Clinical trial NCT02760498
Conditions: Advanced Cutaneous Squamous Cell Carcinoma
Keywords: Metastatic CSCC Unresectable locally advanced CSCC
Sponsor: Regeneron Pharmaceuticals
Start date: 2016-04-07; Completion date: 2023-10-18
Enrollment: 432 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goals of this study are to evaluate the clinical benefit and safety of cemiplimab in participants with metastatic (nodal or distant) Cutaneous Squamous Cell Carcinoma (CSCC), or unresectable locally advanced CSCC.

Detailed description:

Arms: arm 1: Participants received cemiplimab 3 milligrams (mg)/kilogram (kg) intravenously (IV) every 2 weeks (Q2W) during each 8-week treatment cycle, for up to 96 weeks (12 cycles). arm 2: Participants received cemiplimab 3 mg/kg IV Q2W during each 8-week treatment cycle, for up to 96 weeks (12 cycles). arm 3: Participants received cemiplimab 350 mg IV every 3 weeks (Q3W) during each 9-week treatment cycle, for up to 54 weeks (6 cycles). arm 4: Participants received cemiplimab 600 mg IV every 4 weeks (Q4W) during each 8-week treatment cycle, for up to 48 weeks (6 cycles). arm 5: Participants received a single subcutaneous (SC) dose of cemiplimab followed by cemiplimab 350 mg IV Q3W during each 9-week treatment cycle, for up to 54 weeks (6 cycles). arm 6: Participants received cemiplimab 350 mg IV Q3W during each 9-week treatment cycle, for up to 108 weeks (12 cycles).
Interventions: intervention 1: cemiplimab
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 


Clinical Study Protocol 
 
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CONFIDENTIAL 
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the purposes of compliance with all applicable freedom of information laws, and regulations, and their 
equivalents anywhere in the world including but not limited to the US Freedom of Information Act 5 
U.S.C. §552, Regeneron expects that, prior to disclosure to third parties of any information and/or data 
related to, or contained within, this submission, it will be given every opportunity under applicable 
laws to protect its commercial interests and/or its trade secrets including the opportunity to object to 
such disclosure and/or provide redaction proposals. 
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CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 9 
The following table outlines the changes made to the protocol and the affected sections.    
Description of Change 
Brief Rationale 
Section # and Name 
Added provisions to allow 
approximately 18 patients from 
Group 6 who have received ≥27 
weeks of cemiplimab 350 mg IV 
Q3W (without disease 
progression) to switch to 
subcutaneous (SC) dosing, 
provided they meet certain 
criteria. 
To generate PK and 
tolerability data on repeat 
dosing 
 
 
 
Clinical Study Protocol Synopsis: 
Objectives, Study Design, 
Population, Treatment 
Section 1.1.1  Blockade of the PD-
1 Checkpoint with Cemiplimab 
Section 1.2.1  Rationale for Dose 
Selection 
Section 2.3.4  Group 6 Only – 
Patients Who Switch to SC 
Formulation (section added)  
Section 3.1 Study Description and 
Duration 
Section 3.1.1.1 Groups 1 to 4 and 
Group 6 
Section 5.1 Investigational 
Treatment 
Section 6.1 Study Schedule 
Table 7 Study Schedule (Screening 
and Treatment) for Group 6, 
footnote c 
Table 8 Study Schedule for Group 
6 Patients Who After 27 Weeks of 
IV Dosing Opt for Subcutaneous 
Dosing 
 
 (table added) 
Table 9 Follow Up (After Cycle 12 
for Groups 1, 2, and 6 Patients; 
After Cycle 6 for Groups 3 through 
5 Patients), Footnotes m and n 
Section 6.3.4.1 Drug 
Concentration Measurements 
and Samples 
Section 7.2.1 Adverse Events 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Section # and Name 
Section 9.5.2 Efficacy Analyses 
Appendix 3 Cemiplimab 
Pharmacokinetic Sampling and 
Assessment Schedule 
Updated the imAE management 
guidelines to align with the 
Company Core Data Sheet 
(CCDS) for cemiplimab. 
To ensure management of 
imAEs is consistent with the 
CCDS for cemiplimab-rwlc. 
Section 5.3 Dose Modification and 
Study Drug Discontinuation Rules 
(and all subsequent sections) 
Table 2 Dose Reductions (table 
deleted) 
Table 2 General Guidelines for 
Management of Treatment-Related 
Adverse Events (table added) 
Table 4 General Treatment Hold 
Guidelines for Immune Related 
Adverse Events (table deleted) 
Section 5.4.1 Interruption of the 
Infusion 
Section 5.4.2  Termination of the 
Infusion 
Appendix 4 Recommended Dose 
Modification or Discontinuation 
and Supportive Care Guidelines for 
Specific Study Drug-Related 
Adverse Events  
Section 20 References 
Added language regarding 
clinical study conduct and 
oversight related to Coronavirus 
Disease 2019 (COVID-19).   
To describe the continuity 
plan for conducting clinical 
study activities and study 
oversight activities during 
the public health emergency 
due to COVID-19.  
Section 6.1 Study Schedule 
Updated cemiplimab rationale to 
include additional approved 
indications of non-small cell 
lung cancer (NSLC) and basal 
cell carcinoma (BCC). 
For consistency with recent 
marketing approvals of 
cemiplimab in new 
indications. 
Section 1.2.2 Rationale for Study of 
Cemiplimab in CSCC 
Personnel changes 
To reflect changes in 
personnel involved in study 
oversight 
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Clinical Study Protocol 
 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Section # and Name 
Minor clarifications 
Updates made to provide 
clarifications based on 
Protocol Amendment 7 
(previous active version of 
the amendment) 
Clinical Study Protocol Synopsis: 
Statistical Plan 
Section 9.5.4.1 Adverse Events 
Minor editorial changes 
Correction of typographical, 
grammatical, and formatting 
errors. 
Throughout the document 
 
Amendment 8 – Not Implemented 
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CONFIDENTIAL 
Amendment 7 
The following table outlines the changes made to the protocol and the affected sections.   
Change 
Sections Changed 
Added Group 6 to provide additional efficacy 
and safety data for cemiplimab monotherapy 
in patients with advanced CSCC (metastatic 
or unresectable locally advanced) treated with 
cemiplimab 350 mg every 3 weeks (Q3W) IV.  
Group 6 is also designed to provide additional 
exploratory biomarker data. 
 
