjects Only............ 55
Visit Requirements.............................................................................................. 55
Screening...................................................................................................... 55
Treatment Period.......................................................................................... 55
Safety Follow-Up Visit................................................................................ 55
Discontinued Subjects Continuing to be Monitored in the Trial................. 56
Assessing and Recording Adverse Events .......................................................... 56
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 57
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 57
Immediate Reporting of Adverse Events to the Sponsor.................................... 58
Serious Adverse Events ............................................................................... 58
Events of Clinical Interest............................................................................ 59
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 60
Evaluating Adverse Events................................................................................. 60
Sponsor Responsibility for Reporting Adverse Events ...................................... 63
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 63
Statistical Analysis Plan Summary ..................................................................... 63
Responsibility for Analyses/In-House Blinding ................................................. 64
Hypotheses/Estimation......................................................................................... 64
Analysis Endpoints ............................................................................................... 64
Safety Endpoints ................................................................................................. 64
Analysis Populations............................................................................................. 64
Safety Analysis Populations ............................................................................... 64
Statistical Methods................................................................................................ 64
Statistical Methods for Safety Analyses ............................................................. 64
Summaries of Baseline Characteristics, Demographics, and Other Analyses.... 65
Interim Analyses ................................................................................................... 65
Safety Interim Analyses...................................................................................... 65
Multiplicity ............................................................................................................ 65
Sample Size and Power Calculations .................................................................. 65
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Sample Size and Power for Safety Analyses ...................................................... 65
Subgroup Analyses ............................................................................................... 66
Compliance (Medication Adherence).................................................................. 66
Extent of Exposure................................................................................................ 66
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 66
Investigational Product ........................................................................................ 66
Packaging and Labeling Information ................................................................. 67
Clinical Supplies Disclosure................................................................................. 67
Storage and Handling Requirements.................................................................. 67
Discard/Destruction/Returns and Reconciliation .............................................. 67
Standard Policies................................................................................................... 67
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 68
Confidentiality....................................................................................................... 68
Confidentiality of Data ....................................................................................... 68
Confidentiality of Subject Records..................................................................... 68
Confidentiality of Investigator Information........................................................ 68
Confidentiality of IRB/IEC Information............................................................. 69
Compliance with Financial Disclosure Requirements....................................... 69
Compliance with Law, Audit and Debarment ................................................... 69
Compliance with Trial Registration and Results Posting Requirements........ 71
Quality Management System............................................................................... 71
Data Management................................................................................................. 71
Publications ........................................................................................................... 72
11.0
LIST OF REFERENCES......................................................................................... 73
12.0
APPENDICES........................................................................................................... 79
Code of Conduct for Clinical Trials.................................................................... 79
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
by Sample Types ................................................................................................... 82
Common Terminology Criteria for Adverse Events v4. ................................... 83
Eastern Cooperative Oncology Group................................................................ 84
Response Evaluation Criteria in Solid Tumors ................................................. 85
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List of Abbreviations ............................................................................................ 86
13.0
SIGNATURES........................................................................................................... 89
Sponsor's Representative ..................................................................................... 89
Investigator............................................................................................................ 89
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LIST OF TABLES
Table 1
Data From Randomized Controlled Trials With Dacarbazine in Advanced 
Melanoma 1999-2014..................................................................................... 16
Table 2
Adequate Organ Function Laboratory Values................................................ 26
Table 3
Trial Treatment ............................................................................................... 29
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .............................................................. 31
Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ....................................................................................................... 36
Table 6
Laboratory Tests ............................................................................................. 52
Table 7
Evaluating Adverse Events............................................................................. 61
Table 8
Analysis Strategy for Safety Parameters......................................................... 65
Table 9
Product Descriptions....................................................................................... 66
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LIST OF FIGURES
Figure 1
Clinical Trial Design....................................................................................... 13
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 05
28-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.
Amendment 04
03-JUN-2021
Text added or edited for clarity
Amendment 03
14-DEC-2018
Text added or edited for clarity
Amendment 02
17-MAY-2018
Text added for clarity
Amendment 01
27-NOV-2017
Text added for clarity
Original Protocol
22-DEC-2016
N/A
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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 CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
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1.0 TRIAL SUMMARY
Abbreviated Title
A Prospective, Open-label, Phase 4 Study to Evaluate the Safety of 
Pembrolizumab (KEYTRUDA®) in Subjects with Unresectable or 
Metastatic Melanoma or PD-L1 positive Non-small Cell Lung Cancer 
(NSCLC) in India (Keynote-593)
Sponsor Product Identifiers
MK-3475
Pembrolizumab (Keytruda®)
Trial Phase
4
Clinical Indication
Unresectable or metastatic melanoma, and non-small cell lung cancer 
(NSCLC) subjects who are either untreated (PD-L1 ≥50%) or have 
experienced disease progression after a platinum-containing systemic 
therapy (PD-L1 ≥1%)
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
Pembrolizumab (Keytruda®)
Number of trial subjects
Approximately 150 subjects will be enrolled, with a minimum of 25 
unresectable or metastatic melanoma subjects.
Estimated duration of trial
The Sponsor estimates the trial will end approximately 2 years from the 
time the last subject provides documented informed consent.
Duration of Participation
Each subject will participate in the trial from the time the subject provides
documented
informed consent through the final protocol-specified 
contact.  
After a screening phase of 30 days, each subject will be assigned to 
receive trial treatment with pembrolizumab monotherapy until disease 
progression is confirmed by the site per Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1), unacceptable adverse event(s), intercurrent 
illness that prevents further administration of treatment, Investigator’s 
decision to withdraw the subject, non-compliance with trial treatment or 
procedures requirements or administrative reasons requiring cessation of 
treatment, or until the subject has received 35 cycles of pembrolizumab 
(approximately 2 years), whichever occurs first. Each cycle is defined as 
21 days.
After the end of treatment, each subject will be followed for the 
occurrence of adverse events and spontaneously reported pregnancy as 
described under Section 7.2 of the protocol.  
Subjects who discontinue for reasons such as radiologic or clinical disease 
progression, safety events, or investigator or subject decision to stop 
treatment will have an end of treatment (EOT) visit and a 30-day safety 
follow-up visit per Section 7.1.4.1.
A list of abbreviations used in this document can be found in Section 12.6.
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2.0 TRIAL DESIGN
Trial Design
This is a nonrandomized, open-label Phase 4 trial to evaluate the safety of pembrolizumab in 
India in subjects with unresectable or metastatic melanoma, and non-small cell lung cancer 
(NSCLC) subjects who are either untreated (programmed cell death ligand 1 [PD-L1] ≥50%) 
or have experienced disease progression after a platinum-containing systemic therapy 
(PD-L1 ≥1%). The trial will be conducted in conformance with Good Clinical Practices
(GCP). Approximately 150 subjects are planned to be enrolled in this study in India, with a 
minimum of 25 unresectable or metastatic melanoma subjects. Subjects who are eligible per 
this protocol to receive a fixed dose of 200 mg intravenous (IV) pembrolizumab every 3 
weeks for up to 35 cycles will be enrolled after obtaining documented informed consent and 
audiovisual recording of the consenting process, as per local regulatory requirements.
Subjects will have a follow-up visit 30 days after the last dose of pembrolizumab or before 
the start of a new antineoplastic therapy, whichever is earlier. The objective of this study is to 
assess the safety of pembrolizumab in India in subjects with unresectable or metastatic 
melanoma, and metastatic and advanced NSCLC subjects who are either untreated 
(PD-L1 ≥50%) or have experienced disease progression after a platinum-containing systemic 
therapy (PD-L1 ≥1%). This is not a hypothesis-driven study.
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.
Trial Diagram
The trial design is depicted in Figure 1.
Figure 1
Clinical Trial Design
*
Follow-up visit 30 days after the last dose of pembrolizumab or before the start of a new antineoplastic therapy,
whichever is earlier.
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
This study has been designed to evaluate the safety of pembrolizumab in India in subjects 
with unresectable or metastatic melanoma, and NSCLC subjects who are either untreated 
(PD-L1 ≥50%) or have experienced disease progression after a platinum-containing systemic 
therapy (PD-L1 ≥1%) (KEYNOTE-593). There will be no formal hypothesis testing 
performed in this study.
Primary Objective(s) & Hypothesis(es)
(1) Objective: To assess the safety of pembrolizumab in India in subjects with unresectable 
or metastatic melanoma, and NSCLC subjects who are either untreated (PD-L1 ≥50%) or 
have experienced disease progression after a platinum-containing systemic therapy 
(PD-L1 ≥1%).
Secondary Objective(s) & Hypothesis(es)
There are no secondary objectives for this trial.
4.0 BACKGROUND & RATIONALE
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with PD-L1 and programmed cell death ligand 2 (PD-L2).  Based on 
preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking 
activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda™ (pembrolizumab) is indicated for the treatment of patients across a number of 
indications.  Refer to the Investigator’s Brochure (IB)/approved labeling for detailed 
background information on MK-3475.
Pharmaceutical and Therapeutic Background
Programmed Cell Death 1 as a Target in Cancer Treatment:
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [1]. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-
cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; 
hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating 
lymphocytes can be expanded ex vivo and re-infused, inducing durable objective tumor 
responses in cancers such as melanoma [2] [3].
The PD-1 receptor-ligand interaction is a major immune checkpoint pathway hijacked by 
tumors to suppress immune control. The normal function of PD-1, expressed on the cell 
surface of activated T-cells under healthy conditions, is to down-modulate unwanted or 
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excessive immune responses, including autoimmune reactions. PD-1 (encoded by the gene 
Pdcd1) is an immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 
(CD28) and CTLA-4 that has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD-L2) [4] [5].
The structure of murine PD-1 has been resolved [6]. PD-1 and family members are type I
transmembrane glycoproteins containing an Ig Variable–type (IgV-type) domain responsible 
for ligand binding and a cytoplasmic tail 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, and an immunoreceptor tyrosine-based switch motif. 
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to 
the immunoreceptor tyrosine-based switch 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 (ZAP70), which are involved in the CD3 
T-cell signaling cascade [4] [7] [8] [9]. The mechanism by which PD-1 down-modulates T-
cell responses is similar to, but distinct from, that of CTLA-4, because both molecules 
regulate an overlapping set of signaling proteins [10] [11]. As a consequence, the PD-1/PD-
L1 pathway is an attractive target for therapeutic intervention in melanoma and NSCLC.
Melanoma Background
Malignant melanoma is the most lethal form of skin cancer. In the United States of America, 
the reported incidence of melanoma in 2017 is 87,110, with 9,730 deaths attributed to 
melanoma [12]. In the U.S., this approximates 1.6% of all cancer-related deaths. The main 
risk factors for melanoma are white ethnicity and exposure to ultraviolet (UV) radiation. The 
prognosis of melanoma worsens with the disease stage at diagnosis [13]. Patients with 
metastatic disease have a poor prognosis, with a 5-year survival rate of <20% [14]. In Asian 
populations and dark skin types, incidence rates are lower but disease specific survival is also 
lower due to the tendency for atypical locations and unclear etiology. Less than 1% of 
patients at a surgical oncology unit at a regional cancer center in North India were treated for 
melanoma between 1995 and 2002 as reported by Deo et al. [15].  Therefore, although 
melanoma has a low incidence in India, it does carry higher morbidity due to its often late 
presentation [16].
