Clinical trial NCT03515629
Conditions: Non-small Cell Lung Cancer
Keywords: Stage IIIB Stage IV Non-squamous NSCLC Squamous NSCLC
Sponsor: Regeneron Pharmaceuticals
Start date: 2018-07-02; Completion date: 2021-07-29
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to compare the progression-free survival (PFS) of REGN2810 (cemiplimab) plus ipilimumab combination therapy (hereinafter referred to as REGN2810/ipi) and REGN2810 plus 2 cycles only of platinum-based doublet chemotherapy plus ipilimumab combination therapy (hereinafter referred to as "REGN2810/chemo/ipi") with standard-of-care pembrolizumab monotherapy in the first-line treatment of patients with advanced squamous or non-squamous non-small cell lung cancer (NSCLC) whose tumors express programmed death ligand 1 (PD-L1) in ≥50% of tumor cells. The key secondary objectives of the study are to compare the overall survival (OS) of REGN2810/ipi and REGN2810/chemo/ipi with pembrolizumab monotherapy in the first-line treatment of patients with advanced squamous or non-squamous NSCLC whose tumors express PD-L1 in ≥50% of tumor cells and to compare the overall response rate (ORR) of REGN2810/ipi and REGN2810/chemo/ipi with pembrolizumab monotherapy in the first-line treatment of patients with advanced squamous or non-squamous NSCLC whose tumors express PD-L1 in ≥50% of tumor cells.

Detailed description:

Arms: arm 1: Pembrolizumab arm 2: REGN2810/ipi arm 3: REGN2810/chemo/ipi
Interventions: intervention 1: REGN2810/ipi intervention 2: REGN2810/chemo/ipi intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: REGN2810 plus ipilimumab intervention 2: REGN2810 plus chemotherapy plus Ipilimumab intervention 3: Reference drug administered IV infusion

Protocol documents:
Prot_000.pdf: 


Clinical Study Protocol 
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Regeneron Pharmaceuticals, Inc. 
 
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AMENDMENT HISTORY 
Amendment 3 Global 
Change 
Sections Changed 
Clarified that for patients on treatment Arm C, 
pemetrexed maintenance is not allowed. 
Synopsis Study Design 
Clarified that patients in follow-up may be 
offered retreatment up to an additional 
108 week and patients may be required to sign 
a separate ICF per local regulatory 
requirements. 
Section 5.1.3 Follow-up Period 
Section 7.8 Disease Progression While 
Receiving Cemiplimab or Pembrolizumab 
Revised the following secondary endpoint text 
as: 
To assess the predictive utility of baseline 
PD L1 tumor expression levels on clinical 
response. 
Clarified the following in the list of Other 
Secondary Objectives:  Tumor mutation 
burden as assessed by the Foundation 
Medicine “FoundationOne®” panel, sample 
permitting 
Synopsis Objectives 
Section 2.2.2 Other Secondary Objectives 
 
Inclusion criterion revised to add stage IIIC 
patient eligibility for the study and clarified 
that histologic diagnosis of NSCLC may be 
confirmed by the central laboratory. 
Synopsis Study Design and Population 
Section 5.1 Study Description and Duration 
Section 6.2 Study Population 
Section 6.2.1 Inclusion Criteria #2 
Gemcitabine options for platinum based 
doublet is deleted and chemotherapy cycles are 
changed from 4-6 cycles to 4 cycles.  
Following text deleted: Brain scans during the 
treatment and follow-up periods should be 
performed as clinically indicated except for 
patients with a history of metastases, who 
should have surveillance imaging 
approximately every 18 weeks for year 1 and 
every 24 weeks for year 2 or sooner, if 
indicated. 
PK/ADA sample collection time points 
revised. 
Pharmacokinetics and immunogenicity of 
Section 8.2.2.1 Radiographic Tumor 
Assessments 
Table 1 Guidelines for Platinum-Based 
Doublet Chemotherapy Regimens (Treatment 
Arm C)  
Table 5 Schedule of Events:  Treatment Period 
Assessments and Procedures 
Table 6 Schedule of Events: Follow-up Period 
Assessments and Procedures  
Appendix 4 Cemiplimab Pharmacokinetic, 
Immunogenicity, and Biomarker Sampling 
Schedule Clarified that, if possible, a tumor 
biopsy should be collected at the time of 
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cemiplimab are now well understood and 
described by a linear population PK model in 
more than 500 patients from various studies. 
PK/ADA sampling can be reduced, as 
population PK modeling approaches are used 
to describe PK characteristics in individual 
patients and in the overall population of 
patients with NSCLC. 
Clarified that, if possible, a tumor biopsy 
should be collected at the time of progressive 
disease (optional) as described in the 
laboratory manual 
progressive disease (optional) as described in 
the laboratory manual 
Clarified that all patients will have tumor 
evaluated for EGFR mutations, ALK 
rearrangement, and ROS1 fusions confirmed 
by a central laboratory. 
Clarified that tuberculosis testing is for 
potential patients in TB endemic areas.   
 
Exclusion criteria added based on a health 
authority feedback: 
 #24. History of previous organ transplant, 
including stem cell allograft 
#25. 
Meeting the comparator products 
contraindicated criteria as listed in local 
labeling. Investigators should review the 
current label in their local database. 
Section 6.2.2  Exclusion Criteria #3, #23, #24, 
and #25 
Clarified that: Tumor tissue samples will also 
be tested for EGFR mutations and ALK 
translocations as well as for ROS1 fusions by a 
central laboratory, unless these testing has 
already been performed and the results are 
available from other Regeneron NSCLC 
immunotherapy studies. 
Following text deleted: Biomarker procedures 
will include the use of tumor tissue samples for 
validation of additional PD-L1 assays. 
Following text deleted: Additional testing may 
be employed to determine PD-L1 expression 
levels by utilizing another PD-L1 IHC assay in 
the same tissue specimens.  This approach may 
provide a better understanding of the 
performance of PD-L1 expression level as a 
predictive biomarker of response to 
Synopsis Procedures and Assessments 
Section 8.2.1  Procedures Performed only at 
Screening/baseline Visit 
Section 8.2.5  Biomarker Procedures 
Table 4 Schedule of Events: Screening Visit 
Assessments 
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REGN2810.  Of special interest is PD-L1 
expression across different cell types including 
tumor cells, stroma cells, and infiltrating 
immune cells. 
Following text revised as: If possible a tumor 
tissue biopsy sample should be obtained at the 
time of RECIST 1.1 defined progressive 
disease. to obtain information on mechanism of 
resistance. 
Electrocardiogram text revised to delete: Heart 
rate will be recorded from the ventricular rate, 
and the PR, QRS, RR, QT, and QT corrected 
for Bazett’s formula intervals will also be 
recorded.   
Section 8.2.3.5 Electrocardiogram 
Following text added, based on request by 
regulatory authority to evaluate ADA in 
ipilimumab, as follows: 
If necessary, these samples may also be used 
for ADA assessments of ipilimumab. 
Section 8.2.4.2 Anti-Drug Antibody 
Measurements and Samples 
The current text “Each vial will contain a 
volume sufficient to withdraw 5 mL of 
REGN2810 at a concentration of 50 mg/mL” is 
revised to “Each vial will contain withdrawable 
cemiplimab at a concentration of 50 mg/mL 
Section 7.1.1 Cemiplimab 
Section 7.6.1 Packaging, Labeling, and Storage 
Clarified that premedications are not required 
prior to the first administration of cemiplimab. 
And pretreatment with vitamin 
supplementation is to start within 3 days of 
randomization for patients with non-squamous 
NSCLC. 
Following text added: Pemetrexed maintenance 
therapy should be given according to local 
prescribing information and practice 
guidelines. 
Section 7.2 Pretreatments 
Section 7.8 Disease Progression While 
Receiving Cemiplimab or Pembrolizumab 
Section 7.7.2 Permitted Medications and 
Procedures 
Deleted “standard-of-care” wording from when 
mentioned in regards to platinum based 
chemotherapy(ies).”   
Throughout the protocol  
Changed REGN2810 to the generic name, 
cemiplimab and minor editorial changes 
Throughout the protocol 
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Amendment 2 VHP 
Change 
Section Changed 
The following text added to the exclusion 
criterion #10 “patients with HIV or hepatitis 
must have their disease reviewed by the 
specialist (e.g., infectious disease or 
hepatologist) managing this disease prior to 
commencing and throughout the duration of 
their participation in the trial” following 
European Union (EU) regulatory review. 
Section 6.2.2  Exclusion Criteria, #10  
 
Amendment 2 
Change 
Sections Changed 
The current text of Key Secondary Endpoint “A 
patient who has not died will be censored at the 
last known date of contact" has been revised to "A 
patient who is lost to follow-up will be censored at 
the last date that the patient was known to be 
alive", following European Union (EU) regulatory 
review. 
Section 4.2.2  Key Secondary Endpoint 
Revised the exclusion criteria concerning human 
immunodeficiency virus (HIV), hepatitis B virus 
(HBV) and hepatitis C virus (HCV) to clarify that 
patients with uncontrolled infection are excluded, 
but patients with controlled infection are 
permitted, as requested following EU regulatory 
review. 
Section 6.2.2  Exclusion Criteria 
(combined criteria #10 and #11, and 
deleted previous #11) 
The current text: “REGN2810 C2P1 drug product 
is supplied as a sterile liquid solution of 5.6 or 7.4 
mL in a 10 or 20 mL glass vial for IV 
administration.” is revised to “REGN2810 C2P1 
drug product is supplied as a sterile liquid solution 
of 5.6 mL in a 10 mL glass vial for IV 
administration.” as requested following EU 
regulatory review. 
Section 7.1.1  REGN2810 
 
 
The current text “Each vial will contain a volume 
sufficient to withdraw 5 mL or 7 mL of 
REGN2810 at a concentration of 50 mg/mL” is 
Section 7.1.1  REGN2810 
Section 7.6.1  Packaging, Labeling, and 
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Change 
Sections Changed 
revised to “Each vial will contain a volume 
sufficient to withdraw 5 mL of REGN2810 at a 
concentration of 50 mg/mL” as requested 
following EU regulatory review. 
Storage 
The inclusion of the text “or 4-6 cycles” as an 
option in Table 1 is deleted as requested following 
EU regulatory review. 
The current text “REGN2810 will be administered 
in combination with either platinum-based doublet 
chemotherapy (administered Q3W for 
4 to 6 cycles; REGN2810/ipi or with platinum-
based doublet chemotherapy (administered Q3W 
for 2 cycles) and ipilimumab (administered Q6W 
for up to 4 doses; REGN2810/chemo/ipi) and then 
alone for the remainder of the treatment period.” is 
revised to “REGN2810 will be administered in 
combination with either ipilimumab (administered 
Q6W for up to 4 doses; REGN2810/ipi) or with 
platinum-based doublet chemotherapy 
(administered Q3W for 2 cycles) and ipilimumab 
(administered Q6W for up to 4 doses; 
REGN2810/chemo/ipi) and then alone for the 
remainder of the treatment period.” 
Table 1  Guidelines for Platinum-Based 
Doublet Chemotherapy Regimens 
(Treatment Arm C) 
Section 7.1.1  REGN2810. 
Added tuberculosis screening, as requested 
following EU regulatory review. 
Section 6.2.2  Exclusion Criteria (new 
criterion number 23) 
Table 4  Schedule of Events:  Screening 
Visit Assessments and Procedures 
Section 8.2.1  Procedures Performed 
Only at the Screening/Baseline Visit 
Section 8.2.3.6  Laboratory Testing 
Added testing for amylase and lipase, as requested 
following EU regulatory review. 
Table 4  Schedule of Events:  Screening 
Visit Assessments and Procedures 
Table 5  Schedule of Events:  Treatment 
Period Assessments and Procedures 
Section 8.2.3.6  Laboratory Testing 
Revised the protocol to include regular thyroid 
function testing for Arm B as requested following 
EU regulatory review. 
Table 5  Schedule of Events:  Treatment 
Period Assessments and Procedures 
Section 8.2.3.6  Laboratory Testing 
 
Amendment 1 
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Change 
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The redesigned study is a phase 3, randomized, 
global, open-label, pivotal, study of the efficacy 
and safety of REGN2810/ipilimumab versus 
REGN2810/chemotherapy/ipilimumab versus 
pembrolizumab monotherapy in patients with 
stage IIIB or stage IV squamous or non squamous 
NSCLC whose tumors express PD L1 in ≥50% of 
tumor cells and who have received no prior 
systemic treatment for their advanced disease. 
In the redesigned study, the study arms A and C 
remain the same; arm B will evaluate REGN2810 
in combination with ipilimumab instead of 
chemotherapy. 
Rationale revised to reflect the new study design.  
Because this is the first study to evaluate the 
combination of REGN2810 and ipilimumab, and 
the combination or platinum doublet 
chemotherapy and ipilimumab, there will be an 
early review of data to ensure patient safety after 
the first 10 patients in the REGN2810/ipilimumab 
and the first 10 patients in the 
REGN2810/chemo/ipilimumab treatment arm 
have completed 4 weeks of follow-up following 
the first dose of REGN2810/ipilimumab or 
REGN2810/chemo/ ipilimumab respectively.  An 
additional safety review will be performed by the 
IDMC after the first 10 patients in the 
REGN2810/ ipilimumab and REGN2810/chemo/ 
ipilimumab regimen have received all 4 doses of 
ipilimumab and have been followed for at least 6 
weeks after the last dose.  This analysis will 
include all patients who have been exposed to the 
combination treatment. 
Enrollment to Arm C does not need to be halted 
pending the results of the additional safety 
evaluation, but stopping criteria related to this 
evaluation was incorporated into the protocol. 
Rationale for combination of REGN2810 and 
ipilimumab has been revised to reflect the new 
study design. 
Tumor mutation burden as assessed by the 
Foundation Medicine “FoundationOne®” panel, 
sample permitting 
Clinical Study Protocol Synopsis: 
Objectives, Study Design, Treatments, 
Endpoints, Statistical Plan 
Section 1 Introduction 
Section 2.1 Primary Objectives 
Section 2.2.1 Key Secondary Objectives 
Section 2.2.2 Other Secondary Objectives 
Section 3.1 Hypothesis  
Section 3.2.1 Rationale for Study Design 
Section 3.2.2 Rationale for Endpoints and 
Objectives 
Section 3.2.4 Rational for Combination of 
REGN2810 and Ipilimumab  
Section 3.2.5 Rationale for Combination of 
REGN2810 and Ipilimumab and Limited (2 
Cycles) Platinum-Based Doublet 
Chemotherapy 
Section 4.2.3 Other Secondary Endpoints 
Section 5 Study Design 
Figure 1 Study Flow Diagram 
Section 5.1 Study Description and Duration 
Section 5.1.1 Screening 
Section 5.1.2 Treatment Period 
Section 5.1.4 Description of Study Stopping 
Rules  
Section 5.1.5  Dose Limiting Toxicities 
Section 5.1.6 Maximum Tolerated dose 
Section 7.5  Method of Treatment 
Assignment 
Section 10.1 Statistical Hypothesis 
Table 5  Schedule of Events:  Treatment 
Period Assessment and Procedures 
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Change 
Sections Changed 
Because this is the first study to evaluate the 
combination of REGN2810 and ipilimumab, and 
the combination or platinum doublet 
chemotherapy and ipilimumab description of 
study stopping rules revised. 
Description of dose limiting toxicities revised. 
The following changes were implemented: 
 Revised AST or ALT >5 times upper limit 
of normal (ULN) and/or total bilirubin 
>3 times ULN as a DLT criterion.  
 Added Grade 4 anemia  
DLT criteria include all Grade 3 immune-related 
AEs (irAEs).  Any Grade 3 irAE which would 
result in permanent discontinuation of the 
REGN2810/ipilimumab or 
REGN2810/ipilimumab/chemo (or permanent 
discontinuation of ipilimumab), as outlined in the 
“Dosing Discontinuation” subsection of Section 
7.3.1 of the protocol, or which would result in 
permanent discontinuation of REGN2810, as 
outlined in the guidelines in Appendix 3 of the 
protocol, will be considered a DLT.  This 
specifically includes the following Grade 3 irAEs: 
pneumonitis, colitis/diarrhea, nephritis. 
The following statement added: 
The use of the PD-L1 IHC 22C3 pharmDx assay 
for decisions regarding treatment with 
REGN2810 is considered investigational. 
Section 3.2.3  Rationale for Choice of 
Patient Population Based on the ≥50% 
Programmed death Death-1 Expression Cut-
off 
Section 5.1.1 Screening 
Due to a new statistical design, enrollment of 
approximately 585 subjects is needed to generate 
enough progression free survival (PFS) events.  
Therefore, the approximate number of planned 
subjects is reduced to 585 from 675.  An interim 
analysis for secondary endpoint of OS will be 
performed at the time of primary analysis for 
PFS. 
 
Clinical Study Protocol Synopsis:  
Population, Statistical Plan 
Section 5.2 Planned Interim Analysis 
Section 6.1 Number of Patients Planned 
Section 7.5 Method of Treatment 
Assignment 
Section 10.2 Justification of Sample Size 
Section 10.6 Interim Analysis 
Age limit requirements for the Japanese patients 
revised in Inclusion Criterion #1 as follows: Men 
Section 6.2.1  Inclusion Criteria #1, #2, and 
#3 
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Change 
Sections Changed 
and women ≥18 years of age (≥21 years of age for 
Japanese patients) 
Based on the health authority feedback, inclusion 
criterion #2 revised to specify the following 
patient eligibility as follows: 
Patients with stage IV disease if they have not 
received prior systemic treatment for recurrent or 
metastatic NSCLC are eligible to participate in 
the study. 
Following guidance on biopsy sites provided: 
 Archival or fresh biopsies are acceptable 
 If an archival biopsy is used, it has to be 
less than 5 months old 
 The biopsy should be from a metastatic or 
recurrent site which has not previously 
been irradiated 
 Exception: the primary lung tumor is still 
in place and the other metastatic sites are 
either not accessible (brain) or cannot be 
used (bone) or the biopsy would put the 
patient at risk 
Exclusion criterion #3 modified to add a 
statement indicating that all patients should have 
tumor evaluated for EGFR mutations, ALK 
rearrangement, and ROS1 fusions. 
Exclusion criterion #5 revised to add the 
following:  A history of radiation pneumonitis in 
the radiation field is permitted as long as 
pneumonitis resolved ≥6 months prior to 
enrollment. 
Exclusion criterion #10 updated to add additional 
description of infection with human 
immunodeficiency virus, hepatitis B or hepatitis 
C infection; or diagnosis of immunodeficiency 
Exclusion criterion #20 updated to include men of 
childbearing potential. 
Section 6.2.2  Exclusion Criteria  #3,  #5, 
#10, and #20 
Table 4  Schedule of Events:  Screening 
Visit Assessments and Procedures  
Study treatment for Arm B revised  
Guidelines for Platinum-based chemotherapy for 
treatment Arm C revised to remove the 
maintenance column from the table. 
Section 7.1 Investigational and Reference 
Treatments 
Section 7.1.4 Platinum-Based Doublet 
Chemotherapy 
Table 1 Guidelines for Platinum-Based 
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Change 
Sections Changed 
Doublet Chemotherapy Regimens 
(Treatment Arm C) 
Because of study design revisions, the dose 
modification and treatment discontinuation rules 
have been updated. 
Section 7.3.1  REGN2810 Plus Ipilimumab 
Combination Therapy Dosing Delay Rules 
Section 7.3.2  REGN Plus Ipilimumab and 
Chemotherapy Combination Therapy 
Dosing Delay Rules 
Section 7.3.3  REGN2810 as Combination 
Therapy  
Following text added: 
irAEs of any grade in patients previously treated 
with PI3-K inhibitor 
Section 9.3.3 Adverse Events of Special 
Interest 
Acute infusion reactions are defined as any AE 
that occurs during the infusion or within one day 
after the infusion is completed, instead of within 2 
hours. 
Section 7.4.1 Acute Infusion Reactions 
Section 9.3.4 Infusion Reactions 
Any treatment administered from the time of 
informed consent until 90 days (instead of 30 
days) after the last study treatment will be 
considered concomitant medication.   
Section 7.7 Concomitant Medications 
Disease progression while Receiving REGN2810 
or pembrolizumab description revised. 
Section 7.8  Disease Progression While 
Receiving REGN2810 or Pembrolizumab 
The following sentence deleted: This testing does 
not need to be repeated if it has been done 
previously and the results are available. 
Section 8.2.5 Biomarker Procedures 
Justification of the sample size was revised. 
Definitions of primary, secondary, and other 
analysis sets revised to reflect the new statistical 
design for the study. 
Multiplicity considerations revised due to 
hierarchical testing.  
An interim analysis for secondary endpoint of OS 
will be performed at the time of primary analysis 
for PFS. 
Clinical Study Protocol Synopsis:  
Statistical Plan 
Section 10.2 Justification of sample size 
Section 10.3.3 Other Analysis Set 
Section 10.4.5.1 Primary Efficacy Analyses 
Section 10.4.5.2 Secondary Efficacy 
Analyses 
Section 10.5 Multiplicity Considerations 
Section 10.6 Interim Analysis 
A written informed consent should be obtained 
for treatment beyond radiologic disease 
progression, acknowledging that this practice is 
not considered standard in the treatment of 
Section 14.2 Informed Consent 
 
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Change 
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cancer. 
The diagram for colitis adverse event 
management in Appendix 3 has been modified to 
require permanent discontinuation of cemiplimab 
for grade 4 colitis 
Appendix 3 Recommended Dose 
Modification or Discontinuation and 
Supportive Care Guidelines for Specific 
REGN2810 Drug Related Adverse  
ADA sample collection time points revised 
Appendix 4 REGN2810 Pharmacokinetic, 
Immunogenicity, and Biomarker Sampling 
Schedule 
Concomitant Medication Recording during 
follow-up added 
Table 6 Schedule of Events:  Follow-Up 
Period Assessments and Procedures 
Data Quality Assurance section added 
Section 18 Data Quality Assurance  
Minor editorial changes 
Throughout the protocol 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Randomized, Phase 3, Open-Label Study of Combinations of REGN2810 
(Cemiplimab, Anti-PD-1 Antibody), Platinum-based Doublet Chemotherapy, 
and 
Ipilimumab 
(Anti-CTLA-4 
Antibody) 
Versus 
Pembrolizumab 
Monotherapy in First-Line Treatment of Patients With Advanced or 
Metastatic Non-Small Cell Lung Cancer With Tumors Expressing PD-L1 
≥50% 
Site Locations 
Patients will be randomized at approximately 200 global study sites. 
Objectives 
The primary objective of the study is to compare the progression-free survival 
(PFS) of  cemiplimab plus ipilimumab combination therapy (hereinafter 
referred to as cemiplimab/ipi) and cemiplimab plus 2 cycles only of platinum-
based doublet chemotherapy plus ipilimumab combination therapy 
(hereinafter referred to as “cemiplimab/chemo/ipi”) with pembrolizumab 
monotherapy in the first-line treatment of patients with advanced squamous or 
non-squamous non-small cell lung cancer (NSCLC) whose tumors express 
programmed death ligand 1 (PD-L1) in ≥50% of tumor cells. 
The key secondary objectives of the study are the following: 
 
To compare the overall survival (OS) of cemiplimab/ipi and 
cemiplimab/chemo/ipi with pembrolizumab monotherapy in the 
first-line treatment of patients with advanced squamous or 
non-squamous NSCLC whose tumors express PD-L1 in ≥50% of tumor 
cells 
 
To compare the objective response rate (ORR) of cemiplimab/ipi and 
cemiplimab/chemo/ipi with pembrolizumab monotherapy in the 
first-line treatment of patients with advanced squamous or non-
squamous NSCLC whose tumors express PD-L1 in ≥50% of tumor 
cells 
The other secondary objectives are the following: 
 
To evaluate the safety and tolerability of cemiplimab/ipi and 
cemiplimab/chemo/ipi compared to pembrolizumab monotherapy in the 
first-line treatment of patients with advanced squamous or non-
squamous NSCLC whose tumors express PD-L1 in ≥50% of tumor 
cells 
 
To compare the OS at 12 and 18 months of cemiplimab/ipi or 
cemiplimab/chemo/ipi with pembrolizumab monotherapy in the first-
line treatment of patients with advanced squamous or non-squamous 
NSCLC whose tumors express PD-L1 in ≥50% of tumor cells 
 
To compare quality of life (QOL) in patients with advanced squamous 
or non-squamous NSCLC whose tumors express PD-L1 in ≥50% of 
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tumor cells receiving cemiplimab/ipi or cemiplimab/chemo/ipi with 
QOL in those patients receiving pembrolizumab monotherapy 
 
To assess immunogenicity as measured by anti-drug antibodies (ADAs) 
for cemiplimab 
 
To assess the predictive utility of baseline PD-L1 tumor expression 
levels on clinical response  
 
To characterize the pharmacokinetics (PK) of cemiplimab when 
administered 
in 
combination 
with 
platinum-based 
doublet 
chemotherapy and/or ipilimumab 
 
To conduct exposure-response (E-R) analyses for relevant biomarkers 
(exploratory PK/pharmacodynamic analyses) and E-R analyses for 
safety and efficacy endpoints, as appropriate 
Study Design 
This is a phase 3, randomized, global, open-label, pivotal study of the efficacy 
and 
safety 
of 
cemiplimab/ipi 
versus 
cemiplimab/chemo/ipi 
versus 
pembrolizumab monotherapy in patients with stage IIIB, IIIC or stage IV 
squamous or non-squamous NSCLC whose tumors express PD-L1 in ≥50% 
of tumor cells and who have received no prior systemic treatment for their 
advanced disease. 
The study will consist of the following 3 periods:  screening, treatment, and 
follow-up. 
Patients will undergo a screening evaluation to determine their eligibility 
within 28 days prior to randomization.  Eligible patients will be randomized 
1:1:1 to one of the following treatment arms: 
 
Treatment Arm A:  pembrolizumab monotherapy 200 mg every 
3 weeks (Q3W) for 108 weeks 
 
Treatment Arm B:  cemiplimab 350 mg Q3W for 108 weeks plus 
ipilimumab 50 mg every 6 weeks (Q6W) for up to 4 doses 
 
Treatment Arm C:  cemiplimab 350 mg Q3W for 108 weeks plus 
platinum-based doublet chemotherapy Q3W for 2 cycles and 
ipilimumab 50 mg every 6 weeks (Q6W) for up to 4 doses.  Patients 
in this arm will not be permitted to receive pemetrexed maintenance. 
Patients will receive their assigned treatment for the 108-week treatment 
period.  Treatment may be discontinued early due to Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST 1.1)-defined progressive 
disease, unacceptable toxicity, withdrawal of consent, death, initiation of 
another anti-cancer treatment, or, for patients in Treatment Arms B and C, in 
specific instances of confirmed complete response (CR) or partial response 
(PR).  Patients who experience RECIST 1.1-defined progressive disease on 
therapy may continue treatment if the investigator judges the patient to be 
experiencing clinical benefit and if the patient has not completed the 
108-week treatment period.  If further progressive disease (defined as an 
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additional 10% increase in tumor burden from the time of initial progressive 
disease) is confirmed, treatment must be discontinued and other anti-cancer 
therapy considered, if appropriate.  A similar approach to treatment beyond 
first evidence of progression may be offered to patients receiving 
pembrolizumab in Treatment Arm A. 
After discontinuing study treatment, patients will enter the follow-up period. 
Each patient will have the first follow-up visit 14 to 30 days after the last 
study treatment if treatment is discontinued early due to progressive disease, 
toxicity, or for another reason, or 14 to 30 days after the last cycle visit.  
Follow-up visit 2 through follow-up visit 7 will occur 28 days (±7 days) from 
the previous visit.  Survival data will then be collected by phone or at an 
office visit every 3 months, until death, loss to follow-up, or withdrawal of 
study consent. 
More than 353 patients have been dosed as of April 2017 with cemiplimab 
with no DLTs observed.  Because this is the first study of the cemiplimab/ipi 
and cemiplimab/chemo/ipi combinations, safety data from the first 10 patients 
treated with cemiplimab/ipi in Treatment Arm B and the first 10 patients 
treated with cemiplimab/chemo/ipi in Treatment Arm C will be reviewed 
after these patients complete 4 weeks of follow-up following the first dose of 
cemiplimab/chemo/ipi.  The data will be reviewed at a meeting of the IDMC.  
If 2 or more DLTs occur in the first 10 patients treated with cemiplimab/ipi or 
in the first 10 patients treated with cemiplimab/chemo/ipi, enrollment for the 
respective treatment arm will be stopped temporarily.  Enrollment in 
Treatment Arms B and C will only be restarted after a formal safety review. 
An additional safety review will be performed by the IDMC after the first 
10 patients in the cemiplimab/ipi and the first 10 patients in the 
cemiplimab/chemo/ipi regimen have received all 4 doses of ipilimumab and 
have been followed for at least 6 weeks after the last dose.  This analysis will 
include all patients who have been exposed to the combination treatment.  
After this evaluation is performed, occurrence of drug related adverse events 
causing treatment discontinuation in ≥25% of treated patients will lead to a 
pause in further enrollment to Arm B or C pending review with the IDMC 
and the study steering committee. 
The outcomes of these safety reviews will be a decision to do one of the 
following: 
 
Continue the study as planned after discussions with 
investigators and regulatory authorities 
 
Continue the study without the second cycle of chemotherapy 
 
Increase the interval for ipilimumab administration from 6 to 
12 weeks in Treatment Arm B or C 
 
Discontinue Treatment Arm B or C 
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Study Duration 
The approximate duration of the active study assessments for each patient, 
excluding screening, will be 32 months.  This encompasses 25 months of 
study treatment plus 7 months of follow-up visits.  After the active study 
assessments are complete, all patients will be followed for survival. 
End of Study Definition 
The end of study is defined as the last visit of the last patient. 
Population 
 
 
Sample Size: 
Approximately 585 patients will be randomized. 
 
Target Population: 
Patients in this study will include men and women ≥18 years of age, 
diagnosed with stage IIIB, or IIIC NSCLC who are not eligible for definitive 
chemo/radiation therapy or patients with or stage IV non-squamous or 
squamous NSCLC, whose tumors express PD-L1 in ≥50% of tumor cells 
(measured using the PD-L1 immunohistochemistry 22C3 pharmDx assay 
[Dako, North America, Inc.]) and who have received no prior systemic 
treatment for their advanced disease. 
Treatments 
 
 
Study Drug: 
 
Dose/Route/Schedule: 
Cemiplimab administered at 350 mg as an intravenous (IV) infusion Q3W for 
108 weeks in combination with ipilimumab administered IV over 
approximately 90 minutes at 50 mg Q6W for up to 4 doses. 
 
Study Drug: 
 
Dose/Route/Schedule: 
Cemiplimab administered at 350 mg as an IV infusion Q3W for 108 weeks in 
combination with platinum-based doublet chemotherapy administered IV 
Q3W for 2 cycles and with ipilimumab administered IV over approximately 
90 minutes at 50 mg Q6W for up to 4 doses. 
 
Reference Drug 
 
Dose/Route/Schedule: 
Pembrolizumab administered at 200 mg as an IV infusion Q3W for 
108 weeks. 
Endpoints 
 
 
Primary: 
The primary endpoint is PFS as assessed by a blinded Independent Review 
Committee (IRC) based on RECIST 1.1 assessments. 
 