 
Clinical Study Protocol Synopsis: Site 
Locations, Objectives, Study Design, Study 
Duration, Sample Size, Treatments, 
Variables, Statistical Plan, Secondary 
Endpoints 
Section 1.1.1 Blockade of the PD-1 
Checkpoint with Cemiplimab 
Section 1.2.1 Rationale for Dose Selection 
Section 2.1 Primary Objectives 
Section 2.2 Secondary Objectives 
Section 2.3.3 Group 6 Only 
Section 3.1 Study Description and Duration 
Section 3.1.1.1 Groups 1 to 4, and Group 6 
Section 3.1.1.3 Considerations Regarding 
Prior Idelalisib 
Section 3.1.2 End of Study Definition 
Section 3.2 Planned Interim Analysis 
Section 4.1 Number of Patients Planned 
Section 4.2 Study Population 
Section 4.2.1 Inclusion Criteria  
Section 4.2.2 Exclusion Criteria 
Section 5.3.1 Dose Modification 
Section 5.5 Method of Treatment Assignment 
Section 6.1 Study Schedule 
Table 7 Study Schedule (Screening and 
Treatment) for Group 6  
Table 11: Follow-Up (After Cycle 12 for 
Groups 1, 2, and  Patients; After Cycle 6 for 
Groups 3 through 5 Patients), footnote l 
Section 6.2.2 Follow-up 
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CONFIDENTIAL 
Change 
Sections Changed 
Section 6.3.1 Procedures Required only at the 
Screening/Baseline Visit 
Section 6.3.2 Efficacy Procedures 
Section 6.3.3 Safety Procedures (all 
subsections) 
Section 6.3.4 Pharmacokinetic and Antibody 
Procedures (all subsections) 
Section 6.3.5 Biomarker Measurements and 
Samples 
Section 6.3.5.1 Tumor Biomarker Procedures 
Section 8.2.1 Primary Efficacy Endpoints 
Section 8.2.2 Secondary Endpoints 
Section 8.2.3 Exploratory Endpoints  
Section 8.4 Exploratory Biomarker Variables 
– Group 6 
Section 9.1 Statistical Hypothesis 
Section 9.2 Justification of Sample Size 
Section 9.6 Multiplicity Considerations 
Section 9.7 Interim Analysis 
Appendix 2 Composite Response Criteria for 
Patients with Locally Advanced CSCC 
Appendix 3 Cemiplimab Pharmacokinetic 
Sampling and Assessment Schedule 
Appendix 5 Guidelines for Biopsies for 
Locally Advanced CSCC 
Appendix 10 Statistical Analyses 
Collect additional PK samples at follow-up 
visits 3 and 4 to provide information on non-
linearity of PK of cemiplimab 
Table 9 Follow-Up (After Cycle 12 for 
Groups 1, 2, and 6 Patients; After Cycle 6 for 
Groups 3 through 5 Patients) 
Removed exclusion of patients with allergy or 
hypersensitivity to doxycycline or tetracycline 
as these are not utilized in the current 
manufacturing process. 
Section 4.2.2 Exclusion Criterion #11   
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CONFIDENTIAL 
Change 
Sections Changed 
Clarified the definitions for efficacy analyses 
per Regulatory Authority feedback 
Clinical Study Protocol Synopsis: Primary 
Endpoints, Secondary Endpoints 
Section 8.2.1 Primary Efficacy Endpoints 
Section 8.2.2 Secondary Endpoints 
Requirements relating to pregnancy and birth 
control in women of childbearing potential 
(WOCBP) and their partners were revised in 
accordance with Clinical Trial Facilitation 
Group (CTFG) guidance. 
Section  4.2.2 Exclusion Criterion, #16  
Table 7 Study Schedule (Screening and 
Treatment) for Group 6 
Modifications for consistency and clarity, and 
administrative updates. 
Section 1.2.2 Rationale for Study of 
Cemiplimab in CSCC  
Section 2.3.1 Groups 2 and 4 
Section 3.1.1.2 Group 5 (Pilot Study) 
Section 3.1 Study Description and Duration 
Section 5.1 Investigational Treatment 
Section 5.3.2.1 Immune-Related Adverse 
Events  
Section 5.6.1 Packaging, Labeling, and 
Storage 
Table 4 Study Schedule (Screening and 
Treatment) for Group 3, footnote m 
Table 5 Study Schedule (Screening and 
Treatment) for Group 4 
Table 5 Study Schedule (Screening and 
Treatment) for Group 4, footnote n 
Section 8 Study Variables and Endpoints 
Correction of typographical, grammatical, and 
formatting errors. 
Throughout 
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CONFIDENTIAL 
Amendment 6 DE 
This is a country-specific amendment for Germany.  The following table outlines the changes 
made to the protocol and the affected sections.   
Change 
Sections Changed 
The protocol was updated to clarify that 18F-
fluorodeoxyglucose positron emission 
tomography (18F-FDG-PET) requirements 
will not apply to patients enrolled at sites in 
Germany to accommodate a request from the 
German Central Ethics Committee (CEC). 
Clinical Study Protocol Synopsis: Objectives, 
Variables, Procedures and Assessments 
Section 2.3 Exploratory Objectives 
Table 5 Study Schedule (Screening and 
Treatment) for Group 4, footnote u  
Section 6.3.2 Efficacy Procedures 
Section 8.2.3 Exploratory Outcome Measures 
The secondary objective and endpoint to 
assess overall response rate (ORR) in Group 4 
according to 18F-FDG-PET using European 
Organisation for Research and Treatment of 
Cancer (EORTC) criteria was changed to an 
exploratory objective and endpoint due to the 
investigational nature of this assessment. 
Clinical Study Protocol Synopsis: Objectives, 
Variables 
Section 2.2 Secondary Objectives 
Section 2.3 Exploratory Objectives 
Section 8.2.2 Secondary Outcome Measures 
Section 8.2.3 Exploratory Outcome Measures 
PET-CT was updated to 18F-FDG-PET for 
consistency in terminology in the document. 
Section 6.3.2 Efficacy Procedures 
Section 8.2.3 Exploratory Outcome Measures 
Administrative changes 
Title Page: Scientific/Medical Monitor 
 