Therapies in Melanoma
In India, approved therapies for advanced melanoma include interferon and dacarbazine. In 
line with other global markets, there is a need for more efficacious therapies to be available 
in India. Treatment options for unresectable and metastatic melanoma are rapidly expanding. 
Surgery is the definitive treatment for early-stage melanoma, and medical management is 
reserved for both adjuvant therapy for early-stage melanoma and for treatment of advanced 
melanoma [17]. Prior to 2011, dacarbazine was the most active single agent for metastatic 
melanoma, with an overall response rate of 15% to 21% [18] [19]. There have been no 
randomized controlled studies demonstrating improvement in survival with dacarbazine 
relative to best supportive care or any other control agent. A review of 9 of the largest 
randomized controlled trials published between 1999 and 2014 using single-agent 
dacarbazine as the control arm is presented in Table 1 and indicates the limited activity of 
this agent in melanoma. Collectively, in nearly 1700 subjects randomized to single-agent 
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dacarbazine, the overall response rates (ORRs) ranged from 6% to 12%, with the median 
duration of response ranging from 7 to 11 months (response duration is not reliable in most 
studies due to the small fraction of subjects who respond to treatment). In addition, no other 
conventional cytotoxic chemotherapies (as either single agents or combinations) have 
demonstrated superiority to single-agent dacarbazine in the treatment of melanoma in 
randomized controlled trials. A historical benchmark for effect size in terms of progression-
free survival (PFS) and overall survival (OS) was suggested in a retrospective analysis of 
2100 metastatic melanoma subjects treated in 42 different clinical trials (70 treatment arms) 
from 1997 to 2005. Korn et al. reported median PFS of 1.7 months (95% confidence interval 
[CI]: 1.6 months, 1.8 months) with a 14.5% 6-month PFS rate (95% CI: 12.9%, 16.1%) [20]. 
Median OS was 6.2 months (95% CI: 5.9 months, 6.5 months) with a reported 1-year 
survival rate of 25.5% (95% CI: 23.6%. 27.4%). The experience with dacarbazine and the 
Korn et al. meta-analysis underscore the limitations of chemotherapies and the challenges of 
developing effective agents to treat metastatic melanoma [21] [22] [23] [20] [24] [25] [26] 
[27] [28] [29] [30] [31] [32] [33].
Table 1
Data From Randomized Controlled Trials With Dacarbazine in Advanced 
Melanoma 1999-2014
Reference 
(Author, Year)
Agents
N
ORR %
(CR+PR)
Median 
Response 
Duration 
(months)
Median 
PFS 
(months)
Median OS 
(months)
Haushchild, 2014
Dacarbazine
63
6.0
NR
2.7
15.6
Dabrafenib
187
50.0
5.5
6.9
20.0
Flaherty, 2012
Dacarbazine or 
paclitaxel
108
8.0
NR
1.5
NR
Trametinib
214
22.0
NR
4.8
NR
Patel, 2011
Dacarbazine
388
9.8
11.2
2.2
9.4
Temozolomide
401
14.5
4.6
2.3
9.1
Robert, 2011
Dacarbazine
252
10.3
8.1
2.2
9.1
Ipilimumab-
Dacarbazine
250
15.2
19.3
2.2
11.2
Chapman 2012,
NICE 2012
Dacarbazine
337
8.6
NR
1.6
10.3
Vemurafenib
338
57.0
NR
6.9
13.6
Bediken, 2006
Dacarbazine
385
7.5
NR
1.6
7.8
Oblimersen-
Dacarbazine
386
13.5
NR
2.6
9.0
Avril, 2004
Dacarbazine
117
7.2
6.9
NR
5.6
Fotemustine
112
15.5
5.8
NR
7.3
Middleton, 2000
Dacarbazine
149
12.1
NR
1.5
6.4
Temozolomide
156
13.5
NR
1.9
7.7
Chapman, 1999
Dacarbazine
118
10.2
NR
NR
6.3
Dartmoutha
108
18.5
NR
NR
7.7
All 1999-2014
Dacarbazine
1917
8.9 (avg)
6.0-12.1
6.9-11.2
1.5-2.7
5.6-15.6
a Dartmouth regimen = dacarbazine, cisplatin, carmustine, tamoxifen
Avg = average; CR = complete response; N = sample size; NR= not reported; ORR = overall response rate; OS = overall 
survival; PFS = progression-free survival; PR = partial response
[25], [21], [27], [23], [28], [29], [30], [31], [32], [24]
Since 2011, 3 new agents were approved in the United States for the treatment of BRAF
mutant melanoma: vemurafenib, dabrafenib, and trametinib, which produce response rates of 
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22-57% and have demonstrated a survival advantage relative to chemotherapy [27] [24] [22]. 
Of note, vemurafenib demonstrated statistically significant superiority in OS to dacarbazine 
(median 13.6 months versus 10.3 months; hazard ratio [HR] 0.76; p<0.01) [23] [24]. The 
median response duration of approximately 7 months observed with these agents is similar to 
the durability observed with conventional chemotherapies. In the United States, a 
combination of dabrafenib and trametinib was approved for treatment of patients with BRAF 
mutant melanoma based on the demonstration of durable response rate. Based on 
independent review committee (IRC) assessment using RECIST 1.1, ORR was 57% (95% 
CI; 43, 71) and 46% (95% CI; 33, 60) for the combination arm and the dabrafenib alone arm, 
respectively. The median duration of response was 7.6 months for both arms [34]. In a 
randomized Phase 3 trial recently reported, dabrafenib plus trametinib demonstrated 
improved OS compared with vemurafenib monotherapy (HR 0.69; 95% CI: 0.53, 0.89; 
p=0.005). It is important to note these agents are not indicated for up to 60% of melanoma 
subjects whose tumors do not contain a BRAF mutation [24] [27] [32] [35]. In addition, a 
major limitation with kinase inhibitors in the treatment of BRAF mutant melanoma is a 
nearly universal development of resistance to these agents leading to the lack of response 
durability. Although high response rates (RRs) offer benefits to the majority of subjects with 
BRAF mutant melanoma, most subjects develop resistance rather quickly and experience 
progressive disease Moreover, published literature indicates that subjects who experience 
progressive disease after the above-mentioned kinase inhibitors tend to experience rapid
progressive disease that cannot be easily salvaged with other available therapies [36]. 
Ipilimumab (IPI), an anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)
monoclonal antibody (mAb), demonstrated that immune modulation could be effective in the 
treatment of metastatic melanoma. In a Phase 3 study, IPI administered with or without a 
gp100 peptide vaccine was compared with gp100 alone in subjects with previously treated 
metastatic melanoma. An ORR of 10.9% (Investigator assessment per RECIST 1.1), a 
median PFS of 2.9 months, an OS rate at 12 months of 45.6%, and a median OS of 10.1 
months were observed in the IPI monotherapy arm. In addition, a relative reduction of 34% 
(p=0.003) in the risk of death was demonstrated for IPI compared with the vaccine alone. A 
reduction of the risk of death (28%; p<0.001) was also demonstrated for IPI in the first-line 
setting when combined with dacarbazine in comparison with dacarbazine alone, and the 
ORRs were 15% and 10% (investigator assessment per RECIST 1.1) in the IPI/dacarbazine 
arm and dacarbazine alone arm, respectively. Notably, inspection of the Kaplan-Meier PFS 
curves in this study indicated that comparison of median was less informative than inspection 
of curves, as the median PFS was reached before the first tumor assessment time point 
followed by a significant separation of the curve. The IPI/dacarbazine arm did show a 
statistically significant PFS improvement (HR 0.76; p=0.006) over the dacarbazine alone 
arm. Median OS in the IPI/dacarbazine and dacarbazine arms was 11.2 months and 9.1 
months, respectively. The 1-year OS rate for the IPI/dacarbazine arm was 47.3%; the rate for 
the dacarbazine arm was 36.3%. In 2011, the Food and Drug Administration (FDA) approved 
IPI for treatment of subjects with unresectable or metastatic melanoma in the United States. 
The European Medicines Agency (EMA) subsequently approved IPI for treatment of subjects 
with advanced melanoma in the European Union (EU).
Although the IPI results support the concept that responses to immunotherapy are long
lasting (first demonstrated by high-dose interleukin-2 [IL-2]), given the 10% response rate
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observed with IPI, a majority of subjects may not experience a significant clinical benefit. 
Furthermore, treatment with IPI is associated with an approximate 23% incidence of severe 
or life-threatening (Grade 3 or 4) drug-related adverse reactions and a 3% incidence of fatal
drug-related adverse reactions [37] [38]. High-dose IL-2, another available immunotherapy, 
achieves durable complete responses (CRs) in a small percentage (~5%) of subjects, although 
OS benefit has never been established in a randomized controlled study. In addition, high-
dose IL-2 should be used only in a hospital setting with an intensive care facility due to its 
unfavorable toxicity profile [39]. Thus, there is a great need for an immunotherapy with an 
improved therapeutic index.
Pembrolizumab in Treatment of Metastatic Melanoma
Pembrolizumab has shown in a randomized Phase 3 study (KEYNOTE-006) a significant 
benefit in OS, PFS and response rate in patients with unresectable or metastatic melanoma
compared to ipilimumab [40]. Additionally, pembrolizumab demonstrated a favorable safety 
profile compared to ipilimumab. Furthermore, in a randomized Phase 2 study (KEYNOTE-
002), pembrolizumab has demonstrated improved PFS over standard of care chemotherapy in 
ipilimumab-refractory subjects with advanced melanoma [41]. Refer to the IB for 
comprehensive non-clinical and clinical information about pembrolizumab.
On 04-SEP-2014, the U.S. FDA granted accelerated approval for pembrolizumab 2 mg/kg 
every 3 weeks (Q3W) to be used in advanced melanoma patients with progressive disease
following IPI and, if BRAF V600 mutation was positive, a BRAF inhibitor [42]. The 
approval was based on a strong efficacy and safety profile demonstrated in 4 melanoma 
expansion parts of the Phase 1 trial; the B2 IPI-refractory population was the subject 
population for the approval. On 18-DEC-2015, the U.S. FDA granted full approval of 
pembrolizumab for the treatment of patients with unresectable or metastatic melanoma. This
indication included first-line treatment of patients with unresectable or metastatic melanoma 
with pembrolizumab.
Pembrolizumab was approved in India for unresectable or metastatic melanoma on 16-JUN-
2016.
Lung Cancer Background
Lung cancer is the most common malignancy and contributor to cancer-related deaths in the 
world [43]. Lung cancer is a significant burden in India as well, with an estimate incidence
according to GLOBOCAN 2012 of 70,275 in all ages and from both sexes [44] [45] [46].
Lung cancer, therefore, ranks fourth among the various types of cancer (excluding 
nonmelanoma skin cancer) in India. However, it is suspected that incidence calculations in 
India are likely gross under-estimations. While epidemiological studies link smoking to the 
cause of lung cancer among men in India, such is not the case for women, suggesting other 
contributing risk factors likely exist. Furthermore, studies have shown that 90% of the lung 
cancer cases present in inoperable or advanced stages [45].