Secondary: 
The key secondary endpoints will be OS and ORR.   
Other secondary endpoints will include the following: 
 The 
safety 
and 
tolerability 
of 
cemiplimab/ipi 
and 
cemiplimab/chemo/ipi measured by the incidence of treatment-
emergent adverse events (TEAEs), dose-limiting toxicities (DLTs), 
serious adverse events (SAEs), deaths, and laboratory abnormalities   
 Overall survival at 12 months and 18 months 
 Quality of life as measured by the European Organization for Research 
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and Treatment of Cancer Quality of Life Questionnaire Core 30 
(EORTC QLQ-C30) and European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire Lung Cancer 13 
(EORTC QLQ-LC13) 
 Tumor mutation burden as assessed by the Foundation Medicine 
“FoundationOne®” panel, sample permitting 
Procedures and Assessments 
Procedures to be performed at screening will include informed consent; 
assessment of inclusion/exclusion criteria; recording of medical, oncology, 
and concomitant medications histories; recording of demographics; collection 
and testing of tumor tissue samples for PD-L1 assessment and for epidermal 
growth factor receptor and anaplastic lymphoma kinase mutations and C-ros 
oncogene receptor tyrosine kinase fusions; baseline radiographic tumor 
assessment and tumor burden assessment; chest X-ray; serum pregnancy 
testing; 12-lead electrocardiogram; complete physical examination including 
vital signs, height, and weight assessments; Eastern Cooperative Oncology 
Group (ECOG) performance status assessment; adverse event (AE) recording; 
and laboratory testing.  Samples for an optional genomic sub-study may also 
be obtained. 
During the treatment period, the following procedures will be performed to 
assess efficacy and safety: QOL measurement using validated patient 
questionnaires, physical examination, ECOG performance status assessment; 
vital signs; laboratory testing, including pregnancy testing for women of 
childbearing potential; recording of AEs and concomitant medications.  
Computed tomography or magnetic resonance imaging (or positron emission 
tomography) for radiographic tumor burden assessment and tumor burden 
assessment based on RECIST 1.1 criteria will be performed at pre-specified 
time points throughout the study.   
Other assessments will include cemiplimab concentration measurement, 
cemiplimab ADA assessment, and biomarker assessments.  . 
Survival data will then be collected by phone or at an office visit every 
3 months, until death, loss to follow-up, or withdrawal of study consent. 
Statistical Plan 
The 
primary 
statistical 
hypothesis 
is 
that 
cemiplimab/ipi 
or 
cemiplimab/chemo/ipi will prolong PFS as compared with standard-of –care 
pembrolizumab monotherapy in treatment-naïve patients with squamous and 
non-squamous NSCLC whose tumors express PD-L1 in ≥50% of tumor cells.  
The secondary hypothesis is that cemiplimab/ipi or cemiplimab/chemo/ipi 
will improve OS in the study patients whose tumors express PD-L1 in ≥50% 
of tumor cells. 
This study assumes a median PFS of 10 months for patients treated with 
pembrolizumab monotherapy and a median PFS of 15 months for patients 
treated with each of the cemiplimab combination therapies.  The assumptions 
correspond to a 50% increase in median PFS and a hazard ratio (HR) of 
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0.6667.  Under these assumptions, and for each cemiplimab combination 
treatment arm versus the pembrolizumab comparison, 256 PFS events are 
needed to yield an approximately 90% power to detect statistical significance 
at a 2-sided 0.05 level. 
Considering a uniform enrollment rate and a combined enrollment, and PFS 
follow-up duration of approximately 36 months (24 months for enrollment 
and approximately 12 months follow-up for PFS), and a 10% dropout rate per 
year, enrollment of approximately 585 randomized patients (195 patients per 
arm) is needed to generate enough PFS events for each cemiplimab 
combination treatment arm versus the pembrolizumab comparison with 90% 
power.  Under the enrollment assumption and the alternative hypothesis, it is 
estimated that at the time when not less than142 PFS events are observed in 
the pembrolizumab arm, each of the cemiplimab combination treatment arms 
plus the pembrolizumab arm will yield 256 PFS events in total.  In order to 
harmonize the timing of the primary analysis for the 2 comparisons, the 
primary endpoint of PFS will be performed after 142 PFS events are observed 
in the pembrolizumab treatment arm. 
Assuming a median OS of 18 months for patients treated with pembrolizumab 
monotherapy and a median OS of 24 months for patients treated with each of 
the cemiplimab combination therapies, a corresponding HR of 0.75 is 
anticipated if OS is distributed exponentially in each treatment arms.  If the 
final analysis of OS is performed 12 months after the analysis of PFS, 
enrollment of 585 patients will yield approximately a power of 59% for the 
analysis of OS at a 2-sided alpha level of 0.05. 
For PFS, it is projected that an observed HR of 0.78 or lower, corresponding 
to an increase in median PFS of 2.8 months or more (10 versus 12.8 months), 
would result in a statistically significant improvement in PFS.  For OS, it is 
also projected that an observed HR of 0.77 or lower, corresponding to an 
increase in median OS of 5.4 months or more (18 versus 23.4 months), would 
result in a statistically significant improvement in OS. 
The primary endpoint of PFS will be analyzed by stratified log-rank test using 
status of histology (non-squamous versus squamous) as the stratification 
factor.  The HR and its 95% confidence interval will be estimated by a 
stratified Cox regression model using the treatment as covariate. 
For the 2 cemiplimab combinations versus pembrolizumab comparisons, and 
the test of primary endpoint of PFS, secondary endpoints of OS and ORR, a 
familywise type-I error rate of 0.05 is controlled by the hierarchical 
gatekeeping approach with the order of tests listed below: 
1. PFS for cemiplimab/chemo/ipi vs. pembrolizumab 
2. PFS for cemiplimab/ipi vs. pembrolizumab 
3. OS for cemiplimab/chemo/ipi vs. pembrolizumab 
4. OS for cemiplimab/ipi vs. pembrolizumab 
5. ORR for cemiplimab/chemo/ipi vs. pembrolizumab 
6. ORR for cemiplimab/ipi vs. pembrolizumab 
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Safety observations and measurements, including drug exposure, AEs, 
laboratory data, vital signs, and ECOG performance status, will be 
summarized and presented in tables and listings.  Cemiplimab concentrations 
in serum will be reported over time as individual values with descriptive 
statistics.   
For continuous variables, descriptive statistics will include the following 
information:  the number of patients reflected in the calculation (n), mean, 
median, 
standard 
deviation, 
minimum, 
and 
maximum. 
 
Baseline 
characteristics and AEs will be summarized using descriptive statistics. 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACTH 
Adrenocorticotropic hormone 
ADA 
Anti-drug antibody 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
Anti-CTLA-4 
Anti-cytotoxic T-lymphocyte-associated antigen 4 
Anti-PD-1 
Anti-programmed death-1 
Anti-PD-L1 
Anti-programmed death ligand 1 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
BOR 
Best overall response 
BP 
Blood pressure 
C2P1 
Cell Line 2 Process 1 
CBC 
Complete blood count 
CD 
Cluster of differentiation 
Ceoi 
Concentration at end of infusion 
CHO 
Chinese hamster ovary 
CI 
Confidence interval 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form  
CSCC 
Cutaneous squamous cell carcinoma 
CT 
Computed tomography 
CTLA-4 
Cytotoxic T-lymphocyte-associated antigen 4 
Ctrough 
Pre-infusion concentration 
CTX 
Cyclophosphamide 
CV% 
Variability in exposure 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
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EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form  
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EORTC QLQ-
C30 
European Organization for Research and Treatment of Cancer: Quality of Life 
Questionnaire Core 30 
EORTC QLQ-
LC13 
European Organization for Research and Treatment of Cancer: Quality of Life 
Questionnaire Lung Cancer 13 
E-R 
Exposure-response 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FIH 
First-in-human 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HCV 
Hepatitis C virus 
hfRT 
Hypofractionated radiation therapy 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IHC 
Immunohistochemistry 
irAE 
Immune-related adverse event 
ipi 
Ipilimumab 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
irTEAE 
Immune-related treatment-emergent adverse event 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
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LAM 
Lactational amenorrhea method 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
n 
Number of patients reflected in the calculation 
N/A 
Not applicable 
NAb 
Neutralizing anti-drug antibody 
NCI-CTCAE 
National Cancer Institute: Common Terminology Criteria for Adverse Events 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PD-1 
Programmed death-1 
PD-L1, PD-L2 
Programmed death ligand 1, programmed death ligand 2 
PE 
Physical examination 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PPD 
Purified protein derivative 
PR 
Partial response 
PT 
Preferred term 
PT/PTT 
Prothrombin time/partial thromboplastin time 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
Q6W 
Every 6 weeks 
Q9W 
Every 9 weeks 
Q12W 
Every 12 weeks 
Q18W 
Every 18 weeks 
Q24W 
Every 24 weeks 
QOL 
Quality of life 
R 
Randomized 
RCC 
Renal cell carcinoma 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RNA 
Ribonucleic acid 
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ROS1 
C-ros oncogene 1 receptor tyrosine kinase 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SmPC 
Summary of Product Characteristics 
SOC 
System organ class 
T4 
Thyroxine 
TEAE 
Treatment-emergent adverse event 
teoi 
Time of end of infusion 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................19 
1. 
INTRODUCTION ......................................................................................................30 
2. 
STUDY OBJECTIVES ..............................................................................................34 
2.1. 
Primary Objective .......................................................................................................34 
2.2. 
Secondary Objectives .................................................................................................34 
2.2.1. 
Key Secondary Objectives ..........................................................................................34 
2.2.2. 
Other Secondary Objectives .......................................................................................35 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................35 
3.1. 
Hypothesis ..................................................................................................................35 
3.2. 
Rationale .....................................................................................................................36 
3.2.1. 
Rationale for Study Design .........................................................................................36 
3.2.2. 
Rationale for Endpoints and Objectives .....................................................................36 
3.2.3. 
Rationale for Choice of Patient Population Based on the ≥50% Programmed 
Death-1 Expression Cut-off ........................................................................................37 
3.2.4. 
Rationale for Combination of Cemiplimab and Ipilimumab ......................................38 
3.2.5. 
Rationale for Combination of Cemiplimab and Ipilimumab and Limited 
(2 Cycles) Platinum-Based Doublet Chemotherapy ...................................................38 
3.2.6. 
Rationale for Cemiplimab Dose Selection .................................................................39 
3.2.7. 
Rationale for Ipilimumab Dose Selection ...................................................................40 
3.2.8. 
Rationale for Pembrolizumab as Comparator .............................................................41 
4. 
STUDY VARIABLES................................................................................................41 
4.1. 
Demographic and Baseline Characteristics ................................................................41 
4.2. 
Primary and Secondary Endpoints..............................................................................41 
4.2.1. 
Primary Endpoint ........................................................................................................41 
4.2.2. 
Key Secondary Endpoints ...........................................................................................41 
4.2.3. 
Other Secondary Endpoints ........................................................................................41 
4.3. 
Pharmacokinetic Variables .........................................................................................42 
4.4. 
Anti-Drug Antibody Variables ...................................................................................42 
5. 
STUDY DESIGN .......................................................................................................43 
5.1. 
Study Description and Duration .................................................................................43 
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5.1.1. 
Screening ....................................................................................................................44 
5.1.2. 
Treatment Period ........................................................................................................44 
5.1.3. 
Follow-up Period ........................................................................................................46 
5.1.4. 
Description of Study Stopping Rules .........................................................................47 
5.1.5. 
Dose-Limiting Toxicities ............................................................................................48 
5.1.6. 
Maximum Tolerated Dose ..........................................................................................49 
5.1.7. 
End of Study Definition ..............................................................................................50 
5.2. 
Planned Interim Analysis ............................................................................................50 
5.3. 
Study Committees .......................................................................................................50 
5.3.1. 
Independent Review Committee .................................................................................50 
5.3.2. 
Independent Data Monitoring Committee ..................................................................50 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............51 
6.1. 
Number of Patients Planned .......................................................................................51 
6.2. 
Study Population .........................................................................................................51 
6.2.1. 
Inclusion Criteria ........................................................................................................51 
6.2.2. 
Exclusion Criteria .......................................................................................................52 
6.3. 
Premature Withdrawal from the Study .......................................................................55 
6.4. 
Replacement of Patients .............................................................................................55 
7. 
STUDY TREATMENTS............................................................................................55 
7.1. 
Investigational and Reference Treatments ..................................................................55 
7.1.1. 
Cemiplimab .................................................................................................................55 
7.1.2. 
Ipilimumab ..................................................................................................................56 
7.1.3. 
Pembrolizumab ...........................................................................................................57 
7.1.4. 
Platinum-Based Doublet Chemotherapy ....................................................................57 
7.2. 
Pre-treatments .............................................................................................................58 
7.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................59 
7.3.1. 
Cemiplimab Plus Ipilimumab Combination Therapy Dosing Delay Rules................59 
7.3.2. 
Cemiplimab Plus Ipilimumab and Chemotherapy Combination Therapy .................62 
7.3.3. 
Cemiplimab as Combination Therapy With Chemotherapy ......................................65 
7.3.4. 
Immune-Related Adverse Events ...............................................................................67 
7.3.5. 
Ipilimumab ..................................................................................................................69 
7.3.6. 
Pembrolizumab ...........................................................................................................69 
7.3.7. 
Platinum-Based Doublet Chemotherapy ....................................................................70 
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7.3.8. 
Permanent Study Treatment Discontinuation .............................................................70 
7.4. 
Management of Acute Reactions ................................................................................70 
7.4.1. 
Acute Infusion Reactions ............................................................................................70 
7.4.1.1. 
Interruption of the Infusion .........................................................................................72 
7.4.1.2. 
Termination of the Infusion ........................................................................................73 
7.5. 
Method of Treatment Assignment ..............................................................................73 
7.5.1. 
Blinding/Masking .......................................................................................................73 
7.6. 
Treatment Logistics and Accountability .....................................................................74 
7.6.1. 
Packaging, Labeling, and Storage ..............................................................................74 
7.6.2. 
Supply and Disposition of Treatments .......................................................................74 
7.6.3. 
Treatment Accountability ...........................................................................................75 
7.6.4. 
Treatment Compliance ................................................................................................75 
7.7. 
Concomitant Medications ...........................................................................................75 
7.7.1. 
Prohibited Medications and Procedures .....................................................................76 
7.7.2. 
Permitted Medications and Procedures ......................................................................76 
7.8. 
Disease Progression While Receiving Cemiplimab or Pembrolizumab .....................76 
7.9. 
Post-study Treatments and Procedures .......................................................................77 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................77 
8.1. 
Schedule of Events .....................................................................................................77 
8.1.1. 
Footnotes for the Schedule of Events Table 5 and Table 6 ........................................88 
8.1.2. 
Early Termination Visit ..............................................................................................88 
8.1.3. 
Unscheduled Visits .....................................................................................................88 
8.2. 
Study Procedures ........................................................................................................88 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................88 
8.2.2. 
Efficacy Procedures ....................................................................................................89 
8.2.2.1. 
Radiographic Tumor Assessments .............................................................................89 
8.2.2.2. 
Tumor Burden Assessments .......................................................................................90 
8.2.2.3. 
Survival Data Collection .............................................................................................90 
8.2.2.4. 
Quality of Life Questionnaires ...................................................................................91 
8.2.3. 
Safety Procedures .......................................................................................................91 
8.2.3.1. 
Physical Examination .................................................................................................91 
8.2.3.2. 
Eastern Cooperative Oncology Group Performance Status ........................................91 
8.2.3.3. 
Weight and Height ......................................................................................................91 
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8.2.3.4. 
Vital Signs ..................................................................................................................91 
8.2.3.5. 
12-Lead Electrocardiogram ........................................................................................92 
8.2.3.6. 
Laboratory Testing ......................................................................................................92 
8.2.3.7. 
Concomitant Medication Recording ...........................................................................93 
8.2.3.8. 
Adverse Event Recording ...........................................................................................93 
8.2.4. 
Pharmacokinetic and Anti-Drug Antibody Procedures ..............................................94 
8.2.4.1. 
Drug Concentration Measurements and Samples .......................................................94 
8.2.4.2. 
Anti-Drug Antibody Measurements and Samples ......................................................94 
8.2.5. 
Biomarker Procedures ................................................................................................94 
8.2.6. 
Future Biomedical Research .......................................................................................95 
8.2.6.1. 
Genomics Sub-study - Optional..................................................................................95 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................96 
9.1. 
Obligations of Investigator .........................................................................................96 
9.2. 
Obligations of Sponsor ...............................................................................................96 
9.3. 
Definitions ..................................................................................................................96 
9.3.1. 
Adverse Event .............................................................................................................96 
9.3.2. 
Serious Adverse Event ................................................................................................97 
9.3.3. 
Adverse Events of Special Interest .............................................................................97 
9.3.3.1. 
Immune-Related Adverse Events ...............................................................................98 
9.3.4. 
Infusion Reactions ......................................................................................................98 
9.4. 
Recording and Reporting Adverse Events ..................................................................98 
9.4.1. 
Adverse Events ...........................................................................................................98 
9.4.2. 
Serious Adverse Events ..............................................................................................99 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................99 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................99 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................99 
9.4.6. 
Follow-up ..................................................................................................................100 
9.5. 
Evaluation of Severity and Causality .......................................................................100 
9.5.1. 
Evaluation of Severity ..............................................................................................100 
9.5.2. 
Evaluation of Causality .............................................................................................101 
9.6. 
Safety Monitoring .....................................................................................................101 
9.7. 
Investigator Alert Notification ..................................................................................102 
10. 
STATISTICAL PLAN..............................................................................................102 
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10.1. 
Statistical Hypothesis ................................................................................................102 
10.2. 
Justification of Sample Size......................................................................................102 
10.3. 
Analysis Sets .............................................................................................................103 
10.3.1. 
Efficacy Analysis Sets ..............................................................................................103 
10.3.2. 
Safety Analysis Set ...................................................................................................103 
10.3.3. 
Other Analysis Sets ...................................................................................................103 
10.4. 
Statistical Methods ....................................................................................................103 
10.4.1. 
Patient Disposition ....................................................................................................104 
10.4.2. 
Demography and Baseline Characteristics ...............................................................104 
10.4.3. 
Medical History ........................................................................................................104 
10.4.4. 
Prior Medications/Concomitant Medications ...........................................................104 
10.4.5. 
Efficacy Analyses .....................................................................................................105 
10.4.5.1. 
Primary Efficacy Analyses .......................................................................................105 
10.4.5.2. 
Secondary Efficacy Analyses ...................................................................................105 
10.4.5.3. 
Subgroup Analyses ...................................................................................................105 
10.4.6. 
Safety Analyses ........................................................................................................106 
10.4.6.1. 
Adverse Events .........................................................................................................106 
10.4.6.2. 
Other Safety Analyses ..............................................................................................107 
10.4.6.3. 
Treatment Exposure ..................................................................................................107 
10.4.6.4. 
Treatment Compliance ..............................................................................................107 
10.4.7. 
Analysis of Drug Concentration Data .......................................................................107 
10.4.8. 
Analysis of Anti-Drug Antibody Data ......................................................................107 
10.4.9. 
Analysis of Biomarker Data .....................................................................................107 
10.5. 
Multiplicity Considerations ......................................................................................108 
10.6. 
Interim Analysis ........................................................................................................108 
10.7. 
Additional Statistical Data Handling Conventions ...................................................108 
10.8. 
Statistical Considerations Surrounding the Premature Termination of a Study .......109 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS ...................................109 
11.1. 
Data Management .....................................................................................................109 
11.2. 
Electronic Systems ....................................................................................................109 
12. 
STUDY MONITORING ..........................................................................................110 
12.1. 
Monitoring of Study Sites .........................................................................................110 
12.2. 
Source Document Requirements ..............................................................................110 
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12.3. 
Case Report Form Requirements ..............................................................................110 
13. 
AUDITS AND INSPECTIONS ...............................................................................110 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................111 
14.1. 
Good Clinical Practice Statement .............................................................................111 
14.2. 
Informed Consent .....................................................................................................111 
14.3. 
Patients’ Confidentiality and Data Protection ..........................................................111 
14.4. 
Institutional Review Board/Ethics Committee .........................................................112 
15. 
PROTOCOL AMENDMENTS ................................................................................112 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................112 
16.1. 
Premature Termination of the Study .........................................................................112 
16.2. 
Close-out of a Site ....................................................................................................112 
17. 
STUDY DOCUMENTATION .................................................................................113 
17.1. 
Certification of Accuracy of Data .............................................................................113 
17.2. 
Retention of Records ................................................................................................113 
18. 
DATA QUALITY ASSURANCE ............................................................................113 
19. 
CONFIDENTIALITY ..............................................................................................114 
20. 
FINANCING AND INSURANCE ...........................................................................114 
21. 
PUBLICATION POLICY ........................................................................................114 
22. 
REFERENCES .........................................................................................................115 
23. 
INVESTIGATOR’S AGREEMENT ........................................................................120 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................144 
 
LIST OF TABLES 
Table 1: 
Guidelines for Platinum-Based Doublet Chemotherapy Regimens 
(Treatment Arm C) .....................................................................................................58 
Table 2: 
Cemiplimab Guidelines for Temporary and Permanent Discontinuations for 
Toxicity .......................................................................................................................66 
Table 3: 
General Cemiplimab Treatment Hold Guidelines for Immune-Related 
Adverse Events ...........................................................................................................69 
Table 4: 
Schedule of Events:  Screening Visit Assessments and Procedures ...........................78 
Table 5: 
Schedule of Events:  Treatment Period Assessments and Procedures .......................80 
Table 6: 
Schedule of Events:  Follow-up Period Assessments and Procedures .......................86 
 
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LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................43 
 
LIST OF APPENDICES 
Appendix 1. Factors to Consider in Assessing the Relationship of Adverse Events to 
Study Drug and Study Conduct ................................................................................121 
Appendix 2. Response Evaluation Criteria in Solid Tumors:  RECIST Guideline 
(Version 1.1) .............................................................................................................122 
Appendix 3. Recommended Dose Modification or Discontinuation and Supportive 
Care Guidelines for Specific cemiplimab Drug-Related Adverse Events ................129 
Appendix 4. Cemiplimab Pharmacokinetic, Immunogenicity, and Biomarker Sampling 
Schedule ....................................................................................................................143 
 