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CONFIDENTIAL 
Amendment 6 Global 
The following table outlines the changes made to the protocol and the affected sections.   
Change 
Sections Changed 
Two new cohorts were added, Group 4 and 
Group 5, to enroll patients with advanced 
CSCC, a term that encompasses both 
metastatic [nodal or distant] CSCC (mCSCC) 
and locally advanced CSCC (laCSCC) in 
patients who are not suitable candidates for 
surgery: 
• Group 4 consists of 63 patients with 
advanced CSCC (mCSCC and 
laCSCC) who will receive cemiplimab 
600 mg Q4W administered 
intravenously.  The primary endpoint 
for this group is ORR per central 
review. 
• Group 5 consists of 10 patients with 
advanced CSCC who will receive a 
single subcutaneous dose of 
cemiplimab 438 mg followed by 
cemiplimab 350 mg IV Q3W.  As a 
pilot cohort, there is no primary 
endpoint assigned to Group 5. 
Clinical Study Protocol Synopsis: Objectives, 
Study Design,  Study Duration, Population, 
Treatments, Variables, Procedures and 
Assessments, Statistical Plan 
Section 1.1.1 Blockade of the PD-1 
Checkpoint with Cemiplimab 
Section 1.2.1 Rationale for Dose Selection  
Section 2.1 Primary Objectives  
Section 2.2 Secondary Objectives 
Section 2.3 Exploratory Objective (Group 2 
and Group 4) 
Section 2.3.2 Exploratory Objective (Group 5 
only) 
Section 3.1 Study Description and Duration 
Section 3.1.1 Study Groups 
Section 3.1.1.2 Pilot Study Group 
Section 4.1 Number of Patients Planned 
Section 4.2 Patient Population 
Section 4.2.1 Inclusion Criteria, #2, #5, #11, 
#12, #14, #15 
Section 4.2.2 Exclusion Criteria #19 and #20 
Section 5.1 Investigational Treatment 
Section 5.3.2.1 Immune-Related Adverse 
Events 
Section 5.5 Method of Treatment Assignment 
Section 5.6.1 Packaging, Labeling and 
Storage 
Section 6.1 Study Schedule 
Table 4 Study Schedule (Screening and 
Treatment) for Group 3, footnote n (revised) 
and footnote t (added) 
Section 6.3.2 Efficacy Procedures 
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CONFIDENTIAL 
Change 
Sections Changed 
Table 5 Study Schedule (Screening and 
Treatment) for Group 4 
Table 6 Study Schedule (Screening and 
Treatment) for Group 5 (SC Cemiplimab First 
Dose) 
Table 9 Study Schedule: Follow-Up (After 
Cycle 12 for Group 1 and Group 2 Patients, or 
After Cycle 6 for Group 3 through 5 Patients) 
Section 6.2.1 Unscheduled Visits 
Section 6.2.2 Follow-Up 
Section 6.3.1 Procedures Required only at the 
Screening/Baseline Visit 
Section 6.3.2 Efficacy Procedures 
Section 6.3.3.1 Vital Signs 
Section 6.3.3.2 Physical Examination 
Section 6.3.3.3 Electrocardiogram 
Section 6.3.3.5 Immunoglobulin Levels 
Section 6.3.3.6 Laboratory Testing 
Section 6.3.4.1 Drug Concentration 
Measurements and Samples 
Section 6.3.4.2 Anti-drug Antibody 
Measurement and Samples 
Section 6.3.5.1 Tumor Biomarker Procedures 
Section 6.3.6 Group 3, 4, and 5 Only: 
Guidance Regarding Patients Who Wish to 
Continue Treatment Beyond Planned 
Treatment Period 
Section 8.2.1 Primary Efficacy Outcome 
Measure 
Section 8.2.2 Secondary Outcome Measures 
Table 12 The 95% Binomial Exact 
Confidence Intervals for Observed ORR in 
Group 4 Given a Sample Size of 60 Patients 
(Based on 92% Power) 
Section 9.5.2 Efficacy Analyses 
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CONFIDENTIAL 
Change 
Sections Changed 
Section 9.6 Multiplicity Considerations 
Section 20 References 
Appendix 1 Response Evaluation Criteria in 
Solid Tumors: RECIST Guideline (Version 
1.1) 
Appendix 2 Composite Response Criteria for 
Patients with Locally Advanced CSCC 
Appendix 5 Guidelines for Biopsies for 
Locally Advanced CSCC 
A secondary objective to measure tumor 
response via PET response criteria in solid 
tumors (EORTC) has been added to Group 4, 
along with accompanying Appendix 9. 
Section 2.2 Secondary Objectives 
Appendix 9 Adapted European Organization 
for Research and Treatment of Cancer 
(EORTC) PET Criteria (For Groups 4) 
End of Study definition revised as follows:  
The end of study for all groups is 
approximately 1.5 years after completion of 
the treatment at the end of extended follow-up 
(unless the patient enters retreatment).  The 
schedules of events for each group define 
when end of study would be after they enter 
retreatment). 
Clinical Study Protocol Synopsis:  Study 
Duration 
Section 3.1.2 End of Study Definition 
The posttreatment follow-up plan has been 
extended. Patients who do not experience 
progressive disease (PD) will be followed for 
up to 1.5 years with periodic assessments.  
Section 3.1 Study Description and Duration 
Idelalisib was exclusionary for patients 
enrolled under Amendments 4 and 5 into 
Groups 1 to 3.  In this amendment, patients 
treated with prior idelalisib are no longer 
excluded from the study.   
Section 3.1.1.3 Considerations Regarding 
Prior Idelalisib 
Section 4.2.2 Exclusion Criteria #21 (deleted 
from list) 
Clarified the interim analysis for Group 2 
patients. 
Section 3.2 Planned Interim Analysis 
Removed the withdrawal volumes for 
consistency across the program. 
Section 5.1 Investigational Treatment 
Section 5.6.1 Packaging, Labeling, and 
Storage 
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CONFIDENTIAL 
Change 
Sections Changed 
Clarified that dose reductions are not part of 
the Adverse Events management plan for 
Groups 4 and 5. 
Section 5.3.1 Dose Modification 
Immune-related adverse events description is 
revised to add the following: Immune-related 
endocrinopathies can have subtle 
presentations. In a patient with fatigue or 
weakness, there should be low index of 
suspicion for immune-related endocrinopathy, 
including checking thyroid-stimulating 
hormone (TSH), T4, cortisol, and 
adrenocorticotropic hormone ACTH levels if 
clinically appropriate. 
Section 5.3.2.1 Immune-Related Adverse 
Events 
Clarified that the grading criteria for ISRs in 
Section 5.4.3 are different than NCI-CTCAE 
version 4.03 grading of ISRs, because the 
criteria in Section 5.4.3 are more descriptive 
of potential local reactions to this class of 
drug. 
Section 5.4.3 Injection Site Reactions  
Section 7.3.1 Evaluation of Severity 
Optional collection of circulating tumor DNA 
(ctDNA) samples for Group 4 added. 
Table 5 Study Schedule (Screening and 
Treatment) for Group 4 
Section 6.3.5.1 Tumor Biomarker Procedures 
Acute injection site reactions are defined for 
Group 5. 
Section 7.2.1 Adverse Events 
Section 7.2.3 Other Events that Require 
Accelerated Reporting to the Sponsor 
Changes were made to align with current 
language for all protocols. 
Section 8.3 Anti-drug Antibody Variables 
Statistical hypothesis revised to add the 
following: 
Group 4: H0: ORR = 20% vs. H1: ORR ≠ 20% 
Section 9.1 Statistical Hypothesis 
Pharmacokinetic analysis will be done from 
the Group 5 patients to inform dose and 
schedule for a possible future subcutaneous 
cohort. 
Section 9.2 Justification of Sample Size 
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CONFIDENTIAL 
Change 
Sections Changed 
Clarified the on-treatment period as the day 
from first dose of study drug to 105 days after 
the last dose of study drug or to follow-up 
visit, whichever is longer. 
Section 9.5.4.1 Adverse Events 
Appendix 3 was updated for Groups 1, 2, and 
3 to be consistent with the ADA sampling as 
presented in Table 9.  
Appendix 3 Cemiplimab Pharmacokinetic 
Sampling and Assessment Schedule 
Minor editorial and grammatical changes 
Throughout the document 
REGN2810 will be referred by its generic 
name, cemiplimab, for consistency 
throughout the program.  
Throughout the document 
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CONFIDENTIAL 
Amendment 5 Global 
The following table outlines the changes made to the protocol and the affected sections 
Change 
Sections Changed 
In response to 
, 
added an interim analysis for Group 2 and 
revised the statistical considerations (ie, 
secondary efficacy outcome measures, 
analysis sets, definition of the observation 
period for treatment-emergent adverse 
events). 
Synopsis – Secondary Variables 
Section 3.2 Planned Interim Analysis 
Section 8.2.2 Secondary Outcome Measures 
Section 9.3.1 Full Analysis Set 
Section 9.3.2. Per Protocol Set (deleted) 
Section 9.5.2 Efficacy Analyses 
Section 9.5.4.1 Adverse Events 
Section 9.7 Interim Analysis 
Revised footnote “t” in Table 5 and footnote 
“s” in Table 6 for clarity to emphasize that all 
patients who discontinue study treatment 
should enter the follow-up schedule of events, 
unless there was a progression of disease or 
other factors (eg, withdrawal of consent) 
Table 3 Study Schedule (Screening and 
Treatment) for Groups 1 and 2 
Study Schedule (Screening and Treatment) 
for Group 3 
Specified that tumor staging (according to 
AJCC cancer staging manual, 7th edition) 
will be collected as part of baseline 
characteristics 
Section 8.1 Demographic and Baseline 
Characteristics 
Section 20 References 
Clarified that use of the Canfield tracing 
application is optional 
Appendix 6 
 