Non-small cell lung cancer represents approximately 80% to 85% of all lung cancer [47]. At 
the time of diagnosis, approximately 70% of subjects with NSCLC have advanced disease
which is not amenable to surgical resection. Of those patients diagnosed with early stage 
NSCLC and treated with surgery, a significant percentage subsequently develop distant 
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recurrence [48]. These factors contribute to the dismal 5-year relative survival rates of 17.7% 
in patients diagnosed with NSCLC, and a mere 4.3% in those with metastatic disease [49].
Therapies in Non-Small Cell Lung Cancer
In India, the standard of care for advanced NSCLC includes molecular classification for 
epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutation 
status. However, accessibility of such testing to a majority of patients may be limited at this 
time [50]. Recommended and approved therapies for patients with driver mutations include 
EGFR tyrosine kinase inhibitors (TKIs). Platinum-based doublet chemotherapy is standard of 
care for patients without driver mutations or patients that have progressed on TKIs in India
[51]. Thus, while combination chemotherapy and TKIs are available, current therapeutic 
options in India for NSCLC are not sufficient.
Platinum-based combination chemotherapy with or without maintenance therapy was the 
standard first-line therapy for patients with metastatic NSCLC whose tumors do not harbor 
oncogenic drivers, such as epidermal EGFR mutations or ALK translocations, until studies of 
pembrolizumab first-line therapy [52]. Regimens used in NSCLC include cisplatin or 
carboplatin in combination with paclitaxel, gemcitabine, pemetrexed, or docetaxel [53]. 
Multiple Phase 3 studies have demonstrated similar efficacy for most platinum doublets in 
NSCLC patients [54]. 
The use of targeted therapies for patients with nonsquamous NSCLC whose tumors are 
known to harbor specific molecular alterations has resulted in higher RRs and improved 
outcomes. Approved agents for treatment-naïve, metastatic, EGFR-mutant lung cancers 
include erlotinib, gefitinib, and afatinib. Crizotinib and ceritinib are approved TKIs in the 
first-line treatment of patients whose tumors harbor ALK- or ROS1-translocations. For 
patients with NSCLC containing a V600E BRAF mutation, the combination of trametinib 
and drabrafenib is approved. Despite advances in the ability to molecularly characterize 
tumors and in targeted therapy development, the majority of patients with metastatic NSCLC 
do not harbor tumors with an actionable target, and those who do become resistant to these 
inhibitors. 
However, for the majority of patients with no targetable oncogenic driver mutation receiving 
first-line platinum-based doublets with or without maintenance chemotherapy, the options 
primarily include single-agent docetaxel or pemetrexed (for nonsquamous NSCLC). 
Response rates are modest at less than 10%, with median PFS of approximately 2.4 to 2.9 
months and median OS ranging from 5.5 to 8.3 months. With increasing use of pemetrexed 
in the first-line and maintenance settings, docetaxel is the most widely accepted second-line 
therapy for the majority of patients with metastatic NSCLC with progressive disease (PD) 
after first-line therapy. 
Resistance to targeted therapies in patients with adenocarcinoma of the lung who harbor 
sensitizing mutations is inevitable, and relapse occurs in almost all individuals, resulting in 
PD after approximately 9 to 13 months. As mentioned previously, based on improvement in 
RR and PFS compared to conventional chemotherapy, EGFR TKIs (including gefitinib, 
erlotinib, and afatinib) are well accepted first-line treatments in this subset of patients. The 
only third generation EGFR TKI to overcome acquired resistance in the presence of a T790M 
mutation is osimertinib. In a Phase 3 study that randomized patients with T790M positive 
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NSCLC who had progressed on an EGFR TKI in a 2:1 fashion to receive osimertinib or 
pemetrexed-platinum doublet, osimertinib demonstrated an improvement in median PFS 
(10.1 months vs 4.4 months; HR 0.30 [95% CI: 0.23, 0.41], p<0.001) and an ORR of 71% 
versus (vs) 31% (odds ratio, 5.39; [95% CI: 3.47, 8.48], p<0.001) when compared to 
chemotherapy [55]. These results led to approval of osimertinib in patients with T790M 
positive EGFR TKI acquired resistance. For the remainder of patients with an EGFR
sensitizing mutation who develop resistance to TKIs and whose tumors do not harbor a 
T790M mutation, treatment includes a platinum-based doublet at the time of progression 
with RRs of 20% to 30% and a median PFS of 4 to 5 months [56].
For 3% to 7% of patients with lung adenocarcinoma with echinoderm microtubule protein-
like 4 (EML4)/ALK translocation, crizotinib, and ceritinib are now approved agents in the 
first-line setting. Recently, alectinib, a potent and selective ALK inhibitor with central 
nervous system (CNS) penetration, was approved as second-line therapy in patients with 
crizotinib-refractory ALK-rearranged NSCLC. In a Phase 2 study, alectinib yielded an ORR 
of 50% (95% CI: 41, 59) and a PFS of 8.9 months (95% CI: 5.6 to 11.3 months) [57].
Pembrolizumab in Treatment of Non-Small Cell Lung Cancer
The standard of care in NSCLC was revolutionized by regulatory approval of pembrolizumab 
as monotherapy and in combination with chemotherapy [58]. Pembrolizumab was approved 
as monotherapy in subjects with metastatic NSCLC whose tumor expressed programmed cell 
death 1 ligand 1 (PD-L1) with a tumor proportion score (TPS) ≥50% without targetable 
EGFR or ALK genetic aberrations based on the primary analysis of KEYNOTE (KN)-024 
(see [Section 7.4] for details) [59]. The TPS is the percentage of tumor cells that express PD-
L1, identified using immunohistochemical (IHC) analysis. 
Pembrolizumab in combination with pemetrexed and carboplatin for patients with treatment-
naïve metastatic nonsquamous NSCLC without targetable EGFR or ALK genetic aberrations, 
irrespective of PD-L1 tumor expression, was approved in the U.S. based on an interim 
analysis of KN021 [60], a randomized, open-label trial comparing pembrolizumab plus 
carboplatin and pemetrexed Q3W followed by pembrolizumab Q3W for 24 months and 
indefinite pemetrexed maintenance therapy to carboplatin and pemetrexed alone followed by 
indefinite pemetrexed maintenance therapy. In the pembrolizumab plus chemotherapy group, 
33 of 60 subjects (55%; 95% confidence interval [CI]: 42, 68) achieved an objective response 
compared with 18 of 63 subjects (29%; 95% CI: 18, 41) in the chemotherapy alone group 
(estimated treatment difference 26% [95% CI: 9, 42]; p=0·0016) [60]. PFS was significantly 
longer with pembrolizumab plus chemotherapy compared with chemotherapy alone (hazard 
ratio [HR]: 0.53 [95% CI: 0.31, 0.91], p=0·010). No difference in OS was noted over the 
median follow-up of 10.6 months. Yet, in a recent update with an extended median follow-up 
of 18.7 months (range, 0.8 – 29.0 months) the median OS was not reached (NR) (95% CI: 
22.8, NR) with pembrolizumab plus chemotherapy compared to 20.9 months (95% CI: 14.9, 
NR) with chemotherapy alone (HR: 0.59 [95% CI: 0.34, 1.05], p=0.03) [61]. Notably, 
patients in the chemotherapy alone group were able to crossover to the pembrolizumab group 
upon central verification of progression. These findings are being further explored in an 
ongoing international, randomized, double-blind, Phase 3 trial, KN189.
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NSCLC remains a challenge for patients in India. Upon approval of pembrolizumab for 
NSCLC in India, pembrolizumab will offer a more effective treatment option with a good 
benefit/risk ratio.
Rationale
Rationale for the Trial and Selected Subject Population
The purpose of this Phase 4 study is to fulfill the Indian regulatory post-approval requirement 
for an interventional Phase 4 study for pembrolizumab while granting permission to market 
the product in India. The safety data collected in this study will help to inform the safety 
profile of pembrolizumab in subjects treated in India with unresectable or metastatic 
melanoma and NSCLC subjects who are either untreated (PD-L1 ≥50%) or have received a 
minimum of 2 cycles of a platinum-containing systemic therapy (PD-L1 ≥1%). Due to the 
low incidence rate of melanoma in India, the number of melanoma subjects is anticipated to 
be lower than the number of NSCLC subjects.
Pembrolizumab monotherapy is the current standard of care for the treatment of patients with 
good Eastern Cooperative Oncology Group (ECOG) performance status (ECOG 0 or 1) and 
previously untreated, advanced, or metastatic NSCLC with a programmed cell death ligand 1 
(PD-L1) TPS ≥50% with no EGFR or ALK genomic tumor aberrations. Approximately 30% 
of patients with newly diagnosed, advanced NSCLC highly express PD-L1 to a TPS ≥50%
[59].
Rationale for Dose Selection/Regimen/Modification
The planned dose of pembrolizumab for this trial is 200 mg every 3 weeks (Q3W) for up to 
35 cycles, disease progression, unacceptable toxicity, death due to any cause, investigator 
decision, or patient decision or withdrawal of consent, whichever occurs first. The initial 
dose approved by the U.S. Food and Drug Administration (FDA) for treatment of melanoma 
subjects was 2 mg/kg Q3W.  Currently, clinical trials evaluating pembrolizumab are using a 
fixed dose of 200 mg Q3W and the current U.S. FDA-approved dose for both melanoma and 
NSCLC is 200 mg Q3W.  The use of a fixed dose is based on PK findings summarized 
below.
The PK profile of pembrolizumab is consistent with that of other humanized monoclonal 
antibodies, which typically have a low clearance and a limited volume of distribution.  A 
population PK model, which characterized the influence of body weight and other subject 
covariates on exposure using available data from 1139 subjects (from Keynote-001 and 
Keynote-002) has been performed.  The majority of these subjects (1077; 94.6%) had 
advanced melanoma.  The distribution of exposures from the 200 mg fixed dose were 
predicted to considerably overlap those obtained with the 2 mg/kg dose, and importantly, 
maintained individual subject exposures within the exposure range established in melanoma 
as associated with maximal clinical response.  This comparison also demonstrated that the 
200 mg Q3W regimen provided no substantive differences in PK variability (range of the 
distribution of individual exposures) as seen with weight-based dosing.
In translating to other solid tumor indications, similarly flat exposure-response relationships 
for efficacy and safety as observed in subjects with melanoma can be expected, as the 
antitumor effect of pembrolizumab is driven through immune system activation rather than 
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through a direct interaction with tumor cells, rendering it independent of the specific tumor 
type.  In addition, available PK results in subjects with melanoma, NSCLC, and other solid 
tumor types support a lack of meaningful difference in PK exposures obtained at tested doses 
among tumor types.
A fixed-dose regimen is expected to simplify the dosing regimen (potentially reducing dosing 
errors), as well as be more convenient for physicians.  A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities, as well as reducing waste.
Rationale for the Use of Comparator/Placebo
This is a single-arm, open-label, study using pembrolizumab. There is no comparator or 
placebo.
Rationale for Endpoints
Efficacy Endpoints
Efficacy endpoints are not being assessed in this study, but are collected during this trial for 
patient management as therapy will need to be discontinued for disease progression either by 
clinical signs or symptoms or radiographic progression.