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1. 
INTRODUCTION 
Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of 
cancer-related mortality worldwide (Siegel 2016, Bray 2013). Non-small cell lung cancer 
(NSCLC) accounts for 80% to 85% of all lung cancers and is composed of several 
histopathological subtypes, the most common of which are adenocarcinoma (40% to 60%) and 
squamous cell carcinoma (30%).  The majority of patients with NSCLC are found to have 
advanced cancer at the time of diagnosis (Leighl 2012).  With chemotherapy, these patients have 
a median overall survival (OS) of up to 12 to 18 months and a 5-year survival rate of 
approximately 18% (Leighl 2012, Siegel 2016). 
Systemic treatment with platinum-based doublet regimens, with or without maintenance 
treatment, has been, until recently, the standard first-line treatment for all patients with advanced 
NSCLC whose tumors do not have an epidermal growth factor receptor (EGFR) mutation, an 
anaplastic lymphoma kinase (ALK) mutation, or a C-ros oncogene 1 receptor tyrosine kinase 
(ROS1) fusion (Besse 2014, Ettinger 2016, Reck 2014).  Despite initial treatment with 
platinum-based doublet regimens, the disease often progresses, and additional treatment options 
have been limited.  
In recent years, immunotherapies have been investigated as potential therapeutic approaches that 
will improve long-term survival and quality of life (QOL) in patients with advanced NSCLC.  A 
complex cross-talk between cancer cells and the host immune system that can both inhibit and 
enhance tumor growth has recently been clarified (Vinay 2015).  Tumors modulate and evade the 
host immune response through a number of mechanisms, including formation of an 
immune-suppressive environment within the tumor.  Programmed death-1 (PD-1) is a 
co-receptor expressed on the surface of activated T cells that mediates immunosuppression.  The 
binding of PD-1 to one of its ligands, programmed death ligand 1 (PD-L1) or programmed death 
ligand 2 (PD-L2), results in inhibition of a cytotoxic T-cell response.  Increased expression of 
PD-L1 in the tumor microenvironment facilitates escape from the immune-surveillance 
mechanism (T-cell-induced anti-tumor activity).  In contrast, blockade of this interaction results 
in an enhanced T-cell response with anti-tumor activity. 
A number of diagnostic PD-L1 assays have been developed to inform treatment decisions 
(reviewed in Ratcliffe 2017).  The assays demonstrate that there is a broad range of PD-L1 
expression levels in tumor cells from NSCLC tumor samples (D’Incecco 2015, Kerr 2015).  A 
high level of expression has been correlated with poor patient prognosis and resistance to 
standard-of-care chemotherapy (Creelan 2014).  Blockade of the PD-1/PD-L1 T-cell checkpoint 
pathway has been shown to be an effective and well-tolerated approach to stimulating the 
immune response and has achieved significant objective responses in patients with NSCLC 
(Topalian 2012).  Among patients with advanced, previously treated squamous and 
non-squamous NSCLC, OS was significantly improved in patients treated with the 
PD-1 inhibitor nivolumab compared to the OS in patients treated with docetaxel, regardless of 
PD-L1 expression (Borghaei 2015, Brahmer 2015).  Similarly, patients with previously treated 
PD-L1-positive NSCLC who were treated with the PD-1 inhibitor pembrolizumab had improved 
OS compared to those treated with docetaxel (PD-L1 expression on at least 1% of tumor cells) 
(Herbst 2016).  These data established the use of PD-1 inhibitors in the second-line treatment 
paradigm of patients with NSCLC (KEYTRUDA® [pembrolizumab] Package Insert, 
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KEYTRUDA European Union [EU] Summary of Product Characteristics [SmPC], 
OPDIVO® [nivolumab] Package Insert, OPDIVO EU SmPC, Ettinger 2016). 
A third PD-L1 inhibitor, TECENTRIQ® (atezolizumab), was recently approved in the US for the 
treatment of metastatic NSCLC in patients with disease progression during or after treatment 
with platinum-based chemotherapy.  Approval was based on 2 studies that demonstrated 
improved efficacy over docetaxel (Fehrenbacher 2016, Rittmeyer 2017). 
Programmed cell death-1/ programmed death ligand 1 inhibitors are currently being investigated 
both as monotherapy (eg, KEYNOTE-024 and CheckMate 026) and in combination with 
standard-of-care chemotherapy regimens (eg, Rizvi 2016, Antonia 2014, Gadgeel 2016) or other 
immunotherapies (eg, CheckMate 012 [Hellmann 2017]) in the first-line treatment of patients 
with advanced NSCLC.  Results from clinical studies, described in detail below, have been 
encouraging, and results of KEYNOTE-024 led to approval of pembrolizumab as first-line 
treatment in metastatic NSCLC patients whose tumors express PD-L1 in ≥50% of tumor cells. 
In the phase 1 multicohort study, CheckMate 012, 56 patients with advanced squamous or 
non-squamous, treatment-naïve NSCLC received nivolumab in combination with 4 cycles of 
platinum-based chemotherapy.  Response rates ranged from 33% to 47% with 1-year OS rates of 
50% to 87% (Rizvi 2016).  In patients treated with a PD-1/PD-L1 inhibitor in combination with 
chemotherapy, response rates ranging from 33% to 77% and median progression-free 
survival (PFS) ranging from 4.8 to 10 months have been observed in PD-L1 unselected tumors 
(Antonia 2014, Langer 2016).  In tumors expressing high levels of PD-L1, even greater 
anti-tumor responses have been observed with response rates of 44% to 75% (Langer 2016, 
Gadgeel 2016) and a median PFS of 15 months (Gadgeel 2016).  These limited data suggest that 
while monotherapy may be effective in the tumors with high PD-L1 expression, combination 
chemotherapy may be equally or more effective in patients with any degree of PD-L1 
expression. 
KEYNOTE-024 was an open-label, phase 3 study that included 305 patients with previously 
untreated, advanced NSCLC whose tumors expressed PD-L1 in ≥50% of tumor cells.  The 
patients were randomized to receive either pembrolizumab or the investigator’s choice of 
platinum-based chemotherapy.  Crossover from the chemotherapy group to the pembrolizumab 
group was permitted in the event of disease progression.  Median progression-free survival (PFS) 
was 10.3 months (95% confidence interval [CI]:  6.7 months to not reached) in the 
pembrolizumab group versus 6.0 months (95% CI:  4.2 to 6.2 months) in the chemotherapy 
group (hazard ratio [HR] for disease progression or death: 0.50; 95% CI:  0.37 to 0.68; 
p <0.001).  The response rate was higher in the pembrolizumab group than in the chemotherapy 
group (44.8% versus 27.8%).  Furthermore, compared to the chemotherapy group, for the 
pembrolizumab group the median duration of response (DOR) was longer (not reached 
[range:  1.9+ to 14.5+ months] versus 6.3 months [range:  2.1+ to 12.6+ months]) and treatment-
related adverse events (AEs) of any grade and of grades >3, 4, or 5 were less frequent (occurring 
in 73.4% versus 90.0% and 26.6% versus 53.3%, respectively) (Reck 2016).  The results of this 
study led to approval of pembrolizumab in the United States (US), Japan, and some European 
countries for first-line treatment of advanced NSCLC in patients whose tumors express PD-L1 in 
≥50% of tumor cells as determined by the PD-L1 immunohistochemistry (IHC) 22C3 pharmDx 
assay (Dako, North America, Inc., PD-L1 IHC 22C3 pharmDx Package Insert; Roach 2016).  
This was the first Food and Drug Administration (FDA) approval of a checkpoint inhibitor for 
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first-line treatment of lung cancer.  This approval also expanded the pembrolizumab indication 
for second-line treatment of lung cancer to include all patients with NSCLC expressing PD-L1 
≥1%. 
In contrast to KEYNOTE-024, the phase 3 CheckMate 026 study, investigating the efficacy of 
first-line treatment with nivolumab compared to platinum-based doublet chemotherapy in 
patients with advanced PD-L1-positive NSCLC (defined as present in 1% or more tumor cells), 
did not meet its primary endpoint (Socinski 2016).  Even in a subset analysis of those patients 
with PD-L1 expression in ≥50% of tumor cells, nivolumab failed to demonstrate any 
improvement over chemotherapy.  There is currently no proven explanation for this discrepancy 
between the 2 studies.  A total of 541 patients were randomized 1:1 to the nivolumab or 
chemotherapy treatment group.  Patients who progressed on chemotherapy could cross over to 
nivolumab as second-line treatment.  In the 423 patients whose tumors express PD-L1 in ≥5% of 
tumor cells, PFS was 4.2 months with nivolumab and 5.9 months with chemotherapy (HR:  1.15; 
95% CI:  0.91 to 1.45; p=0.25).  Overall survival was 14.4 months for nivolumab versus 
13.2 months for chemotherapy (HR:  1.02; 95% CI:  0.80 to 1.30).   
Programmed cell death-1/PD-L1 inhibitors have also been investigated in combination with 
standard-of-care chemotherapy regimens.  Most recently, results with pembrolizumab in 
chemotherapy-naïve patients with non-squamous NSCLC in combination with carboplatin and 
pemetrexed (KEYNOTE-021, Cohort G [n=123]) have shown a median PFS of 10 months and 
median OS that was not reached (Langer 2016).  Mean confirmed response rates ranged from 
54% (PD-L1 expression ≥1% to 49%) to 60% (PD-L1 expression ≥50%), and median PFS 
ranged from 14 to 15 months.  Patients whose tumors expressed PD-L1 <1% showed a median 
PFS of 6 months, which is historically observed with first-line chemotherapy regimens alone.  
These results led to the approval of pembrolizumab in combination with carboplatin and 
pemetrexed 
as 
first-line 
treatment 
in 
patients 
with 
non-squamous 
NSCLC 
(KEYTRUDA Package Insert). 
A 
second 
type 
of 
immuno-oncology 
agent, 
anti-cytotoxic 
T-lymphocyte-associated 
antigen 4 (anti-CTLA-4), has also been demonstrated to be clinically active in advanced cancers.  
Ipilimumab, a fully human monoclonal anti-CTLA-4 immunotherapy, has demonstrated clinical 
activity as monotherapy in melanoma (Wolchok 2010, O’Day 2010) and prostate cancer 
(Slovin 2013) and is now approved in the US and EU for treatment of unresectable or metastatic 
melanoma and for the adjuvant treatment of melanoma (YERVOY® Package Insert, 
YERVOY EU SmPC).   
In addition to immuno-oncology agents as monotherapy, the potentially additive or synergistic 
effects of immuno-oncology therapeutics with different mechanisms of action are now being 
evaluated in NSCLC (reviewed in Buchbinder and Desai 2016).  Nivolumab as combination 
immunotherapy with ipilimumab was evaluated in CheckMate 012, a phase 1 study in 
treatment-naïve patients with advanced NSCLC (Hellmann 2017).  Patients received nivolumab 
plus ipilimumab at one of 3 dose regimens or nivolumab monotherapy (monotherapy treatment 
group results not reported in Hellmann 2017).  Confirmed response rates were 47% 
(95% CI:  31% to 64%) in patients receiving nivolumab every 2 weeks (Q2W) plus ipilimumab 
every 12 weeks (Q12W) and 38% (95% CI:  23% to 55%) in patients receiving nivolumab Q2W 
plus ipilimumab every 6 weeks (Q6W).  Median DOR was not reached in either treatment group 
(median follow-up times of 12.8 months in the patients receiving nivolumab Q2W plus 
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ipilimumab Q12W and 11.8 months in the patients receiving nivolumab Q2W plus ipilimumab 
Q6W.  The greatest percentage of responses was noted in patients with tumors that expressed 
PD-L1.  In patients whose tumors expressed PD-L1 in ≥1% of tumor cells, confirmed objective 
responses were achieved in 12 of 21 (57%) patients in the ipilimumab Q12W treatment group 
and 13 of 23 (57%) patients in the ipilimumab Q6W treatment group (Hellmann 2017).  The 
1-year survival rate in patients treated with nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg 
Q6W or Q12W was 100% in patients with tumors that expressed PD-L1 in ≥50% of tumor cells 
(n=13) and was 76% in all-comers (all patients regardless of PD-L1 status [n=77]), compared to 
73% for patients receiving nivolumab monotherapy (n=52).  One-year survival in patients with 
tumors that expressed PD-L1 in >1% of tumor cells was 91% in the nivolumab 3 mg/kg plus 
ipilimumab 1 mg/kg Q12W treatment group and 83% in the nivolumab 3 mg/kg plus ipilimumab 
1 mg/kg Q6W treatment group (n=23 in each treatment group) compared to 73% in the 
nivolumab monotherapy treatment group (n=32) (Gettinger 2016).  The improved efficacy in 
NSCLC patients whose tumors expressed PD-L1 contrasts to the phase 3 study in patients with 
melanoma (Larkin 2015), where addition of anti-CTLA-4 to anti-PD-1 provided benefit 
predominantly to those patients whose tumors had low baseline PD-L1 expression. 
Combination immunotherapy with durvalumab (anti-PD-L1) plus tremelimumab (anti-CTLA-4) 
is currently being evaluated in multiple cancer types, including urothelial carcinoma 
(NCT02516241), squamous cell carcinoma of the head and neck (NCT02551159), and renal cell 
carcinoma (RCC) (NCT02762006). In patients with NSCLC, the durvalumab plus tremelimumab 
combination demonstrated clinical activity, regardless of PD-L1 expression levels. 
Investigator-reported confirmed responses occurred in 23% of patients (95% CI:  9% to 44%) in 
the durvalumab plus tremelimumab combination therapy group, including 22% (95% CI:  3% to 
60%) of patients with PD-L1-positive tumors (tumors that expressed PD-L1 on ≥25% of tumor 
cells) and 29% (95% CI: 8% to 58%) of patients with PD-L1-negative tumors (tumors that 
expressed PD-L1 on <25% of tumor cells) (Antonia 2016).  Recently, however, a phase 3 trial of 
durvalumab in combination with tremelimumab failed to significantly improve PFS over 
standard-of-care 
chemotherapy 
in 
PD-L1-positive 
patients 
with 
advanced 
NSCLC 
(AstraZeneca Press Release, 27 July 2017). 
Ipilimumab plus chemotherapy also demonstrated improved median OS over chemotherapy 
alone (12.2 versus 8.3 months; p=0.23) in previously untreated patients with NSCLC when 
chemotherapy was given first followed by ipilimumab (“phased ipilimumab”).  Median 
immune-related PFS, the primary endpoint, was significantly improved in patients receiving 
phased ipilimumab over chemotherapy alone (5.7 versus 4.6 months; p=0.05) (Lynch 2012).  
Cemiplimab is a high-affinity, fully human, hinge-stabilized IgG4P antibody directed to the 
PD-1 receptor that potently blocks the interaction of PD-1 with its ligands, PD-L1 and PD-L2.  
Additional studies underway with cemiplimab are described in the Investigator’s Brochure.  
Pre-clinical data indicate that cemiplimab has similar efficacy to other approved anti-PD-1 
antibodies; clinical data to date confirm the pre-clinical data.  Regeneron Pharmaceuticals, Inc. 
(Regeneron) is developing cemiplimab as a foundational immuno-oncology agent to be 
combined with maximal flexibility with other anti-cancer immunotherapies currently in 
pre-clinical development. 
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Please refer to the latest edition of the Investigator’s Brochure for an overview of relevant safety 
data (including patient exposure and immune-related adverse events [irAEs]) and efficacy data 
from clinical studies with cemiplimab. 
Study R2810-ONC-16111 is a randomized, open-label, phase 3 study of cemiplimab plus 
ipilimumab combination therapy (cemiplimab/ipi) or cemiplimab plus 2 cycles of platinum based 
doublet chemotherapy and ipilimumab combination therapy (cemiplimab/chemo/ipi) versus 
pembrolizumab monotherapy in patients with advanced or metastatic, squamous or non-
squamous NSCLC whose tumors express PD-L1 in ≥50% of tumor cells and who have received 
no prior systemic treatment for their advanced disease.  The main objective of the study is to 
determine if cemiplimab/ipi or cemiplimab/chemo/ipi improves PFS over standard-of-care 
pembrolizumab in this patient population.  Additional objectives include further characterization 
of OS, objective response rate (ORR), safety, pharmacokinetics (PK), and QOL. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to compare the progression-free survival (PFS) of 
cemiplimab (cemiplimab) plus ipilimumab combination therapy (hereinafter referred to as 
cemiplimab/ipi) and cemiplimab plus 2 cycles only of platinum-based doublet chemotherapy 
plus ipilimumab combination therapy (hereinafter referred to as “cemiplimab/chemo/ipi”) with 
pembrolizumab monotherapy in the first-line treatment of patients with advanced squamous or 
non-squamous non-small cell lung cancer (NSCLC) whose tumors express programmed death 
ligand 1 (PD-L1) in ≥50% of tumor cells. 
2.2. 
Secondary Objectives 
2.2.1. 
Key Secondary Objectives 
The key secondary objectives of the study are the following: 
 To compare the OS of cemiplimab/ipi and cemiplimab/chemo/ipi with 
pembrolizumab monotherapy in the first-line treatment of patients with advanced 
squamous or non-squamous NSCLC whose tumors express PD-L1 in ≥50% of tumor 
cells 
 To compare the ORR of cemiplimab/ipi and cemiplimab/chemo/ipi with 
pembrolizumab monotherapy in the first-line treatment of patients with advanced 
squamous or non-squamous NSCLC whose tumors express PD-L1 in ≥50% of tumor 
cells 
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2.2.2. 
Other Secondary Objectives 
The other secondary objectives are the following: 
 To evaluate the safety and tolerability of cemiplimab/ipi and cemiplimab/chemo/ipi 
compared to pembrolizumab monotherapy in the first-line treatment of patients with 
advanced squamous or non-squamous NSCLC whose tumors express PD-L1 in ≥50% 
of tumor cells 
 To compare the OS at 12 and 18 months of cemiplimab/ipi and cemiplimab/chemo/ipi 
with pembrolizumab monotherapy in the first-line treatment of patients with 
advanced squamous or non-squamous NSCLC whose tumors express PD-L1 in ≥50% 
of tumor cells 
 To compare QOL in patients with advanced squamous or non-squamous NSCLC 
whose tumors express PD-L1 in ≥50% of tumor cells receiving cemiplimab/ipi or 
cemiplimab/chemo/ipi with QOL in those patients receiving pembrolizumab 
monotherapy 
 To assess immunogenicity as measured by anti-drug antibodies (ADAs) for 
cemiplimab 
 To assess the predictive utility of baseline PD-L1 tumor expression levels on clinical 
response  
 To characterize the PK of cemiplimab when administered in combination with 
platinum-based doublet chemotherapy and/or ipilimumab 
 To conduct exposure-response (E-R) analyses for relevant biomarkers (exploratory 
PK/pharmacodynamic analyses) and E-R analyses for safety and efficacy endpoints, 
as appropriate 
 Tumor mutation burden as assessed by the Foundation Medicine “FoundationOne®” 
panel, sample permitting 
3. 
HYPOTHESIS AND RATIONALE  
3.1. 
Hypothesis 
The hypothesis of this study is that cemiplimab and ipilimumab for up to 4 cycles of combination 
therapy (cemiplimab/ipi) or cemiplimab plus platinum-based doublet chemotherapy for 2 cycles 
and ipilimumab for up to 4 cycles of combination therapy (cemiplimab/chemo/ipi) will prolong 
median PFS compared with pembrolizumab monotherapy in the first-line treatment of patients 
with advanced or metastatic NSCLC whose tumors express PD-L1 in ≥50% of tumor cells. 
Historically, median PFS in patients with stage IIIB/IV squamous and non-squamous NSCLC 
treated with platinum-based doublet chemotherapy has ranged from approximately 2.7 to 
6.4 months (El-Shenshawy 2012, Kelly 2001, Rosell 2002, Scagliotti 2002, Schiller 2002, 
Shimizu 2013, Reck 2016).  With the emergence of immunotherapy and the recognition that 
NSCLC tumors express PD-L1, the effects of a variety of PD-1/PD-L1 inhibitors as 
monotherapy and in combination with chemotherapy are being investigated.  Accumulating 
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clinical data suggest that anti-PD-1 monotherapy may prolong PFS and OS in NSCLC, with the 
greatest clinical benefit observed in tumors expressing PD-L1, especially at high levels. 
Anti-PD-1 monotherapy as first-line treatment in patients with advanced NSCLC has 
demonstrated efficacy (Gettinger 2016, Garon 2015) and a significant improvement in PFS 
compared to chemotherapy (Reck 2016).  Combination immunotherapies for NSCLC have also 
demonstrated clinical activity (Hellmann 2017). 
Cemiplimab clinical study data (see Section 1) in addition to the demonstrated clinical activity of 
ipilimumab in combination with nivolumab support the hypothesis that the combination of 
cemiplimab/ipi or cemiplimab/chemo/ipi may prolong PFS in patients with advanced or 
metastatic, squamous or non-squamous NSCLC whose tumors express PD-L1 in ≥50% of tumor 
cells. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design  
This study is a randomized, open-label, phase 3 study evaluating the efficacy of cemiplimab/ipi 
or cemiplimab/chemo/ipi compared with pembrolizumab monotherapy in patients with advanced 
or metastatic, squamous or non-squamous NSCLC whose tumors express PD-L1 in ≥50% of 
tumor cells and who have received no prior systemic treatment for their advanced disease.  This 
study will be open-label because the differences in administration and known distinct toxicities 
of the therapies do not lend themselves to blinding. 
Because this is the first study to evaluate the combination of cemiplimab and ipilimumab and the 
combination or platinum doublet chemotherapy and ipilimumab, there will be an early review of 
data to ensure patient safety after the first 10 patients in the cemiplimab/ipi and the first 
10 patients in the cemiplimab/chemo/ipi treatment arm have completed 4 weeks of follow-up 
following the first dose of cemiplimab/ipi or cemiplimab/chemo/ipi respectively.  An additional 
safety review will be performed by the Independent Data Monitoring Committee (IDMC) after 
the first 10 patients in the cemiplimab/ipi and cemiplimab/chemo/ipi regimen have received all 
4 doses of ipilimumab and have been followed for at least 6 weeks after the last dose.  This 
analysis will include all patients who have been exposed to the combination treatment.  
The study population is limited to previous and current smokers as the benefit of PD-1 blockade 
has not been shown to the same extent in non-smokers likely due to the lower mutational burden 
in this population (Reck 2016). 
3.2.2. 
Rationale for Endpoints and Objectives 
The primary objective of this study is to compare the PFS of cemiplimab/ipi or 
cemiplimab/chemo/ipi to pembrolizumab monotherapy.  Based on data released for another PD-1 
antibody, prolongation of PFS is expected in patients with NSCLC whose tumors express PD-L1 
in ≥50% of tumor cells.  Overall survival is clearly the ultimate endpoint of benefit, but an 
improvement in OS may be obscured due to patients who progress and elect to begin second-line 
treatment with pembrolizumab, nivolumab or atezolizumab as recommended in the recent 
National Comprehensive Cancer Network recommendations (Ettinger 2016).  Therefore, OS will 
be a secondary endpoint.  This approach is consistent with the 2015 FDA Guidance for Industry 
on Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and 
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Biologics (FDA 2015) and the December 2015 European Medical Agency Guideline on the 
Evaluation of Anticancer Medicinal Products in Man (EMA 2015), which contains specific 
guidance on NSCLC. 
Progression-free survival, defined as the time to tumor progression (based on Response 
Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1] criteria [Eisenhauer 2009]) or 
death, was chosen as the primary endpoint because PFS is recognized as a marker of clinical 
benefit.  Progression-free survival is an approvable endpoint in the US and is also acceptable in 
the EU for studies where the experimental treatment is likely to be well tolerated.  Progressive 
disease will be determined based on the RECIST 1.1 criteria (Eisenhauer 2009).  The first 
radiographic tumor assessment will occur after 9 weeks of study treatment, and subsequent 
assessments will occur every 9 weeks (Q9W) during year 1, Q12W during year 2, and Q12W in 
follow-up or until RECIST 1.1-defined progressive disease or early treatment discontinuation for 
another reason.  Further, to diminish bias in the assessment of progressive disease in this 
open-label study, an Independent Review Committee (IRC), which will be blinded to treatment 
assignment, will be utilized to adjudicate tumor responses.  Overall survival at 12 months, 
18 months, and end of treatment will be assessed as secondary endpoints, despite the 
acknowledged limitations.  Additionally, efficacy responses to be assessed will include 
assessment of ORR.  From a patient perspective, preservation of QOL is important; therefore, 
QOL will be assessed through the use of 2 validated questionnaires. 
3.2.3. 
Rationale for Choice of Patient Population Based on the ≥50% Programmed 
Death-1 Expression Cut-off 
Data suggest that tumor cell PD-L1 expression may correlate with anti-PD-1 clinical activity in 
both squamous and non-squamous NSCLC (Gadgeel 2016, Gettinger 2015, Hellmann 2017).  In 
an exploratory analysis of an ongoing study, nivolumab monotherapy in chemotherapy-naïve 
patients with advanced NSCLC resulted in higher response rates, more prolonged PFS, and 
higher 1-year OS rates as the level of PD-L1 expression increased (1%, 5%, 10%, 25%, and 
50%) (Gettinger 2015). 
The KEYNOTE-024 study included 305 treatment-naïve patients with advanced NSCLC whose 
tumors expressed PD-L1 in ≥50% of tumor cells (as measured by the PD-L1 IHC 22C3 
pharmDx assay [Dako, North America, Inc.]), which led to the US FDA approval of 
pembrolizumab (KEYTRUDA, Merck & Co., Inc.) as first-line treatment in this patient 
population (Reck 2016). 
Bristol-Meyers Squibb, Inc. recently reported that their first-line NSCLC study of nivolumab 
monotherapy had failed because the primary endpoint of PFS was not met.  The study was 
designed to assess the benefit of nivolumab monotherapy in a patient population whose tumors 
expressed PD-L1 in ≥5% of tumor cells (as measured with the PD-L1 IHC 28-8 pharmDx) 
(Socinski 2016).  Therefore, in this study, only patients whose tumors express PD-L1 in ≥50% of 
tumor cells (measured using the PD-L1 IHC 22C3 pharmDx assay) will be eligible to participate.  
The use of the PD-L1 IHC 22C3 pharmDx assay for decisions regarding treatment with 
cemiplimab is considered investigational. 
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3.2.4. 
Rationale for Combination of Cemiplimab and Ipilimumab  
Combination immunotherapies that include an anti-CTLA-4 agent and an anti-PD-1/PD-L1 agent 
have the potential for additive or synergistic effects (reviewed in Buchbinder and Desai 2016). 
Clinical activity of the combination of anti-PD-L1 and anti-CTLA-4 has been demonstrated in 
studies of durvalumab plus tremelimumab combination therapy (Antonia 2016; Section 1) and 
nivolumab plus ipilimumab combination therapy (described in detail below). 
Ipilimumab has shown promise in multiple tumor types and is approved as monotherapy and in 
combination with nivolumab for advanced melanoma.  Ipilimumab plus nivolumab combination 
therapy was approved for the treatment of advanced melanoma based on the results of 
CheckMate 067 that demonstrated significantly improved PFS in patients treated with the 
combination (11.5 months; 95% CI:  8.9 to 16.7 months) compared with ipilimumab 
monotherapy (2.9 months; 95% CI:  2.8 to 3.4 months; HR for death or disease progression, 
0.42; 99.5% CI:  0.31 to 0.57; p<0.001) and nivolumab monotherapy (6.9 months; 95% CI:  4.3 
to 9.5 months; HR for the comparison with ipilimumab, 0.57; 99.5% CI:  0.43 to 0.76; p<0.001) 
(Larkin 2015). 
Ipilimumab plus nivolumab combination therapy has also demonstrated clinical activity in 
NSCLC (see Section 1 ) as first-line treatment in advanced NSCLC.  In the CheckMate 012 
study, confirmed response rates were 47% (95% CI:  31% to 64%) in patients receiving 
nivolumab Q2W plus ipilimumab Q12W and 38% (95% CI:  23% to 55%) in patients receiving 
nivolumab Q2W plus ipilimumab Q6W.  The greatest percentage of responses was noted in 
patients with tumors that expressed PD-L1 (Hellmann 2017), which is in contrast with the phase 
3 study in melanoma (Larkin 2015), in which addition of anti-CTLA 4 to anti PD-1 provided 
benefit predominantly in those patients with low baseline PD-L1 positivity.  The 1 year survival 
rate in patients with tumors that expressed PD-L1 in ≥50% of tumor cells (n=13) was 100% and 
in all-comers (n=77) was 76%, compared to 73% for patients receiving nivolumab monotherapy 
(n=52) (Gettinger 2016; see Section 1 for additional details).  Cemiplimab and ipilimumab are 
immuno-oncology agents with different mechanisms of action.  Cemiplimab is a monoclonal 
antibody to the PD-1 receptor that blocks PD-1/PD-L1-mediated T-cell inhibition, whereas 
ipilimumab is an inhibitor of CTLA-4.  Based on the unique mechanisms of action, the 
anti-PD-1/anti-PD-L1 action of cemiplimab and the anti-CTLA-4 action of ipilimumab have the 
potential for additive or synergistic effects (Buchbinder and Desai 2016).  This effect may be 
particularly pronounced in the population of patients whose tumors express PD-L1 in ≥50% of 
tumor cells.  
3.2.5. 
Rationale for Combination of Cemiplimab and Ipilimumab and Limited 
(2 Cycles) Platinum-Based Doublet Chemotherapy 
Recent unpublished data have indicated that administration of 2 preliminary cycles of 
platinum-based doublet chemotherapy before the introduction of a secondary anti-CTLA-4 
and/or anti-PD-1/PD-L1 agent may improve the overall efficacy; therefore, this regimen has also 
been adopted in this study.   
Blockade of the PD-1/PD-L1 T-cell checkpoint pathway is an effective and well-tolerated 
approach to stimulating the immune response and has achieved significant objective responses in 
advanced melanoma, RCC, and NSCLC (Topalian 2012).  However, optimal therapy will likely 
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require combining immuno-oncology agents with conventional therapies and/or novel 
immunotherapy approaches.  Combinatorial approaches of immuno-oncology agents plus 
chemotherapy have demonstrated encouraging results in NSCLC (reviewed in Gainor 2016).  
For example, KEYNOTE-021, described in Section 1, evaluated pembrolizumab in combination 
with carboplatin and pemetrexed.  Response rates ranged from 54% (PD-L1 expression ≥1% to 
49%) to 60% (PD-L1 expression ≥50%), and median PFS ranged from 14 to 15 months 
(Langer 2016).  Evaluation of the combination of cemiplimab plus platinum-based doublet 
chemotherapy will allow comparison of the safety and potential benefits in the population of 
NSCLC patients whose tumors express PD-L1 in ≥50% of tumor cells. 
The recent trial of durvalumab in combination with tremelimumab failed to achieve statistically 
significant improvement in PFS over standard-of-care chemotherapy in PD-L1-positive patients 
with advanced NSCLC (AstraZeneca Press Release, 27 July 2017).  This raises some concern 
whether the initial promising results of the combination of nivolumab and ipilimumab seen in 
CM-012 (Hellmann 2017) will bear out in larger trials.  The time required to mobilize an 
effective anti-tumor response may sometimes take weeks to months and, in the setting of a 
rapidly growing tumor, may not arise before progression has occurred.  As the recent data 
studying various combinations of immunotherapy and chemotherapy have shown, concomitant 
chemotherapy may not appreciably interfere with immunotherapy benefit.  Therefore, in this 
study the combination of cemiplimab and ipilimumab will be accompanied by administration of 
the first 2 cycles of standard platinum doublet chemotherapy (on an every 3 weeks [Q3W] 
schedule).  The rationale is that initial tumor control mediated by chemotherapy will provide 
more time for an effective immune response to mature, and may, in fact, be enhanced by 
chemotherapy-induced cell death, and augmented antigen presentation.  The rationale for 
limiting the chemotherapy to 2 cycles is to limit the risk of triple combination-related toxicities 
and to limit the interference of longer administration of the cytotoxic regimens with the 
immuno-oncology combination therapy. 
3.2.6. 
Rationale for Cemiplimab Dose Selection 
The proposed cemiplimab dose of 350 mg Q3W given by the intravenous (IV) route was selected 
in this study for patients with NSCLC to better align with the dosing schedule of planned 
concurrent treatment with ipilimumab (50 mg Q6W for 4 doses).  The cemiplimab dose of 
350 mg Q3W was also selected for an ongoing pivotal phase 3 study in patients with NSCLC.   
In the ongoing first-in-human (FIH) study (study R2810-ONC-1423), the 3 mg/kg Q2W IV dose 
has shown anti-tumor activity and acceptable safety in NSCLC patients among other patient 
types; efficacy was also observed at the 1 mg/kg Q2W dose.  As many standard chemotherapy 
treatments for NSCLC are dosed on a Q3W schedule, the clinical development strategy of 
cemiplimab coalesced around a Q3W treatment interval.  The ongoing clinical development of 
cemiplimab also seeks to incorporate a flat dosing paradigm.   
The preference of a flat dose over a body weight adjusted dose for anti-PD-1 monoclonal 
antibodies is supported by a wide safety margin (no maximum tolerated dose [MTD] observed), 
a flat E-R relationship for safety and efficacy over the therapeutic dosing range, and similar 
variability in exposure (CV%) after flat and body weight adjusted dose (Freshwater 2017, 
Zhao 2017a).  In fact, pembrolizumab and nivolumab were initially approved at a body-weight 
adjusted dose of 2 mg/kg Q3W and 3 mg/kg Q2W, respectively, and were recently approved by 
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US FDA at flat doses of 200 mg Q3W and 240 mg Q2W, respectively, for the treatment of 
melanoma and NSCLC (KEYTRUDA Package Insert, OPDIVO Package Insert). The European 
Medicines Agency have also approved a flat dose of 200mg Q3W of pembrolizumab for NSCLC 
that has not been previously treated with chemotherapy. 
A flat IV cemiplimab dose of 350 mg Q3W was selected based on population PK modeling and 
simulation, since this dose is expected to provide exposure that closely replicates the exposure 
observed in patients (mean weight: 80 kg) for the 3 mg/kg Q2W IV regimen in 
study R2810-ONC-1423 (NCT02383212).  Simulations of cemiplimab exposure in 1000 patients 
using population PK analyses have demonstrated the following: 
1. The variability in cemiplimab exposure was similar for body weight-adjusted doses as 
compared to flat doses, therefore supporting flat dose selection.  
2. A 350 mg Q3W dose in patients with an expected mean body weight of 80 kg resulted in 
similar (20% difference) Ctrough, area under the curve from time 0 to week 12 (AUC12W), 
and peak concentration (Cmax) as compared to the 3 mg/kg Q2W dose used in the FIH 
study.  Cemiplimab concentrations with 350 mg Q3W exceeded those observed with 
1 mg/kg Q2W, a dose that demonstrated clinical efficacy in the FIH study, and Ctrough 
values with 350 mg Q3W exceeded concentrations of ~5 to 20 mg/L, above which 
saturation of PD-1 target occupancy is expected to occur based on linearity assessment on 
single-dose pharmacokinetics in cynomolgus monkeys. 
The 350 mg Q3W dose of cemiplimab is, therefore, being proposed as the optimal dose in the 
phase 3 studies in patients with NSCLC and across the cemiplimab program. 
There are some populations (eg, in Japan or other countries in Asia-Pacific Rim, where on 
average, the body weight in the population is slightly lower as compared to Western patients 
(with body weight distribution around a mean of 60 kg versus 80 kg) (Shimizu 2016), and body 
weight is a known covariate of exposure for monoclonal antibodies.  The average body weight of 
the patient population in the FIH study R2810-ONC-1423 was approximately 80 kg.  As 
supported by population PK modeling and simulation of cemiplimab exposure in 1000 patients, 
when cemiplimab is administered as a flat dose, a small (approximately 16%) but clinically 
unimportant increase in exposure of cemiplimab in serum is predicted on average in Asian and/or 
Japanese patients versus the existing data in Western patients.  With the lack of any added safety 
signal in the existing clinical data at doses up to 10 mg/kg, the existing data support the use of 
the 350 mg Q3W treatment regimen for the global development of cemiplimab. 
3.2.7. 
Rationale for Ipilimumab Dose Selection 
Recent data presented by Bristol-Meyers Squibb, Inc. demonstrated higher tumor shrinkage in 
patients treated with nivolumab at 3 mg/kg Q2W plus ipilimumab at 1 mg/kg Q6W or Q12W 
compared to nivolumab monotherapy (Zhao 2017b).  The incidence of AEs was similar for 
nivolumab monotherapy and nivolumab plus ipilimumab at 1 mg/kg Q6W or Q12W, but was 
higher in treatment groups with more frequent and/or higher ipilimumab dosing.  Based on the 
presented risk-benefit assessment (Zhao 2017b) and E-R analyses, the recommended dose of 
ipilimumab in NSCLC is 1 mg/kg Q6W, which is equivalent to approximately 50 mg, the dose 
proposed in the present study.   
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3.2.8. 
Rationale for Pembrolizumab as Comparator 
Pembrolizumab is currently recommended as first-line treatment for advanced or metastatic 
NSCLC in patients whose tumors express PD-L1 in ≥50% of tumor cells (Ettinger 2016) and 
will, therefore, serve as the active comparator in this study.   
4. 
STUDY VARIABLES  
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, ethnicity, weight, 
gender, and height) and disease characteristics, including PD-L1 status and medical and 
oncology history. 
4.2. 
Primary and Secondary Endpoints 
4.2.1. 
Primary Endpoint 
The primary endpoint is PFS as assessed by a blinded IRC based on RECIST 1.1 assessments.  
Progression-free survival will be defined as the time from randomization to the date of the first 
documented tumor progression, as determined by the IRC (based on RECIST 1.1 assessments 
[Eisenhauer 2009; see Appendix 2]) or death due to any cause.  Patients will be censored 
according to the rules listed below: 
1. Patients who do not have a documented tumor progression or death will be censored on 
the date of their last evaluable tumor assessment.   
2. Patients who do not have any evaluable tumor assessments after randomization and did 
not die will be censored on the date of randomization.   
Rationale for PFS as the primary endpoint is provided in Section 3.2.2.  
4.2.2. 
Key Secondary Endpoints 
The key secondary endpoints in the study will be OS and ORR. 
Overall survival will be defined as the time from randomization to the date of death.  A patient 
who is lost to follow-up will be censored at the last date that the patient was known to be alive. 
Objective response rate will be defined as the number of patients with a best overall response 
(BOR) of confirmed complete response (CR) or partial response (PR) divided by the number of 
patients in the efficacy analysis set.  
Best overall response will be defined as the BOR, as determined by the IRC per RECIST 1.1, 
between the date of randomization and the date of the first objectively documented progression 
or the date of subsequent anti-cancer therapy, whichever comes first. 
4.2.3. 
Other Secondary Endpoints 
Other secondary endpoints will include the following: 
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 The safety and tolerability of cemiplimab/ipi and cemiplimab/chemo/ipi measured by 
the incidence of treatment-emergent adverse events (TEAEs), dose-limiting toxicities 
(DLTs), serious adverse events (SAEs), deaths, and laboratory abnormalities   
 Overall survival at 12 months and 18 months 
 Quality of life as measured by the European Organization for Research and Treatment 
of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
Lung Cancer 13 (EORTC QLQ-LC13)  
 Tumor mutation burden as assessed by the Foundation Medicine “FoundationOne®” 
panel, sample permitting 
See Section 4.4 for immunogenicity variables. 
4.3. 
Pharmacokinetic Variables 
Cemiplimab concentrations in the serum of patients randomized to the cemiplimab/ipi or 
cemiplimab/chemo/ipi groups (Treatment Arms B and C, respectively) will be assessed at 
multiple time points throughout the treatment and follow-up periods. 
Pharmacokinetic variables may include, but are not limited to, the following: 
 Ceoi – concentration at end of infusion 
 Ctrough – pre-infusion concentration 
 teoi – time of end of infusion 
4.4. 
Anti-Drug Antibody Variables 
Anti-drug antibody variables will be measured in samples from patients randomized to the 
cemiplimab/ipi or cemiplimab/chemo/ipi groups (Treatment Arms B and C, respectively).  Anti-
drug antibody variables include status of ADA response and titer as follows: 
 Treatment-boosted ADA response - defined as a positive response in the ADA assay 
after the first dose that is greater than or equal to 9-fold over baseline titer levels, 
when baseline results are positive 
 Treatment-emergent ADA response - defined as a positive response in the ADA assay 
after the first dose when baseline results are negative or missing 
The treatment-emergent responses will be further categorized into persistent, indeterminate, 
and transient responses.  
 Titer category is defined based on values as (titer value category): 
 Low (titer <1000) 
 Moderate (1000 ≤ titer ≤10,000) 
 High (titer >10,000) 
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confirmed, cemiplimab must be discontinued and other anti-cancer therapy considered, if 
appropriate. 
After discontinuing study treatment, patients will enter the follow-up period. 
The approximate duration of the active study assessments for each patient, excluding screening, 
will be 32 months.  This encompasses 25 months of study treatment plus 7 months of follow-up 
visits.  After the active study assessments are complete, all patients will be followed for survival. 
5.1.1. 
Screening 
Patients will undergo a screening evaluation to determine their eligibility within 28 days prior to 
randomization (Table 4).  PD-L1 expression in a tumor tissue sample (archival tissue, 
if ≤5 months old, or recently obtained on-study biopsy collected during screening; for collection 
instructions, refer to the laboratory manual) will be assessed using the PD-L1 IHC 22C3 
pharmDx assay that reports 50% positivity, as determined by a central laboratory (Section 8.2.5).  
Patients whose tumors express PD-L1 in ≥50% of tumor cells will continue in screening.  
Patients whose tumors express PD-L1 in <50% of tumor cells will be excluded from the study. 
Of note the use of the PD-L1 IHC 22C3 pharmDx assay for decisions regarding treatment with 
cemiplimab is considered investigational. 
Tumor tissue samples will also be tested for EGFR and ALK mutations as well as for ROS1 
fusions in a central laboratory.  Patients whose tumors are positive for any of these 
mutations/fusions (by testing at screening or by previous result) will not be eligible for the study. 
Baseline radiographic tumor assessments should also be performed within 28 days prior to 