Made editorial changes for clarity and 
consistency 
Study Schedule (Screening and Treatment) 
for Group 3 
Section 8.2.1 Primary Efficacy Outcome 
Measure 
Section 8.2.2 Secondary Outcome Measures 
Section 9.5.3 Exploratory Analyses 
Appendix 8 Factors to Consider in Assessing 
the Relationship of AEs to cemiplimab or 
Study Conduct 
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CONFIDENTIAL 
Amendment 4 Global 
The following table outlines the changes made to the protocol and the affected sections 
Change 
Sections Changed 
An exclusion criterion has been added for the 
following reason:  Patients who have 
previously been treated with idelalisib will be 
excluded from treatment with cemiplimab as a 
result of the safety findings for 3 patients with 
indolent lymphoma previously treated with 
idelalisib, a phosphatidylinositol 3-kinase 
(PI 3-K) inhibitor, in study R1979-ONC-
1504. Following a single dose of cemiplimab 
monotherapy in each case, 2 patients 
experienced severe stomatitis and/or skin 
reactions.  The third patient experienced 
myositis and myasthenia gravis after 2 doses 
of cemiplimab. 
Section 4.2.2 Exclusion Criteria #21 
Additional safety guidance language added 
for the management of patients developing 
stomatitis or mucositis 
Section 5.3.2 Study Treatment Hold or 
Discontinuation 
An adverse event of special interest (AESI) 
has been added to the list of AESIs: 
An irAE of any grade in a patient previously 
treated with a PI 3-K inhibitor. 
Section 7.2.3 Other Events that Require 
Accelerated Reporting to the Sponsor 
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CONFIDENTIAL 
Amendment 3 Global 
Changes to the protocol are summarized in the table below. 
Change 
Section Affected 
The primary purpose of this amendment is to 
enroll metastatic (nodal or distant) cutaneous 
squamous cell carcinoma (CSCC) patients 
who are dosed at 350 mg flat dose every 3 
weeks (Q3W) as Group 3.  This cohort opens 
after the completion of enrollment to Group 1 
and provides data in support of Q3W dosing 
in CSCC patients. 
Updated number of patients to up to 182 adult 
patients (Group 3: 53 patients). 
Primary objective, study description, schedule 
of events, duration, treatment assignment, 
primary and secondary variables, secondary 
outcomes measure, follow-up, and statistical 
plan of the study are revised to include the 
additional group. 
Additionally, the amendment contains 
clarifications and minor revisions suggested at 
the external Steering Committee Meeting of 7 
April. 
Clinical Study Protocol Synopsis: Objectives, 
Study Design, Study Duration, Population, 
Treatments, Endpoints, Statistical Plan 
Section 1.2.1 Rationale for Dose Selection  
Section 2.1 Primary Objectives  
Section 3.1 Study Description and Duration 
Section 3.1.1 Study Groups 
Section 4.1 Number of Patients Planned 
Section 4.2 Patient Population 
Section 4.2.1 Inclusion Criteria, #2, #5 
Section 5.1 Investigational Treatment 
Section 5.3.1 Dose Modification 
Table 2 Dose Reductions 
Section 5.5 Method of Treatment Assignment 
Study Schedule (Screening and Treatment) 
for Group 3 
 Study Schedule:  Follow-Up (After Cycle 12 
for Group 1 and Group 2 Patients, or after 
Cycle 6 for Group 3 Patients) 
Section 6.2.1 Unscheduled Visits 
Section 6.2.2 Follow-up 
Section 6.3.1 Procedures Required Only at the 
Screening/Baseline Visit 
Section 6.3.2 Efficacy Procedures 
Section 6.3.6 Group 3 Only:  Guidance 
Regarding Patients Who Wish to Continue 
Treatment Beyond 54 Weeks 
Section 8.2.1 Primary Efficacy Outcome 
Measure 
Section 8.2.2 Secondary Outcomes Measure 
Section 9.1 Statistical hypothesis 
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CONFIDENTIAL 
Section 9.2 Justification of Sample Size 
The 95% Binomial Exact Confidence 
Intervals for Observed ORR in Group 1 and 
Group 3 Given a Sample Size of 50 Patients 
(Based on 85% Power) 
Section 9.5.2 Efficacy Analyses 
Section 9.6 Multiplicity Considerations 
Appendix 1 Response Evaluation Criteria in 
Solid Tumors: RECIST Guideline 
(Version 1.1) 
Appendix 2 Composite Response Criteria for 
Patients with Locally Advanced CSCC 
Appendix 3 Cemiplimab Pharmacokinetic 
Sampling and Assessment Schedule 
Added clarification regarding the 
3 independent central imaging review 
committees. 
Section 3.3.3 Independent Review 
Committees 
Added clarification for procedures if visits are 
missed. 
Section 5.3.2 Study Treatment Hold or 
Discontinuation 
Removed ADA sample at the end of study 
visit. 
Clarify when PK samples will be collected. 
End of study definition added. 
Table 3 Study Schedule (Screening and 
Treatment) for Groups 1 and 2, footnotes m, 
n, t 
Updated HBV, HCV, and HIV screening at 
the screening/baseline visit. 
Section 6.3.1 Procedures Required Only at the 
Screening/Baseline Visit 
Removed language “in triplicate” for ECG 
recordings. 
Table 3 Study Schedule (Screening and 
Treatment) for Groups 1 and 2, footnote f 
Section 6.3.3.3 Electrocardiogram 
Clarified SAEs in event of hospitalization or 
death. 
Section 7.1.2 Serious Adverse Event 
Removed the NCI-CTCAE v4.03 and 
clarified when AEs should be reported. 
Section 7.2.1 Adverse Events 
Clarified timing in the event an SAE occurs 
after last dose of study treatment. 
Section 7.2.2 Serious Adverse Events 
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Clarified when to report pregnancy. 
Section 7.2.3 Other events that Require 
Accelerated Reporting to the Sponsor 
Added text about relationship of AEs to study 
conduct. 
Section 7.3.2 Evaluation of Causality 
Updated ADA variables definitions. 
Section 8.3 Anti-drug Antibody Variables 
Updated title of appendix. 
Appendix 8 Factors to Consider in Assessing 
the Relationship of AEs to Cemiplimab or 
Study Procedure 
Minor editorial/grammatical updates 
Throughout document 
Appendix 1 EORTC-QLQ-C30 (VERSION 
3) deleted.  The study teams are expected to 
complete QOL data per Schedules of Events. 
 