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anti-cancer 
treatments are included as safety endpoints for the study including, but not limited to, the 
incidence of, causality, severity, and outcome of adverse events/serious adverse events; 
changes in vital signs and laboratory values. Adverse events will be assessed as defined by
Common Terminology for Adverse Events (CTCAE), Version 4.0.
Planned Exploratory Biomarker Research
Not applicable for this study.
Future Biomedical Research
Not applicable for this study.
Benefit/Risk
The study is designed to provide information about the safety of pembrolizumab for patients 
being treated in India for advanced melanoma and NSCLC.
It cannot be guaranteed that subjects in clinical trials will directly benefit from treatment 
during participation.
Pembrolizumab is safe and well tolerated, as evidenced by a low rate of toxicity Grade 3 to 5 
drug-related adverse events (13.8%), discontinuations due to adverse events (11.9%), and 
deaths due to drug-related adverse events (3.9%). Furthermore, the frequency of immune-
mediated adverse reactions is low, and these events are readily managed in the clinical 
setting. The safety and efficacy data generated to date provided a favorable benefit-risk 
assessment for the use of pembrolizumab as a treatment for subjects with a number of 
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carcinomas including advanced/metastatic melanoma, NSCLC
and head and neck 
nonsquamous cell carcinoma.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and informed consent documents.
The protocol-specified clinical procedures for this study do not impart any additional risk 
beyond that found in standard clinical practice.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/female subjects in India who are of at least 18 years of age with a histologically 
confirmed diagnosis of unresectable or metastatic melanoma, and NSCLC subjects who are 
either untreated (PD-L1 ≥50%) or have experienced disease progression after a platinum-
containing systemic therapy (PD-L1 ≥1%) will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide documented informed consent and agrees to
audiovisual recording of the documented informed consent process, per local 
regulations for the study. 
2. Be at least 18 years of age on the day of providing documented informed consent.
3. Have one of the below diagnoses:
MELANOMA SUBJECTS
a.
Have a histologically confirmed diagnosis of unresectable Stage III or metastatic 
melanoma (Stage IV) not amenable to local therapy.
b. Have received no more than 1 line of prior systemic therapy for unresectable 
Stage III or Stage IV melanoma (including mitogen activated protein kinase 
inhibitors).
c.
Have a Lactate Dehydrogenase (LDH) <1.5 × upper limit of normal (ULN) by 
local lab.
NSCLC SUBJECTS
a.
Have a life expectancy of at least 3 months
b. 2nd Line Treatment and Beyond Subjects:
Have a histologically or cytologically confirmed diagnosis of stage IIIB//IIIC/IV 
(including any future updates to AJCC guideline or recurrent NSCLC.
i) Have tumor that expresses PD-L1 (PD-L1 ≥1%).
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ii) Have received prior treatment with at least two cycles of a platinum-
containing doublet for Stage IIIB/IV or recurrent disease. A platinum-
containing doublet is defined as a platinum-based cytotoxic systemic agent 
administered 
in 
the 
same 
cycle 
as 
another 
cytotoxic 
systemic 
chemotherapeutic agent. Completion of treatment with a platinum-containing 
doublet as neoadjuvant/adjuvant therapy within 6 months of providing 
documented informed consent will satisfy the prior treatment requirement. 
iii) Have received an EGFR tyrosine kinase inhibitor (either erlotinib, 
gefitinib, or afatinib) in a similar manner to that above for the platinum-
containing doublet if they have an EGFR sensitizing mutation.
iv) Have received crizotinib in a similar manner to that above for the 
platinum-containing doublet if they have an ALK translocation.
Note: In subjects treated previously with a tyrosine kinase inhibitor separately 
from a platinum-containing doublet; the order of treatment does not matter.
c.
1st Line Treatment Subjects:
Have a histologically or cytologically confirmed diagnosis of Stage IV NSCLC: 
i) Have tumors demonstrate PD-L1 strong expression (PD-L1 ≥50%) 
ii) Do not have an EGFR sensitizing mutation AND be ALK translocation 
negative,
iii) Have received no systemic anti-cancer therapy for their metastatic 
NSCLC.
Note: Completion of treatment with chemotherapy and/or radiation as part of 
neoadjuvant/adjuvant/definitive therapy is allowed as long as therapy 
was completed at least 6 months prior to the diagnosis of metastatic 
disease.
All NSCLC subjects must also meet the following requirements:
a.
Have provided a formalin fixed tumor tissue sample for PD-L1 biomarker 
analysis from a recent biopsy of a tumor lesion not previously irradiated; For 1st
line subjects, biopsies obtained PRIOR to the administration of any systemic 
therapy administered for the treatment of a subject’s tumor (such as 
neoadjuvant/adjuvant/definitive therapy) will not be permitted for analysis. For 
2nd line treatment and beyond subjects, no systemic antineoplastic therapy may be 
administered between the PD-L1 biopsy and initiating study medication. 
Although 2nd line treatment and beyond subjects using tyrosine kinase inhibitors 
prior to treatment on this protocol may continue using these until it is time to 
begin the appropriate wash out period for these medications. For subjects in 
whom obtaining a new tumor biopsy will be medically inappropriate, the 
investigator may consult with the Sponsor’s study clinical director, and if there is 
agreement, the investigator may submit an archival formalin fixed, paraffin-
embedded tumor specimen for PD-L1 analysis. Fine needle aspirates 
Endobronchial Ultrasound (EBUS) or cellblocks are not acceptable. Needle or 
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excisional biopsies, or resected tissue is required. The tissue sample must be 
received and evaluated by the laboratory prior to randomization.
b. Investigators must be able to produce the source documentation of the EGFR 
mutation status or ALK translocation status. If unable to test for these molecular 
changes, formalin fixed paraffin-embedded tumor tissue of any age should be 
submitted to a central laboratory designated by the Sponsor for such testing. 
Subjects will not be randomized until EGFR mutation and ALK translocation 
status is available in source documentation at the site.
NOTE: If a subject is known to have one molecular alteration (either 
sensitizing EGFR mutation or ALK translocation), then testing for the other 
alteration is not required.
NOTE: If a subject is known to have a mutation in KRAS, then testing for an 
EGFR mutation or for an ALK translocation will not be required given that all 
of these molecular alterations are mutually exclusive in subjects with 
nonsquamous NSCLC.
NOTE: For subjects enrolled who are known to have a tumor of 
predominantly squamous histology, molecular testing for EGFR mutation and 
ALK translocation will not be required as this is not standard of care and is 
not part of current diagnostic guidelines.
4. Have adequate organ function as defined in Table 2. Specimens must be collected 
within 10 days prior to the start of trial treatment.
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Table 2
Adequate Organ Function Laboratory Values
System
Laboratory value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin a
≥9.0 g/dL or ≥5.6 mmol/L    
Renal
Creatinine OR
Measured or calculated b 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 OR
≤5 × ULN for subjects with liver metastases
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
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.
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.
5. Have measurable disease per RECIST 1.1 as assessed by the local site 
investigator/radiologist. Target lesions situated in a previously irradiated area are 
considered measurable if progression has been demonstrated in such lesions.
Cutaneous lesions not visible on scans are not considered measurable.
6. Have an ECOG performance status of 0 to 1.
7. Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of trial treatment. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.  
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8. Female subjects of childbearing potential must be willing to use an adequate method 
of contraception as outlined in Section 5.7.2 – Contraception, for the course of the 
study through 120 days after the last dose of trial treatment.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
9. Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 5.7.2 – Contraception, starting with the first dose 
of study therapy through 120 days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. NSCLC Subjects only (1st Line, 2nd Line, and Beyond Subjects):  Has a tumor 
specimen that is not evaluable for PD-L1 expression by the laboratory. 
2. Is currently participating in or has participated in a trial of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of trial 
treatment.
Note:  Subjects who have entered the follow-up phase of an investigational trial may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
3. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or 
with an agent directed to another T-cell receptor (ie, CTLA-4, OX-40, CD137) or has 
previously participated in a pembrolizumab (MK-3475) clinical trial.
4. Has received prior anti-cancer therapy including investigational agent or device 
within 4 weeks, or completed palliative radiotherapy within 7 days, prior to allocation 
Exception to this rule would be use of denosumab, which is not excluded.
a. Note: Subjects must have recovered from all AEs due to previously therapies to 
≤Grade 1 or baseline. Subjects with ≤ Grade 2 neuropathy may be eligible.
b. Note: If subjects had major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting trial treatment.
5. Is expected to require any other form of antineoplastic therapy while participating in 
the trial.
6. Is on systemic corticosteroid therapy within 7 days before the planned date for first 
dose of treatment or any other form of immunosuppressive medication.
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(exceeding 10 mg daily dose of prednisone or equivalent) or any other form of 
immunosuppressive therapy within 7 days before the first dose of trial treatment.
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8. Has an active autoimmune disease that has required systemic treatment in the past 2 
years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.
9. Has a known additional malignancy that is progressing or requires active treatment. 
Note: Subjects with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (eg, cervical cancer in situ, breast carcinoma) that have 
undergone potentially curative therapy are not excluded.
10. Has had an allogeneic tissue/solid organ transplant.
11. Has a history of or current radiographically detectable (even if asymptomatic and/or 
previously treated) central nervous system metastases and/or carcinomatous 
meningitis as assessed by local site investigator. Baseline brain magnetic resonance 
imaging (MRI) is required at screening. 
12. Has a severe hypersensitivity (≥ Grade 3) to any excipients in pembrolizumab
(excipients are listed in the pembrolizumab IB).
13. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or current pneumonitis/interstitial lung disease.
14. Has an active infection requiring systemic therapy including known history of active 
TB (Bacillus tuberculosis).
15. Has a known history of human immunodeficiency virus (HIV) infection. No HIV 
testing is required unless mandated by local health authority.
16. Has a known history of or is positive for hepatitis B (HbsAg reactive) or hepatitis C 
(HCV RNA [qualitative] is detected). Note: Without known history, testing needs to 
be performed to determine eligibility.
17. Has a known psychiatric or substance abuse disorder that would interfere with 
cooperation with the requirements of the trial.
18. If subject received prior radiation therapy to a symptomatic metastatic lesion 
(excluding brain or other central nervous system metastases), the subject must have 
recovered to CTCAE Grade 1 or Grade 0 from the AEs due to radiation therapy.
19. Is at the time of providing documented informed consent a regular user (including 
‘recreational use’) of any illicit drug or has a recent history (within the last 3 months) 
of substance abuse (including alcohol).
20. 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 
after the last dose of trial treatment.
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21. Has received a live vaccine within 30 days before the first dose of trial treatment.  
Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette–Guérin (BCG), 
and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines (eg, 
FluMist®) are live attenuated vaccines and are not allowed.
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation 
for the full duration of the study, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.
Trial Treatment(s)
Pembrolizumab is to be used in this trial as outlined below in Table 3.
Table 3
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each cycle
Experimental
All trial treatments will be administered in an out-patient clinic setting.
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
where possible (eg, not applicable in the case where multiple lots or batches may be required 
due to the length of the study etc.). 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
Dose Selection (Preparation)
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual. 
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Dose Modification (Escalation/Titration/Other)
5.2.1.2.1 Immune-Related 
Events 
and 
Dose 
Modification 
(Withhold, 
Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 4. 