randomization (Table 4).  These assessments will not be reviewed by the IRC for eligibility 
assessment. 
Informed consent must be obtained prior to any study-related procedures.  Assessments 
performed as part of standard-of-care that fall within the screening window (28 days prior to 
randomization) but before informed consent is obtained may be used for screening and need not 
be repeated for enrollment eligibility. 
5.1.2. 
Treatment Period 
Eligible patients will be randomized to one of the following treatment arms: 
Treatment Period: Treatment Arm A 
 Treatment Arm A:  pembrolizumab monotherapy 200 mg Q3W for 108 weeks  
Patients randomized to Treatment Arm A will receive pembrolizumab 200 mg as an IV infusion 
on day 1 of every treatment cycle (Q3W) for 108 weeks or until RECIST 1.1-defined progressive 
disease or early treatment discontinuation for another reason, including unacceptable toxicity, 
withdrawal of consent, death, or initiation of another anti-cancer treatment.  Details of study 
treatment discontinuation criteria are discussed in Section 7.3. 
Treatment Period: Treatment Arm B 
 Treatment Arm B:  cemiplimab 350 mg Q3W for 108 weeks plus ipilimumab 50 mg 
Q6W for up to 4 doses (cemiplimab/ipi) 
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Patients randomized to Treatment Arm B will receive the following treatments in combination: 
 Cemiplimab 350 mg as an IV infusion on day 1 of every treatment cycle (Q3W) for 
108 weeks or until RECIST 1.1-defined progressive disease or early treatment 
discontinuation for another reason, including unacceptable toxicity, withdrawal of 
consent, death, or initiation of another anti-cancer treatment, or in specific instances 
of confirmed CR or PR 
 Ipilimumab 50 mg flat dose administered IV on day 1 of every other treatment cycle 
(ie, every 42 days or Q6W) for up to 4 doses. 
Treatment Period: Treatment Arm C 
 Treatment Arm C:  Cemiplimab 350 mg Q3W for 108 weeks plus platinum-based 
doublet chemotherapy Q3W for 2 cycles and ipilimumab 50 mg Q6W for up to 
4 doses (cemiplimab/chemo/ipi) 
Patients randomized to Treatment Arm C will receive the following treatments in combination: 
 Cemiplimab 350 mg as an IV infusion on day 1 of every treatment cycle (Q3W) for 
108 weeks or until RECIST 1.1-defined progressive disease or early treatment 
discontinuation for another reason, including unacceptable toxicity, withdrawal of 
consent, death, initiation of another anti-cancer treatment, or in specific instances of 
confirmed CR or PR   
 Platinum-based doublet chemotherapy Q3W for 2 cycles (depending on patient 
tolerability and disease assessment) 
 The choice of platinum-based doublet chemotherapy will be at the discretion of 
the investigator from one of the options listed in Section 7.1.4 and is to be decided 
and documented prior to randomization. 
 Patients in this arm will not be permitted to receive pemetrexed maintenance. 
 Ipilimumab 50 mg flat dose administered IV on day 1 of every other treatment cycle 
(ie, every 42 days or Q6W) for up to 4 doses. 
Treatment Period: All Treatment Arms 
Details of the treatment regimens are provided in Section 7.1, and details of dose modifications 
and study drug permanent and temporary discontinuation criteria are discussed in Section 7.3. 
Randomization will be stratified by histology (non-squamous versus squamous).   
Treatment should begin within 3 days of randomization.  Details of the treatment regimens are 
provided in Section 7.1.  Treatment period length will depend on the treatment arm to which a 
patient is randomized. 
For the purposes of this study, a treatment cycle will be defined as 21 days or 3 weeks. 
Laboratory results for safety assessments must be available prior to dosing on day 1 of each 
dosing cycle (Table 5).   
Radiographic tumor assessments will be obtained in all patients Q9W beginning at 
week 9 (day 63 ± 5 days) during year 1 and Q12W beginning at week 55 (first radiographic 
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tumor assessment in year 2 performed at end of week 54) during year 2, until IRC-assessed 
RECIST 1.1-defined progressive disease, withdrawal of consent, death, or initiation of another 
anti-cancer treatment.  See Section 8.2.2.1 for detailed timing of radiographic tumor assessments.  
Patients who discontinue for reasons other than progression who are not attending treatment 
visits may have radiographic tumor assessments between Q9W and Q12W until 
RECIST 1.1-defined progressive disease, withdrawal of consent, death, or initiation of another 
anti-cancer treatment. 
Progressive disease will be defined using RECIST 1.1 criteria (Appendix 2).  Investigators and 
the blinded IRC (Section 5.3.1) will assess response to therapy using RECIST 1.1 criteria.  
RECIST 1.1-defined progressive disease determined by the investigator will be used for clinical 
management of the patient.  RECIST 1.1-based tumor burden assessments by the blinded IRC 
will be used for evaluation of efficacy endpoints. 
Patients that experience RECIST 1.1-defined progressive disease on therapy may continue 
treatment if the investigator judges the patient to be experiencing clinical benefit and if the 
patient has not completed the 108-week treatment period (Section 7.8).  Alternatively, these 
patients may opt to initiate a new anti-cancer treatment.  If a patient continues treatment beyond 
the initial determination of progressive disease, study assessments should continue as per 
Table 5.  If on the next scheduled radiographic tumor assessment, RECIST 1.1-defined further 
progressive disease is confirmed (Section 7.8), therapy will be discontinued.  Further progression 
will be defined as an additional 10% increase in tumor burden from the time of initial 
progressive disease.   
Safety will be assessed through the occurrence of AEs, recording of concomitant medications, 
vital sign evaluation, physical examination, Eastern Cooperative Oncology Group (ECOG) 
performance status, and laboratory analyses (Table 5).   
To assess disease-related symptoms, patients will be asked to complete QOL questionnaires at 
time points specified in Table 5. 
Blood samples will be collected from patients in Treatment Arms B and C to measure serum 
concentrations of cemiplimab and cemiplimab ADA titers.  Blood samples will be collected to 
measure biomarkers associated with clinical response to cemiplimab including cytokines, 
circulating tumor nucleic acids, and other potential biomarkers of interest (Table 5). 
After at least 6 months (24 weeks) of treatment, a patient with confirmed CR may choose to stop 
cemiplimab treatment early and be followed for the duration of the study.  A patient with a PR 
that has stabilized after 6 months and is no longer changing after 3 successive tumor assessments 
may also choose to stop cemiplimab treatment early and be followed for the duration of the 
study. 
5.1.3. 
Follow-up Period 
Patients who discontinue study treatment due to progressive disease should return to the clinic 
14 to 30 days after the last study treatment to complete the end of study assessments (follow-up 
visit 1).  
Patients who discontinue study treatment for reasons other than progressive disease should return 
to the clinic 14 to 30 days (±7 days) after the last cycle visit for follow-up visit 1 and then 
continue with follow-up visit 2 through follow-up visit 7.   
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Survival data will then be collected by phone or at an office visit every 3 months, until death, 
loss to follow-up, or withdrawal of study consent. 
Follow-up procedures are outlined in Table 6. 
Follow-up Period:  All Treatment Arms 
 Patients will enter follow-up after completion of the 108-week treatment period, when 
the decision is made to discontinue pembrolizumab monotherapy or cemiplimab 
combination therapy, or at the time of initial RECIST 1.1-defined progressive disease 
while on study treatment.   
 Patients who completed the treatment period without RECIST 1.1-defined 
progressive disease or who discontinued study treatment early for reasons other than 
RECIST 1.1-defined progressive disease should continue to have radiographic tumor 
assessments Q12W.  
 Patients who opt to be treated with other anti-cancer treatments will be expected to 
complete all follow-up assessments as specified in Table 6. 
Follow-up Period:  Treatment Arms B and C only 
 Patients who discontinued cemiplimab treatment early (but after at least 6 months 
[24 weeks] of treatment) due to CR, PR, and entered follow-up at that time who then 
have RECIST 1.1-defined progressive disease while in follow-up may be offered the 
option of retreatment with cemiplimab 350 mg Q3W for an additional 108 weeks(see 
Section 7.8 ).  Study assessments for these patients will be performed as specified in 
Table 5.  
 Follow-up study assessments will be performed as specified in Table 6.  Patients 
assigned to Treatment Arms B and C will have blood samples taken for PK and ADA 
testing as specified in Table 6. 
5.1.4. 
Description of Study Stopping Rules 
More than 353 patients have been dosed as of April 2017 with cemiplimab with no DLTs 
observed.  Because this is the first study of the cemiplimab/ipi and cemiplimab/chemo/ipi 
combination, safety data from the first 10 patients treated with cemiplimab/ipi in 
Treatment Arm B and the first 10 patients treated with cemiplimab/chemo/ipi in 
Treatment Arm C will be reviewed after these patients complete 4 weeks of follow-up following 
the first dose of cemiplimab/chemo/ipi.  The data will be reviewed at a meeting of the IDMC.  If 
2 or more DLTs occur in the first 10 patients treated with cemiplimab/ipi or in the first 
10 patients treated with cemiplimab/chemo/ipi, enrollment for the respective treatment arm will 
be stopped temporarily.  Enrollment in Treatment Arms B and C will only be restarted after a 
formal safety review. 
An additional safety review will be performed by the IDMC after the first 10 patients in the 
cemiplimab/ipi and the first 10 patients in the cemiplimab/chemo/ipi regimen have received all 
4 doses of ipilimumab and have been followed for at least 6 weeks after the last dose.  This 
analysis will include all patients who have been exposed to the combination treatment.  
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After this evaluation is performed, a frequency or severity of drug related adverse events causing 
discontinuation of treatment in ≥25% of treated patients will lead to a pause in further enrollment 
to Arm B or C pending review with the IDMC and the study steering committee. 
The outcomes of these safety reviews will be a decision to do one of the following: 
 Continue the study as planned after discussions with investigators and regulatory 
authorities 
 Continue the study without the second cycle of chemotherapy 
 Increase the interval for ipilimumab administration from 6 to 12 weeks in Treatment 
Arm B or C 
 Discontinue Treatment Arm B or C  
5.1.5. 
Dose-Limiting Toxicities 
The DLT observation period for determination of safety is defined as 28 days starting with 
cycle 1 day 1, with the intent to monitor safety and tolerability of cemiplimab/ipi and 
cemiplimab/chemo/ipi. 
Any of the below outlined events occurring during the DLT observation period and considered to 
be at least possibly related to cemiplimab/ipi or cemiplimab/chemo/ipi will qualify as a DLT. 
A DLT is defined as the following: 
Nonhematologic Toxicity 
1. Grade ≥2 uveitis (considered as a potential irAE) 
2. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times upper 
limit of normal (ULN) and/or total bilirubin >3 times ULN 
3. Any grade ≥3 nonhematologic toxicity, with the exception of the following: 
a. Grade 3 nausea, vomiting, or diarrhea unless persistent (>7 days of duration) despite 
maximal supportive care measures, as prescribed by the treating physician 
b. Grade ≥3 laboratory abnormalities that are considered clinically insignificant and do 
not meet criteria for an AE 
c. Grade 3 infusion-related reactions that respond to medical management 
d. Any Grade 3 irAE (as defined by experience with other immunomodulatory drugs; 
see Section 7.3.4 for the description of common irAEs) other than uveitis that 
improves within 14 days to grade 2 or lower with medical management (including 
treatment with steroids).   
e. Any Grade 3 irAE which would result in permanent discontinuation of the 
cemiplimab/ipi/chemo (or permanent discontinuation of ipilimumab), as outlined in 
Section 7.3.1, or which would result in permanent discontinuation of cemiplimab, as 
outlined in the guidelines in Appendix 3, should be considered a DLT.  This 
specifically includes the following Grade 3 irAEs:  pneumonitis, colitis/diarrhea, 
nephritis. 
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Hematologic Toxicity 
1. Grade 4 neutropenia lasting more than 7 days 
2. Grade 4 thrombocytopenia 
3. Grade 3 thrombocytopenia with bleeding 
4. Grade ≥3 febrile neutropenia (fever ≥38.5°C with absolute neutrophil count <1.0 × 109/L) 
or grade ≥3 neutropenia with documented infection 
5. Grade 4 anemia 
The frequency, time to onset, and severity of toxicities, as well as the success of standard 
medical management and dosing interruptions/delays (Section 7.3.1), will be analyzed to 
determine if a given toxicity should be considered a DLT.  Both irAEs and non-irAEs that meet 
the definition of a DLT will be considered to be DLTs. 
In 
general, 
because 
there 
is 
no 
clinical 
experience 
with 
cemiplimab/ipi 
and 
cemiplimab/chemo/ipi, any AE that has been clearly described for other agents that block the 
PD-1/PD-L1 and/or CTLA-4 pathways or the combination will be treated initially as unexpected 
in this study.  Such TEAEs will be monitored and especially considered on an ongoing basis to 
assess expectedness, including possible differences in event frequency or severity from that 
observed with other PD-1/PD-L1 and CTLA-4 blockers. 
The TEAEs that appear to meet the DLT definition will be discussed between the sponsor and 
the investigator.  The final decision of whether or not the TEAE meets the DLT definition will be 
based on a careful review of all relevant data and consensus between the Medical Monitor, 
Clinical Development Lead, and the designated Risk Management Lead from the 
Pharmacovigilance and Risk Management department.  The investigator may also be consulted. 
Regardless of whether a patient remains on study treatment and/or continues to participate in 
study procedures, such an event will count as a DLT, if the event occurs during the DLT 
observation period. 
5.1.6. 
Maximum Tolerated Dose 
If 2 or more of the first 10 patients from Treatment Arm B who are dosed with cemiplimab/ipi 
experience a DLT during the DLT monitoring period, the dosing interval for ipilimumab could 
be increased from Q6W to Q12W.  If 2 or more DLTs occur in the first 10 patients treated in 
Treatment Arm B, enrollment to this treatment arm will be stopped temporarily and will be 
restarted only after the formal early safety review. 
If 2 or more of the first 10 patients from Treatment Arm C who are dosed with 
cemiplimab/chemo/ipi experience a DLT during the DLT monitoring period, the dosing interval 
for ipilimumab could be increased from Q6W to Q12W or the number of cycles of platinum 
doublet chemotherapy reduced from 2 to 1.  If 2 or more DLTs occur in the first 10 patients 
treated in Treatment Arm C, enrollment to this treatment arm will be stopped temporarily and 
will be restarted only after the formal early safety review. 
An additional safety review will be performed by the IDMC after the first 10 patients in the 
cemiplimab/ipi and cemiplimab/chemo/ipi regimen have received all 4 doses of ipilimumab and 
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have been followed for at least 6 weeks after the last dose.  This analysis will include all patients 
who have been exposed to the combination treatment.  
The MTD is defined as the dose level immediately below the level at which dosing is stopped 
due to the occurrence of 2 or more DLTs.  If the study is not stopped due to the occurrence of a 
DLT, it will be considered that the MTD has not been determined. 
Based on data with cemiplimab and other anti-PD-1 investigational compounds, it is possible 
that an MTD may not be defined in this study. 
5.1.7. 
End of Study Definition 
The end of study is defined as the last visit of the last patient. 
5.2. 
Planned Interim Analysis 
An interim analysis for secondary endpoint of OS will be performed at the time of primary 
analysis for PFS.  There will be an early safety review by the IDMC as detailed in Section 5.1.4. 
5.3. 
Study Committees  
Two independent study committees will be utilized:  an IRC (Section 5.3.1) and an IDMC 
(Section 5.3.2). 
5.3.1. 
Independent Review Committee 
A blinded IRC composed of members who are independent from the sponsor, and the study 
investigators will review all available (de-identified) radiographic tumor assessments to 
determine tumor response based on RECIST 1.1 criteria.  The IRC-determined tumor response 
will be used in the analysis of the PFS and ORR endpoints.  Details of the IRC responsibilities 
and procedures will be specified in the IRC charter. 
5.3.2. 
Independent Data Monitoring Committee 
An IDMC, composed of members who are independent from the sponsor and the study 
investigators, will monitor patient safety by conducting formal reviews of accumulated safety 
data that will be blinded by treatment group; if requested, the IDMC may have access to the 
treatment allocation code or any other requested data for the purposes of a risk-benefit 
assessment. 
The IDMC will provide the sponsor with appropriate recommendations on the conduct of the 
clinical study to ensure the protection and safety of the patients enrolled in the study.  The IDMC 
will also institute any measures that may be required for ensuring the integrity of the study 
results during the study execution.   
All activities and responsibilities of the IDMC are described in the IDMC charter. 
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6. 
SELECTION, 
WITHDRAWAL, 
AND 
REPLACEMENT 
OF 
PATIENTS 
6.1. 
Number of Patients Planned 
Approximately 585 patients will be randomized at approximately 200 global sites.  Of the 
585 patients, it is estimated that approximately two-thirds of the patients will have non-squamous 
histology and one-third will have squamous histology. 
6.2. 
Study Population 
Patients in this study will include men and women ≥18 years of age, who are diagnosed with 
stage IIIB, or IIIC NSCLC who are not eligible for definitive chemo/radiation therapy or patients 
with or stage IV non-squamous or squamous NSCLC, whose tumors express PD-L1 in ≥50% of 
tumor cells (using the PD-L1 IHC 22C3 pharmDx assay) and who have received no prior 
systemic treatment for their advanced disease.   
To be eligible for the study, patients must meet all of the inclusion criteria (Section 6.2.1) and 
none of the exclusion criteria (Section 6.2.2). 
6.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Men and women ≥18 years of age (≥21 years of age for Japanese patients) 
2. Patients with histologically or cytologically documented squamous or non-squamous 
NSCLC with stage IIIB, or IIIC disease who are not candidates for treatment with 
definitive concurrent chemo/radiation or patients with stage IV disease if they have not 
received prior systemic treatment for recurrent or metastatic NSCLC. The histologic 
diagnosis of NSCLC may be confirmed by the central laboratory. 
 Patients who received adjuvant or neoadjuvant platinum-doublet chemotherapy (after 
surgery and/or radiation therapy) and developed recurrent or metastatic disease more 
than 6 months after completing therapy are eligible. 
3. Availability of an archival or on-study obtained formalin-fixed, paraffin-embedded tumor 
tissue sample   
 Guidance on biopsy sites:  
a. Archival or fresh biopsies are acceptable 
b. If an archival biopsy is used, it has to be less than 5 months old 
c. The biopsy should be from a metastatic or recurrent site which has not previously 
been irradiated 
d. Exception: the primary lung tumor is still in place and the other metastatic sites 
are either not accessible (brain) or cannot be used (bone) or the biopsy would put 
the patient at risk 
4. Expression of PD-L1 in ≥50% of tumor cells determined by the commercially available 
PD-L1 IHC 22C3 pharmDx assay performed by the central laboratory.  
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5. At least 1 radiographically measureable lesion by computed tomography (CT) or 
magnetic resonance imaging (MRI) per RECIST 1.1 criteria (see Appendix 2).  Target 
lesions may be located in a previously irradiated field if there is documented 
(radiographic) RECIST 1.1-defined progressive disease in that site. 
6. ECOG performance status of ≤1. 
7. Anticipated life expectancy of at least 3 months. 
8. Adequate organ and bone marrow function as defined below: 
a. Hemoglobin ≥10.0 g/dL 
b. Absolute neutrophil count ≥1.5 × 109/L 
c. Platelet count ≥100,000/mm3  
d. Glomerular filtration rate >30 mL/min/1.73 m2   
e. Total bilirubin ≤1.5 × upper limit of normal (ULN) (if liver metastases ≤3 × ULN), 
with the exception of patients diagnosed with clinically confirmed Gilbert’s syndrome 
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × ULN or 
≤5 × ULN, if liver metastases 
g. Alkaline phosphatase ≤2.5 × ULN (or ≤5.0 × ULN, if liver or bone metastases) 
h. Not meeting criteria for Hy’s law (ALT >3 × ULN and bilirubin >2 × ULN). 
9. Willing and able to comply with clinic visits and study-related procedures. 
10. Provide signed informed consent. 
11. Able to understand and complete study-related questionnaires. 
6.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Patients who have never smoked, defined as smoking ≤100 cigarettes in a lifetime.  
2. Active or untreated brain metastases or spinal cord compression.  Patients are eligible if 
central nervous system (CNS) metastases are adequately treated and patients have 
neurologically returned to baseline (except for residual signs or symptoms related to the 
CNS treatment) for at least 2 weeks prior to enrollment.  Patients must be off 
(immunosuppressive doses of) corticosteroid therapy (see exclusion criterion 7 for details 
on timing of discontinuation of corticosteroid therapy). 
3. Patients with tumors tested positive for EGFR and ALK gene mutations or ROS1 fusions. 
All patients should have tumor evaluated for EGFR mutations, ALK rearrangement, and 
ROS1 fusions confirmed by a central laboratory. 
4. Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent. 
5. History of interstitial lung disease (eg, idiopathic pulmonary fibrosis, organizing 
pneumonia), active, noninfectious pneumonitis that required immune-suppressive doses 
of glucocorticoids to assist with management, or of pneumonitis within the last 5 years.  
A history of radiation pneumonitis in the radiation field is permitted as long as 
pneumonitis resolved ≥6 months prior to enrollment. 
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6. Ongoing or recent evidence of significant autoimmune disease that required treatment 
with systemic immunosuppressive treatments, which may suggest risk for immune-
related treatment-emergent adverse events (irTEAEs).  The following are not 
exclusionary: vitiligo, childhood asthma that has resolved, residual hypothyroidism that 
required only hormone replacement, or psoriasis that does not require systemic treatment. 
7. Patients with a condition requiring corticosteroid therapy (>10 mg prednisone/day or 
equivalent) within 14 days of randomization.  Physiologic replacement doses are allowed 
even if they are >10 mg of prednisone/day or equivalent, as long as they are not being 
administered for immunosuppressive intent.  Inhaled or topical steroids are permitted, 
provided that they are not for treatment of an autoimmune disorder. 
8. Previous treatment with idelalisib at any time (ZYDELIG®). 
9. Another malignancy that is progressing or requires treatment, with the exception of 
nonmelanomatous skin cancer that has undergone potentially curative therapy, in situ 
cervical carcinoma, or any other localized tumor that has been treated, and the patient is 
deemed to be in complete remission for at least 2 years prior to enrollment, and no 
additional therapy is required during the study period. 
10.  Known active hepatitis B (known positive result) or hepatitis C (known positive result) 
and known quantitative HCV RNA results greater than the lower limits of detection of 
the assay).  Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis 
B virus (HBV) or hepatitis C virus (HCV) infection; or diagnosis of immunodeficiency: 
Exceptions: 
a. Patients with HIV who have controlled infection (undetectable viral load and CD4 
count above 350 either spontaneously or on a stable anti-viral regimen) are 
permitted. 
b. Patients with hepatitis B (hepatitis B surface antigen positive) who have 
controlled infection (serum hepatitis B virus DNA PCR that is below the limit of 
detection AND receiving anti-viral therapy for hepatitis B) are permitted.  
c. Patients who are hepatitis C virus antibody positive (HCV Ab+) who have 
controlled infection (undetectable HCV RNA by PCR either spontaneously or in 
response to a successful prior course of anti-HCV therapy) are permitted. 
Patients with HIV or hepatitis must have their disease reviewed by the specialist (eg, 
infectious disease or hepatologist) managing this disease prior to commencing and 
throughout the duration of their participation in the trial. 
11. Active infection requiring systemic therapy within 14 days prior to randomization. 
12. Prior therapy with anti-PD-1 or anti-PD-L1.  Prior exposure to other immunomodulatory 
or vaccine therapy such as anti-CTLA-4 antibodies is permitted, but the last dose of such 
an antibody should have been at least 6 months prior to the first dose of study treatment. 
13. Treatment-related immune-mediated AEs from immune-modulatory agents (including 
but not limited to anti-PD-1/PD-L1 monoclonal antibodies, anti-CTLA-4 monoclonal 
antibodies, and PI3K-δ inhibitors) that have not resolved to baseline at least 3 months 
prior to initiation of treatment with study therapy.  Patients are excluded from treatment 
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with cemiplimab if they experienced immune-mediated AEs related to prior treatment 
with a blocker of the PD-1/PD-L1 pathway that were grade 3 or 4 in severity and/or 
required discontinuation of the agent, regardless of time of occurrence. 
14. Receipt of an investigational drug or device within 30 days of screening or within 
5 half-lives of the investigational drug or therapy being studied (whichever is longer). 
15. Receipt of a live vaccine within 30 days of planned start of study medication. 
16. Major surgery or significant traumatic injury within 4 weeks prior to first dose. 
17. Documented allergic or acute hypersensitivity reaction attributed to antibody treatments 
in general or to agents specifically used in the study. 
18. Known psychiatric or substance abuse disorder that would interfere with participation 
and/or with the requirements of the study, including current use of any illicit drugs. 
19. Pregnant or breastfeeding women. 
20. Women of childbearing potential* and men who are unwilling to practice highly effective 
contraception prior to the initial dose/start of the first treatment, during the study, and for 
at least 6 months after the last dose. Highly effective contraceptive measures include 
stable use of combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, 
injectable, implantable) associated with inhibition of ovulation initiated 2 or more 
menstrual cycles prior to screening; intrauterine device (IUD); intrauterine 
hormone-releasing system (IUS); bilateral tubal ligation; vasectomized partner; and or 
sexual abstinence†, ‡. 
* Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential.  Pregnancy testing and contraception are not 
required for women with documented hysterectomy or tubal ligation. 
† Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments. 
‡ Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are 
not acceptable methods of contraception.  Female condom and male condom should 
not be used together. 
Sexually active men and their partners must use highly effective contraception as 
described above.  Contraception is not required for men with documented vasectomy. 
21. Patients who are committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities will be excluded from this study. 
22. Member of the clinical site study team and/or his/her immediate family, unless prior 
approval granted by the Sponsor. 
23.  Active or latent tuberculosis. Latency should be confirmed by purified protein derivative 
(PPD)/QuantiFERON testing according to local guidelines in potential patients from 
tuberculosis-endemic areas. 
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24. History of previous organ transplant, including stem cell allograft 
25. Meeting the comparator products contraindicated criteria as listed in local labeling. 
Investigators should review the current label in their local database.  
6.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor has the right to withdraw a patient from the study if it is no 
longer in the interest of the patient to continue in the study, or if the patient’s continuation in the 
study places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow 
study procedures).  An excessive rate of withdrawals would render the study uninterpretable; 
therefore, unnecessary withdrawal of patients should be avoided. 
Patients who are withdrawn prematurely from the study will be asked to complete study 
assessments, as described in Section 8.1.2. 
Rules for discontinuation of study treatment (permanent) are discussed in Section 7.3.8. 
6.4. 
Replacement of Patients 
Patients prematurely discontinued from the study or study drug will not be replaced. 
7. 
STUDY TREATMENTS 
7.1. 
Investigational and Reference Treatments 
Eligible patients will be randomized to receive one of the following treatment arms:   
 Treatment Arm A:  pembrolizumab monotherapy 200 mg Q3W for 108 weeks 
 Treatment Arm B:  cemiplimab 350 mg Q3W for 108 weeks plus ipilimumab 50 mg 
Q6W for up to 4 doses (cemiplimab/ipi) 
 Treatment Arm C:  cemiplimab 350 mg Q3W for 108 weeks plus platinum-based 
doublet chemotherapy Q3W for 2 cycles and ipilimumab 50 mg Q6W for up to 
4 doses (cemiplimab/chemo/ipi) 
Patients will receive their assigned treatment for the 108-week treatment period or until 
RECIST 1.1-defined progressive disease or until early treatment discontinuation for another 
reason. 
Study treatment will be administered by the investigator or other designated study personnel. 
7.1.1. 
Cemiplimab  
Cemiplimab is a covalent heterotetramer consisting of 2 disulfide-linked human heavy chains, 
each of which is covalently bonded through disulfide linkages to a human kappa light chain.  The 
antibody possesses an approximate molecular weight of 143.6 kDa based on the primary 
sequence.  There is a single N-linked glycosylation site on each heavy chain, located within the 
constant region in the Fc portion of the molecule.  The cemiplimab heavy chain possesses an 
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IgG4 isotype constant region.  The variable domains of the heavy and light chains combine to 
form PD-1 binding site within the antibody. 
Cemiplimab is manufactured by Regeneron Pharmaceuticals, Inc. 
Cemiplimab (50 mg/mL) is manufactured with Cell Line 2 Process 1 (C2P1) and formulated in 
an aqueous buffered solution at pH 6.0 containing 10 mM histidine, 5% (w/v) sucrose, 1.5% 
(w/v) L-proline, and 0.2% (w/v) polysorbate 80.  Cemiplimab C2P1 drug product is supplied as a 
sterile liquid solution of 5.6 mL in a 10 mL glass vial for IV administration. 
Cemiplimab will be supplied as a liquid in sterile, single-use vials.  Each vial will contain 
withdrawable cemiplimab at a concentration of 50 mg/mL.  See Section 7.6 for details on 
packaging, labeling, and storage. 
Cemiplimab will be administered in an outpatient setting as a 30-minute (±10 minutes) 
IV infusion. 
Instructions on dose preparation are provided in the pharmacy manual.  Instructions on 
management of acute infusion reactions are provided in Section 7.4.1. 
Cemiplimab will be administered in combination with either ipilimumab (administered Q6W for 
up to 4 doses;  cemiplimab/ipi) or platinum-based doublet chemotherapy (administered Q3W for 
2 cycles) and ipilimumab (administered Q6W for up to 4 doses; cemiplimab/chemo/ipi) and then 
alone for the remainder of the treatment period.  
When administered in combination with ipilimumab and chemotherapy, infuse chemotherapy, 
then cemiplimab, then ipilimumab on the same day.  Use separate infusion bags and filters for 
each infusion. 
When administered in combination with ipilimumab, infuse cemiplimab first followed by 
ipilimumab on the same day.  Use separate infusion bags and filters for each infusion. 
When administered in combination with platinum-based chemotherapy doublet agents, the 
chemotherapy agents should be infused first, followed by cemiplimab, on the same day.  Use 
separate infusion bags and filters for each infusion. 
7.1.2. 
Ipilimumab 
Ipilimumab should be procured by the study sites as local commercial products in some countries 
and where allowed by local regulations; for other countries, Regeneron may provide the 
ipilimumab to the study sites.  See Section 7.6 for details on packaging, handling, and storage. 
Ipilimumab 50 mg flat dose will be administered IV over approximately 90 minutes on day 1 
every 42 days (Q6W) for up to 4 doses in combination with cemiplimab.  Administration should 
adhere to the local prescribing information and practice guidelines. 
Instructions on dose preparation are provided in the pharmacy manual.  Instructions on 
management of acute infusion reactions are provided in Section 7.4.1. 
Ipilimumab should be infused after cemiplimab on the same day.  Separate infusion bags and 
filters will be used for each infusion.  
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7.1.3. 
Pembrolizumab 
Pembrolizumab should be procured by the study sites as local commercial products in some 
countries and where allowed by local regulations; for other countries, Regeneron may provide 
the pembrolizumab to the study sites.  See Section 7.6 for details on packaging, handling, and 
storage. 
Pembrolizumab 200 mg will be administered IV over approximately 30 minutes on day 1 every 
21 days (Q3W) for 108 weeks, until RECIST 1.1-defined progressive disease or until early 
treatment discontinuation for another reason.  Administration will be according to the local 
prescribing information and practice guidelines. 
Instructions on dose preparation are provided in the pharmacy manual.  Instructions on 
management of acute infusion reactions are provided in Section 7.4.1. 
7.1.4. 
Platinum-Based Doublet Chemotherapy 
Chemotherapy will be administered Q3W in combination with cemiplimab as outlined in Table 1 
for 2 cycles (depending on randomized treatment arm, patient tolerability, and disease 
assessment) or until RECIST 1.1-defined progressive disease or early treatment discontinuation 
for another reason.  Chemotherapy will be administered according to local prescribing 
information and practice guidelines. 
The choice of chemotherapy will be one of the regimens shown in Table 1.  The investigator may 
choose from one of these regimens provided (Table 1).  Assignment of the chemotherapy choice 
must be made prior to randomization.  Chemotherapy should be procured by the study sites as 
local commercial products in some countries and where allowed by local regulations; for other 
countries, Regeneron may provide the chemotherapy to the study sites.  Preference should be 
given to regimens that are allowed by local regulations. 
The sequence of drug administration is platinum-based chemotherapy doublet agents followed 
by cemiplimab. 
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Table 1: 
Guidelines for Platinum-Based Doublet Chemotherapy Regimens (Treatment 
Arm C) 
Option 
Chemotherapy Regimen 
Dosing Frequency 
1 
Paclitaxel 200 mg/m2 IV plus 
carboplatin AUC of 
5 or 6 mg/mL/minute IV 
Day 1 every 21 days (Q3W) for 2 cycles  
Calculate dose of carboplatin using the Calvert formula. 
2 
Paclitaxel 200 mg/m2 IV plus cisplatin 
75 mg/m2 IV 
Day 1 every 21 days (Q3W) for 2 cycles  
3 
Pemetrexed 500 mg/m2 IV plus 
carboplatin AUC of 
5 or 6 mg/mL/minute IV 
Day 1 every 21 days (Q3W) for 2 cycles  
Calculate dose of carboplatin using the Calvert formula. 
4 
Pemetrexed 500 mg/m2 IV plus 
cisplatin 75 mg/m2 IV 
Day 1 every 21 days (Q3W) for 2 cycles  
Abbreviations:  AUC=area under the curve; IV=intravenous; N/A=not applicable  
These are general guidelines.  The dosages should be according to the local prescribing 
information and practice guidelines. 
Note that patients with glomerular filtration rate (GFR) <50 mL/min/1.73 m2 may NOT receive 
cisplatin-containing regimens.  
7.2. 
Pre-treatments 
Pre-medications should be procured by the study sites as local commercial products in some 
countries and where allowed by local regulations; for other countries, Regeneron may provide 
the pre-medications.  Preference should be given to regimens that are allowed by local 
regulations. 
Pre-medications are not required prior to the first administration of cemiplimab.  Pre-medications 
will be allowed at subsequent doses depending on the need to manage any observed low-grade 
infusion reactions (See Section 7.4.1.1). 
For chemotherapy, pre-medications should be administered in accordance with the local 
prescribing information and practice guidelines.  In general, it is recommended that patients 
receive corticosteroids, diphenhydramine, and an H2-receptor blocker prior to receipt of 
paclitaxel.  It is recommended that patients receiving pemetrexed receive vitamin 
supplementation (folic acid and vitamin B12) and corticosteroids.  Pre-treatment with vitamin 
supplementation is to start within 3 days of randomization for patients with non-squamous 
NSCLC.  Patients receiving cisplatin should be adequately hydrated prior to the infusion of 
therapy and receive highly effective combination antiemetic therapy. 
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7.3. 
Dose Modification and Study Treatment Discontinuation Rules 
7.3.1. 
Cemiplimab Plus Ipilimumab Combination Therapy Dosing Delay Rules 
Patients in Treatment Arm B who experience protocol-defined DLTs (see Section 5.1.5; either 
during or outside of the DLT observation period) will be required to temporarily discontinue 
treatment with cemiplimab/ipi.   
In addition to DLTs, during the cemiplimab/ipi treatment period, administration of cemiplimab 
(and of ipilimumab, if an AE occurred on the day of a planned ipilimumab dosing) must be 
delayed due to the following AEs: 
 Either febrile neutropenia or neutropenia <500 cells/mm³ for >1 week despite the use 
of growth factors 
 Any grade ≥2 non-skin, drug-related AE, except for fatigue and laboratory 
abnormalities and except for AEs that require study treatment discontinuation (as 
listed below) 
 Any grade 3 drug-related laboratory abnormality (except for lymphopenia, AST, 
ALT, or total bilirubin or asymptomatic lipase or amylase) 
 Grade 3 lymphopenia will not require a dose delay 
 If the patient had a baseline AST, ALT, or total bilirubin level that was 
within normal limits, dosing should be delayed for a drug-related 
grade ≥2 toxicity 
 If the patient had a baseline AST, ALT, or total bilirubin level that was 
within the grade 1 toxicity range, dosing should be delayed for a 
drug-related grade ≥3 toxicity 
 Any grade 3 drug-related amylase or lipase abnormality that is not 
associated with symptoms or clinical manifestations of pancreatitis will 
not require a dose delay 
 Any grade 3 skin drug-related AE 
 Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the 
investigator, warrants delaying the dose of study treatment 
Resumption of treatment may be at the initial dose regimen or the dosing interval for ipilimumab 
could be increased from Q6W to Q12W, based upon the discretion of the investigator and the 
sponsor.  Dose modification of cemiplimab will not be permitted. 
A repeat occurrence of the same DLT after resumption of treatment will require permanent 
discontinuation of cemiplimab/ipi or cemiplimab/chemo/ipi respectively. 
Criteria for Restarting Cemiplimab Plus Ipilimumab Dosing 
Patients may resume treatment with cemiplimab/ipi when the drug-related AE(s) resolve to grade 
≤1 or baseline value, with the following exceptions: 
 Patients may resume study treatment in the presence of grade 2 fatigue. 
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 Patients who have not experienced a grade 3 drug-related skin AE may resume study 
treatment in the presence of grade 2 skin toxicity. 
 Patients with baseline grade 1 AST, ALT, or total bilirubin level who require dose 
delays for reasons other than a 2-grade shift in AST, ALT, or total bilirubin may 
resume study treatment in the presence of grade 2 AST, ALT, OR total bilirubin. 
 Patients with AST, ALT, and/or total bilirubin values meeting discontinuation criteria 
should have study treatment permanently discontinued. 
 Drug-related pulmonary toxicity, diarrhea, or colitis must resolve to baseline before 
study treatment is resumed. 
 Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume study treatment. 
 Any AE that meets the discontinuation rules below requires that the patient 
discontinue study treatment. 
Dosing Discontinuation Rules 
The following categories require permanent discontinuation of cemiplimab/ipi: 
 Any grade 2 drug-related uveitis, eye pain, or blurred vision that does not respond to 
topical therapy and does not improve to grade 1 severity within the re-treatment 
period or that requires systemic treatment, require study treatment discontinuation. 
 Any grade 3 non-skin, drug-related AE lasting >7 days require study treatment 
discontinuation, with the following exceptions for laboratory abnormalities, 
drug-related uveitis, pneumonitis, bronchospasm, colitis, diarrhea, hypersensitivity 
reactions, infusion reactions, and endocrinopathies: 
 Grade 3 drug-related uveitis, pneumonitis, bronchospasm, colitis, diarrhea, 
hypersensitivity reaction, or infusion reaction of any duration require study 
treatment discontinuation 
 Grade 3 drug-related endocrinopathies adequately controlled with only 
physiologic 
hormone 
replacement 
do 
not 
require 
study 
treatment 
discontinuation 
 Grade 3 drug-related laboratory abnormalities do not require study treatment 
discontinuation except for the following: 
 Grade 3 drug-related thrombocytopenia >7 days or associated with 
bleeding requires study treatment discontinuation 
 Any drug-related liver function test abnormality that meets the following 
criteria requires study treatment discontinuation: 
 