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Amendment 2 Global 
The primary purpose of this amendment is to revise the text for toxicity management.   
In addition, there have been several other changes: 
• To integrate comments raised by regulatory authorities to provide a common global 
protocol 
• A new section that outlines the role of study committees has been added 
• Some inclusion/exclusion criteria have been clarified 
• Some footnotes to the Study Schedule Tables have been modified 
• Description of the follow-up period has been revised 
• Clarified time points and research procedures for biopsies 
• Minor edits 
Amendment 2DE 
The purpose of this amendment was to incorporate the following changes and clarifications 
requested by the Paul Ehrlich Institute in Germany:   
• Add baseline testing for hepatitis B virus (HBV), hepatitis C virus (HCV), and human 
immunodeficiency virus (HIV) 
• Clarify exclusion criteria for active infection requiring therapy, and for known allergy 
to doxycycline or tetracycline 
• Extend posttreatment follow-up to 5 half-lives (105 days) after the last dose of 
cemiplimab 
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Amendment 1 
The purpose of this amendment was to incorporate the following changes and clarifications 
: 
• Provide further justification for including patients with regional nodal metastases in 
Group 1 rather than Group 2 
• Clarification of the note for patients with hepatic metastases who wish to enroll in 
Group 1 (Inclusion 5, Hepatic Function) 
• Revise Table 3 to require dose reduction for grade 3 nonhematological toxicities, grade 
4 hematological toxicities, and grade 3 thrombocytopenia lasting greater than seven 
days or associated with bleeding 
• Additional guidelines for administration of premedication with subsequent treatments 
for patients who experience infusion-related hypersensitivity reactions that are less than 
grade 3 and who plan to continue treatment 
• Language added to Appendix 3 to clarify the approach to response assessments of 
externally visible tumors; a section on criteria for assessing response in extensively 
ulcerated lesions has been added. 
• New language added to Appendix 7 on profile view to be obtained at baseline, and at 
subsequent visits as appropriate 
Other minor modifications include: 
• Clarification that patients who do not experience progressive disease will be followed 
for an additional non-treatment period of up to approximately 6 months with scans 
performed every 8 weeks 
• Clarification regarding concomitant medications 
• Time window added for vital signs collection 
• Follow-up visit 4 will not require PK sample collection; the list of PK variables has 
been updated. 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
 
Title 
A Phase 2 Study of REGN2810, a Fully Human Monoclonal Antibody to 
Programmed Death-1 (PD-1), in Patients with Advanced Cutaneous 
Squamous Cell Carcinoma 
Site Locations 
Up to 100 sites globally 
Objectives 
Primary Objectives 
For Groups 1 to 4, the primary objective of this study is to estimate the 
clinical benefit of cemiplimab monotherapy for patients with: metastatic 
(nodal or distant) CSCC, or unresectable locally advanced CSCC.  Group 1 
consists of patients with metastatic (nodal or distant) CSCC treated with 
cemiplimab 3 mg/kg intravenously (IV) every 2 weeks (Q2W).  Group 2 
consists of patients with unresectable locally advanced CSCC, treated with 
cemiplimab 3 mg/kg IV Q2W.  Group 3 consists of patients with metastatic 
(nodal or distant) CSCC treated with cemiplimab 350 mg IV every 3 weeks 
(Q3W).  Group 4 consists of patients with advanced CSCC (metastatic 
[nodal or distal] or unresectable locally advanced) treated with cemiplimab 
600 mg IV every 4 weeks (Q4W). Clinical benefit is measured by ORR 
according to central review in each group.  For Group 6, the primary 
objective is to provide additional efficacy and safety data for cemiplimab 
monotherapy in patients with advanced CSCC (metastatic [nodal or distant] 
or locally advanced) treated with cemiplimab 350 mg IV Q3W.  
Secondary Objectives 
Secondary objectives for Groups 1 to 4, and Group 6 are:  
• 
To estimate ORR according to investigator review  
• 
To estimate the duration of response (DOR), progression-free 
survival (PFS), and overall survival (OS) by central and 
investigator review 
• 
To estimate the complete response (CR) rate by central review 
• 
To assess the safety and tolerability of cemiplimab  
• 
To assess the PK of cemiplimab  
• 
To assess the immunogenicity of cemiplimab 
For Groups 1 to 5 only: 
• 
To assess the impact of cemiplimab on quality of life using 
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)  
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Group 6 only:  To assess relationships between PD-L1 status (by 
immunohistochemistry [IHC]) and efficacy measures (ORR, DOR, PFS). 
Exploratory Objectives (Group 2 and 4 only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
Exploratory Objectives (Group 5 only) 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Exploratory Objectives (Group 6 only) 
 
 
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Exploratory Objectives (Group 6 Only – Patients who switch to SC 
formulation) 
Protocol Amendment 9 allows Group 6 patients who have received IV 
cemiplimab for at least 27 weeks without experiencing disease progression 
to switch to SC cemiplimab (optional). This is to extend clinical 
experience with SC cemiplimab upon repeated SC doses and the 
assessment of local tolerability at the site of SC injection. For these 
patients, the following exploratory objectives will be evaluated:  
 
 
 
 
 
 
  
 
  
 
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Study Design 
This is a phase 2, non-randomized, 6-group, multicenter pivotal trial 
evaluating the efficacy and safety of cemiplimab in patients with advanced 
CSCC. Tumor assessments will be made at the end of each treatment cycle.  
Extensive safety evaluations will occur on day 1 of each cycle; routine safety 
evaluations will be conducted at each cemiplimab dosing visit.  
Groups 1 and 2 patients:  Patients with metastatic CSCC are enrolled in 
Group 1 and patients with locally advanced CSCC are enrolled in Group 2 
to receive up to twelve 56-day (8-week cycles) treatment cycles for a total 
of up to 96 weeks of treatment.  Each patient will receive cemiplimab 
3 mg/kg Q2W.  
Group 3 patients:  This cohort enrolls patients with metastatic CSCC. 
Group 3 only begins enrollment after completion of enrollment to Group 1. 
Patients will receive cemiplimab 350 mg IV Q3W until the 54-week 
treatment period (9-week cycles) is complete, or until disease progression, 
unacceptable toxicity, or withdrawal of consent.  No research biopsies are 
required.  
Group 4 patients:  The dose regimen in Group 4 is 600 mg IV Q4W for up 
to 48 weeks in patients with advanced CSCC.  
Group 5 patients: Patients in this cohort will receive 1 dose of 
cemiplimab 438 mg SC, followed by cemiplimab 350 mg IV Q3W for up to 
54 weeks total treatment.  The bioavailability of cemiplimab SC will be 
assessed to determine a recommended dose of cemiplimab administered SC 
for future studies. 
Note on enrollment: Prior to the implementation of Group 6, Groups 4 and 
5 had completed enrollment. 
Group 6 patients:  This cohort enrolls patients with advanced CSCC.  The 
dose regimen is 
 for up to 108 weeks (9 week cycles). 
For Groups 1 to 5, patients who do not experience PD during the treatment 
or follow-up period will be followed for an extended follow-up period of up 
to approximately 1 year.  Patients in Group 6 will complete 6 months of 
follow-up and will not go into extended follow-up after the 6-month follow-
up is completed. 
Patients in Group 6 who have completed ≥ 27 weeks of IV study treatment 
(without disease progression) will be given the option to receive subsequent 
doses as cemiplimab SC 
 