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Table 4
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.    Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.
2.    Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid dose 
is not ≤10 mg/day within 12 weeks of the last treatment. 
3.    The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.    If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after 
corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
   Administer 
corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone 
or 
equivalent) 
followed by taper
   Monitor participants for signs and symptoms of 
pneumonitis
   Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate corticosteroid 
treatment
   Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Diarrhea / Colitis 
Grade 2 or 3
Withhold
   Administer 
corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone 
or 
equivalent) 
followed by taper
   Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
   Participants with ≥Grade 2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis
   Participants with diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids. If sufficient 
oral fluid intake is not feasible, fluid and electrolytes 
should be substituted via IV infusion.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
AST 
/ 
ALT 
Elevation 
or 
Increased 
Bilirubin
Grade 2
Withhold
   Administer 
corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone 
or 
equivalent) 
followed by taper
   Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
   Administer 
corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone 
or 
equivalent) 
followed by taper
T1DM 
or 
Hyperglycemia
New onset T1DM 
or 
Grade 
3 
or 
4 
hyperglycemia 
associated 
with 
evidence of β-cell 
failure
Withhold a
   Initiate insulin replacement 
therapy for participants with 
T1DM
   Administer 
anti-
hyperglycemic in participants 
with hyperglycemia
   Monitor participants for hyperglycemia or other signs 
and symptoms of diabetes
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypophysitis
Grade 2
Withhold
   Administer 
corticosteroids 
and 
initiate 
hormonal 
replacements 
as 
clinically 
indicated
   Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal insufficiency)
Grade 3 or 4
Withhold 
or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue
   Treat 
with 
non-selective 
beta-blockers 
(eg, 
propranolol) or thionamides 
as appropriate
   Monitor for signs and symptoms of thyroid disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
Hypothyroidism
Grade 2-4
Continue
   Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
   Monitor for signs and symptoms of thyroid disorders
Nephritis 
and 
renal dysfunction
Grade 2
Withhold
   Administer 
corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper
   Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
All Other irAEs
Persistent Grade 2
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold 
or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 
diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a     The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b     Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs (eg, 
vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management of Infusion-Reactions Related to 
Pembrolizumab
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 5. 
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Table 5
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 
(MK 3475) with:
Diphenhydramine 50 mg PO
(or 
equivalent 
dose 
of 
antihistamine).
Acetaminophen 500-1000 mg 
PO
(or equivalent dose of 
analgesic).
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 
(eg, 
renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the 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
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Other Allowed Dose Interruption for Pembrolizumab 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (eg, elective surgery, unrelated medical events, vacation, and/or 
holidays). Subjects should be placed back on trial treatment within 3 weeks of the scheduled 
interruption, unless otherwise discussed with and approved by the Sponsor. The reason for 
interruption should be documented in the subject’s study record.
Timing of Dose Administration
200 mg pembrolizumab 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. However, 
given the variability of infusion pumps from site to site, a window of -5 minutes +10 minutes 
is permitted (ie, infusion time is 30 minutes: -5 min/+10 min). 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).
Every effort should be made to begin the first dose of trial treatment on the day of treatment 
allocation/randomization, but if this is not achieved, trial treatment should be initiated no 
later than 3 days from the date of treatment allocation/randomization. All subsequent cycles 
of trial treatment may be administered up to 3 days before or 3 days after the scheduled Day 
1 of each cycle, up to and including Cycle 9, due to administrative reasons per the 
investigator’s judgment. From Cycle 10 onwards, trial treatment may be administered up to 5 
days before or 5 days after the scheduled Day 1 of each cycle. All trial treatments will begin 
on Day 1 of each cycle after all pre-dose study procedures and assessments have been 
completed as detailed on the Trial Flow Chart – Section 6.0.
The Pharmacy Manual contains specific instructions for pembrolizumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.
Trial Blinding 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
Subjects participating in this trial will be allocated by non-random assignment.
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
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 
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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), herbal supplements, and IV medications and fluids. If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and 
date may also be included on the eCRF.
Palliative and supportive care is permitted during the course of the trial for underlying 
medical conditions and management of symptoms. Surgery for tumor control or symptom 
management is not permitted during the study. Palliative radiotherapy is permitted to a single 
lesion if considered medically necessary by the treating physician. Trial therapy should be 
held during the course of palliative radiotherapy and should be resumed no earlier than the 
next scheduled administration of trial therapy. The specifics of the radiation treatment, 
including the location, will be recorded.
All concomitant medications received within 30 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for serious AEs and ECIs as defined in Section 7.2.3.2.
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy

Note:  Radiation therapy to a symptomatic solitary lesion, in the absence of disease 
progression and excluding the brain and CNS, may be allowed at the investigator’s 
discretion and approval by the Sponsor. 

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed. 
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
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
adverse experience. Brief, limited use of systemic corticosteroids (≤7 days) are permitted 
where such use is considered standard of care (eg, for chronic obstructive pulmonary 
disease [COPD] exacerbation). Please note that inhaled or topical steroids are allowed, 
and systemic steroids at doses ≤10 mg/day prednisone or equivalent are allowed, as 
described in Section 5.6.
Subjects who, in the assessment of the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Subjects may receive other medications that the investigator deems to be medically 
necessary.
Rescue Medications & Supportive Care
Supportive Care Guidelines
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 5.2.1.2, Table 4. Where appropriate, these guidelines include the use of oral or 
intravenous corticosteroids as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the Investigator determines the events to be 
related to pembrolizumab. 
Note: if after the evaluation the event is determined not to be related, the Investigator does 
not need to follow the treatment guidance (as outlined below). Refer to Table 4 in Section 
5.2.1.2 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to AEs such as 
diarrhea, nausea, or vomiting.
Contraception
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
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Female subjects will be considered of non-reproductive potential if they are either: 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women <45 years of age a high follicle-stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving trial treatment and for 120 days after 
the last dose of trial treatment by complying with 1 of the following:  
(1) practice abstinencea from heterosexual activity; 
OR 
(2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception areb:

Single method (1 of the following is acceptable):
o
intrauterine device (IUD)
o
vasectomy of a female subject’s male partner 
o
contraceptive rod implanted into the skin

Combination method (requires use of 2 of the following):
o
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
o
cervical cap with spermicide (nulliparous women only)  
o
contraceptive sponge (nulliparous women only) 
o
male condom or female condom (cannot be used together)
o
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or
subcutaneous contraceptive injection
a Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and internal review 
boards/ethical review committees (IRBs/ERCs). Periodic abstinence (e.g., calendar, 
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ovulation, symptothermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception. 
b If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites 
in this country/region.
Subjects should be informed that taking the trial treatment may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the 
study, subjects of childbearing potential must adhere to the contraception requirements
(described above) from the day of trial treatment initiation (or 14 days prior to the initiation 
of trial treatment for oral contraception) throughout the study period up to 120 days after the 
last dose of trial treatment. If there is any question that both female and male subjects of 
childbearing potential will not reliably comply with the requirements for contraception, those 
subjects should not be enrolled into the study.
Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will be immediately discontinued from treatment. The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed or 
terminated. The outcome of the pregnancy will be reported to the Sponsor without delay and 
within 24 hours if the outcome is a serious adverse experience (eg, death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn). The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor. If 
a male subject impregnates his female partner, the study personnel at the site must be 
informed immediately and the pregnancy must be reported to the Sponsor and followed as 
described in Section 7.2.
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breastfeeding are not eligible for enrollment.
Subject Withdrawal/Discontinuation Criteria
Discontinuation of Treatment
Discontinuation of pembrolizumab does not represent withdrawal from the trial.
As certain data on clinical events beyond trial treatment discontinuation may be important to 
the study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued trial treatment.  Therefore, all subjects who discontinue trial 
treatment prior to completion of the treatment period will still continue to participate in the 
trial as specified in Section 6.0 – Trial Flow Chart and Section 7.1.5.3 – Discontinued 
Subjects Continuing to be Monitored in the Trial.
Subjects may discontinue trial treatment at any time for any reason or be dropped from trial 
treatment at the discretion of the investigator should any untoward effect occur.  In addition, 
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a subject may be discontinued from trial treatment by the investigator or the Sponsor if trial 
treatment is inappropriate, the trial plan is violated, or for administrative and/or other safety 
reasons.  Specific details regarding procedures to be performed at trial treatment
discontinuation are provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from trial treatment but continue to be monitored in the trial 
for any of the following reasons:
1.
The subject or subject’s legally acceptable representative requests to discontinue trial
treatment.
o
Confirmed radiographic disease progression by RECIST 1.1 outlined in Section 7.1.5
o
Unacceptable adverse experiences as described in Section 7.2
o
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
o
Intercurrent illness other than another malignancy as noted above that prevents 
further administration of treatmento
Recurrent Grade 2 pneumonitis
o
A confirmed positive serum pregnancy test
o
Non-compliance with trial treatment or procedure requirements
o
Investigator’s decision to discontinue treatment
o
Completion of 35 cycles with pembrolizumab
o
Note: 35 cycles (approximately. 2 years) are calculated from the first dose (Cycle 1 
Day 1)  
o
Discontinuation of study treatment after a complete response. Discontinuation of trial 
treatment may be considered for subjects who have attained an investigator-
determined confirmed CR per RECIST 1.1 and have been treated for at least 8 cycles 
(at least 24 weeks) and had at least 2 doses of pembrolizumab beyond the date when 
the initial CR was declared.  These subjects will not continue to be assessed by 
imaging thereafter.
Withdrawal from the Trial
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the trial, they will no longer receive trial treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, are outlined in 
Section 7.1.4 – Other Procedures.
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Subject Replacement Strategy
A subject who discontinues or withdraws from the trial will not be replaced.
Beginning and End of the Trial
The overall trial begins when the first subject (or their legally acceptable representative) 
provides documented informed consent. The overall trial ends when the last subject 
completes the last study-related phone-call or visit, withdraws from the trial or is lost to 
follow-up (i.e. the subject is unable to be contacted by the investigator).