AST or ALT >5 to 10 × ULN for >2 weeks 
 
AST or ALT >10 × ULN 
 
Total bilirubin >5 × ULN 
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 
Concurrent AST or ALT >3 × ULN and total bilirubin >2 × ULN 
 Any grade 4 drug-related AE or laboratory abnormality requires study treatment 
discontinuation, except for the following events, which do not require study treatment 
discontinuation: 
 Grade 4 neutropenia ≤7 days 
 Grade 4 lymphopenia or leukopenia 
 Isolated grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis 
 Isolated grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of onset 
 Grade 4 drug-related endocrinopathy AEs, such as adrenal insufficiency, 
adrenocorticotropic 
hormone 
(ACTH) 
deficiency, 
hyperthyroidism, 
hypothyroidism, or glucose intolerance, that resolve or are adequately controlled 
with physiologic hormone replacement (corticosteroids, thyroid hormones) or 
glucose controlling agents, as applicable, may not require study treatment 
discontinuation per approval from the Medical Monitor 
 Any study treatment delay resulting in no dosing for >6 weeks (cemiplimab), 
>12 weeks (ipilimumab Q6W), or >18 weeks (ipilimumab Q12W, if dose was revised 
to Q12W due to a toxicity or another reason) requires study treatment 
discontinuation, with the exception of dosing delays to manage drug-related AEs, 
such as prolonged steroid tapers and with the exception of delays noted in the next 
bulleted item 
 Study treatment delays resulting in no dosing for >6 weeks (cemiplimab), >12 weeks 
(ipilimumab Q6W), or >18 weeks (ipilimumab Q12W, if dose was revised to Q12W 
due to a toxicity or another reason) that occur for non-drug-related reasons are 
permitted and may not require study treatment discontinuation, if approved by the 
Medical Monitor 
 Any AE, laboratory abnormality, or intercurrent illness, which in the judgment of the 
investigator, presents a substantial clinical risk to the patient with continued 
cemiplimab or ipilimumab dosing requires study treatment discontinuation. 
If the investigator determines that an AE is definitely related to ipilimumab based on the 
Reference Safety Information in the Investigator’s Brochure or based on local prescribing 
information and practice guidelines, the patient may discontinue treatment with ipilimumab and 
continue treatment with only cemiplimab. 
Additional guidelines for discontinuation of ipilimumab are provided in Section 7.3.5. 
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7.3.2. 
Cemiplimab Plus Ipilimumab and Chemotherapy Combination Therapy  
Dosing Delay Rules 
Patients in Treatment Arm C who experience protocol-defined DLTs (see Section 5.1.5; either 
during or outside of the DLT observation period) will be required to temporarily discontinue 
treatment with cemiplimab/chemo/ipi.   
In addition to DLTs, during the cemiplimab/chemo/ipi therapy period, administration of 
cemiplimab (and of ipilimumab, if an AE occurred on the day of a planned ipilimumab dosing), 
must be delayed due to the following AEs: 
 Either febrile neutropenia or neutropenia <500 cells/mm³ for >1 week despite the use 
of growth factors 
 Any grade ≥2 non-skin, drug-related AE, except for fatigue and laboratory 
abnormalities and except for AEs that require study treatment discontinuation (as 
listed below) 
 Any grade 3 drug-related laboratory abnormality (except for lymphopenia, AST, 
ALT, or total bilirubin or asymptomatic lipase or amylase) 
 Grade 3 lymphopenia will not require a dose delay 
 If the patient had a baseline AST, ALT, or total bilirubin level that was 
within normal limits, dosing should be delayed for a drug-related 
grade ≥2 toxicity 
 If the patient had a baseline AST, ALT, or total bilirubin level that was 
within the grade 1 toxicity range, dosing should be delayed for a 
drug-related grade ≥3 toxicity 
 Any grade 3 drug-related amylase or lipase abnormality that is not 
associated with symptoms or clinical manifestations of pancreatitis will 
not require a dose delay 
 Any grade 3 skin drug-related AE 
 Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the 
investigator, warrants delaying the dose of study treatment 
Resumption of treatment may be at the initial dose regimen or the dosing interval for ipilimumab 
could be increased from Q6W to Q12W, based upon the discretion of the investigator and the 
sponsor.  Dose modification of cemiplimab will not be permitted. 
A repeat occurrence of the same DLT after resumption of treatment will require permanent 
discontinuation of cemiplimab/chemo/ipi. 
Criteria for Restarting Cemiplimab Plus Ipilimumab and Chemotherapy Dosing 
Patients may resume treatment with cemiplimab/chemo/ipi when the drug-related AE(s) resolve 
to grade ≤1 or baseline value, with the following exceptions: 
 Patients may resume study treatment in the presence of grade 2 fatigue. 
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 Patients who have not experienced a grade 3 drug-related skin AE may resume study 
treatment in the presence of grade 2 skin toxicity. 
 Patients with baseline grade 1 AST, ALT, or total bilirubin level who require dose 
delays for reasons other than a 2-grade shift in AST, ALT, or total bilirubin may 
resume study treatment in the presence of grade 2 AST, ALT, OR total bilirubin. 
 Patients with AST, ALT, and/or total bilirubin values meeting discontinuation criteria 
should have study treatment permanently discontinued. 
 Drug-related pulmonary toxicity, diarrhea, or colitis must resolve to baseline before 
study treatment is resumed. 
 Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume study treatment. 
 Any AE that meets the discontinuation rules below requires that the patient 
discontinue study treatment. 
Dosing Discontinuation Rules 
The following categories require permanent discontinuation of cemiplimab/chemo/ipi: 
 Any grade 2 drug-related uveitis, eye pain, or blurred vision that does not respond to 
topical therapy and does not improve to grade 1 severity within the re-treatment 
period, or that requires systemic treatment, requires study treatment discontinuation. 
 Any grade 3 non-skin, drug-related AE lasting >7 days require study treatment 
discontinuation, with the following exceptions for laboratory abnormalities, 
drug-related uveitis, pneumonitis, bronchospasm, colitis, diarrhea, hypersensitivity 
reactions, infusion reactions, and endocrinopathies: 
 Grade 3 drug-related uveitis, pneumonitis, bronchospasm, colitis, diarrhea, 
hypersensitivity reaction, or infusion reaction of any duration require study 
treatment discontinuation 
 Grade 3 drug-related endocrinopathies adequately controlled with only 
physiologic 
hormone 
replacement 
do 
not 
require 
study 
treatment 
discontinuation 
 Grade 3 drug-related laboratory abnormalities do not require study treatment 
discontinuation except for the following: 
 Grade 3 drug-related thrombocytopenia >7 days or associated with 
bleeding requires study treatment discontinuation 
 Any drug-related liver function test abnormality that meets the following 
criteria requires study treatment discontinuation: 
 
AST or ALT >5 to 10 × ULN for >2 weeks 
 
AST or ALT >10 × ULN 
 
Total bilirubin >5 × ULN 
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 
Concurrent AST or ALT >3 × ULN and total bilirubin >2 × ULN 
 Any grade 4 drug-related AE or laboratory abnormality requires study treatment 
discontinuation, except for the following events, which do not require study 
treatment discontinuation: 
 Grade 4 neutropenia ≤7 days 
 Grade 4 lymphopenia or leukopenia 
 Isolated grade 4 amylase or lipase abnormalities that are not associated 
with symptoms or clinical manifestations of pancreatitis 
 Isolated grade 4 electrolyte imbalances/abnormalities that are not 
associated 
with 
clinical 
sequelae 
and 
are 
corrected 
with 
supplementation/appropriate management within 72 hours of onset 
 Grade 4 drug-related endocrinopathy AEs, such as adrenal insufficiency, 
ACTH 
deficiency, 
hyperthyroidism, 
hypothyroidism, 
or 
glucose 
intolerance, that resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose 
controlling agents, as applicable, may not require study treatment 
discontinuation per approval from the Medical Monitor 
 Any study treatment delay resulting in no dosing for >6 weeks (cemiplimab), 
>12 weeks (ipilimumab Q6W), or >18 weeks (ipilimumab Q12W, if dose was revised 
to Q12W due to a toxicity or another reason) requires study treatment 
discontinuation, with the exception of dosing delays to manage drug-related AEs, 
such as prolonged steroid tapers and with the exception of delays noted in the next 
bulleted item 
 Study treatment delays resulting in no dosing for >6 weeks (cemiplimab), >12 weeks 
(ipilimumab Q6W), or >18 weeks (ipilimumab Q12W, if dose was revised to Q12W 
due to a toxicity or another reason) that occur for non-drug-related reasons are 
permitted and may not require study treatment discontinuation, if approved by the 
Medical Monitor 
 Any AE, laboratory abnormality, or intercurrent illness, which, in the judgment of the 
investigator, presents a substantial clinical risk to the patient with continued 
cemiplimab or ipilimumab dosing, requires study treatment discontinuation. 
If the investigator determines that an AE is definitely related to ipilimumab based on the 
Reference Safety Information in the Investigator’s Brochure or based on local prescribing 
information and practice guidelines, the patient may discontinue treatment with ipilimumab and 
continue treatment with only cemiplimab. 
Additional guidelines for discontinuation of ipilimumab are provided in Section 7.3.5. 
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7.3.3. 
Cemiplimab as Combination Therapy With Chemotherapy 
The following cemiplimab treatment hold guidelines should be followed for patients in 
Treatment Arm C following completion of ipilimumab dosing (when cemiplimab will be 
monotherapy). 
Cemiplimab treatment may be held upon occurrence of a drug-related AE at any time on the 
study.  Resumption of cemiplimab treatment after resolution or stabilization of the condition is 
allowed at the discretion of the investigator and sponsor, if resuming treatment is thought to be in 
the best interest of the patient, with the exception of the following categories: 
 Patients with events that require cemiplimab to be discontinued permanently or held 
for more than 84 days from the last scheduled dose. 
 Patients with grade ≥2 uveitis.  Patients with grade 2 uveitis will generally be 
discontinued from cemiplimab treatment, unless there is resolution to grade ≤1 as 
outlined in Appendix 3 AND discussion with and approval by the Medical Monitor.  
All patients with grade ≥3 uveitis will be permanently discontinued from cemiplimab.  
Dose modification of cemiplimab will not be permitted.   
Guidelines for cemiplimab temporary discontinuations, including delays and interruptions, 
criteria for restarting, and permanent discontinuations for toxicity are outlined in Table 2 and 
Appendix 3. 
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Table 2: 
Cemiplimab Guidelines for Temporary and Permanent Discontinuations for 
Toxicity 
Toxicity 
Grade 
Hold 
Treatment? 
Restarting 
Criteria 
Restarting 
Dose/Schedule 
Discontinuation 
Criteria 
Hematological 
toxicity 
(other 
than 
grade 
3 
thrombocytopenia 
>7 days 
or 
associated 
with bleeding) 
1, 2, 3 
No 
N/A 
N/A 
N/A 
4 
Yes 
Toxicity 
resolves to 
grades 0 to 
1 
or 
baseline 
Same 
dose 
and 
schedule 
 
Toxicity 
does 
not 
resolve within 84 days 
of last infusion. 
Permanent 
discontinuation 
should be considered 
for any severe or 
life-threatening event. 
Grade 
3 
thrombocytopenia 
>7 days 
or 
associated 
with bleeding 
3 
Yes 
Toxicity 
resolves to 
grades 0 to 
1 
or 
baseline 
Same 
dose 
and 
schedule 
 
Toxicity 
does 
not 
resolve within 84 days 
of last infusion. 
Permanent 
discontinuation 
should be considered 
for any severe or 
life-threatening event. 
Nonhematological 
toxicity 
Note:  Exceptions to be 
treated as for grade 1 
toxicity: 
 
Grade 2 alopecia 
 
Grade 2 fatigue 
 
Clinically 
insignificant 
lab 
abnormality 
not 
meeting AE criteria 
1 
No 
N/A 
N/A 
N/A 
2 
Consider 
withholding 
for persistent 
symptoms 
Toxicity 
resolves to 
grades 0 to 
1 
or 
baseline 
Clinical AE resolves 
within 4 weeks:  Same 
dose and schedule  
Clinical AE does not 
resolve 
within 
4 weeks:  Discontinue 
Toxicity 
does 
not 
resolve within 84 days 
of last infusion. 
 
3 
Yes 
Toxicity 
resolves to 
grades 0 to 
1 
or 
baseline 
Same 
dose 
and 
schedule 
 
Toxicity 
does 
not 
resolve within 84 days 
of last infusion. 
4 
Yes 
N/A 
N/A 
Patient 
must 
be 
discontinued. 
Abbreviations:  AE=adverse event; irAE=immune-related adverse event; N/A=not applicable 
For additional information regarding potential irAEs, see Table 3 and Appendix 3. 
 