 provided the criteria outlined in 
the protocol are met.  Group 6 patients who opt to switch to SC cemiplimab 
will continue SC cemiplimab until the completion of 108 weeks of total 
planned therapy of cemiplimab (IV + SC combined), disease progression, or 
unacceptable toxicity. 
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Study Duration 
Screening (up to 4 weeks) for all 6 groups.  Groups 1 and 2 will receive up 
to 96 weeks of treatment.  Group 3 will receive up to 54 weeks of treatment.  
Group 4 will receive up to 48 weeks of treatment. Group 5 will receive up 
to 54 weeks of treatment.  Groups 1 to 5 will receive up to approximately 
1.5 years of follow-up.  Group 6 will receive up to 108 weeks of treatment 
and up to 6 months of follow-up.   
Population 
 
 
Sample Size: 
Up to approximately 433 adult patients are planned to enroll: Group 1 
(metastatic [nodal or distant]): 53 patients planned (actual enrollment, 
59 patients); Group 2 (unresectable locally advanced): 76 patients planned 
(actual enrollment, 78 patients); Group 3 (metastatic [nodal or distant]): 
53 patients planned (actual enrollment, 56 patients); Group 4 advanced 
CSCC (metastatic [nodal or distant] or locally advanced): 63 patients 
planned (actual enrollment, 63 patients); Group 5 (advanced CSCC): 10 
patients planned (actual enrollment, 9 patients); Group 6 (advanced CSCC): 
167 patients planned. 
 
Target Population: 
Patients with metastatic CSCC or with unresectable locally advanced CSCC. 
Treatments 
 
Study Drug 
 
Dose/Route/Schedule: 
Groups 1 and 2:  cemiplimab 3 mg/kg IV administered over 30 minutes 
(±10 minutes) every 14 days (Q2W) for up to 96 weeks. 
Group 3:  Cemiplimab 350 mg IV administered over 30 minutes 
(±10 minutes) every 21 days (Q3W) for up to 54 weeks. 
Group 4:  Cemiplimab 600 mg IV administered over 30 minutes 
(±10 minutes) every 28 days (Q4W) for up to 48 weeks 
Group 5: One dose of cemiplimab 438 mg SC.  Three weeks after the SC 
dose, patients receive cemiplimab 350 mg IV over 30 minutes (±10 minutes) 
every 21 days (Q3W) for up to 54 weeks total treatment.  
Group 6:  Cemiplimab 
 
 
 
 
 
 
 
. 
Group 6 patients who switch to SC dosing: Cemiplimab 
 
 
  