Clinical Criteria for Early Trial Termination
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
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6.0 TRIAL FLOW CHART
Screening
Week/Cycle (21-day Cycle)
Visit 10 
and 
Beyond 
(21-day 
Cycle)
End of Treatment
(EOT)17
Treatment 
Discontinuation
Safety Follow-up17
At time of 
treatment 
discontinuation
(30 days after EOT 
or prior to start of 
new antineoplastic 
therapy)
Treatment Cycle
-30 to -1
1
2
3
4
5
6
7
8
9
10-35
Week (approximate)
0
3
6
9
12
15
18
21
24
Scheduling Window: Days
±3
±3
±3
±3
±3
±3
±3
±3
±5
+7
+7
Administrative Procedures
Informed Consent 1
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X 
(dispense)
X (collect)
Demographics/Medical 
History and Prior 
Medications2
X
Review Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X 
X
X
X
X
X
X
X3
ECOG Performance Status
X4
X4
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and Weight5
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG6
X
X
X
X6
X
X
Administration of 
Pembrolizumab (30-min 
Infusion)
X
X
X
X
X
X
X
X
X
X
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Screening
Week/Cycle (21-day Cycle)
Visit 10 
and 
Beyond 
(21-day 
Cycle)
End of Treatment
(EOT)17
Treatment 
Discontinuation
Safety Follow-up17
At time of 
treatment 
discontinuation
(30 days after EOT 
or prior to start of 
new antineoplastic 
therapy)
Treatment Cycle
-30 to -1
1
2
3
4
5
6
7
8
9
10-35
Week (approximate)
0
3
6
9
12
15
18
21
24
Scheduling Window: Days
±3
±3
±3
±3
±3
±3
±3
±3
±5
+7
+7
Laboratory Procedures/Assessments7
Hepatitis B and C8
X
Pregnancy Test- Urine or 
Serum β-HCG9
X
X
X
X
X
X
X
X
X
X
X
X
PT/INR and aPTT10
X
X
CBC With Differential11
X
X
X
X
X
X
X
X
X
X
X
X
Comprehensive Serum 
Chemistry Panel11
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis12
X
X
X
X
X
X
T3, 
FreeT4
(FT4),
and 
TSH13
X
X
X
X
X
X
X
X
ALK Translocation Testing, 
NSCLC subjects only15
X
EGFR 
Mutation 
Testing, 
NSCLC subjects only15
X
Disease Assessments
Tumor Imaging14
X
X
X
X14
X14
Brain Imaging14
X
X
X14
X14
Tumor 
Biopsies/Archival 
Tissue 
Collection
Tumor Tissue Collection, 
NSCLC subjects only16
X
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Screening
Week/Cycle (21-day Cycle)
Visit 10 
and 
Beyond 
(21-day 
Cycle)
End of Treatment
(EOT)17
Treatment 
Discontinuation
Safety Follow-up17
At time of 
treatment 
discontinuation
(30 days after EOT 
or prior to start of 
new antineoplastic 
therapy)
Treatment Cycle
-30 to -1
1
2
3
4
5
6
7
8
9
10-35
Week (approximate)
0
3
6
9
12
15
18
21
24
Scheduling Window: Days
±3
±3
±3
±3
±3
±3
±3
±3
±5
+7
+7
1.
Documented informed consent and audiovisual recording of the documented informed consent process must be obtained prior to performing any protocol-specific procedure. 
Results of a test performed as part of routine clinical management are acceptable in lieu of a screening test if performed within 30 days prior to Cycle 1, Day 1). Assign 
Baseline number when the study informed consent is documented.
2.
Includes history of treatment for the primary diagnosis, including prior systemic, radiation treatment and surgical treatment, and best response to prior systemic treatments
within the previous 10 years. Date of last prior cancer treatment must be documented. Radiographic studies performed prior to study entry may be collected for review by the 
investigator. Report complete medication history taken within 30 days prior to the screening visit (Visit 1).
3.
All AEs should be reported for at least 30 days following treatment cessation. Serious adverse events and ECIs should be reported for 90 days following treatment cessation. 
A serious adverse event considered drug-related by the investigator should be reported regardless of how long has elapsed since treatment cessation. Pregnancies and lactation 
events should be reported for 120 days following treatment cessation or for 30 days if the subject initiates new anticancer therapy.
4.
ECOG of 0 or 1 is required at screening and at C1D1.
5.
Vital signs to include temperature, pulse, respiratory rate, and blood pressure. If a subject’s baseline weight does not fluctuate by more than 10%, this weight can be used to 
calculate dose. Height will be measured at screening only.
6.
A 12-lead ECG will be performed at Screening and at every fourth cycle starting on Cycle 4.
7.
Routine laboratory tests (serum or plasma chemistry and hematology) for screening must be performed within 10 days prior to administration of the first dose. If a subject 
starts screening 10 days prior to administration of trial treatment, a second screening visit is required to collect the lab specimens within the specified timeframe. 
8.
Testing will be performed by the local laboratory at Screening: Hepatitis B and C serologies should be obtained for subjects without a known history of hepatitis B or C. 
Those with a known history are ineligible. Include HCV RNA (qualitative) and HbsAg.
9.
For females of reproductive potential, urine or serum pregnancy test should be performed within 72 hours prior to day 1 of each treatment cycle and 30 days post treatment if 
required or as specified per local regulatory guidance. A serum test can be done if urine is not appropriate. Additionally, if urine test is positive or is not evaluable, a serum 
test is required. Subjects must be excluded/discontinued in the event of a positive test result.
10. PT/INR and aPTT should be collected at Screening and at the Safety Follow-up Visit after discontinuation of study therapy. Coagulation parameters will be determined 
throughout the study if clinically indicated. PT/INR and aPTT will be analyzed by the local study site laboratory.
11. Routine laboratory tests (e.g., CBC with differential, comprehensive serum or plasma chemistry panel, and urinalysis) will be performed by the local study site laboratory or 
their contract laboratory. Additionally, CBC with differential and comprehensive serum or plasma chemistry panel are to be collected up to 48 hours prior to Day 1 dosing of 
any Cycle.  
12. Following baseline and Cycle 2, urinalysis should be performed every fourth cycle.
13. Analysis of T3, FT4, and TSH will be performed by the local study site laboratory or their contract laboratory. Following Cycle 2, testing will be performed every other cycle.
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Screening
Week/Cycle (21-day Cycle)
Visit 10 
and 
Beyond 
(21-day 
Cycle)
End of Treatment
(EOT)17
Treatment 
Discontinuation
Safety Follow-up17
At time of 
treatment 
discontinuation
(30 days after EOT 
or prior to start of 
new antineoplastic 
therapy)
Treatment Cycle
-30 to -1
1
2
3
4
5
6
7
8
9
10-35
Week (approximate)
0
3
6
9
12
15
18
21
24
Scheduling Window: Days
±3
±3
±3
±3
±3
±3
±3
±3
±5
+7
+7
14. Tumor imaging will be performed within 30 days prior to enrollment. CT scans are the required modality for measurable disease unless a subject has a contraindication (e.g. 
severe contrast allergy), in which case MRI is acceptable. Premedication for contrast allergy, including steroids, is permissible. Imaging timing should follow calendar days 
and should not be adjusted for delays in cycle starts. Imaging should be performed 12 weeks (±7 days) after the first cycle of treatment and then every 9 weeks (±7 days), or 
as clinically indicated. Brain MRI should be performed at screening, 12 weeks (±7 days) after the first cycle of treatment, and then every 18 weeks (±7 days), or as clinically 
indicated. For subjects for whom an MRI is contraindicated, brain CT scan is acceptable. In subjects who discontinue trial treatment, 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. This is the final required tumor imaging.
15. This test is only required for NSCLC subjects (1st line, 2nd line, and beyond treatment subjects). This test is not required for melanoma subjects. Site must be able to provide 
documentation of the subject’s tumor EGFR mutation and ALK translocation status. If the site is unable to provide this source documentation, then the Sponsor will offer this 
molecular testing of the tumor.
16. Tumor tissue from NSCLC subjects only (1st line, 2nd line, and beyond treatment subjects) for biomarker analysis from an archival tissue sample (acceptable for EGFR and 
ALK testing) or newly obtained formalin fixed tumor tissue from a recent biopsy of a tumor lesion not previously irradiated (required for PD-L1 determination; acceptable for 
EGFR and ALK testing) must be provided and evaluated by the laboratory before randomization. No systemic antineoplastic therapy may have been received by the subject 
between the time of the biopsy for PD-L1 testing and the first administration of study medication. Detailed instructions for tissue collection, processing and shipment are 
provided in the Procedures Manual. Biopsy should be obtained of a non-target lesion, but if obtained from a target lesion then a new baseline scan should be acquired.
17. EOT and Safety Follow-up visits may be combined if a decision is made to end treatment 30 or more days since the last dose of treatment.
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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
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.  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.
An audio-video recording of the informed consent process shall be maintained by the 
Investigator for record if required by applicable regulatory guidelines. Sufficient measures 
will be taken to maintain the confidentiality of the recordings of the trial subjects.
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.  
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The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
as well as the Sponsor to ensure that the subject qualifies for the trial prior to enrollment.
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 documented 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.
Medical History
A medical history will be obtained by the investigator or qualified designee.
Medical history will include all active conditions, and any condition diagnosed within the 
previous 10 years that are considered to be clinically significant by the investigator. Disease 
details regarding the subject’s melanoma or NSCLC will be recorded separately and not 
listed as medical history.
7.1.1.4.1 Subsequent Antineoplastic Therapy Status
The investigator or qualified designee will review all new antineoplastic therapy initiated 
after the last dose of trial treatment. If a subject initiates a new antineoplastic therapy within 
30 days after the last dose of trial treatment, the “30-day Safety Follow-up visit” should
occur prior to starting the new antineoplastic therapy.
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 30 days before first dose of trial medication.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. All concomitant medication will be recorded on the eCRF, including all 
prescription, OTC, herbal supplements, and IV medications and fluids. If changes occur 
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during the study period, documentation of drug dosage, frequency, route, and date will also 
be included on the eCRF.
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 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.
Assignment of Treatment/Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment number.  The treatment number identifies the subject for all procedures occurring 
after treatment allocation.  The assigned screening number will become the subject’s 
treatment number. Once a treatment 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 number.
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment for >12 weeks require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
See Section 7.1.2.6.
Clinical Procedures/Assessments
Review Adverse Events 
The Investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs specified in the Trial Flow Chart (Section 6.0) and more frequently, if 
clinically indicated. Adverse experiences will be graded and recorded throughout the trial 
and during the follow-up period as defined by CTCAE, Version 4.0 (see [Section 12.4]).
Toxicities will be characterized in terms regarding seriousness, causality, toxicity grading, 
and action taken with regard to trial treatment.
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated 
to determine if it is possibly an event of a potentially immunologic etiology; see 
Section 5.6.1 regarding the identification, evaluation, and management of AEs of a potential 
immunological etiology.
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs. Subjects should be assessed for possible ECIs prior to each dose. Laboratory results 
should be evaluated and subjects should be asked for signs and symptoms suggestive of an 
immune-related adverse event. Subjects who develop an adverse event thought to be 
immune-related should have additional testing to rule out other etiologic causes. If laboratory 
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results or symptoms indicate a possible immune-related adverse event, then additional testing 
should be performed to rule out other etiologic causes. If no other cause is found, then it is 
assumed to be immune-related.
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG Performance Status (see [Section
12.5]) at screening, prior to dosing on Day 1 of each treatment cycle, at EOT, and during the 
safety follow up, as specified in the Trial Flow Chart (Section 6.0). 
Physical Examination
The investigator or clinical designee will perform a complete physical examination during 
the screening period, Day 1 of each cycle, EOT, and the 30-day safety follow-up visit. 
Clinically significant abnormal findings should be recorded as medical history. Additional 
full physical examinations should be performed as specified in the Trial Flow Chart 
(Section 6.0). After the first dose of trial treatment new clinically significant abnormal 
findings should be recorded as AEs.
Vital Signs and Weight
Vital sign measurements include blood pressure, pulse, respiratory rate, body temperature, 
and weight. Height will be measured at screening only.
12-Lead Electrocardiograms
Baseline ECGs will be obtained at screening, with additional ECGs obtained every fourth 
cycle, starting on Cycle 4 Day 1, EOT, the safety follow-up visit and as clinically indicated 
for all subjects. Clinically significant abnormal findings found at screening should be 
recorded as medical history. Clinically significant abnormal findings after the screening ECG 
must be recorded as an adverse event. 