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Appendix 3 includes recommendations on the management of specific treatment-related AEs and 
when to delay and/or discontinue cemiplimab.  These guidelines are intended to be applied when 
the investigator determines the events to be treatment-related. 
If the investigator determines that an AE is definitely related to chemotherapy based on the 
Reference Safety Information in the Investigator’s Brochure or based on local prescribing 
information and practice guidelines, the patient may discontinue treatment with chemotherapy 
and continue treatment with only cemiplimab/ipi.  Additional reasons for cemiplimab permanent 
discontinuation include the following: 
 Cemiplimab dosing will be permanently discontinued in the event of pregnancy. 
 In the event of an infusion reaction of grade 3 or greater severity during or directly 
following cemiplimab infusions, dosing should be stopped and the patient must be 
permanently discontinued from cemiplimab treatment.  Infusion reactions are defined 
in Section 9.3.4. 
 In addition, cemiplimab for any patient may be discontinued for other safety reasons 
or compliance issues at the discretion of the investigator or sponsor.  A patient may 
choose to discontinue cemiplimab or study participation at any time for any reason. 
After at least 6 months (24 weeks) of treatment, patients in Treatment Arms B and C with 
confirmed CR may choose to stop cemiplimab treatment early and be followed for the duration 
of the study.  A patient with a PR that has stabilized after 6 months and is no longer changing 
after 3 successive tumor assessments may also choose to stop cemiplimab treatment early and be 
followed for the duration of the study. 
A patient who permanently discontinues cemiplimab treatment should continue follow-up in the 
study without additional cemiplimab treatment until RECIST 1.1-defined progressive disease, 
completion of all study assessments, or closure of the study (Section 6.3 and Section 8.1.2). 
7.3.4. 
Immune-Related Adverse Events 
Investigators must be extremely vigilant and be ready to intervene early in the management of 
irAEs because the onset of symptoms of irAEs (eg, pneumonitis) may be subtle.  Immune-related 
TEAEs have been reported with cemiplimab and with other anti-PD-1 antibodies; these are 
considered consistent with the mechanism of action of anti-PD-1 antibodies. 
An irTEAE can occur shortly after the first dose or several months after the last dose of 
treatment.  All AEs of unknown etiology associated with drug exposure should be evaluated for a 
possible immune etiology.  Efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes prior to labeling an AE as an irTEAE.  Suggested management 
guidelines are provided in Appendix 3 for certain anti-PD-1 irTEAEs including but not limited 
to: 
 Gastrointestinal events (colitis, colitis microscopic, enterocolitis, enterocolitis 
hemorrhagic, gastrointestinal perforation, diarrhea, stomatitis) 
 Pneumonitis events (pneumonitis, acute interstitial pneumonitis) 
 Hepatic events (ALT/AST increased, autoimmune hepatitis, transaminases 
increased) 
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 Endocrine events (autoimmune thyroiditis, blood thyroid stimulating hormone 
[TSH] increased, diabetic ketoacidosis, diabetes mellitus, hyperthyroidism, 
hypophysitis, hypopituitarism, hypothyroidism, thyroid disorder, thyroiditis, adrenal 
insufficiency, Type 1 diabetes mellitus) 
 Uveitis (iritis, iridocyclitis, uveitis) 
 Renal events (nephritis, autoimmune nephritis, tubulointerstitial nephritis) 
 Skin events (dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis 
exfoliative, dermatitis exfoliative generalized, exfoliative rash, pruritus, pruritus 
generalized, rash, rash erythematous, rash generalized, rash macular, rash 
maculopapular, rash maculovesicular, rash morbilliform, rash papular, rash pruritic, 
rash rubelliform, rash scarlatiniform, rash vesicular, vitiligo) 
 Nervous system events (encephalitis, paraneoplastic encephalomyelitis, myasthenia 
gravis) 
Based on the emerging safety profile of cemiplimab and other antibodies targeting the 
PD-1/PD-L1 axis (Weber 2015, Naidoo 2015), the following working case definitions are 
provided to help investigators distinguish irTEAEs from non-immune AEs.  These case 
definitions pertain to the more commonly reported irTEAEs associated with PD-1 inhibition 
(Weber 2015, Naidoo 2015) and are not exhaustive of all possible irAEs.  Clinical presentations 
of less common irAEs, including neurologic, musculoskeletal, cardiac, renal, and ocular events 
(Zimmer 2016, Hofmann 2016), should be reviewed in patients with concerning presentations. 
The investigator should refer to the latest version of the Investigator’s Brochure for further 
details and guidance.  The case definitions have not been validated and are intended only as 
guidance for investigators to help distinguish irTEAEs from non-immune AEs.  Investigators’ 
clinical judgment may include other factors when determining immune relatedness.  The case 
definitions for irAEs may evolve as clinical experience increases with cemiplimab and other 
antibodies targeting the PD-1/PD-L1 axis. 
Detailed guidance of management of irAEs is provided in Appendix 3.  In the event of irAEs that 
are not addressed in Appendix 3, general guidance is provided in Table 3.  The recommendations 
in Table 3 and Appendix 3 should be seen as guidelines, and the treating physician should 
exercise clinical judgment based on the symptoms and condition of the individual patient. 
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Table 3: 
General Cemiplimab Treatment Hold Guidelines for Immune-Related 
Adverse Events 
Severity 
Withhold/Discontinue 
Cemiplimab 
Treatment? 
Supportive Care 
Grade 1 
No action. 
Provide symptomatic treatment. 
Grade 2 
May withhold treatment. 
Consider 
systemic 
corticosteroids 
in 
addition 
to 
appropriate symptomatic treatment. 
Grade 3 
Grade 4 
Withhold treatment. 
Discontinue 
if 
unable 
to 
reduce 
corticosteroid dose to <10 mg per day 
prednisone equivalent within 12 weeks of 
toxicity. 
For any severe (grade 3-4) irAE, if symptoms worsen or 
do not improve on adequate corticosteroids within 48 to 
72 hours, consider adding additional immunosuppressive 
agents (to be selected from agents such as: infliximab, 
CTX, cyclosporine, and mycophenolate mofetil).  Referral 
of the patient to a specialized unit for assessment and 
treatment should be considered. 
Abbreviations:  CTX=cyclophosphamide; irAE=immune-related adverse event 
7.3.5. 
Ipilimumab 
Ipilimumab-related toxicities should be managed in accordance with local prescribing 
information and practice guidelines.   
Ipilimumab should also be discontinued for the following reasons: 
 Ipilimumab combination dosing will be permanently discontinued in the event of 
pregnancy.  
 In the event of an infusion reaction of grade 3 or greater severity during or directly 
following infusions, dosing should be stopped and the patient must be permanently 
discontinued from ipilimumab treatment.  Infusion reactions are defined in 
Section 9.3.4. 
 Ipilimumab may be discontinued for other safety reasons or compliance issues at the 
discretion of the investigator or sponsor.  A patient may choose to discontinue 
cemiplimab plus ipilimumab combination therapy or study participation at any time 
for any reason.  
 Any reason listed in the local prescribing information and practice guidelines. 
If a patient experiences a toxicity that is known to be associated only with ipilimumab therapy, 
ipilimumab will be discontinued but cemiplimab may be continued.   
7.3.6. 
Pembrolizumab 
Dose modification/reduction or temporary cessation of pembrolizumab should be managed in 
accordance with the regional guidelines.   
Pembrolizumab dosing will be permanently discontinued in the event of pregnancy. 
In addition, pembrolizumab for any patient may be discontinued for other safety reasons or 
compliance issues at the discretion of the investigator or sponsor.  A patient may choose to 
discontinue pembrolizumab or study participation at any time for any reason. 
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A patient who permanently discontinues pembrolizumab should continue follow-up in the study 
without additional pembrolizumab treatment until RECIST 1.1-defined progressive disease, 
completion of all study assessments, or closure of the study (Section 6.3 and Section 8.1.2). 
In the event of an infusion reaction of grade 3 or greater severity during or directly following 
pembrolizumab, dosing should be stopped and the patient must be permanently discontinued 
from treatment. 
For dose delay and discontinuation rules due to pembrolizumab toxicities, see local prescribing 
information and practice guidelines.  
7.3.7. 
Platinum-Based Doublet Chemotherapy 
Dose modification/reduction or temporary cessation of a given chemotherapy should be managed 
in accordance with the local prescribing guidelines for the specific chemotherapy agent. 
Chemotherapy should be permanently discontinued for safety reasons, compliance issues, 
intolerance due to toxicity, or other reasons as provided by local prescribing information and 
practice guidelines and standard of care. 
If a patient experiences a toxicity that is known to be associated with chemotherapy, 
chemotherapy treatment will be discontinued but cemiplimab treatment may be continued.   
A patient who permanently discontinues from chemotherapy should continue follow-up in the 
study without additional chemotherapy treatment until RECIST 1.1-defined progressive disease, 
completion of all study assessments, or closure of the study (see Section 6.3 and Section 8.1.2). 
7.3.8. 
Permanent Study Treatment Discontinuation 
Patients who permanently discontinue from study treatment and who do not withdraw from the 
study will be asked to return to the clinic for all remaining study visits per the visit schedule. 
Patients who permanently discontinue from study treatment and who opt to withdraw from the 
study will be asked to complete study assessments, per Section 8.1.2. 
7.4. 
Management of Acute Reactions 
7.4.1. 
Acute Infusion Reactions 
Emergency equipment and medication for the treatment of infusion reactions must be available 
for immediate use.  Vital signs should be closely monitored according to Table 4, Table 5, and 
Table 6.  All infusion reactions must be reported as AEs (as defined in Section 9.4.1) and graded 
using the grading scales as instructed in Section 9.5.1. 
Acute infusion reactions are defined as any AE that occurs during the infusion or within 1 day 
after the infusion is completed.  Emergency equipment and medication for the treatment of these 
potential adverse effects (eg, antihistamines, bronchodilators, IV saline, corticosteroids, 
acetaminophen, and/or epinephrine) must be available for immediate use.  Infusion reactions 
must be graded according to the current version of the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) grading scale (Section 9.5.1). 
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In the event of an infusion reaction of grade 3 or greater severity during or directly following 
cemiplimab, ipilimumab, or pembrolizumab, dosing must be stopped and the patient must be 
permanently discontinued from treatment.  Infusion reactions are defined in Section 9.3.4. 
Acute infusion reactions may include cytokine release syndrome, angioedema, or anaphylaxis, 
and differ from allergic/hypersensitive reactions, although some of the manifestations are 
common to both AEs.  Signs and symptoms usually develop during or shortly after drug infusion 
and generally resolve completely within 24 hours of completion of infusion.   
Signs/symptoms may include the following: 
 Allergic reaction/hypersensitivity (including drug fever) 
 Arthralgia (joint pain) 
 Bronchospasm 
 Cough 
 Dizziness 
 Dyspnea (shortness of breath) 
 Fatigue (asthenia, lethargy, malaise) 
 Headache 
 Hypertension 
 Hypotension 
 Myalgia (muscle pain) 
 Nausea 
 Pruritus/itching 
 Rash/desquamation 
 Rigors/chills 
 Sweating (diaphoresis) 
 Tachycardia 
 Tumor pain (onset or exacerbation of tumor pain due to treatment) 
 Urticaria (hives, welts, wheals) 
 Vomiting 
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7.4.1.1. 
Interruption of the Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
 Cough 
 Rigors/chills 
 Rash, pruritus (itching) 
 Urticaria (hives, welts, wheals) 
 Diaphoresis (sweating) 
 Hypotension 
 Dyspnea (shortness of breath) 
 Vomiting 
 Flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of 
the original rate.   
If investigators feel there is a medical need for treatment or discontinuation of the infusion other 
than described above, they should use clinical judgment to provide the appropriate response 
according to typical clinical practice. 
For patients who experience infusion-related hypersensitivity reactions that are less than grade 3 
and who plan to continue treatment, premedication will be required for retreatment. 
For grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated), the following prophylactic medications are recommended for future infusions:  
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at 
least 30 minutes prior to subsequent cemiplimab infusions. 
For grade 2 symptoms (moderate reaction that requires therapy or infusion interruption but for 
which symptoms resolve promptly with appropriate treatment such as antihistamines, 
nonsteroidal anti-inflammatory drugs, narcotics, corticosteroids, and/or IV fluids; prophylactic 
medications indicated ≤24 hours), the following prophylactic medications are recommended for 
future infusions:  diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 
325 to 1000 mg at least 30 minutes prior to subsequent cemiplimab infusions.  If necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used. 
See the local prescribing information for management of infusion interruptions for 
pembrolizumab and ipilimumab. 
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7.4.1.2. 
Termination of the Infusion 
The infusion should be terminated and NOT restarted if any of the following AEs occur: 
 Anaphylaxis 
 Laryngeal/pharyngeal edema 
 Severe bronchospasm 
 Chest pain 
 Seizure 
 Severe hypotension 
 Other neurological symptoms (confusion, loss of consciousness, paresthesia, 
paralysis, etc) 
 Any other symptom or sign that, in the opinion of the investigator, warrants 
discontinuation of the infusion 
In the event of an infusion reaction of grade 3 or greater severity during or directly following 
cemiplimab, ipilimumab, or pembrolizumab, dosing should be stopped and the patient must be 
permanently discontinued from treatment. 
See the local prescribing information for management of infusion termination for 
pembrolizumab and ipilimumab. 
7.5. 
Method of Treatment Assignment  
Each patient who signs the informed consent form (ICF) will be assigned a patient number and 
tracked centrally as described in the interactive voice response system (IVRS)/interactive web 
response system (IWRS) manual.  Approximately 585 patients will be randomized in a 
1:1:1 ratio according to a central randomization scheme provided by an IVRS/IWRS to the 
designated study pharmacist (or qualified designee).  Patients will be randomized after providing 
informed consent, after completing screening assessments, and after the investigator has verified 
patient eligibility.  Randomization will be stratified by histology (non-squamous versus 
squamous).   
Patients will be randomized 1:1:1 to receive pembrolizumab monotherapy, cemiplimab/ipi, or 
cemiplimab/chemo/ipi. 
The choice of chemotherapy will be at the discretion of the investigator and is to be decided and 
documented prior to randomization. 
7.5.1. 
Blinding/Masking 
This is an open-label study.  To reduce bias, endpoint assessments will be performed by an IRC 
blinded to treatment assignment.  
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7.6. 
Treatment Logistics and Accountability 
7.6.1. 
Packaging, Labeling, and Storage 
Cemiplimab  
Open-label cemiplimab will be supplied as a liquid in sterile, single-use vials that will display the 
product lot number on the label.  Each vial will contain withdrawable cemiplimab at a 
concentration of 50 mg/mL.  Cemiplimab will be refrigerated at the site at a temperature of 2°C 
to 8°C.  The temperature of the storage refrigerator should be checked and recorded at least daily 
as prescribed in the pharmacy manual.  Further storage instructions will be provided in the 
pharmacy manual. 
A pharmacist or other qualified individual will be identified at each site to prepare cemiplimab 
for administration.  Details on storage and preparation for drug product for IV administration 
will be provided in the pharmacy manual. 
Ipilimumab 
Instructions on storage will be provided in the pharmacy manual.  A pharmacist or other 
qualified individual will be identified at each site to prepare ipilimumab for administration.  
Detailed preparation and administration instructions will be provided to the sites in the pharmacy 
manual. 
Ipilimumab will be refrigerated at the site at a temperature of 2°C to 8°C, and refrigerator 
temperature will be logged daily. 
Platinum-Based Doublet Chemotherapy 
Instructions on storage for chemotherapy agents will be provided in the pharmacy manual.  A 
pharmacist or other qualified individual will be identified at each site to prepare platinum-based 
doublet chemotherapy for administration.  Detailed preparation and administration instructions 
will be provided to the sites in the pharmacy manual. 
Pembrolizumab 
Instructions on storage will be provided in the pharmacy manual.  A pharmacist or other 
qualified individual will be identified at each site to prepare pembrolizumab for administration.  
Detailed preparation and administration instructions will be provided to the sites in the pharmacy 
manual. 
Pembrolizumab will be refrigerated at the site at a temperature of 2°C to 8°C, and refrigerator 
temperature will be logged daily. 
7.6.2. 
Supply and Disposition of Treatments 
Cemiplimab  
Study drug will be shipped at a temperature of 2°C to 8°C to the investigator or designee at 
regular intervals or as needed during the study.  At specified time points during the study (eg, 
interim site monitoring visits), at the site close-out visit, and following drug reconciliation and 
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documentation by the site monitor, all opened and unopened study drug will be destroyed or 
returned to the sponsor or designee. 
Ipilimumab 
Open-label ipilimumab will be supplied locally or may be provided by Regeneron.  
Platinum-Based Doublet Chemotherapy 
Open-label platinum-based doublet chemotherapy agents will be supplied locally or may be 
provided by Regeneron. 
Pembrolizumab 
Open-label pembrolizumab will be supplied locally or may be provided by Regeneron.  
7.6.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug.  These records 
should contain the dates, quantity, and study medication 
 Dispensed to each patient, 
 Returned from each patient (if applicable), and 
 Disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; anonymized photocopies must be provided to the sponsor at the conclusion of 
the study. 
7.6.4. 
Treatment Compliance 
All treatments will be administered at the study site, and administration will be recorded on the 
electronic case report form (eCRF).  All dosing records for each patient will be kept by the site. 
All drug compliance records must be kept current and made available for inspection by the 
sponsor and regulatory agency inspectors. 
7.7. 
Concomitant Medications  
Any treatment administered from the time of informed consent until 90 days after the last study 
treatment will be considered concomitant medication.  This includes medications that were 
started before the study and are ongoing during the study, as well as any therapies started in the 
follow-up period to treat a study-drug-related AE.  All concomitant treatments must be recorded 
in the study eCRF with the generic name, dose, dose unit, frequency, indication, and start/stop 
date, as appropriate. 
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7.7.1. 
Prohibited Medications and Procedures 
While participating in this study, a patient may not receive any investigational drug or treatment 
for treatment of a tumor other than pembrolizumab monotherapy or cemiplimab plus 
study-specified chemotherapy regimens or ipilimumab combination therapy.   
Treatment with idelalisib, bevacizumab, or necitumumab is not one of the protocol–defined 
treatment options.  If the treating physician believes that treatment with one of these 
3 medications is required for a patient considering enrollment to the study and study-specified 
treatment options are not sufficient, they should not enroll in the study. 
Any other medication that is considered necessary for the patient’s welfare and is not expected to 
interfere with the evaluation of the study treatment may be given at the discretion of the 
investigator. 
7.7.2. 
Permitted Medications and Procedures 
It is recommended that patients do not receive concomitant systemic corticosteroids such as 
hydrocortisone, prednisone, prednisolone, or dexamethasone at any time throughout the study, 
except in the case of a life-threatening emergency and/or to treat an irAE. 
Physiologic replacement doses of systemic corticosteroids are permitted, even at doses 
>10 mg/day prednisone or equivalent.  A brief course of corticosteroids for prophylaxis (eg, 
contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type 
hypersensitivity reaction caused by contact allergen) is permitted. 
Treatments for bone metastases (bisphosphonates and denosumab) are permitted. 
Pemetrexed maintenance therapy should be given according to local prescribing information and 
practice guidelines. 
7.8. 
Disease Progression While Receiving Cemiplimab or Pembrolizumab 
It is recognized that some patients treated with immunotherapy or platinum-based chemotherapy 
may derive clinical benefit despite initial evidence of progressive disease.  Patients treated with 
cemiplimab 350 mg and pembrolizumab will be permitted to continue treatment beyond initial 
RECIST 1.1-defined progressive disease if the investigator perceives the patient to be 
experiencing clinical benefit and the patient has not completed the 108-week treatment period 
and provided that he/she meets the following criteria: 
 Investigator assessed no rapid disease progression. 
 Patient continues to meet all other study eligibility criteria. 
 Patient is tolerant of the cemiplimab containing regimen and has a stable performance 
status. 
 Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression. 
Patients may be required to sign a separate ICF per local regulatory requirements.  
Imaging should be performed within 9 weeks of the initial assessment of progressive disease to 
determine whether there has been a decrease in the original tumor size or continued progressive 
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disease.  In these patients, further progression will be defined as an additional 10% increase in 
tumor burden from the time of initial progressive disease; this includes an increase in the sum of 
all target lesions and/or the development of new target lesions.  If further progressive disease is 
confirmed, cemiplimab must be discontinued and other anti-cancer therapy considered, if 
appropriate. 
If a patient continues treatment with cemiplimab or pembrolizumab beyond the initial 
determination of progressive disease, study assessments should continue as per Table 5.   
7.9. 
Post-study Treatments and Procedures 
Patients will be contacted quarterly by telephone for survival status, if available, until death, loss 
to follow-up, or study termination by the sponsor. 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events 
Study assessments and procedures are presented in Table 4 for screening, in Table 5 for the 
treatment period, and in Table 6 for the follow-up period. 
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Study Procedure 
Year 1 
Year 2 (Starting at Cycle 19) 
Notes 
Day 1, 
Cycle 
1 
Day 1, 
Each Cycle 
(Every 21 Days 
±3 Days) 
Day 1, 
Every Other 
Cycle 
(Every 42 
Days 
±3 Days) 
Every 3 Cycles 
(9 Weeks 
[63 Days] 
±5 Days) 
Day 1, 
Each Cycle 
(Every 
21 Days 
±3 Days) 
Every 3 
Cycles 
(9 Weeks 
[63 Days] 
±5 Days) 
Every 
4 Cycles 
(12 Weeks 
±5 Days) 
acquired 
as 
clinically 
indicated, per the discretion of 
the investigator. 
Hematology 
(CBC 
with 
Differential) 
X 
X 
 
 
X 
 
 
 Blood samples may be 
collected ≤72 hours prior to 
dosing on the day 1 visit of 
each cycle. 
 Results 
must 
be 
obtained/reviewed prior to 
dosing. 
 Screening 
laboratory 
examinations 
performed 
within 7 days of cycle 1 day 
1 do not need to be repeated 
for 
this 
visit 
unless 
clinically indicated. 
Serum Chemistry 
X 
X 
X 
(ACTH must 
be tested in 
Treatment 
Arm C; only 
prior 
to 
ipilimumab 
dosing) 
 
X 
 
 
 Blood 
sample 
may 
be 
collected ≤72 hours prior to 
dosing on the day 1 visit of 
each cycle. 
 Results 
must 
be 
obtained/reviewed prior to 
dosing. 
 Screening 
laboratory 
examinations 
performed 
within 7 days of cycle 1 day 
1 do not need to be repeated 
for 
this 
visit 
unless 
clinically indicated. 
Amylase and lipase testing 
X 
 
 
X 
 
X 
 
 
Coagulation Testing 
(X) 
(X) 
 
 
(X) 
 
 
As clinically indicated 
TSH 
X 
 
X (Treatment 
Arm B and C; 
X (after 
ipilimumab 
 
X 
 
 For Treatment Arm B and 
C, TSH (and free T4 if TSH 
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8.1.1. 
Footnotes for the Schedule of Events Table 5 and Table 6 
1. Pre-dose is defined as before the start of the first cemiplimab infusion (specific to PK 
drug concentration and ADA samples in Table 5).  Pre-dose samples may be collected 
≤72 hours prior to day 1 dosing. 
2. Pre-infusion is defined as before the start of subsequent cemiplimab infusions (specific to 
PK drug concentration and ADA samples in Table 5).  
8.1.2. 
Early Termination Visit 
Patients who withdraw from the study during the treatment period will be asked to return to the 
clinic to complete follow-up visit 1 study assessments (Table 6) as an early termination visit.  
Patients who withdraw from the study during the follow-up period will be asked to return to the 
clinic to complete visits of the follow-up period as indicated in Table 6. 
Patients who discontinue study treatment due to progressive disease should return to the clinic 14 
to 30 days after the last study treatment to complete the end of study assessments (follow-up 
visit 1).  
Patients who discontinue study treatment for a reason other than progressive disease should 
return to the clinic 14 to 30 days (±7 days) after the last cycle visit for follow-up visit 1 and then 
continue with follow-up visit 2 through follow-up visit 7.   
8.1.3. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for 
any other reason, as warranted.  In response to adverse events of special interest (AESIs), such as 
anaphylaxis or hypersensitivity, ADA samples may be collected closer to the event, based on the 
judgment of the investigator and/or Medical Monitor. 
8.2. 
Study Procedures 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
Informed consent must be obtained prior to any study-related procedures.  Assessments 
performed as part of standard-of-care that fall within the screening window (28 days prior to 
randomization) but before informed consent is obtained may be used for screening and need not 
be repeated for enrollment eligibility. 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population (see Table 4):   
 
Collection of tumor tissue sample for biomarker assessment by the central laboratory 
 A formalin-fixed, paraffin-embedded tissue block or unstained slide of a tumor 
tissue sample (archival tissue, if ≤5 months old, or recently obtained, on-study 
tumor biopsy collected during screening) must be provided.  Tumor biopsies 
should be of sufficient size to ensure an adequate amount of tissue for analysis 
(excisional, incisional, or core needle; fine-needle aspirates are not acceptable).  
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Complete instructions on the collection, processing, handling, and shipment of all 
samples are provided in the laboratory manual. 
 Tumor tissue samples will also be tested for EGFR and ALK mutations as well as 
for ROS1 fusions by a central laboratory unless this testing has already been 
performed and the results are available from other Regeneron NSCLC 
immunotherapy studies.  
 
Medical/oncology history 
 
Demographics 
 
Baseline radiographic tumor assessment of the chest, abdomen, pelvis, and all other 
known or suspected sites of disease by CT or MRI (or positron emission tomography 
[PET]).  The same imaging modality should be used throughout the study.  If PET is 
used at baseline, it should be used throughout the study. 
 
Baseline tumor burden assessment 
 
Baseline safety assessments (see Table 4) 
 
Tuberculosis Testing 
 
Serum pregnancy test in women of childbearing potential within 72 hours prior to 
administration of the first study treatment  
 
Sample for a genomics sub-study (optional) 
For the complete list of procedures performed at screening to determine eligibility, including 
those that are used throughout the study (ie, not only for determining eligibility), see Table 4. 
8.2.2. 
Efficacy Procedures 
8.2.2.1. 
Radiographic Tumor Assessments 
High-resolution CT with contrast and contrast-enhanced MRI are the preferred imaging 
modalities for assessing radiographic tumor response.  In patients in whom contrast is strictly 
contraindicated, non-contrast scans will suffice.  The chest, abdomen, and pelvis must be imaged 
along with any other known or suspected sites of disease.  If more than 1 imaging modality is 
used at screening, the most accurate imaging modality according to RECIST 1.1 should be used 
when recording data.  The same imaging modality used at screening should be used for all 
subsequent assessments. 
At screening, CT or MRI of the brain with contrast (unless contraindicated) should be performed 
in patients with a known history of treated brain metastasis, if not performed in the prior 60 days.  
Additional sites of known disease (including CNS) should be imaged at screening. 
After the baseline tumor assessment, radiographic tumor assessments will be obtained in all 
patients Q9W beginning at week 9 (day 63 ± 5 days) during year 1 and Q12W beginning at 
week 55 (first radiographic tumor assessment in year 2 performed at end of week 54) during 
year 2, until RECIST 1.1-defined progressive disease, withdrawal of consent, death, or initiation 
of another anti-cancer treatment.  Patients who discontinue for reasons other than progression 
who are not attending treatment visits may have radiographic tumor assessments between Q9W 
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and Q12W until RECIST 1.1-defined progressive disease, withdrawal of consent, death, or 
initiation of another anti-cancer treatment. 
Radiographic tumor assessments will occur at the following time points: 
End of week 9 ± 5 days (end of cycle 3) 
End of week 18 ± 5 days (end of cycle 6) 
End of week 27 ± 5 days (end of cycle 9) 
End of week 36 ± 5 days (end of cycle 12) 
End of week 45 ± 5 days (end of cycle 15) 
End of week 54 ± 5 days (end of cycle 18) 
End of week 66 ± 5 days (end of cycle 22) 
End of week 78 ± 5 days (end of cycle 26) 
End of week 90 ± 5 days (end of cycle 30) 
End of week 102 ± 5 days (end of cycle 34) 
In the follow-up period, radiographic assessments for patients who have not experienced 
progressive disease should be performed Q12W or until RECIST 1.1-defined progressive 
disease, withdrawal of consent, death, or initiation of another anti-cancer treatment.  
Tumor assessments should be performed even if dosing is interrupted.  Weeks are in reference to 
the calendar week and should not be adjusted due to dosing delays/interruptions.   
For patients identified as having RECIST 1.1-defined progressive disease while receiving or 
after completion of study treatment, subsequent imaging should be performed within 9 weeks of 
the initial tumor assessment of progression. 
8.2.2.2. 
Tumor Burden Assessments 
Tumor measurements will be performed in accordance with RECIST 1.1 criteria 
(Eisenhauer 2009; Appendix 2) and should be performed by the same investigator or radiologist 
for each assessment, to the extent feasible. 
Investigators and the blinded IRC (Section 5.3.1) will assess response to therapy using 
RECIST 1.1 criteria.  RECIST 1.1-defined progressive disease determined by the investigator 
will be used for clinical management of the patient.  RECIST 1.1-based tumor burden 
assessments by the blinded IRC will be used for evaluation of efficacy endpoints. 
8.2.2.3. 
Survival Data Collection 
Every effort will be made to collect survival data on all patients, including patients who 
withdraw from the study for any reason but have not withdrawn consent to collect survival 
information, as indicated in Table 6.  If the death of a patient is not reported, the date of the last 
patient contact in this study will be used in the determination of the patient’s last known date 
alive.  
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8.2.2.4. 
Quality of Life Questionnaires  
Patient-reported outcomes will be measured at the frequency indicated in Table 5 and Table 6 
using the following validated patient self-administered questionnaires:  EORTC QLQ-C30 and 
EORTC QLQ-LC13 (Berman 1994, Bjordal 2000).  Patients will be asked to complete these 
questionnaires prior to any study procedures being performed at a given study visit (during the 
treatment and follow-up periods). 
8.2.3. 
Safety Procedures 
8.2.3.1. 
Physical Examination 
A complete or limited physical examination will be performed at the visits specified in Table 4, 
Table 5, and Table 6.  Care should be taken to examine and assess any abnormalities that may be 
present, as indicated by the patient’s medical history. 
Complete physical examination performed prior to the first dose on cycle 1 day 1, or at other 
visits if indicated, will include examination of the skin, head, eyes, nose, throat, neck, joints, 
lungs, heart, pulse, abdomen (including liver and spleen), lymph nodes, and extremities, as well 
as a brief neurologic examination. 
Limited physical examination will include, at least, examination of the lungs, heart, abdomen, 
and skin. 
8.2.3.2. 
Eastern Cooperative Oncology Group Performance Status 
Eastern Cooperative Oncology Group performance status will be measured at a frequency 
indicated in Table 4, Table 5, and Table 6. 
8.2.3.3. 
Weight and Height 
Body weight measurements will be obtained at screening according to Table 4 and at follow-up 
according to Table 6.  Weight should be obtained with the patient wearing undergarments or very 
light clothing, with no shoes, and with an empty bladder.  The same scale should be used 
throughout the study.  The use of calibrated balance scales is recommended, if possible.  
Self-reported weights are not acceptable. 
Height should be measured at screening; self-reported heights are not acceptable. 
8.2.3.4. 
Vital Signs 
Vital signs, including temperature, seated blood pressure, heart rate, and respiratory rate, will be 
collected at time points according to Table 4, Table 5, and Table 6.  Vital signs should be 
performed before blood is drawn during visits requiring blood draws. 
Blood pressure should be measured in the same arm at all study visits (when feasible) and after 
the patient has been resting quietly in the seated position for at least 5 minutes. 
At cycle 1 day 1 and on all subsequent treatment days, vital signs will be collected prior to 
infusion of treatment.  Vital signs must also be obtained approximately 15 minutes (± 10 
minutes) after completion of the infusion. 
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8.2.3.5. 
12-Lead Electrocardiogram 
A standard 12-lead electrocardiogram (ECG) will be performed at screening and when clinically 
indicated during the active treatment period (Table 4 and Table 5).  Electrocardiograms should 
be performed before blood is drawn during visits requiring blood draws.   
The patient should be relaxed and in a recumbent position for at least 5 minutes before recording 
an ECG.  The ECG will be reviewed by the investigator or qualified designee at the site and will 
be available for comparison with subsequent ECGs.  The ECG tracing will be retained with the 
source.   
Any ECG finding that is judged by the investigator as a clinically significant change (worsening) 
compared to the baseline value will be considered an AE, recorded, and monitored. 
8.2.3.6. 
Laboratory Testing 
Hematology, chemistry, coagulation, thyroid function, and pregnancy testing samples will be 
analyzed by the site’s local laboratory. 
Samples for laboratory testing will be collected at time points according to Table 4, Table 5, and 
Table 6.  Tests will include the following: 
Hematology (Complete Blood Count with Differential) 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells 
 
Lymphocytes 
White blood cells 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
For hematology, blood samples may be collected ≤72 hours prior to dosing on the day 1 visit of 
each cycle.  Results must be obtained/reviewed prior to dosing.   
Serum Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Magnesium 
Chloride 
Blood urea nitrogena 
Phosphorus 
Bicarbonateb 
Aspartate aminotransferase  
Uric acid 
Calcium 
Alanine aminotransferase 
Adrenocorticotropic hormonec  
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase  
 