 
Study Variables and 
Endpoints 
 
Primary 
 
 
The primary efficacy endpoint for this study is ORR according to central 
review during the 12 treatment cycles (Groups 1, 2, and 6), or 6 treatment 
cycles (Groups 3 and 4. Overall response rate will be assessed separately for 
patients with metastatic CSCC or unresectable locally advanced CSCC: 
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Secondary 
• 
For patients with metastatic disease, RECIST version 1.1 will 
be used to determine ORR.  Patients in which all response 
assessments are performed on radiologic scans according to 
RECIST 1.1, the determination of the independent radiologic 
response assessment committee will serve as the central 
response assessment.  Clinical or composite response criteria 
may be used for patients with externally visible target lesions, 
if all metastatic lesions are not measurable by RECIST (such as 
may occur in patients with bone-only metastases). 
• 
For patients with unresectable locally advanced disease, clinical 
response criteria will be used to determine ORR, for externally 
visible tumor(s) use bi-dimensional measurements according to 
World Health Organization (WHO) criteria. Composite 
response criteria will be used for patients who have both target 
lesions measurable by clinical response criteria and by RECIST 
1.1 to determine ORR. In patients achieving a CR, tumor 
biopsies will be used in the final determination of complete 
versus PR.  ORR will be calculated from time of enrollment. 
The secondary efficacy endpoints are: 
• 
ORR for Groups 1 to 6  by investigator assessments  
- 
For metastatic patients in which all response assessments 
are performed on radiologic scans according to RECIST 
1.1, the term “composite response assessment” is not 
applicable.  The investigator’s response assessment for such 
patients will be RECIST 1.1 assessment. 
- 
For unresectable locally advanced patients in which all 
response assessments are performed on photographs 
according to Clinical Response Criteria for Externally 
Visible Tumors, the term “composite response assessment” 
is not applicable.  The investigator’s response assessment 
for such patients will be according to Clinical Response 
Criteria for Externally Visible Tumors. 
- 
For patients in which target lesion response assessments are 
performed with both scans (according to RECIST 1.1) and 
photographs (according to Clinical Response Criteria for 
Externally Visible Tumors), the investigator’s response 
assessment will be according to Composite Response 
Criteria. 
• 
Duration of response (DOR)– measured from the time 
measurement criteria are first met for CR/partial response 
(PR), whichever is recorded first, until the first date of 
recurrent or progressive disease or death due to any cause in 
patients with best overall response (BOR) of CR or PR.  
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• 
PFS – measured from time of enrollment until the first date of 
recurrent or progressive disease, or death due to any cause 
• 
OS – measured from time of enrollment until death due to any 
cause 
• 
CR rate 
• 
Change in scores of patient-reported outcomes on EORTC 
QLQ-C30 (except Group 6) 
• 
AEs  
• 
Cemiplimab concentrations in serum  
• 
Anti-drug antibodies (ADA) 
• 
For Group 6 only:  To assess relationships between PD-L1 
status (by IHC) and efficacy measures (ORR, DOR, PFS). 
Procedures and 
Assessments 
Tumor imaging (computed tomography [CT] or magnetic resonance 
imaging [MRI]) and digital medical photography (for externally visible 
lesions) will be performed to measure tumor burden and to characterize the 
efficacy profile of study treatments using response criteria. 
Physical examination, laboratory tests, vital signs, electrocardiogram 
(ECG), pregnancy test for women of childbearing potential, and recording 
of AEs and concomitant medications will be performed to ensure patient 
safety and to characterize the safety profiles of study treatments. 
Other assessments will include: 
• 
Peripheral blood samples for PK  
• 
Peripheral blood samples to assess anti-cemiplimab antibodies   
• 
Tumor biopsies  
• 
Quality of life assessments 
• 
[18F]-FDG PET scans (Group 4, excluding patients enrolled at sites 
in Germany) 
Statistical Plan 
The sample sizes for each registrational group were selected such that the 
lower limit of the 95% confidence intervals of the estimated ORRs will be 
clinically meaningful. The non-clinically meaningful ORR of 15% for 
Groups 1, 3, and 4 will be excluded using the lower limit of 95% CI if the 
observed ORR is 28.0% or more.  For Groups 1 and 3, 50 patients (in each 
group) will be required to provide at least 85% power to reject a null 
hypothesis.  Although these groups have some statistical assumptions, 
efficacy in each group is analyzed independently.  For Group 2, 72 patients 
will be required to provide at least 90% power to reject a null hypothesis. 
The non-clinically meaningful ORR of 25% for Group 2 will be excluded 
using the lower limit of 95% CI if the observed ORR is 36.1% or more.  For 
Group 4 (advanced CSCC), 60 patients will be required for 92% power to 
reject the null hypothesis.  The non-clinically meaningful ORR of 20% will 
be excluded using the lower limit of the 95% CI if the observed ORR is 
31.7% or more.  The sample sizes will be further increased by 5% to account 
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for patients who withdraw prematurely from the study.  Hence, the total 
planned sample sizes will be 53 patients for Group 1, 76 patients for 
Group 2, 53 patients for Group 3, and 63 patients for Group 4.   The 
statistical design for Group 6 will be capable of demonstrating a point 
estimate of ORR (per independent central review) in which the lower bound 
of the 95% confidence interval excludes the highest centrally reviewed ORR 
in the literature for any prospective study of systemic anticancer treatment 
(other than cemiplimab) for CSCC that enrolled at least 30 patients and 
included independent central review.  The statistical plan for Group 6 is 
capable of testing for an ORR (per independent central review) that excludes 
28% at the lower bound of the 95% confidence interval. 
The total study will enroll up to approximately 433 patients.  
Demographic and baseline characteristics will be summarized descriptively 
by group and extent of prior therapy. 
The primary endpoint for efficacy analyses is the ORR, by central review.  
For patients in which all response assessments are done by RECIST 1.1 
analysis of radiologic scans, the independent radiology review is the central 
review.  For patients whose response assessments include photos and 
radiologic scans, the independent composite review committee will serve as 
the central review.  The investigator-assessed ORR will be considered as a 
secondary analysis.  Patients who are deemed as not evaluable according to 
RECIST 1.1 or inevaluable by the composite efficacy criteria will be 
considered as not reaching PR/CR for ORR. 
The primary analyses of efficacy are based on the exact binomial confidence 
interval approach, ie, whether the lower limit of 95% confidence interval 
will exclude a historical control ORR that is not deemed clinically 
meaningful for each group, respectively.  The secondary analyses of efficacy 
as measured by DOR, duration of disease control, PFS, and OS will be 
summarized by median and its 95% confidence interval using the Kaplan-
Meier method. 
For Groups 1 to 5, the quality of life of patients will be repeatedly measured 
by the EORTC QLQ-C30 at the day 1 of each treatment cycle.  The change 
in scores of QLQ-C30 will be summarized descriptively at each postbaseline 
time point. The summary scores of QLQ-C30 will also be graphically 
depicted by longitudinal plots. 
Safety observations and measurements including drug exposure, AEs, 
laboratory data, vital signs, and Eastern Cooperative Oncology Group 
(ECOG) performance status will be summarized and presented in tables and 
listings.  
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................3 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................22 
1. 
INTRODUCTION AND RATIONALE .....................................................................41 
1.1. 
Introduction .................................................................................................................41 
1.1.1. 
Blockade of the PD-1 Checkpoint with Cemiplimab .................................................43 
1.2. 
Rationale .....................................................................................................................44 
1.2.1. 
Rationale for Dose Selection ......................................................................................44 
1.2.2. 
Rationale for Study of Cemiplimab in CSCC .............................................................45 
2. 
STUDY OBJECTIVES ..............................................................................................47 
2.1. 
Primary Objectives .....................................................................................................47 
2.2. 
Secondary Objectives .................................................................................................47 
2.3. 
Exploratory Objectives ...............................................................................................47 
2.3.1. 
Groups 2 and 4 ............................................................................................................47 
2.3.2. 
Group 5 Only ..............................................................................................................48 
2.3.3. 
Group 6 Only ..............................................................................................................48 
2.3.4. 
Group 6 Only – Patients Who Switch to SC Formulation ..........................................48 
3. 
STUDY DESIGN .......................................................................................................50 
3.1. 
Study Description and Duration .................................................................................50 
3.1.1. 
Study Groups ..............................................................................................................51 
3.1.1.1. 
Groups 1 to 4 and Group 6 .........................................................................................51 
3.1.1.2. 
Group 5 (Pilot Study)..................................................................................................53 
3.1.1.3. 
Considerations Regarding Prior Idelalisib ..................................................................53 
3.1.2. 
End of Study Definition ..............................................................................................53 
3.2. 
Planned Interim Analysis ............................................................................................54 
3.3. 
Study Committees .......................................................................................................54 
3.3.1. 
Independent Data Monitoring Committee ..................................................................54 
3.3.2. 
Study Steering Committee ..........................................................................................54 
3.3.3. 
Independent Review Committees ...............................................................................54 
4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............55 
4.1. 
Number of Patients Planned .......................................................................................55 
4.2. 
Study Population .........................................................................................................55 
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4.2.1. 
Inclusion Criteria ........................................................................................................55 
4.2.2. 
Exclusion Criteria .......................................................................................................58 
4.3. 
Premature Withdrawal from the Study or from Study Treatment ..............................61 
4.3.1. 
Reasons for Premature Withdrawal or Discontinuation of Study Treatment .............61 
4.3.2. 
Discontinuation of Study Treatment ...........................................................................61 
4.3.3. 
Withdrawal from Study Participation .........................................................................62 
4.4. 
Replacement of Patients .............................................................................................62 
5. 
STUDY TREATMENTS............................................................................................63 
5.1. 
Investigational Treatment ...........................................................................................63 
5.2. 
Pretreatments ..............................................................................................................63 
5.3. 
Dose Modification and Study Drug Discontinuation Rules .......................................63 
5.3.1. 
Dose Modification ......................................................................................................63 
5.3.2. 
General Guidance for Management of Adverse Events .............................................64 
5.3.2.1. 
Identification of Immune-Related Adverse Events ....................................................65 
5.3.2.2. 
Management of Immune-Related Adverse Events .....................................................65 
5.3.3. 
Discontinuation of Study Treatment ...........................................................................67 
5.3.4. 
Reasons for Permanent Discontinuation of Study Treatment.....................................67 
5.3.4.1. 
Reasons for Temporary Discontinuation of Study Drug ............................................67 
5.4. 
Management of Infusion/Allergic/Hypersensitivity Reactions ..................................67 
5.4.1. 
Interruption of the Infusion .........................................................................................68 
5.4.2. 