Administration of Pembrolizumab (30-minute Infusion)
Administration of pembrolizumab will be witnessed by the investigator and/or trial staff. The 
total volume of trial treatment infused will be compared to the total volume prepared to 
determine compliance with each dose administered.
The instructions for preparing and administering pembrolizumab will be provided in the 
Pharmacy Manual.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood volumes 
drawn/collected by visit and by sample type per subject can be found in Section 12.2.
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Table 6.
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Table 6
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Hemoglobin
Platelet count
WBC (total and 
differential)e
RBC
Absolute 
lymphocyte counte
Absolute 
neutrophil counte
Albumin
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Bicarbonatec
Calcium
Chloride
Creatinine
Glucose
Phosphorus
Potassium
Sodium
Total bilirubin  
Direct bilirubin
Total protein
Blood urea nitrogen
Blood
Glucose
Protein
Specific gravity 
Microscopic 
exam, 
if 
abnormal results are noted
Pregnancy test (serum or 
urine)a
PT/INR
aPTT
Total T3 or free T3, FT4, 
and TSHb,d
Anti-HCV
HCV viral loadd
HCV genotyped
anti-HBsd
HbsAg 
Anti-HBc (total and 
IgM)d
HbeAgd
anti-Hbed
HBV viral loadd
Anti-HDVd
AFP
CRP
GGT
a
Perform on women of childbearing potential only 72 hours prior to Day 1 of Cycle 1. Pregnancy tests must be repeated 
prior to every cycle if required or as specified per local regulatory guidance.
b
T3 is preferred; if not available free T3 may be tested. 
c
If this test is not done as part of local standard of care, this test does not need to be performed.  
d
If the local laboratory is unable to perform these tests, the site should submit the sample to the central laboratory for 
testing. Details are provided in the Procedure Manual.
e
Report % or absolute results per standard of practice. Report the results in the same manner throughout the trial.
AFP=alpha-fetoprotein; aPTT=activated partial thrombin time; CRP=C-reactive protein; FT4=free thyroxine; 
GGT=gamma-glutamyl transferase; HBc=Hepatitis B core; HbeAg=Hepatitis B e antigen; Hbe=hemoglobin E; 
HBs=hepatitis B surface; HbsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; 
HDV=hepatitis D virus; IgM=gamma M immunoglobulin; INR=insulin receptor; PT=prothrombin time; RBC=red blood 
cells; T3= triiodothyronine; TSH=thyroid-stimulating hormone (thyrotropin); WBC=white blood cells.
Laboratory tests for screening should be performed within 10 days prior to the first dose of 
trial treatment. An exception is hepatitis and thyroid serologies, which may be performed 
within 30 days prior to first dose. After Cycle 1, pre-dose laboratory safety tests can be 
conducted up to 72 hours prior to dosing unless otherwise noted on the flow charts. 
Laboratory test results must be reviewed by the Investigator or qualified designee and found 
to be acceptable prior to administration of each dose of trial treatment. Unresolved abnormal 
laboratory values that are drug-related AEs should be followed until resolution. Laboratory 
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tests do not need to be repeated after the end of treatment if laboratory results are within the 
normal range.  
Pregnancy Test
All women who are being considered for participation in the trial, and who are not surgically 
sterilized or postmenopausal, must be tested for pregnancy within 72 hours of each cycle of 
trial treatment and 30 days post-treatment, if required or as specified per local regulatory 
guidance. If a urine test is positive or not evaluable, a serum test will be required. Subjects 
must be excluded/discontinued from the trial in the event of a positive or borderline-positive 
test result.
Other Procedures
Withdrawal/Discontinuation
Subjects who discontinue treatment prior to completion of the trial 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 EOT 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 and subjects will return to the clinic for a safety follow-up visit 30 days after 
EOT or prior to start of the new antineoplastic therapy, whichever occurs first.
7.1.4.1.1 Lost to Follow-up
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:

The site must attempt to contact the subject and reschedule the missed visit.  If the 
subject is contacted, the subject should be counseled on the importance of maintaining 
the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the subject at 
each missed visit (e.g. phone calls and/or a certified letter to the subject’s last known 
mailing address or locally equivalent methods). These contact attempts should be 
documented in the subject’s medical record.

Note:  A subject is not considered lost to follow-up until the last scheduled visit for the 
individual subject.  The amount of missing data for the subject will be managed via the 
pre-specified data handling and analysis guidelines.
Subject Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
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Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical trial that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
trial site.
Tumor and Brain Imaging
Initial tumor imaging will be performed within 30 days prior to enrollment. Computed 
tomography (CT) scans are the required modality for measurable disease unless a subject has 
a contraindication (eg, severe contrast allergy), in which case MRI is acceptable. 
Premedication for contrast allergy, including steroids, is permissible. Imaging timing should 
follow calendar days and should not be adjusted for delays in cycle starts. Imaging should be 
performed 12 weeks (±7 days) after the first cycle of treatment and then every 9 weeks (±7 
days), or as clinically indicated. 
Brain MRI must be performed at screening, 12 weeks (±7 days) after the first cycle of 
treatment, and then every 18 weeks (±7 days), or as clinically indicated. For subjects for 
whom an MRI is contraindicated, brain CT scan is acceptable.
In subjects who discontinue trial treatment, 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. This is the final required tumor imaging.
Participants may be permitted to continue treatment beyond confirmed RECIST 1.1-defined 
progression as long as investigator-assessed clinical stability is observed, and the participant 
is tolerating study drug following Sponsor consultation and approval.
Clinical stability is defined as the following: 

Absence of symptoms and signs (including worsening of laboratory values) indicating 
progression of disease

Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Detailed instructions for tumor and brain imaging are provided in the Site Imaging Manual.
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Tumor Biopsy/Archival Tissue Collection, NSCLC Subjects Only
Tumor tissue, for NSCLC subjects only, for biomarker analysis from formalin fixed paraffin-
embedded tumor tissue sample or newly obtained formalin fixed biopsy of a tumor lesion not 
previously irradiated must be provided in the form of a tissue block or unstained slides and 
evaluated before allocation. Biopsy of lesions on study should be limited to non-target 
lesions or new lesions if their pathologic etiology is ambiguous.
To perform testing for PD-L1, the laboratory (local or central) must use the PD-L1 IHC 22C3 
pharmDx in strict accordance with the manufacturer’s instructions, which is the only assay 
acceptable for this study. 
For 1st line NSCLC subjects only, subjects whose tumors demonstrate PD-L1≥50%
expression is eligible for enrollment. 2nd line treatment and beyond NSCLC subjects must 
demonstrate PD-L1≥1% expression for eligibility. A fine needle aspirate, EBUS or cytologic 
specimen will not be acceptable. Needle or excisional biopsies, or resected tissue is required. 
Newly obtained formalin fixed specimens are encouraged.
Detailed instructions for NSCLC subject tissue collection, processing and shipment are 
provided in the Procedures Manual. Older biopsy material or surgical specimens may be used 
to assess EGFR mutation status and ALK translocation status, if not already documented 
when the subject provides documented informed consent.
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.
Screening
Approximately 30 days prior to treatment allocation/randomization, potential candidates to 
be enrolled in this trial will be evaluated to determine that they fulfill the entry requirements 
as set forth in Section 5.1.  Screening procedures may be repeated after consultation with the 
Sponsor.
If additional time is needed for screening procedures, an extension of the screening window 
by up to 7 days may be approved following mandatory Sponsor consultation.
Treatment Period
The treatment period will continue every 21 days for up to 35 cycles (approximately 2 years) 
as long as subjects are receiving benefit from trial treatment and have not had disease 
progression or met any criteria for study withdrawal. Please refer to section 5.8.2.
Safety Follow-Up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anticancer treatment, whichever 
comes first. This visit may be combined with the EOT visit if a decision is made to end 
treatment 30 or more days since the last dose of treatment.
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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 the resolution of the AE to Grade 0-1 or until the 
beginning of a new anticancer therapy, whichever occurs first.  Serious AEs that occur within 
90 days of the end of treatment or before initiation of a new anticancer treatment should also 
be followed and recorded.
Discontinued Subjects Continuing to be Monitored in the Trial
Subjects will be required to return to the clinic approximately 30 days after the last dose of 
trial treatment for a safety follow-up visit. Subjects should report any AEs up to 90 days after 
the last dose of the trial treatment. A serious adverse event considered drug-related by the 
investigator should be reported regardless of how long has elapsed since treatment cessation.
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.
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.
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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 trial, an overdose of pembrolizumab will be defined as any dose of 1000 
mg or greater (≥5 times the indicated dose).  
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the subject should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated.
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).
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 trial 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).
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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), including the pregnancy of a male subject's female partner 
that occurs during the trial.
Pregnancies and lactations of subjects and female partners of male subjects from the time 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 in subjects 
and female partners of male subjects that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 
30 days following cessation of trial 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
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 another 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 7 for additional details regarding each of the above criteria.
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Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death.
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, 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, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, 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 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.
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).
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Immediate Reporting of AEs to the Sponsor must be done. Any such event will be submitted 
to the Sponsor within 24 hours either by electronic or paper media.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated safety data to ensure the safety of the 
subjects in the trial. Any suspected endpoint which upon review is not progression of the 
cancer under study will be forwarded to global safety as a serious adverse event 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.
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Table 7
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.
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 any final database lock, changes are made to the 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 
other non-confirmatory analyses made after the protocol has been finalized, but prior to final 
database lock, will be documented in a supplemental SAP (sSAP) and referenced in the 
Clinical Study Report (CSR) for the study. Post hoc exploratory analyses will be clearly 
identified in the CSR.
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2-8.12.  
Study Design Overview
A Prospective, Open-label, Phase 4 Study to Evaluate the Safety of 
Pembrolizumab (Keytruda®) in Subjects with Unresectable or Metastatic 
Melanoma or PD-L1 positive Non-Small Cell Lung Cancer (NSCLC) in 
India
Treatment Assignment
All subjects to be assigned to the same dose/schedule of pembrolizumab 
Analysis Populations
ASaT
Primary Endpoint(s)
Safety and tolerability of the protocol treatment as characterized by the 
adverse event experience
Statistical Methods for Key 
Safety Analyses
Descriptive statistics will be provided for the rate of safety endpoints.
Interim Analyses
An ongoing safety review will be conducted for this study. An interim 
data listing for safety evaluation will be conducted at 1 year from the date 
at which the first subject is enrolled into the study.
Multiplicity
Not applicable
Sample Size and Power 
The planned sample size is approximately 150 subjects (with a minimum 
of 25 subjects with unresectable or metastatic melanoma, and ~125 
NSCLC subjects who are either untreated (PD-L1 ≥50%) or have 
experienced disease progression after a platinum-containing systemic 
therapy (PD-L1 ≥1%). No hypothesis testing will be performed. The goal
is to characterize the AEs associated with the use of pembrolizumab in 
the treatment of subjects, as described above, in India. 
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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.
This trial is being conducted as a non-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.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0
Analysis Endpoints
The safety endpoints that will be evaluated are listed below.