a The urea test is acceptable instead of blood urea nitrogen at centers where this is commonly used instead of the 
blood urea nitrogen. 
b The partial pressure of carbon dioxide (PCO2) test is an acceptable test at centers where this is commonly used 
instead of the bicarbonate test. 
c Adrenocorticotropic hormone (ACTH) will be included only for the 4 cycles when ipilimumab is administered and 
only in Treatment Arm C. 
For chemistry, blood samples may be collected ≤72 hours prior to dosing on the day 1 visit of 
each cycle.  Results must be obtained/reviewed prior to dosing.  For Treatment Arm C, ACTH 
should be tested during the 4 cycles in which ipilimumab is administered. 
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Other Laboratory Tests 
Coagulation Tests:  Prothrombin time/partial thromboplastin time will be analyzed by the 
investigative site’s local laboratory.  Testing will be performed at screening and then as clinically 
indicated. 
Thyroid Function Tests:   
Thyroid-stimulating hormone will be analyzed by the site’s local laboratory.  
For Treatment Arm B and C, TSH will be tested at screening, before the 4 ipilimumab doses 
every 6 weeks then Q9W, and as clinically indicated.  If TSH is outside of normal range, a free 
thyroxine (T4) should be measured at the investigative site’s local laboratory.  Thyroid function 
test (and free T4 if TSH is abnormal) must be tested ≤72 hours prior to dosing ipilimumab, and 
the results must be reviewed prior to dosing ipilimumab, and on cycles when ipilimumab is not 
dosed.   
For Treatment Arm A, TSH is tested at screening and as clinically indicated.  If TSH is outside 
normal range, a free T4 should be measured at the investigative site’s local laboratory. 
Tuberculosis Testing:  PPD/QuantiFERON testing according to local guidelines in 
tuberculosis-endemic areas. 
Amylase and Lipase Testing:  Testing will be performed at screening and every 9 weeks. 
Pregnancy Testing:  Women of childbearing potential must have a negative serum pregnancy 
test within 72 hours prior to study treatment administration on cycle 1 day 1 and a negative urine 
pregnancy test prior to study treatment administration on day 1 of each subsequent treatment 
cycle and Q6W, or more frequently per local standard. 
Abnormal Laboratory Values and Laboratory Adverse Events 
 All laboratory values must be reviewed by the investigator or authorized designee. 
 Significantly abnormal test results that occur after start of treatment must be repeated 
to confirm the nature and degree of the abnormality.  When necessary, appropriate 
ancillary investigations should be initiated.  If the abnormality fails to resolve or 
cannot be explained by events or conditions unrelated to the study medication or its 
administration, the Medical Monitor must be consulted.   
 The clinical significance of an abnormal test value, within the context of the disease 
under study, must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 9.4.5. 
8.2.3.7. 
Concomitant Medication Recording 
Concomitant medication will be collected at time points according to Table 4, Table 5, and 
Table 6. See Section 7.7 for details on recording concomitant medications. 
8.2.3.8. 
Adverse Event Recording 
Adverse events will be collected at time points according to Table 4, Table 5, and Table 6.  See 
Section 9.4 for details on recording and reporting AEs. 
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8.2.4. 
Pharmacokinetic and Anti-Drug Antibody Procedures 
In addition to the procedures detailed below, blood samples will also be taken to measure drug 
concentrations/ADA, as appropriate, in case of AESIs. 
8.2.4.1. 
Drug Concentration Measurements and Samples 
Cemiplimab concentrations in serum of patients randomized to Treatment Arms B and C will be 
measured using a validated enzyme-linked immunosorbent assay method at visits and time points 
indicated in Table 5, Table 6, and Appendix 4.  The actual time of each blood draw must be 
recorded.  Pre-dose is defined as before the start of the first cemiplimab infusion.  Pre-dose 
samples may be collected ≤72 hours prior to day 1 dosing.  Pre-infusion is defined as before the 
start of subsequent infusions. 
In addition, measurement of ipilimumab concentrations in serum may be considered in the future 
in the PK samples of patients randomized to Treatment Arm C. 
Any unused samples collected for drug concentration measurements may be used for exploratory 
biomarker research. 
8.2.4.2. 
Anti-Drug Antibody Measurements and Samples 
Anti-drug antibody samples for cemiplimab immunogenicity assessments will be collected from 
patients randomized to Treatment Arms B and C prior to dosing at time points listed in Table 5 
and during the follow-up period as shown in Table 6 (see Appendix 4).  Any unused samples 
collected for immunogenicity assessments may be used for exploratory research or to investigate 
unexpected AEs.  If necessary, these samples may also be used for ADA assessments of 
ipilimumab. 
8.2.5. 
Biomarker Procedures 
For biomarker assessments, a formalin-fixed, paraffin-embedded tissue block or unstained slides 
of a tumor tissue sample (archival tissue, if ≤5 months old, or recently obtained tumor biopsy 
collected during on-study) must be provided.  Tumor biopsies should be of sufficient size to 
ensure an adequate amount of tissue for analysis (excisional, incisional, or core needle; fine-
needle aspirates are not acceptable).  Complete instructions on the collection, processing, 
handling, and shipment of all samples will be provided in the laboratory manual. 
With the use of the collected tumor tissue sample, the following biomarker-based stratification 
strategies will be implemented in this study to determine study eligibility: 
 A PD-L1 IHC 22C3 pharmDx assay will be utilized as the clinical trial assay to 
assess PD-L1 expression levels in recently obtained tumor tissue samples (on-study 
biopsy collected at screening visit or archival tissue, if ≤5 months old) in order to 
qualify patients for enrollment.  The ≥50% PD-L1 positivity cut-off will be used as an 
inclusion criterion for this study.  
 The PD-L1 IHC 22C3 pharmDx assay is a validated, automated, in vitro diagnostic 
assay that was developed as a companion diagnostic for pembrolizumab 
(Roach 2016). During development, the PD-L1 IHC 22C3 pharmDx assay was 
analytically validated for repeatability and reproducibility at 3 independent Clinical 
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Laboratory Improvement Amendments (CLIA)-certified laboratories and clinically 
validated in KEYNOTE-001, a clinical study of pembrolizumab in patients with 
NSCLC. Based on these studies, the PD-L1 IHC 22C3 pharmDx assay was 
demonstrated to be a robust PD-L1 assay and was approved by the FDA as a 
companion diagnostic for pembrolizumab. Further details on the assay are provided in 
the package insert (Dako, PD-L1 IHC 22C3 pharmDx Package Insert).  
Tumor tissue biopsy samples will also be tested for EGFR mutations, ALK translocations, as 
well as for ROS1 fusions for determination of study eligibility by a central laboratory.  This 
testing does not need to be repeated if it has been done previously and the results are available 
from other Regeneron NSCLC immunotherapy studies.  The results must indicate that the patient 
is negative for EGFR mutations, ALK translocations, and ROS1 fusions for enrollment in this 
study. 
After completion of PD-L1 expression analysis, the remaining tumor tissue sample may be used 
to study the biomarkers associated with clinical response to cemiplimab, including but not 
limited to whole exome sequencing of tumor genome and tumor mutational load. 
Biomarker serum and plasma samples will be collected from all patients enrolled in this study at 
multiple time points as indicated in Table 5, Table 6, and Appendix 4 to study the potential 
pharmacodynamics or predictive biomarkers of response to cemiplimab including, but not 
limited to, cytokines and circulating tumor nucleic acids (refer to the laboratory manual).  
Samples will be collected prior to drug administration. 
If possible a tumor tissue biopsy sample should be obtained at the time of RECIST 1.1-defined 
progressive disease to obtain information on mechanism of resistance.  
8.2.6. 
Future Biomedical Research 
The biomarker samples unused for study-related research, as well as unused PK and ADA 
samples, will be stored for up to 15 years after the final date of the database lock.  The unused 
samples may be utilized for future biomedical research of lung carcinoma and other diseases.  No 
additional samples will be collected for future biomedical research.  After 15 years, any residual 
samples will be destroyed. 
8.2.6.1. 
Genomics Sub-study - Optional 
Patients who agree to participate in the genomics sub-study will be required to sign a separate 
genomics sub-study ICF before collection of the samples.  Patients are not required to participate 
in the genomics sub-study in order to enroll in the primary study.  Samples for deoxyribonucleic 
acid (DNA) extraction should be collected on day 1/baseline (pre-dose), but may be collected at 
any study visit (Table 4).   
Deoxyribonucleic acid samples for the genomics sub-study will be double-coded as defined by 
the International Council for Harmonisation (ICH) guideline E15.  Sub-study samples will be 
stored for up to 15 years after the final date of the database lock and may be used for research 
purposes.  The purpose of the genomic analyses is to identify genomic associations with clinical 
or biomarker response, other clinical outcome measures and possible AEs.  In addition, 
associations between genomic variants and prognosis or progression of other diseases may also 
be studied.  These data may be used or combined with data collected from other studies to 
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identify and validate genomic markers related to the study drug or other diseases.  Analyses may 
include sequence determination or single nucleotide polymorphism studies of candidate genes 
and surrounding genomic regions.  Other methods, including whole-exome sequencing, 
whole-genome sequencing, and DNA copy number variation may also be performed.  The list of 
methods may be expanded to include novel methodology that may be developed during the 
course of this study or sample storage period. 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
For the purposes of this section, study treatment refers to cemiplimab, platinum-based doublet 
chemotherapy agents, ipilimumab and pembrolizumab.  
9.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB)/Ethics Committee 
(EC) all unanticipated problems involving risks to patients according to local regulations. 
9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (suspected, unexpected, serious 
adverse reactions) to the health authorities, ECs/IRBs as appropriate, and to the investigators.  
Any AE not listed as an expected event in the Reference Safety Information section of the 
cemiplimab Investigator’s Brochure or in reference safety documents of the other study drugs 
will be considered as unexpected. 
In addition, the sponsor will report all other SAEs to the health authorities, according to local 
regulations. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the study in the clinical study report to health authorities and ECs/IRB, as 
appropriate. 
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug.  Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is 
temporally associated with the use of a study drug, whether or not considered related to the study 
drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
Progression of underlying malignancy will not be considered an AE if it is clearly consistent 
with the typical progression pattern of the underlying cancer (including time course, affected 
organs, etc).  Clinical symptoms of progression may be reported as AEs if the symptom cannot 
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be determined as exclusively due to the progression of the underlying malignancy, or does not fit 
the expected pattern of progression for the disease under study. 
If there is any uncertainty about an AE being due only to progression of the underlying 
malignancy, it should be reported as an AE or SAE as outlined in Section 9.3.2. 
9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (eg, a car accident in which a patient is a passenger). 
 Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
 Requires in-patient hospitalization or prolongation of existing hospitalization.  In-
patient hospitalization is defined as admission to a hospital or an emergency room for 
longer than 24 hours.  Prolongation of existing hospitalization is defined as a hospital 
stay that is longer than was originally anticipated for the event, or is prolonged due to 
the development of a new AE as determined by the investigator or treating physician. 
 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
 Is a congenital anomaly/birth defect. 
 Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse). 
Hospitalization or death due solely to manifestations consistent with typical progression of 
underlying malignancy will not be considered as an SAE. 
Serious AEs must be reported as directed in Section 9.4.2. 
9.3.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the 
sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
investigator to the sponsor can be appropriate.  Such an event might warrant further investigation 
in order to characterize and understand it.  Depending on the nature of the event, rapid 
communication by the study sponsor to other parties (eg, regulators) might also be warranted.  
All AESI, serious and non-serious, must be reported within 24 hours of identification using the 
same reporting process as for SAE reporting, per Section 9.4.2.  Adverse events of special 
interest for this study include the following:  
 Any AE that meets the DLT criteria (defined in Section 5.1.5) 
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 Grade 2 or greater infusion-related reactions 
 Grade 2 or greater allergic/hypersensitivity reactions 
 Grade 3 or greater irAEs 
 irAEs of any grade in patients previously treated with PI3-K inhibitor 
Note:  An irAE can occur shortly after the first dose or several months after the last dose of study 
treatment.  All AEs of unknown etiology associated with cemiplimab exposure should be 
evaluated to determine possible immune etiology.  If an irAE is suspected, efforts should be 
made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes prior to 
labeling an AE as an irAE.  Detailed guidance of management of irAEs is provided in 
Section 7.3.4 and Appendix 3.  The recommendations in Section 7.3.4 and Appendix 3 should be 
seen as guidelines, and the treating physician should exercise clinical judgment based on the 
symptoms and condition of the individual patient.  For any AE that is of a type known to be 
potentially immune-related (eg, rash, colitis, elevated transaminases, endocrine, or pneumonitis) 
but is deemed not to be an irAE by the investigator, the sponsor may request additional 
information.  
9.3.3.1. 
Immune-Related Adverse Events 
Detailed guidance of management of irAEs is provided in Section 7.3.4 and Appendix 3.   
Note regarding irAEs:  For any AE that is of a type known to be potentially immune-related (eg, 
rash, colitis, elevated transaminases, endocrine, or pneumonitis) but is deemed not to be an irAE 
by the investigator, the sponsor may request additional information. 
9.3.4. 
Infusion Reactions 
Infusion-related reactions are known to occur with protein therapeutic infusions and have been 
observed in cemiplimab studies.  Acute infusion reactions are defined as any AEs that occur 
during the infusion or within 1 day after the infusion is completed.  Signs and symptoms usually 
develop during, or shortly after drug infusion and generally resolve completely within 24 hours 
of completion of infusion. 
All infusion reactions must be reported as AEs (defined in Section 9.4.1) and graded using the 
grading scales as instructed in Section 9.5.1. 
9.4. 
Recording and Reporting Adverse Events 
9.4.1. 
Adverse Events 
The investigator (or designee) will seek information on AEs at each patient contact, and record 
all AEs that occur from the time the informed consent is signed until 105 days after the end of 
study treatment.  After informed consent has been obtained but prior to initiation of study 
treatment, only the following categories of AEs should be reported on the AE eCRF: 
 SAEs 
 Non-SAEs associated with a protocol-mandated intervention (eg, AEs related to an 
invasive procedure such as a biopsy) 
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Other AEs that occur prior to first treatment should be reported on the medical history eCRF. 
All AEs after initiation of study treatment and until 90 days after the last study treatment, 
regardless of relationship to study treatment, will be reported on the AE eCRF.  Additionally, 
any SAE or other AE of concern that the investigator believes may be related to study treatment 
and that occurs later than 90 days after last study treatment should be reported. 
Information on follow-up for AEs is provided in Section 9.4.6.  Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours of becoming aware of the event. 
Information not available at the time of the initial report must be documented in a follow-up 
report.  Substantiating data such as relevant hospital or medical records and diagnostic test 
reports may also be requested. 
In the event that the investigator is informed of an SAE that occurs more than 90 days after the 
last dose of study treatment, only those SAEs or other AEs of concern deemed by the 
investigator to be related to study treatment will be reported to the sponsor.  The investigator 
should make every effort to obtain follow-up information on the outcome of any treatment-
related SAE until the event is considered chronic and/or stable. 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of 
learning of the event: 
Symptomatic Overdose of Study Drug:  Accidental or intentional overdose of at least 2 times 
the intended dose of study drug within the intended therapeutic window, if associated with an 
AE. 
Pregnancy:  Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of identification, any 
pregnancy occurring in a female or female partner of a male study patient, during the study or 
within 180 days of the last dose of study drug.  Any complication of pregnancy affecting a 
female study patient or female partner of a male study patient, and/or fetus and/or newborn that 
meets the SAE criteria must be reported as an SAE.  Outcome for all pregnancies should be 
reported to the sponsor. 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
Medical Monitor within 30 days. 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
 the test result is associated with accompanying symptoms, and/or 
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 the test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
 the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the Medical Monitor in the event the investigator feels that an abnormal test finding 
should be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE.  Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale 
outlined in Section 9.5.1. 
9.4.6. 
Follow-up 
Information for any non-SAE that starts during the treatment period or within 90 days after last 
dose of study treatment will be collected from the time of the event until resolution of the event, 
or until the patient’s last study visit, whichever comes first. 
Serious AE information will be collected until the event is considered chronic and/or stable. 
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
The severity of AEs (including test findings classified as AEs) will be graded using the current 
version of the NCI-CTCAE grading system.  Adverse events not listed in the NCI-CTCAE will 
be graded according to the following scale: 
1 (Mild):  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.  
2 (Moderate):  Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADLs)*.  
3 (Severe):  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADLs**. 
4 (Life–threatening):  Life-threatening consequences; urgent intervention indicated. 
5 (Death):  Death related to AE 
*Instrumental ADLs refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADLs refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
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9.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the investigator and will be a clinical 
decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
The possible answers are: 
Not Related:   There is no reasonable possibility that the event may have been caused by 
the study drug. 
Related:   
There is a reasonable possibility that the event may have been caused by 
the study drug. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided in 
Appendix 1. 
The investigator should justify the causality assessment of each SAE. 
Relationship of Adverse Events to Study Conduct: 
The relationship of AEs to study conduct will be assessed by the investigator and will be a 
clinical decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by study conduct? 
The possible answers are: 
Not Related:   There is no reasonable possibility that the event may have been caused by 
study conduct. 
Related:   
There is a reasonable possibility that the event may have been caused by 
study conduct. 
A list of factors to consider when assessing the relationship of AEs to study conduct is provided 
in Appendix 1. 
The investigator should justify the causality assessment of each SAE. 
9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patients at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP).  Any questions or 
concerns should be discussed with the sponsor in a timely fashion.  The sponsor will monitor the 
safety data from across all study sites.  The Medical Monitor will have primary responsibility for 
the emerging safety profile of the compound, but will be supported by other departments (eg, 
Pharmacovigilance and Risk Management; Biostatistics and Data Management).  Safety 
monitoring will be performed on an ongoing basis (eg, individual review of SAEs) and on a 
periodic cumulative aggregate basis. 
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9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical study, as well 
as in any other clinical study using the same investigational drug, of any SAE that meets the 
relevant requirements for expedited reporting (an AE that is serious, unexpected based on the 
Investigator’s Brochure or this protocol, and has a reasonable suspected causal relationship to the 
medicinal/study drug). 
10. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (SAP) for the study.  The SAP 
may be revised during the study to accommodate amendments to the clinical study protocol and 
to make changes to adapt to unexpected issues in study execution and data that may affect the 
planned analyses.  The final SAP will be issued before the database is locked. 
Analysis variables are listed in Section 4. 
10.1. 
Statistical Hypothesis 
The primary statistical hypothesis is that cemiplimab/ipi or cemiplimab/chemo/ipi will prolong 
PFS as compared with standard-of -care pembrolizumab monotherapy in treatment-naïve patients 
with squamous and non-squamous NSCLC whose tumors express PD-L1 in ≥50% of tumor 
cells.  The secondary hypothesis is that cemiplimab/ipi or cemiplimab/chemo/ipi will improve 
OS in the study patients whose tumors express PD-L1 in ≥50% of tumor cells. 
10.2. 
Justification of Sample Size 
In KEYNOTE-024, the median PFS in the pembrolizumab group was 10.3 months (95% CI:  
6.7 months to not reached) versus 6.0 months (95% CI:  4.2 to 6.2 months) in the chemotherapy 
group (Reck 2016). 
This study assumes a median PFS of 10 months for patients treated with pembrolizumab 
monotherapy and a median PFS of 15 months for patients treated with each of the cemiplimab 
combination therapies.  The assumptions correspond to a 50% increase in median PFS and an 
HR of 0.6667.  Under these assumptions, and for each cemiplimab combination treatment arm 
versus the pembrolizumab comparison, 256 PFS events are needed to yield an approximately 
90% power to detect statistical significance at a 2-sided 0.05 level.  
Considering a uniform enrollment rate and a combined enrollment and PFS follow-up duration 
of approximately 36 months (24 months for enrollment and approximately 12 months follow-up 
for PFS) and a 10% dropout rate per year, enrollment of approximately 585 randomized patients 
(195 patients per arm) is needed to generate enough PFS events for each cemiplimab 
combination treatment arm versus the pembrolizumab comparison with 90% power.  Under the 
enrollment assumption and the alternative hypothesis, it is estimated that at the time when 
142 PFS events are observed in the pembrolizumab arm, each of the cemiplimab combination 
treatment arms plus the pembrolizumab arm will yield 256 PFS events in total.  In order to 
harmonize the timing of the primary analysis for the 2 comparisons, the primary endpoint of PFS 
will be performed after 142 PFS events are observed in the pembrolizumab treatment arm. 
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Assuming a median OS of 18 months for patients treated with pembrolizumab monotherapy and 
a median OS of 24 months for patients treated with each of the cemiplimab combination 
therapies, a corresponding HR of 0.75 if OS is distributed exponentially in each treatment arm.  
If the final analysis of OS is performed 12 months after the analysis of PFS, enrollment of 
585 patients will yield approximately a power of 59% for the analysis of OS at a 2-sided alpha 
level of 0.05. 
For PFS, it is projected that an observed HR of 0 78 or lower, corresponding to an increase in 
median PFS of 2.8 months or more (10 versus 12.8 months), would result in a statistically 
significant improvement in PFS.  For OS, it is also projected that an observed HR of 0.77 or 
lower, corresponding to an increase in median OS of 5.4 months or more (18 versus 
23.4 months), would result in a statistically significant improvement in OS. 
10.3. 
Analysis Sets 
10.3.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) includes all randomized patients.  This is the intention-to-treat 
population.  The FAS is based on the treatment allocated (as randomized).  All efficacy 
endpoints will be analyzed using the FAS. 
10.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated).  Treatment compliance/administration and all 
clinical safety variables will be analyzed using the SAF. 
10.3.3. 
Other Analysis Sets 
The PK population includes all randomized patients (safety population) who received 
cemiplimab and who had at least 1 non-missing cemiplimab concentration assay result following 
the first dose of cemiplimab up to the end of the study. 
The ADA analysis set includes all treated patients who received any study drug and had at least 
1 non-missing post-baseline ADA assay result following the first dose of study drug. 
The DLT analysis set includes the first 10 patients treated with cemiplimab/ipi and the first 
10 patients treated with cemiplimab/chemo/ipi who are DLT evaluable, defined as the patients 
who completed the DLT observation period and those patients who discontinued early due to the 
development of a DLT.  This population will be used for the assessment of DLTs.  The patients 
will be analyzed as treated. 
10.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information:  the 
number of patients reflected in the calculation (n), mean, median, standard deviation, minimum, 
and maximum.   
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
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The descriptive summary of time-to-event data will include median time to event and its 95% CI 
using the Kaplan-Meier method. 
10.4.1. 
Patient Disposition 
The following will be provided: 
 The total number of screened patients:  met the inclusion criteria regarding the target 
indication and signed the ICF 
 The total number of patients in the FAS 
 The total number of patients in the SAF 
 The total number of patients who discontinued treatment and the reasons for 
treatment discontinuation 
 The total number of patients who discontinued the study and the reasons for 
discontinuation 
 A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
 A listing of patients prematurely discontinued from treatment and study, along with 
reasons for discontinuation 
10.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined.   
10.4.3. 
Medical History 
Medical history will be summarized by primary system organ class (SOC) and preferred 
term (PT) for each treatment group, with the table sorted by decreasing frequency of SOC, 
followed by PT based on the overall incidence between treatment arms. 
10.4.4. 
Prior Medications/Concomitant Medications 
The number and proportion of patients taking prior/concomitant medication will be summarized 
by decreasing frequency of anatomical therapeutic chemical (ATC) level 2 and ATC level 4 
according to the current version of the World Health Organization Drug Dictionary, based on the 
overall incidence between treatment arms. 
Listings of pre-treatment medication and concomitant medications include generic name, ATC 
levels 2 and 4, indication, study day onset, the study end date (defined similarly as for study 
onset day), ongoing status, dose, frequency, and route.  
For medications started before treatment, the study day onset is defined as date of medication 
start - date of the first dose; for medications started on or after treatment, the study day onset is 
defined as the date of medication start - date of the first dose + 1.  
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10.4.5. 
Efficacy Analyses 
The primary and key secondary endpoints will be tested in the following order: PFS, OS, and 
ORR. 
10.4.5.1. Primary Efficacy Analyses 
The final analysis of PFS will be performed after observing 142 PFS events in the 
pembrolizumab treatment arm. 
The primary endpoint of PFS will be analyzed by stratified log-rank test using status of histology 
(non-squamous versus squamous) as the stratification factor.  The HR and its 95% CI will be 
estimated by a stratified Cox regression model using the treatment as covariate. 
Two sensitivity analyses will be performed using different censoring rules and progressive 
disease event definitions.  The first sensitivity analysis is the same as the primary analysis except 
that it considers initiation of new anti-cancer treatment as a progressive disease event for patients 
without documented progressive disease or death prior to initiation of new anti-tumor treatment.  
The second sensitivity analysis will be performed based on investigator-determined progressive 
disease events. 
10.4.5.2. Secondary Efficacy Analyses 
If the final analysis of PFS is statistically significant for both cemiplimab combination therapy 
versus pembrolizumab treatment, the analysis of the secondary endpoint of OS for cemiplimab 
combinations-versus-pembrolizumab comparison will be performed at the time of PFS analysis 
and 12 months after analysis of PFS using the same method as used in the analysis of PFS.  The 
family-wise type-I error will be controlled at the 2-sided 5% level and detailed in the SAP.   
The ORR for each cemiplimab combination-versus-pembrolizumab comparison will be analyzed 
using the Cochran-Mantel-Haenszel test stratified by histological status (non-squamous versus 
squamous).  An associated odds ratio and 95% CI will be calculated.  Objective response rate 
and the corresponding 95% exact CI will be calculated by the Clopper-Pearson method 
(Clopper 1934) for each treatment arm.  
Overall survival at 12 and 18 months for each treatment arm will be summarized. 
The change in EORTC QLQ-C30 and EORTC QLQ-LC13 scores from the first assessment to 
the end of the study will be summarized descriptively at each post-baseline time point and 
compared using a mixed effects model, if appropriate. 
10.4.5.3. Subgroup Analyses  
To determine the consistency of treatment effect across various demographic and baseline 
subgroups, the estimate of the between-group treatment effect (with a nominal 95% CI) for the 
primary and secondary endpoints will be estimated and plotted within each category of the 
following subgroup variables: 
 Age category (≤65 versus >65 years) 
 Gender (female, male) 
 Race (white, non-white) 
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 ECOG performance status (0, 1) 
 Histology (squamous, non-squamous) 
 Geographic region of enrolling site 
 Ethnicity 
10.4.6. 
Safety Analyses 
Safety observations and measurements, including drug exposure, AEs, laboratory data, vital 
signs, and ECOG performance status, will be summarized and presented in tables and listings. 
Dose-limiting toxicities observed during the DLT evaluation period will be summarized by 
treatment arm and will be assessed using the DLT analysis set. 
10.4.6.1. Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
 The pre-treatment period is defined as the time from signing the ICF to before the 
first dose of study drug. 
 The treatment period is defined as the day from the first dose of study drug to the day 
of the last dose of study drug plus 90 days. 
 The post-treatment period is defined as the time after follow-up visit 1. 
Treatment-emergent AEs are defined as those that are not present at baseline or represent the 
exacerbation of a pre-existing condition during the on-treatment period. 
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA).  Coding will be to the lowest-level terms.  The 
verbatim text, the PT, and the primary SOC will be listed. 
Summaries of all TEAEs by treatment group will include the following: 
 The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
 TEAEs by severity (graded according to the current version of the NCI-CTCAE or 
Section 9.5.1, if not listed in NCI-CTCAE), presented by SOC and PT 
 TEAEs by outcome 
 TEAEs by relationship to study drug (related, not related), presented by SOC and PT 
 AESI 
Deaths and other SAEs will be listed and summarized by treatment group.  
Events of NCI-CTCAE grade 3 and grade 4 severity will be summarized by treatment group.  
Treatment-emergent AEs leading to permanent treatment discontinuation will be listed and 
summarized by treatment group. 
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10.4.6.2. Other Safety Analyses 
Vital Signs 
Vital signs (temperature, heart rate, seated blood pressure, and respiration rate) will be 
summarized by baseline and change from baseline to each scheduled assessment time with 
descriptive statistics. 
Laboratory Tests 
Laboratory test results will be listed, and the number and percentage of patients with 
NCI-CTCAE grade 3 or grade 4 laboratory values will be summarized by laboratory test.  Shift 
tables may be generated, if applicable. 
10.4.6.3. Treatment Exposure 
Treatment duration, dose intensity, and number of cycles administered will be summarized by 
treatment group.   
10.4.6.4. Treatment Compliance 
Treatment compliance, including dose, number of doses, timing, and applicable study 
concomitant procedures, will be summarized by treatment arm.  The analysis methods will be 
detailed in the SAP. 
10.4.7. 
Analysis of Drug Concentration Data 
Cemiplimab concentrations in serum will be reported over time as individual values with 
descriptive statistics.  The PK data in this study may be included in a population PK analysis that 
will be presented in a separate report. 
Blood samples for analysis of ipilimumab concentrations will be stored for possible future 
analysis, the results of which may be reported in the same way as for cemiplimab concentrations. 
10.4.8. 
Analysis of Anti-Drug Antibody Data 
The ADA variables described in Section 4.4 will be summarized using descriptive statistics in 
the ADA analysis set of the cemiplimab treatment arms (Treatment Arms B and C).  Frequency 
tables of the proportion of patients with treatment-emergent, treatment-boosted, persistent ADA 
response, and NAb status in the NAb assay will be presented as absolute occurrence (n) and 
percent of patients (%), presented by treatment arms. 
Plots of cemiplimab concentrations will be examined, and the influence of ADAs on individual 
concentration-time profiles may be evaluated.  Assessment of the impact of ADA on safety and 
efficacy may be provided. 
10.4.9. 
Analysis of Biomarker Data 
Biomarker analyses in this study will be exploratory in nature, and results will be summarized in 
a separate report.  A detailed description of statistical methods that will be used for biomarker 
data analyses will be provided in a separate Biomarker Analytical Plan. 
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10.5. 
Multiplicity Considerations 
For 2 cemiplimab combinations versus pembrolizumab comparisons, and for the tests of primary 
endpoint of PFS, secondary endpoint of OS and ORR, a familywise type-I error rate of 0.05 is 
controlled by the hierarchical gatekeeping approach with the order of tests listed below: 
1. PFS for cemiplimab/chemo/ipi vs. pembrolizumab 
2. PFS for cemiplimab/ipi vs. pembrolizumab 
3. OS for cemiplimab/chemo/ipi vs. pembrolizumab 
4. OS for cemiplimab/ipi vs. pembrolizumab 
5. ORR for cemiplimab/chemo/ipi vs. pembrolizumab 
6. ORR for cemiplimab/ipi vs. pembrolizumab 
The alpha spending for analysis of OS at the time of PFS analysis and the final analysis will be 
controlled at the 2-sided 5% level and detailed in the SAP.  All other statistical comparisons will 
be exploratory in nature and, therefore, not controlled for multiplicity and should be interpreted 
accordingly. 
10.6. 
Interim Analysis 
An interim analysis for secondary endpoint of OS will be performed at the time of primary 
analysis for PFS.  There will be an early safety review conducted by the IDMC as detailed in 
Section 5.1.4. 
10.7. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
Definition of baseline:  
 Unless otherwise specified, the last assessment before the initial administration of 
cemiplimab will be considered the baseline evaluation. 
General rules for handling missing data: 
 Unless otherwise specified, there will be no imputations for missing data. 
 The pattern of missing data and potential prognostic factors for missing data (QOL, 
clinical neurologic assessment, and mental status) will be examined to guide the use 
of proper statistical models. 
 If the start date of an AE or concomitant medication is incomplete or missing, it will 
be assumed to have occurred on or after the intake of study drug, except if an 
incomplete date (eg, month and year) clearly indicates that the event started prior to 
treatment.  If the partial date indicates the same month or year of the intake of study 
drug date, then the start date by the study drug intake date will be imputed; otherwise, 
the missing day or month by the first day or the first month will be imputed.  
Visit windows: 
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 Assessments taken outside of protocol allowable windows will be displayed 
according to the eCRF assessment recorded by the investigator. 
Unscheduled assessments: 
 Extra assessments (laboratory data or vital signs associated with non-protocol-defined 
clinical visits or obtained in the course of investigating or managing AEs) will be 
included in listings, but not by visit summaries.  If more than 1 laboratory value is 
available for a given visit, the first observation will be used in summaries, and all 
observations will be presented in listings. 
10.8. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
The study is expected to end after the last visit of the last patient.   
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 16.1. 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study 
(including data validation, cleaning, correcting, releasing) will be maintained and stored at 
Regeneron. 
A medical coding plan will specify the processes and the dictionary used for coding.  All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history) will be done 
using internationally recognized and accepted dictionaries. 
The eCRF data for this study will be collected using an electronic data capture (EDC) tool.  User 
training must be documented before the user is granted access to the EDC system. 
11.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
 IVRS/IWRS system – randomization, study drug supply 
 EDC system – data capture 
 Statistical Analysis System – statistical review and analysis 
 Pharmacovigilance safety database 
 ARGUS safety database 
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12. 
STUDY MONITORING 
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization monitor) will visit each 
site prior to enrollment of the first patient and periodically during the study.   
12.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
The investigator must keep all source documents on file with the eCRF.  Case report forms and 
source documents must be available at all times for inspection by authorized representatives of 
the sponsor and regulatory authorities. 
12.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on eCRFs within the EDC 
system by trained site personnel.  All required eCRFs must be completed for each and every 
patient enrolled in the study.  After review of the clinical data for each patient, the investigator 
must provide an electronic signature.  A copy of each patient eCRF casebook is to be retained by 
the investigator as part of the study record and must be available at all times for inspection by 
authorized representatives of the sponsor and regulatory authorities. 
Corrections to the eCRF will be entered in the eCRF by the investigator or an authorized 
designee.  All changes, including details regarding the date and person performing corrections, 
will be available via the audit trail, which is part of the EDC system.  For corrections made via 
data queries, a reason for any alteration must be provided. 
13. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
 Informing the sponsor of a planned inspection by the authorities as soon as 
notification is received and authorizing the sponsor’s participation in the inspection 
 Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
 Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
 Taking all appropriate measures requested by the sponsor to resolve the problems 
found during the audit or inspection 
Documents subject to audit or inspection include, but are not limited to, all source documents, 
eCRFs, medical records, correspondence, ICFs, IRB/EC files, documentation of certification and 
quality control of supporting laboratories, and records relevant to the study maintained in any 
supporting pharmacy facilities.  Conditions of study material storage are also subject to 
inspection.  In addition, representatives of the sponsor may observe the conduct of any aspect of 
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the clinical study or its supporting activities both within and outside of the investigator's 
institution. 
In all instances, the confidentiality of the data must be respected. 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS  
14.1. 
Good Clinical Practice Statement  
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with the ICH guidelines for GCP and applicable 
regulatory requirements. 
14.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC.  A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient 
in language that he/she can understand.  The ICF should be signed and dated by the patient and 
by the investigator or authorized designee who reviewed the ICF with the patient.   
 Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
 Patients who can understand but who can neither write nor read will have the ICF 
read to them in the presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, the ICF 
must be reviewed and updated appropriately.  All study patients must be informed of the new 
information and provide their written consent if they wish to continue in the study.  The original 
signed revised ICF must be maintained in the patient’s study record, and a copy must be given to 
the patient. 
A written informed consent should be obtained for treatment beyond radiologic disease 
progression, acknowledging that this practice is not considered standard in the treatment of 
cancer. 
14.3. 
Patients’ Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained.  Patients should be identified by patient identification number only on 
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eCRFs or other documents submitted to the sponsor.  Documents that will not be submitted to 
the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient’s and investigator’s personal data, which may be included in the sponsor database, 
will be treated in compliance with all applicable laws and regulations.  The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third 
party. 
14.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
 The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
 Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in 
which case the IRB/EC should be informed as soon as possible  
 Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their 
functions must be received by the sponsor prior to shipment of drug supplies to the investigator.  
The approval letter should include the study number and title, the documents reviewed, and the 
date of the review. 
Records of the IRB/EC review and approval of all study documents (including approval of 
ongoing studies) must be kept on file by the investigator. 
15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an 
IRB/EC-approved amendment.  Regulatory approvals will also be sought as required by 
regulatory guidance. 
16. 
PREMATURE 
TERMINATION 
OF 
THE 
STUDY 
OR 
CLOSE-OUT OF A SITE 
16.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
16.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
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Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at 
least 30 days’ notice.  The final decision should be made through mutual agreement with the 
sponsor.  Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others:  
 The investigator has received all items and information necessary to perform the 
study, but has not enrolled any patient within a reasonable period of time. 
 The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines.  
 The total number of patients required for the study are enrolled earlier than expected. 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection 
of the patients’ interests. 
17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator.  This signed declaration accompanies each set of patient final 
eCRFs that will be provided to the sponsor. 
17.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities.  The investigator must consult with the sponsor before discarding or 
destroying any essential study documents following study completion or discontinuation.  
Records must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor and the relevant records will be transferred to a mutually 
agreed-upon destination. 
18. 
DATA QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the 
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protocol, GCP, and any applicable regulatory requirement(s).  The planned quality assurance and 
quality control procedures for the study are summarized. 
Data Management 
The sponsor is responsible for the data management of this study including quality checking of 
the data (Section 11.1). 
Study Monitoring 
The investigator must allow study-related monitoring, IRB/EC review, audits, and inspections 
from relevant health regulatory authorities, and provide direct access to source data documents 
(Section 12.1, Section 12.2, and Section 13) 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of subjects/patients are being protected, and that the study is being 
conducted in accordance with the current approved protocol version and any other study 
agreements, ICH GCP, and all applicable regulatory requirements (Section 12.1). 
All subject/patient data collected during the study will be recorded on paper or electronic CRF 
unless the data are transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for affirming that data entries in the CRF are accurate and correct by 
electronically signing a declaration that accompanies each set of patient/subject final CRF 
(Section 12.3 and Section 17.1). 
Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF (Section 12.2). 
The investigator will retain all records and documents, including signed ICFs, pertaining to the 
conduct of this study for at least 15 years after study completion, unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during the 
retention period without the written approval of the sponsor.  No records may be transferred to 
another location or party without written notification to the sponsor Section 17.2 ). 
19. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
20. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
21. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 
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23. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol:  A Randomized, Phase 3, Open-Label Study of Combinations 
of REGN2810 (Cemiplimab, Anti-PD-1 Antibody), Platinum-based Doublet Chemotherapy, and 
Ipilimumab (Anti-CTLA-4 Antibody) Versus Pembrolizumab Monotherapy in First-Line 
Treatment of Patients with Advanced or Metastatic Non-Small Cell Lung Cancer with Tumors 
Expressing PD-L1 ≥50% and agree to abide by all the provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, 
state, or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a 
partnership in which the sponsor is involved.  I will immediately disclose it in writing to the 
sponsor if any person who is involved in the study is debarred, or if any proceeding for 
debarment is pending, or, to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC.  I agree to ensure that 
this information will not be used for any purpose other than the evaluation or conduct of the 
clinical investigation without the prior written consent of the sponsor. 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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APPENDIX 1. FACTORS 
TO 
CONSIDER 
IN 
ASSESSING 
THE 
RELATIONSHIP OF ADVERSE EVENTS TO STUDY 
DRUG AND STUDY CONDUCT 
Is there a reasonable possibility that the event may have been caused by the study drug or study 
conduct? 
No: 
 Due to external causes such as environmental factors or other treatment(s) being 
administered 
 Due to the patient’s disease state or clinical condition 
 Do not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug  
 Do not reappear or worsen when dosing with study drug is resumed 
 Are not a suspected response to the study drug based upon pre-clinical data or prior 
clinical data 
Yes: 
 Could not be explained by environmental factors or other treatment(s) being 
administered 
 Could not be explained by the patient’s disease state or clinical condition 
 Follow a reasonable temporal sequence following the time of administration of the 
dose of study drug  
 Resolve or improve after discontinuation of study drug  
 Reappear or worsen when dosing with study drug is resumed 
 Are known or suspected to be a response to the study drug based upon pre-clinical 
data or prior clinical data   
NOTE:  This list is not exhaustive. 
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APPENDIX 2. RESPONSE 
EVALUATION 
CRITERIA 
IN 
SOLID 
TUMORS:  RECIST GUIDELINE (VERSION 1.1) 
This appendix has been excerpted from the revised Response Evaluation Criteria in Solid 
Tumors (RECIST) guideline (version 1.1; Eisenhauer 2009).  For full details pertaining to the 
RECIST 1.1 criteria, please refer to the publication. 
1. Assessment of Tumor Burden Measurable Disease at Baseline 
Overall tumor burden must be assessed at baseline and will be used as a comparator for 
subsequent measurements.  Tumor lesions will be characterized as measurable or non-
measurable as follows: 
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised RECIST guideline (version 1.1; Eisenhauer 2009).  Changes in the largest 
diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the 
case of malignant lymph nodes are used in the RECIST criteria. 
1.1. Measurable disease  
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of  
 10 mm by computed tomography (CT) scan (CT scan slice thickness no greater than 
5 mm)  
 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
 20 mm by chest X-ray 
 Malignant lymph nodes:  To be considered pathologically enlarged and measurable, 
a lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan 
(CT scan slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
1.2. Non-measurable disease   
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥10 to <15 mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT, magnetic resonance 
imaging [MRI], or positron emission tomography [PET]) are considered as non-measurable. 
1.2.1. Special Considerations 
Bone lesions: 
 Bone scan, PET scan, or plain films are not considered adequate imaging techniques 
to measure bone lesions.  However, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
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or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
 Blastic bone lesions are non-measurable. 
Cystic lesions: 
Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.  “Cystic lesions” thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
locoregional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
1.3. Methods of Assessment 
All measurements must be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 Clinical lesions.  Clinical lesions will only be considered measurable when they are 
superficial and ≥10 mm in diameter as assessed using calipers (eg, skin nodules). 
 Chest X-ray.  Chest CT is preferred over chest X-ray, particularly when progression 
is an important endpoint, since CT is more sensitive than X-ray, particularly in 
identifying new lesions.  Lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung.  
 CT and MRI.  CT is the best currently available and reproducible method to measure 
lesions selected for response assessment.  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5mm or less.  
When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  Magnetic resonance imaging is 
also acceptable in certain situations (eg, for body scans). 
 PET-CT.  At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT performed as 
part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and 
oral contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in accurately 
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measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data that may bias an investigator if it is not routinely or serially 
performed. 
 Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.   
 Endoscopy, laparoscopy.  The utilization of these techniques for objective tumor 
evaluation is not advised.   
 Tumor markers.  Tumor markers alone cannot be used to assess response. 
 Cytology, histology.  These techniques can be used to differentiate between partial 
responses and complete responses in rare cases (eg, residual lesions in tumor types, 
such as germ cell tumors, where known residual benign tumors can remain). 
1.4. Baseline Documentation of Target and Non-Target Lesions 
Target lesions: When more than one measurable lesion is present at baseline all lesions up to a 
maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of all 
involved organs should be identified as target lesions and will be recorded and measured at 
baseline. Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, and should lend themselves to reproducible 
repeated measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline sum.  All 
other pathological nodes (those with short axis ≥10 mm but <15 mm) should be considered 
non-target lesions.  Nodes that have a short axis <10 mm are considered non-pathological and 
should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  The baseline sum 
diameters will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
Non-target lesions: All other lesions (or sites of disease) including pathological lymph nodes 
should be identified as non-target lesions and should also be recorded at baseline. Measurements 
of these lesions are not required, but the presence, absence, or, in rare cases, unequivocal 
progression of each should be noted throughout follow-up. In addition, it is possible to record 
multiple non-target lesions involving the same organ as a single item on the case record form 
(eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
1.5. Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target and non-target lesions. 
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1.5.1. Evaluation of Target Lesions 
 Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
<10 mm (<1 cm). 
 Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also considered progression). 
 Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease, taking as reference the smallest sum 
diameters while on study. 
Special notes on the assessment of target lesions: 
 Lymph nodes:  Lymph nodes identified as target lesions should always have the 
actual short axis measurement recorded and should be measured in the same 
anatomical plane as the baseline examination, even if the nodes regress to below 
10 mm on study.  This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if CR criteria are met, since a normal 
lymph node is defined as having a short axis of <10 mm. 
 Target lesions that become ‘too small to measure’:  All lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm).  If the radiologist is able to 
provide an actual measure, that should be recorded, even if it is below 5 mm.  
However, when such a lesion becomes difficult to assign an exact measure to then:  
(i) if it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.  (ii) if the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned (note:  in case of a lymph node believed to be present and faintly seen but 
too small to measure, a default value of 5 mm should be assigned in this circumstance 
as well).  This default value is derived from the 5 mm CT slice thickness (but should 
not be changed with varying CT slice thickness). 
 Lesions that split or coalesce on treatment:  When non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have coalesced such that they are no longer separable, 
the vector of the longest diameter in this instance should be the maximal longest 
diameter for the ‘coalesced lesion’. 
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1.5.2. Evaluation of Non-target Lesions 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
 Complete Response: Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 Progressive Disease: Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be representative of overall disease status 
change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or investigator). 
1.6. New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal:  ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (eg, some ‘new’ bone 
lesions may be simply healing or flare of pre-existing lesions).  This is particularly important 
when the patient’s baseline lesions show PR or CR.  For example, necrosis of a liver lesion may 
be reported on a CT scan report as a ‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  An example of this is 
the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases.  The patient’s brain metastases are considered to be evidence 
of progressive disease even if he/she did not have brain imaging at baseline.  If a new lesion is 
equivocal, for example because of its small size, continued therapy and follow-up evaluation will 
clarify if it truly represents new disease.  If repeat scans confirm there is definitely a new lesion, 
then progression should be declared using the date of the initial scan.  
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease).  New lesions on the basis of FDG-PET 
imaging can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
progressive disease based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
progressive disease.  If the positive FDG-PET at follow-up is not confirmed as a new 
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site of disease on CT, additional follow-up CT scans are needed to determine if there 
is truly progression occurring at that site (if so, the date of progressive disease will be 
the date of the initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-
up corresponds to a preexisting site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not progressive disease. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to 
false-positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note:  A “positive” FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
1.7. Evaluation of Best Overall Response  
The Best Overall Response is the best response recorded from the start of the treatment until the 
end of treatment taking into account any requirement for confirmation.   The patient's best 
response assignment will depend on the findings of both target and non-target disease and will 
also take into consideration the appearance of new lesions.  
Revised RECIST Version 1.1 (Eisenhauer 2009) is summarized in the table below. 
Response According to Revised Response Evaluation Criteria in Solid Tumors 
(Version 1.1) in Patients with Target (and Non-Target) Lesions 
Target 
Lesions 
Non-target Lesions 
New 
Lesions 
Overall 
Response* 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/non-PD/not evaluated 
No 
PR 
SD 
Non-CR/non-PD/not evaluated 
No 
SD 
PD 
Any 
Yes or no 
PD 
Any 
PD* 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
Abbreviations:  CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease 
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as PD. 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.”  Every effort should 
be made to document the objective progression even after discontinuation of treatment.  
1.8. Missing Assessments and Unevaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point.  If only a subset of lesion measurements are made at an assessment, 
usually the case is also considered not evaluated at that time point, unless a convincing argument 
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can be made that the contribution of the individual missing lesion(s) would not change the 
assigned time point response.  This would be most likely to happen in the case of progressive 
disease.  For example, if a patient had a baseline sum of 50 mm with 3 measured lesions and at 
follow-up only 2 lesions were assessed, but those gave a sum of 80 mm, the patient will have 
achieved progressive disease status, regardless of the contribution of the missing lesion. 
1.9. Best Overall Response:  All Time Points 
The BOR is determined once all the data for the patient is known.  Best response determination 
in trials where confirmation of CR or PR IS NOT required:  Best response in these trials is 
defined as the best response across all time points (eg, a patient who has SD at first assessment, 
PR at second assessment, and progressive disease on last assessment has a BOR of PR).  When 
SD is believed to be best response, it must also meet the protocol-specified minimum time from 
baseline.  If the minimum time is not met when SD is otherwise the best time point response, the 
patient’s best response depends on the subsequent assessments.  For example, a patient who has 
SD at first assessment, progressive disease at second and does not meet minimum duration for 
SD, will have a best response of progressive disease.  The same patient lost to follow-up after the 
first SD assessment would be considered unevaluable. 
2.0. Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study).  The duration of overall CR is measured from the time measurement criteria 
are first met for CR until the first date that recurrent disease is objectively documented. 
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APPENDIX 3. RECOMMENDED 
DOSE 
MODIFICATION 
OR 
DISCONTINUATION 
AND 
SUPPORTIVE CARE GUIDELINES FOR SPECIFIC CEMIPLIMAB DRUG-RELATED 
ADVERSE EVENTS 
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APPENDIX 4. CEMIPLIMAB PHARMACOKINETIC, 
IMMUNOGENICITY, AND BIOMARKER SAMPLING 
SCHEDULE 
Study Visit 
PK Sampling Time
a 
Anti-Drug 
Antibody Sampling 
Timea 
Serum and Plasma 
Biomarker Samples 
Sampling Timea 
Screening 
 