Safety Endpoints
See Section 4.2.3.2 for the initial description of safety measures.
Analysis Populations
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 subjects who received at least 1 dose of trial 
treatment. 
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of trial 
treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Statistical Methods
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and laboratory parameters.
The proportion of subjects with AEs of elevated laboratory values that are reported as ECIs 
described in Section 7.2.3.2 during the study therapy period will be provided along with the 
corresponding 95% Cs, which will be calculated using the Clopper Pearson method.
In addition, the broad AE categories consisting of the percentage of subjects with any AE, a 
drug-related AE, a serious AE, an AE which is both drug-related and serious, and those who 
discontinued due to an AE will be summarized in the same manner Table 8.
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Table 8
Analysis Strategy for Safety Parameters
Safety Endpoint
Within Group 95% CI 
Descriptive Statistics
Any AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs, or PDLCs‡ (incidence ≥1% of 
participants)
X
X
Specific AEs, SOCs or PDLCs† (incidence <1% of participants)
X
Change from Baseline Results (Labs, ECGs, Vital Signs)
X
Note: SOC=System Organ Class; X = results will be provided.  
95% Cis will be calculated using the Clopper Pearson method.
For continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
may be provided in table format.  Mean change from baseline over time may also be plotted 
with the corresponding standard errors.  
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The number and percentage of subjects screened, the primary reasons for screening failure, 
and the primary reason for discontinuation will be displayed. Demographic variables, 
baseline characteristics, primary and secondary diagnoses, and prior and concomitant 
therapies will be summarized either by descriptive statistics or categorical tables.
Interim Analyses
Safety Interim Analyses
An ongoing safety review will be conducted for this study and upon request by the 
Regulatory Agency. The objective of this safety review is to assess the safety data collected 
over the duration of the study; the results obtained will be submitted to the Regulatory 
Agency to seek further direction on the continuation of the study. An interim data listing for 
safety evaluation will be conducted at 1 year from the date at which the first subject is 
enrolled into the study.
Multiplicity
This study does not involve multiplicity adjustments.
Sample Size and Power Calculations
Sample Size and Power for Safety Analyses
Safety is the primary endpoint. No formal sample size calculations are performed for this 
study since the primary objective is not to test a predefined hypothesis, but to collect and 
assess adverse events occurring in subjects treated in a routine clinical setting (see 
Section 4.2.1). If the planned 150 subjects are enrolled, then, if a certain number of subjects 
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experience a specific adverse event, serious adverse event, Grade 3+ adverse event, adverse 
event of special interest (AEOSI) etc. a 95% CI for the true adverse event rate would be:
Number of subjects
(%) with AEs
95% confidence 
interval
 8/150 (   5.33%)
(  2.3%, 10.2%)
15/150 (10.00%)
(  5.7%, 16.0%)
23/150 (15.33%)
(10.0%, 22.1%)
30/150 (20.00%)
(13.9%, 27.3%)
38/150 (25.33%)
(18.6%, 33.1%)
45/150 (30.00%)
(22.8%, 38.0%)
53/150 (35.33%)
(27.7%, 43.5%)
Subgroup Analyses
No subgroup analyses are planned.
Compliance (Medication Adherence)
For each subject, percent compliance will then be calculated using the following formula:
Therapy
on 
be
Should
Doses
of
Number 
Therapy
on 
Doses
of
Number 
Compliance
Percent 

x 100.
Summary statistics will be provided on percent compliance for the ASaT population.
Extent of Exposure
The extent of exposure to trial treatment will be evaluated by summary statistics (N, mean, 
median, standard deviation) and frequencies for the “Number of Doses on Therapy”.
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 9.
Table 9
Product Descriptions
Product Name & 
Potency
Dosage Form
Source/Additional Information
MK-3475 25 mg/ mL 
Solution for Infusion
Provided centrally by the Sponsor. 
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Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive an open-label kit.  The kit provided will contain 2 vials.
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
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 (IRT system) to allocate subjects, to assign   treatment to 
subjects and to manage the distribution of clinical supplies. Each person accessing the IRT 
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.    
Select the appropriate text option(s) below as applicable to the given trial. Delete those 
options that do not apply.  If none of the options apply to the given trial, delete this section.  
For probe Bioequivalence (BE)/Bioavailability (BA) trials, where reference comparators are 
sourced by the trial site:
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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/IEC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
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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.
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.
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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 Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  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 FDAAA or the EMA clinical trial directive 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 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
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.
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.
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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.
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 
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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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in previously untreated melanoma without BRAF mutation. N Engl J Med. 2014 
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Ackerman A, Klein O, McDermott DF, Wang W, Ibrahim N, Lawrence DP, et 
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Weber JS, Dummer R, de Pril V, Lebbe C, Hodi FS. Patterns of onset and 
resolution of immune-related adverse events of special interest with ipilimumab: 
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melanoma. Cancer 2013;119:1675-82.
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Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. 
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pembrolizumab using data from KEYNOTE-001, KEYNOTE-002 and 
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Noronha V, Pinninti R, Patil VM, Joshi A, Prabhash K. Lung cancer in the 
Indian subcontinent. South Asian J Cancer. 2016 Jul-Sep;5(3):95-103.
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Parikh PM, Ranade AA, Govind B, Ghadyalpatil N, Singh R, Bharath R, et al. 
Lung cancer in India: current status and promising strategies. South Asian J 
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in 2012: population fact sheets: India [Internet]. Lyon, France: International 
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from: 
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Sulpher JA, Owen SP, Hon H, Tobros K, Shepherd FA, Sabri E, et al. Factors 
influencing a specific pathologic diagnosis of non-small-cell lung carcinoma. 
Clin Lung Cancer. 2013 May;14(3):238-44.
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Pisters KMW, Le Chevalier T. Adjuvant chemotherapy in completely resected 
non-small-cell lung cancer. J Clin Oncol 2005;23(14):3270-8.
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National Cancer Institute. SEER Stat Fact Sheets: Lung and bronchus cancer 
[Internet]. Bethesda, MD: National Cancer Institute; 2016. Available from: 
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Malik PS, Raina V. Lung cancer: prevalent trends & emerging concepts. Indian J 
Med Res. 2015 Jan;141(1):5-7.
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Oncology Network (ICON); Indian Society of Medical & Pediatric Oncology 
(ISMPO); Molecular Oncology Society (MOS) and Association of Physicians of 
India (API). Indian consensus statement for treatment of advanced non small cell 
lung cancer: first line, maintenance, and second line. Indian J Cancer. 2017 Jan-
Mar;54(1):89-103.
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Peters S, Kerr KM, Stahel R. PD-1 blockade in advanced NSCLC: a focus on 
pembrolizumab. Cancer Treat Rev. 2018 Jan;62:39-49.
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Peters S, Adjei AA, Gridelli C, Reck M, Kerr K, Felip E, et al. Metastatic non-
small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for 
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cancer. N Engl J Med 2002;346:92-8.
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Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS. et al. 
Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N 
Engl J Med. 2017 Feb 16;376(7):629-640.
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Hanna N, Johnson D, Temin S, Baker S Jr, Brahmer J, Ellis PM, et al. Systemic 
Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of 
Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2017 Aug 
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Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase 
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Giroux Leprieur E, Dumenil C, Julie C, Giraud V, Dumoulin J, Labrune S. et al. 
Immunotherapy revolutionises non-small-cell lung cancer therapy: Results, 
perspectives and new challenges. Eur J Cancer. 2017 Jun;78:16-23.
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Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. 
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Powell SF, et al. Carboplatin and pemetrexed with or without pembrolizumab for 
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SF. et al. Updated Results From KEYNOTE-021 Cohort G: A Randomized, 
Phase 2 Study of Pemetrexed and Carboplatin With or Without Pembrolizumab 
As First-Line Therapy for Advanced Nonsquamous Non-Small-Cell Lung 
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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.
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3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered 
trials of marketed products in which treatment is assigned, according to the pre-specified plans for data 
analysis. To the extent scientifically appropriate, MSD seeks to publish the results of other analyses it 
conducts 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.
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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.
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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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by 
Sample Types
Screening
Cycle 
1
C2
C3
C 4
C5
C6
C7
C8
C9
C10-
35
EOT
Follow 
up
15 ml
10.5 
ml
5.5 
ml
5.5 
ml
5.5 
ml
10.5 
ml
5.5 
ml
5.5 
ml
5.5 
ml
10.5ml
10.5ml
13.5 
ml
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Common Terminology Criteria for Adverse Events v4.
The descriptions and grading scales found in the revised NCI CTCAE version 4.0 will be 
used for adverse event reporting (http://ctep.cancer.gov).
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Eastern Cooperative Oncology Group
Grade
Performance Status
0
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry 
out any work activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair.
5
Dead 
*As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. 
Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group 
Chair.
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Response Evaluation Criteria in Solid Tumors
RECIST 1.1* will be used in this study for assessment of tumor response. While either CT or 
MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study.
* As published in the European Journal of Cancer [62]
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List of Abbreviations
Abbreviation
Definition
AE
Adverse event
ALK
Anaplastic lymphoma kinase 
ALT
Alanine aminotransferase
ASaT
All Subjects as Treated
AST
Aspartate aminotransferase
BCG
Bacillus Calmette–Guérin
β-hCG
β-human chorionic gonadotropin
CD28
Cluster of differentiation 28
CD3ζ
CD3 zeta
CI
Confidence Interval
CNS
Central nervous system
CT scan
Computed tomography
CTCAE
Common Terminology for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte-associated antigen 4
EBUS
Endobronchial Ultrasound
eCRF
Electronic case report form
ECI
Event of Clinical Interest
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EGFR
Epidermal growth factor receptor
EMA
European Medicines Agency
EOT
End of treatment
ERC
Ethical review committee
FDA
Food and Drug Administration
FVC
Forced vital capacity
GCP
Good Clinical Practices
HBsAg
Hepatitis B
HIV
Human immunodeficiency virus
HR
Hazard ratio
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Abbreviation
Definition
IB
Investigator’s brochure
IFU
Instructions for use
Ig
Immunoglobulin
IgG4
Immunoglobulin G4
IL-2
Interleukin-2
INR
International normalized ratio
IPI
Ipilimumab
IRB
Internal review board
IRC
Independent review committee
IV
Intravenous
LDH
Lactate Dehydrogenase
mAb
Monoclonal antibody
MRI
Magnetic resonance imaging
NSAIDS
Non-steroidal anti-inflammatory drugs
OS
Overall survival
ORR
Overall response rates
OTC
Over-the-counter
PD
Progressive Disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PEF
Peak expiratory flow
PFS
Progression-free survival
PKCθ
Protein kinase C-theta
PO
By mouth
PT
Prothrombintime
Q3W
Every 3 weeks
RECIST 1.1
Response Evaluation Criteria in Solid Tumors 
RR
Response rate
SAE
Serious adverse event
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Abbreviation
Definition
SOP
Standard operating procedures
T1DM
Type 1 Diabetes Mellitus 
TKI
Tyrosine kinase inhibitor
TPS
Tumor proportion score
T-regs
Regulatory T-cells
TB
Tuberculosis
ULN
Upper limit of normal
US
United States
WBC
White blood cell
ZAP70
Zeta-chain-associated protein kinase
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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
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