 
 
Collect on-study or 
archival (≤5 months old) 
tumor tissue sample 
Cycle 1, day 1 
 
Pre-dose 
 
End of infusionc  
 
Pre-dose 
 
Pre-dose 
 
Collect blood sample for 
DNA 
Cycle 2, day 1 
 
Pre-infusion 
 
End of infusion  
 
 
Pre-infusion 
Cycle 3, day 1 
 
Pre-infusion 
 
End of infusion  
 
 
Cycle 4, day 1 
 
Pre-infusion 
 
End of infusion  
 
 
Pre-infusion 
Cycle 9, day 1  
 
Pre-infusion 
 
Pre-infusion 
 
Cycle 18, day 1 
 
Pre-infusion 
 
End of Infusion 
 
Pre-infusion 
 
Cycle 26, day 1 
 
Pre-infusion 
 
 
Cycle 30, day 1 
 
Pre-infusion 
 
End of infusion  
 
 
Cycle 34, day 1 
 
Pre-infusion 
 
 
End of treatment 
 
Pre-infusion 
 
End of infusion  
 
Pre-infusion 
 
Follow-up visit 1 
 
Collect at visit 
 
 
Collect at visit 
Follow-up visit 2 
 
Collect at visit 
 
 
Follow-up visit 3 
 
Collect at visit 
 
Collect at visit 
 
At 
the 
time 
of 
RECIST 1.1-defined 
progressive disease 
 
 
 
Collect at visit
b  
Abbreviations:  DNA=deoxyribonucleic acid; PK=pharmacokinetic; RECIST 1.1=Response Evaluation Criteria in 
Solid Tumors version 1.1 
a Pre-dose is defined as before the start of the first cemiplimab infusion.  Pre-dose samples may be collected 
≤72 hours prior to day 1 dosing.  Pre-infusion is defined as before the start of subsequent cemiplimab infusions. 
b  If possible, a tumor biopsy should also be collected at this time point (optional) 
c End of infusion is defined as ±10 minutes after the end of infusion 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Scientific/Medical Monitor, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the conduct of the study and the 
data generated. 
Study Title: 
A Randomized, Phase 3, Open-Label Study of Combinations of REGN2810 
(Cemiplimab, Anti-PD-1 Antibody), Platinum-based Doublet Chemotherapy, and Ipilimumab 
(Anti-CTLA-4 Antibody) Versus Pembrolizumab Monotherapy in First-Line Treatment of 
Patients With Advanced or Metastatic Non-Small Cell Lung Cancer With Tumors Expressing 
PD-L1 ≥50%. 
 
Protocol Number: 
R2810-ONC-16111 
Protocol Version: 
R2810-ONC-16111 Amendment 3 Global 
 
 
See appended electronic signature page 
Sponsor’s Responsible Scientific/Medical Monitor 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Representative 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 12 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
Clinical Study Protocol Title: A Randomized, Phase 3, Open-Label Study of Combinations of 
REGN2810 (Cemiplimab, Anti-PD-1 Antibody), Platinum-based 
Doublet 
Chemotherapy, 
and 
Ipilimumab 
(Anti-CTLA-4 
Antibody) Versus Pembrolizumab Monotherapy in First-Line 
Treatment of Patients with Advanced or Metastatic Non-Small 
Cell Lung Cancer with Tumors Expressing PD-L1 ≥50% 
Compound: 
Cemiplimab (R2810; anti-PD-1 mAb) 
Protocol Number: 
R2810-ONC-16111 
Clinical Phase:  
3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
  
Clinical Study Team Leader: 
  
Study Medical Director: 
 
Version/Date: 
Original Statistical Analysis Plan / Aug 9, 2021 
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The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
Study Biostatistician    
See appended electronic signature page 
 (Author) 
 
 
Study Medical Director 
 
See appended electronic signature page 
 (Approver) 
 
 
Head of Biostatistics and Data Management  
See appended electronic signature page 
 (Approver) 
 
 
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TABLE OF CONTENTS 
ABBREVIATIONS AND DEFINITION OF TERMS....................................................................5 
1. 
OVERVIEW .................................................................................................................6 
1.1. 
Background/Rationale ..................................................................................................6 
1.1.1. 
Background ...................................................................................................................6 
1.1.2. 
Rationale .......................................................................................................................6 
1.2. 
Study Objectives ...........................................................................................................7 
2. 
INVESTIGATION PLAN ............................................................................................7 
2.1. 
Study Design .................................................................................................................7 
3. 
ANALYSIS POPULATIONS ......................................................................................8 
4. 
ANALYSIS VARIABLES ...........................................................................................8 
4.1. 
Demographic and Baseline Characteristics ..................................................................8 
4.2. 
Prior Treatment/Concomitant Medications and Procedures .........................................8 
4.3. 
Efficacy Variables ........................................................................................................9 
4.4. 
Safety Variables ............................................................................................................9 
4.4.1. 
Adverse Events and Serious Adverse Events ...............................................................9 
4.4.2. 
Laboratory Safety Variables .........................................................................................9 
4.4.3. 
Other Safety-Related Variables ....................................................................................9 
4.5. 
Pharmacokinetic Variables ...........................................................................................9 
4.6. 
Immunogenicity Variables ..........................................................................................10 
5. 
STATISTICAL METHODS .......................................................................................10 
5.1. 
Demographics and Baseline Characteristics ...............................................................10 
5.2. 
Medical History ..........................................................................................................10 
 
Medical history will be listed. ....................................................................................10 
5.3. 
Prior/Concomitant Medications/Procedures ...............................................................10 
5.4. 
Patient Disposition ......................................................................................................10 
5.5. 
Exposure to Investigational Product ...........................................................................10 
5.6. 
Analyses of Efficacy Variables ..................................................................................11 
5.7. 
Analysis of Safety Variables ......................................................................................11 
5.7.1. 
Adverse Events ...........................................................................................................11 
5.7.2. 
Clinical Laboratory Measurements and Analysis of Other Safety Variables .............11 
5.8. 
Analysis of Pharmacokinetic and Antibody Data .......................................................11 
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5.8.1. 
Analysis of Pharmacokinetic Data ..............................................................................11 
5.8.2. 
Analysis of Anti-Drug Antibody Data ........................................................................11 
6. 
SOFTWARE ...............................................................................................................12 
7. 
REFERENCE .............................................................................................................12 
 
 
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ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADA      
 Anti-drug antibody 
AE 
             Adverse event 
AESI              Adverse event of special interest 
CRF                  Clinical report form 
ECG                  Electrocardiogram 
ECOG               Eastern cooperative oncology group 
EOS 
              End of study 
ICH                   International council for harmonization   
irAE                  Immune-related adverse event 
MedDRA 
  Medical dictionary for regulatory activities 
NSCLC 
  Non-small cell lung cancer 
NCI-CTCAE     Nation cancer institute – common terminology for adverse events  
PD 
               Progressive disease 
PD-1        
   Programmed death-1 (receptor) 
PD-L1     
   Programmed death ligand 1 
PFS 
               Progression-free survival 
PK 
               Pharmacokinetic  
PT                      Preferred term 
RECIST   
   Response evaluation criteria in solid tumor 
SAE 
               Serious adverse event 
SAF 
               Safety analysis set 
SAP 
               Statistical analysis plan 
SAS 
               Statistical analysis systems (software) 
SOC                System organ class 
TEAE      
   Treatment-emergent adverse event 
WHODD 
   World health organization drug dictionary 
 
 
 
 
 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to database lock. 
The SAP is intended to be a comprehensive and detailed description of the strategy to be used in 
the analysis of data for R2810-ONC-16111 study. It is the first and final plan prior to database 
lock based on study protocol Amendment 3.  
R2810-ONC-16111 is a phase 3, randomized, open-label study of combination of cemiplimab, 
platinum-based doublet chemotherapy, and ipilimumab versus pembrolizumab monotherapy in 
the first-line treatment of patients with advanced or metastatic non-small cell lung cancer 
(NSCLC) with tumors expressing PD-L1≥50%.  
Due to program de-prioritization, the sponsor decided to cease enrollment for this study effective 
on Jan 14, 2019. As a result, only 5 patients were randomized into the study. As this study was 
terminated prematurely, the efficacy objectives stated in the study protocol will not be analyzed 
as planned. Only important demographic and safety parameters will be summarized.  
1.1. 
Background/Rationale 
1.1.1. 
Background 
Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of cancer-
related mortality worldwide (Siegel 2016, Bray 2013). NSCLC accounts for 80% to 85% of all 
lung cancers and is composed of several histopathological subtypes, the most common of which 
include adenocarcinoma (40% to 60%) and squamous cell carcinoma (30%). Most patients with 
NSCLC are found to have advanced cancer at the time of diagnosis (Leighl 2012). In recent 
years, immunotherapies have been investigated as potential therapeutic approaches that will 
improve long-term survival and quality of life (QOL) in patients with advanced NSCLC. 
Cemiplimab (REGN2810) is a human IgG4 monoclonal antibody (mAb) to the programmed cell 
death-1(PD-1) receptor that blocks PD-1/ programmed death ligand 1(PD-L1) mediated T cell 
inhibition. Cemiplimab is being evaluated in more than 20 Phase 1-3 clinical studies. 
Cemiplimab has been approved for the treatment for several indications: patients with metastatic 
cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC; patients with locally 
advanced basal cell carcinoma (BCC) after hedgehog pathway inhibitor therapy; first-line 
treatment of patients with advanced NSCLC whose tumors have PD-L1 expression ≥50%.  
1.1.2. 
Rationale 
PD-1/PD-L1 inhibitors are being investigated both as monotherapy (eg, KEYNOTE-024 and 
CheckMate 026) and in combination with standard-of-care chemotherapy regimens (eg, 
Rizvi 2016, Antonia 2014, Gadgeel 2016) or other immunotherapies (eg, CheckMate 012 
[Hellmann 2017]) in the first-line treatment of patients with advanced NSCLC. Results of 
KEYNOTE-024 led to approval of pembrolizumab as first-line treatment in metastatic NSCLC 
patients whose tumors express PD-L1 in ≥50% of tumor cells. Data from CheckMate 012 
suggest that while monotherapy may be effective in the tumors with high PD-L1 expression, 
combination chemotherapy may be equally or more effective in patients with any degree of 
PD-L1 expression. Also, in addition to immuno-oncology agents as monotherapy, the potentially 
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additive or synergistic effects of immuno-oncology therapeutics with different mechanisms of 
action are now being evaluated in NSCLC (reviewed in Buchbinder and Desai 2016). Thus, this 
study was originally designed to compare progression free survival (PFS) of cemiplimab plus 
ipilimumab combination therapy or cemiplimab plus platinum-based doublet chemotherapy and 
ipilimumab combination therapy versus pembrolizumab monotherapy in NSCLC patients whose 
tumors express PD-L1 in ≥50% of tumor cells.  
1.2. 
Study Objectives  
Due to early termination of this study and very small sample size, original objectives will not be 
analyzed as planned. Only important demographic variables and safety parameters will be 
described. The original primary, secondary and exploratory objectives of this study are described 
in Section 2 of the study protocol, version amendment 3.  
2. 
INVESTIGATION PLAN 
2.1. 
Study Design 
This is a phase 3, randomized, global open-label study of the efficacy and safety of cemiplimab 
plus ipilimumab combination versus cemiplimab plus platinum-based doublet chemotherapy and 
ipilimumab combination therapy versus pembrolizumab monotherapy in first-line patients with 
stage IIIB, or IIC or stage IV squamous or non-squamous NSCLC whose tumors express PD-L1 
in ≥50% of tumor cells and who have received no prior systemic treatment for their advanced 
disease.  
R2810-ONC-16111was originally designed to enroll 585 randomized patients (195 patients per 
arm) based on the assumptions specified in Section 10.2 of study protocol.  A decision was made 
to discontinue enrollment of this study, effective on Jan 14, 2019, and administratively close 
study while allowing the enrolled subjects to continue with the study treatments.  A total of 5 
patients were randomized to two treatment arms as below: 
• 3 patients in Arm B with treatment planned as cemiplimab 350 mg Q3W + 
ipilimumab 50 mg Q6W for up to 4 doses.  
• 1 patient in Arm C with treatment planned as cemiplimab 350 mg Q3W + 
(pemetrexed plus carboplatin) Q3W for 2 cycles + ipilimumab 50 mg for up to 4 
doses. 
• 1 patient in Arm C with treatment planned as cemiplimab 350 mg Q3W + (paclitaxel 
plus carboplatin) Q3W for 2 cycles + ipilimumab 50 mg for up to 4 doses. 
The treatment period for all the randomized patients is 108 weeks unless treatment is 
discontinued early due to RECIST 1.1-defined disease progression (PD), unacceptable toxicity, 
withdrawal of consent, initiation of another anti-cancer treatment.  
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), all data analysis will be based on safety 
analysis set (SAF), defined as all enrolled patients who received any amount of study treatment.  
4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Demographic variables include the following:  
• Age at screening in years  
• Sex  
• Race  
• Ethnicity  
• Height (cm) 
• Body weight (kg) 
• Body mass index (BMI, kg/𝑚2) 
• Smoking Status (Past smoker, Current smoker) 
• ECOG performance status (0, 1)  
Baseline tumor characteristics include the following:  
• Histology (Non-squamous, Squamous) 
• Brain metastases status  
• Cancer stage at screening 
4.2. 
Prior Treatment/Concomitant Medications and Procedures 
Medications/Procedures will be recorded from the day of informed consent until the end-of-study 
(EOS) visit. Medications will be coded to the ATC level 2 (therapeutic main group) and ATC 
level 4 (chemical/therapeutic subgroup), according to WHO Drug Dictionary (WHODD). 
Patients will be counted once in all ATC categories linked to the medication. 
Prior medications/procedures:  medications taken or procedures performed prior to 
administration of the study drug.   
Concomitant medications/procedures: medications taken or procedures performed from time of 
informed consent until 90 days after the last study treatment will be considered concomitant 
treatment. 
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4.3. 
Efficacy Variables 
Due to early termination of the study, efficacy variables will only include tumor response per 
investigator assessment using RECIST version 1.1 (Eisenhauer 2009) and tumor lesion 
measurements.  
4.4. 
Safety Variables 
Patient safety will be assessed through the collection of reported adverse events (AEs), clinical 
laboratory data, vital signs, ECG and physical exam. Unless otherwise noted, the baseline value 
is defined as the last available value before the first dose of study treatment.  
4.4.1. 
Adverse Events and Serious Adverse Events 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical 
investigation patient administered a study drug and which does not necessarily have to have a 
causal relationship with the study drug.  
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose according 
to the criteria specified in the study protocol. 
All AEs after initiation of study treatment and until 90 days after the last study treatment, 
regardless of relationship to study treatment, will be reported on the AE eCRF. Additionally, any 
SAE or other AE of concern that the investigator believes may be related to study drug and that 
occurs later than 90 days after last study treatment will be reported.  
The relationship of AEs to study drug will be assessed by the investigator and be determined 
based on protocol specified criteria. All adverse events will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA®). 
4.4.2. 
Laboratory Safety Variables 
The clinical laboratory data consists of serum chemistry, hematology, coagulation, thyroid 
function, pregnancy test and other.  
4.4.3. 
Other Safety-Related Variables 
• Vital signs variables including body temperature, seated blood pressures, heart rate, 
and respiration rate will be collected at protocol-specified time points. 
• A standard 12-lead ECG will be performed at screening and when clinically 
indicated, per the discretion of the investigator, during the active treatment period at 
the visits specified in the study protocol. Variables for PR Interval; QRS Interval; QT 
Interval; RR interval; Ventricular Rate will be collected. 
4.5. 
Pharmacokinetic Variables  
The PK variables are cemiplimab concentrations in serum.  The time points of PK sampling are 
described in the study protocol. 
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4.6. 
Immunogenicity Variables 
Not applicable as ADA analysis was not performed. 
5. 
STATISTICAL METHODS 
At the time of administrative close of study, a total of 5 patients were randomized to 2 treatment 
arms. With limited data, only important demographic and safety parameters will be summarized. 
5.1. 
Demographics and Baseline Characteristics 
Patients demographics and baseline characteristics variables given in Section 4.1 will be 
summarized by treatment arm based on the SAF population. Baseline cancer diagnosis will be 
summarized by histology and cancer stage.  
5.2. 
Medical History 
Medical history will be listed.  
5.3. 
Prior/Concomitant Medications/Procedures 
Prior cancer related medication, prior cancer related radiotherapy, prior cancer related surgery 
and concomitant medications will be listed.  
5.4. 
Patient Disposition 
For patient disposition, a summary table will be provided to include the following:  
• The total number of screened patients/subjects who have signed ICF 
• The total number of randomized patients by treatment group (as randomized) 
• The total number of patients in the SAF by treatment group (as treated) 
• The total number of patients who discontinued treatment and the primary reasons for 
treatment discontinuation  
• The total number of patients who discontinued study and the primary reasons for 
study discontinuation   
5.5. 
Exposure to Investigational Product 
Exposure to cemiplimab during the treatment period will be examined for each patient. The 
following variables will be summarized by treatment arm based on SAF: 
• The total number of cemiplimab doses administered 
• Duration of treatment exposure (in weeks), calculated as the minimum of  
1. [date of last dose – date of first dose +21 days based on Q3 weekly dosing schedule]/7 
or 
2. [date of death – date of first dose +1]/7 
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Protocol: R2810-ONC-16111 
Statistical Analysis Plan 
Date: Aug 9, 2021  
 
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Exposure to other study treatments will be listed.  
5.6. 
Analyses of Efficacy Variables 
Lesion measurement, tumor response per investigator assessment using RECIST 1.1 by patient 
and tumor assessment visits in the SAF population will be provided as a listing.   
5.7. 
Analysis of Safety Variables 
All safety analyses will be performed based on the SAF.  
5.7.1. 
Adverse Events 
For safety variables, 3 observation periods are defined as follows: 
• The pre-treatment period is defined as the time from signing the informed consent 
form (ICF) to before the first dose of study drug. 
• The on-treatment period is defined as the time from the day of first dose of study drug 
to the day of the last dose of study drug plus 90 days (including treatment beyond 
progression), or to 1 day before patients receive another new anti-cancer systemic 
therapy, whichever earlier.  
• The post-treatment period is defined as the time starting 1 day after the end of on-
treatment period. 
Day 1 is the first day of patient receiving study treatment, Day – 1 is the day before, and there is 
no Day 0. 
Treatment-emergent AEs (TEAEs) are defined as AEs that developed or worsened during the on-
treatment period.  
A summary table of TEAEs will be generated to include frequencies and proportions of patients 
reporting at least 1 AE and will be presented by system organ class (SOC), preferred term (PT) 
and national cancer institute common terminology criteria for adverse events (NCI-CTCAE) 
grade.  
5.7.2. 
Clinical Laboratory Measurements and Analysis of Other Safety Variables  
Laboratory values for blood chemistry, hematology will be listed by patient and visit. 
Vital signs, ECG, physical examination findings will be listed by patient and visit.  
5.8. 
Analysis of Pharmacokinetic and Antibody Data  
5.8.1. 
Analysis of Pharmacokinetic Data  
Not applicable. Pharmacokinetic data analysis will not be performed due to early study 
discontinuation. Separate pharmacokinetic report may be issued.  
5.8.2. 
Analysis of Anti-Drug Antibody Data 
Not applicable. ADA analysis was not performed due to early study discontinuation.  
                                        VV-RIM-00165347-1.0 Approved - 24 Aug 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-16111 
Statistical Analysis Plan 
Date: Aug 9, 2021  
 
CONFIDENTIAL 
Page 12 of 12 
 
6. 
SOFTWARE  
All analyses will be done using SAS Version 9.4 or above. 
7. 
REFERENCE  
Antonia SJ, Brahmer JR, Gettinger SN, Quan Man Chow L, Juergens RA, Shepherd FA, et al. 
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with platinum-based doublet chemotherapy (PT-DC) in advanced non-small cell lung cancer 
(NSCLC).  J Clin Oncol. 2014;32:5s(suppl; abstr 8113). 
Bray F, Ren JS, Masuyer E, Ferlay J. Estimates of global cancer prevalence for 27 sites in the 
adult population in 2008. Int J Cancer. 2013;132(5):1133-45. 
Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications 
of their inhibition. Am J Clin Oncol. 2016;39(1):98-106. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
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 Gadgeel SM, Stevenson J, Langer C, Gandhi L, Borghaei H, Patnaik A, et al. Pembrolizumab 
(pembro) plus chemotherapy as front-line therapy for advanced NSCLC: KEYNOTE-021 
cohorts A-C. J Clin Oncol. 2016;34(Suppl); abstract 9016. 
Hellmann MD, Rizvi NA, Goldman JW, Gettinger SN, Borghaei H, Brahmer JR, et al. 
Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer 
(CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 
2017;18(1):31-41. 
ICH. ICH Harmonized tripartite guideline: Statistical principles for clinical trials (E9). 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 1998. 
Leighl NB. Treatment paradigms for patients with metastatic non-small-cell lung cancer: first-, 
second-, and third-line. Curr Oncol. 2012; 19:S52-8. 
Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S, et al. Nivolumab 
in combination with platinum-based doublet chemotherapy for first-line treatment of advanced 
non-small-cell lung cancer.  J Clin Oncol. 2016; 34:2969-79. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016; 66:7-30
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                                        VV-RIM-00165347-1.0 Approved - 24 Aug 2021 GMT-5:00