Termination of the Infusion ........................................................................................68 
5.4.3. 
Injection Site Reactions ..............................................................................................69 
5.5. 
Method of Treatment Assignment ..............................................................................69 
5.5.1. 
Blinding ......................................................................................................................70 
5.6. 
Treatment Logistics and Accountability .....................................................................70 
5.6.1. 
Packaging, Labeling, and Storage ..............................................................................70 
5.6.2. 
Supply and Disposition of Treatments .......................................................................70 
5.6.3. 
Treatment Accountability ...........................................................................................70 
5.6.4. 
Treatment Compliance ................................................................................................70 
5.7. 
Concomitant Medications and Procedures .................................................................71 
5.7.1. 
Concomitant Medications ...........................................................................................71 
5.7.2. 
Prohibited Medications and Concomitant Treatments ...............................................71 
5.7.3. 
Surgery ........................................................................................................................71 
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5.7.4. 
Radiation Therapy ......................................................................................................71 
6. 
STUDY SCHEDULE AND VISIT DESCRIPTIONS ...............................................73 
6.1. 
Study Schedule ...........................................................................................................73 
6.2. 
Study Follow-Up and Treatment Discontinuation ......................................................95 
6.2.1. 
Unscheduled Visits .....................................................................................................95 
6.2.2. 
Follow-up ....................................................................................................................95 
6.3. 
Study Procedures ........................................................................................................96 
6.3.1. 
Procedures Required Only at the Screening/Baseline Visit .......................................96 
6.3.2. 
Efficacy Procedures ....................................................................................................97 
6.3.3. 
Safety Procedures .......................................................................................................99 
6.3.3.1. 
Vital Signs ..................................................................................................................99 
6.3.3.2. 
Physical Examination .................................................................................................99 
6.3.3.3. 
Electrocardiogram .......................................................................................................99 
6.3.3.4. 
Immune Safety Assays .............................................................................................100 
6.3.3.5. 
Immunoglobulin Levels ............................................................................................100 
6.3.3.6. 
Laboratory Testing ....................................................................................................100 
6.3.4. 
Pharmacokinetic and Antibody Procedures ..............................................................101 
6.3.4.1. 
Drug Concentration Measurements and Samples .....................................................101 
6.3.4.2. 
Anti-Drug Antibody Measurements and Samples ....................................................102 
6.3.5. 
Biomarker Measurements and Samples ....................................................................102 
6.3.5.1. 
Tumor Biomarker Procedures...................................................................................102 
6.3.5.2. 
Genomics Sub-Study – Optional ..............................................................................103 
6.3.6. 
Groups 3, 4, and 5 Only: Guidance Regarding Patients Who Wish to 
Continue Treatment Beyond Planned Treatment Period ..........................................103 
7. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING ...........................105 
7.1. 
Definitions ................................................................................................................105 
7.1.1. 
Adverse Event ...........................................................................................................105 
7.1.2. 
Serious Adverse Event ..............................................................................................105 
7.1.3. 
Adverse Events of Special Interest ...........................................................................106 
7.2. 
Recording and Reporting Adverse Events ................................................................106 
7.2.1. 
Adverse Events .........................................................................................................106 
7.2.2. 
Serious Adverse Events ............................................................................................106 
7.2.3. 
Other Events that Require Accelerated Reporting to the Sponsor ...........................107 
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7.2.4. 
Reporting Adverse Events Leading to Withdrawal from the Study .........................108 
7.2.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results ...........................108 
7.2.6. 
Follow-up ..................................................................................................................108 
7.3. 
Evaluation of Severity and Causality .......................................................................108 
7.3.1. 
Evaluation of Severity ..............................................................................................108 
7.3.2. 
Evaluation of Causality .............................................................................................109 
7.4. 
Safety Monitoring .....................................................................................................110 
7.5. 
Investigator Alert Notification ..................................................................................110 
8. 
STUDY VARIABLES AND ENDPOINTS .............................................................111 
8.1. 
Demographic and Baseline Characteristics ..............................................................111 
8.2. 
Primary and Secondary Endpoints............................................................................111 
8.2.1. 
Primary Efficacy Endpoints ......................................................................................111 
8.2.2. 
Secondary Endpoints ................................................................................................111 
8.2.3. 
Exploratory Endpoints ..............................................................................................112 
8.2.4. 
Pharmacokinetic Variables .......................................................................................113 
8.3. 
Anti-Drug Antibody Variables .................................................................................113 
8.4. 
Exploratory Biomarker Variables – Group 6 ............................................................113 
9. 
STATISTICAL PLAN..............................................................................................114 
9.1. 
Statistical Hypothesis ................................................................................................114 
9.2. 
Justification of Sample Size......................................................................................114 
9.3. 
Analysis Sets .............................................................................................................118 
9.3.1. 
Full Analysis Set .......................................................................................................118 
9.3.2. 
Safety Analysis Set ...................................................................................................118 
9.3.3. 
Pharmacokinetic Analysis Set ..................................................................................118 
9.3.4. 
Anti-drug Antibody Set ............................................................................................118 
9.3.5. 
Biomarker Analysis Set ............................................................................................118 
9.4. 
Patient Disposition ....................................................................................................119 
9.5. 
Statistical Methods ....................................................................................................119 
9.5.1. 
Demography and Baseline Characteristics ...............................................................119 
9.5.2. 
Efficacy Analyses .....................................................................................................119 
9.5.3. 
Exploratory Analyses ................................................................................................120 
9.5.4. 
Safety Analysis .........................................................................................................120 
9.5.4.1. 
Adverse Events .........................................................................................................120 
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9.5.4.2. 
Other Safety ..............................................................................................................121 
9.5.4.3. 
Treatment Exposure ..................................................................................................121 
9.5.4.4. 
Treatment Compliance ..............................................................................................121 
9.5.5. 
Analysis of Drug Concentration Data .......................................................................121 
9.5.5.1. 
Descriptive Analysis of Drug Concentrations ..........................................................121 
9.5.6. 
Analysis of Anti-Drug Antibody Data ......................................................................122 
9.5.7. 
Analysis of Biomarker Data .....................................................................................122 
9.5.7.1. 
Sample Size Justification for Biomarker Measurements in Tumor Tissue 
Biopsies.....................................................................................................................122 
9.6. 
Multiplicity Considerations ......................................................................................123 
9.7. 
Interim Analysis ........................................................................................................123 
9.8. 
Additional Statistical Data Handling Conventions ...................................................125 
9.9. 
Statistical Considerations Surrounding the Premature Termination of a Study .......125 
10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS ...................................126 
10.1. 
Data Management .....................................................................................................126 
10.2. 
Electronic Systems ....................................................................................................126 
11. 
STUDY MONITORING ..........................................................................................127 
11.1. 
Monitoring of Study Sites .........................................................................................127 
11.2. 
Source Document Requirements ..............................................................................127 
11.3. 
Case Report Form Requirements ..............................................................................127 
12. 
AUDITS AND INSPECTIONS ...............................................................................128 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................129 
13.1. 
Good Clinical Practice Statement .............................................................................129 
13.2. 
Informed Consent .....................................................................................................129 
13.3. 
Patient Confidentiality and Data Protection .............................................................129 
13.4. 
Institutional Review Board/Ethics Committee .........................................................130 
14. 
PROTOCOL AMENDMENTS ................................................................................131 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................131 
15.1. 
Premature Termination of the Study .........................................................................131 
15.2. 
Close-out of a Site ....................................................................................................131 
16. 
STUDY DOCUMENTATION .................................................................................132 
16.1. 
Certification of Accuracy of Data .............................................................................132 
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16.2. 
Retention of Records ................................................................................................132 
17. 
CONFIDENTIALITY ..............................................................................................132 
18. 
FINANCING AND INSURANCE ...........................................................................132 
19. 
PUBLICATION POLICY ........................................................................................132 
20. 
REFERENCES .........................................................................................................133 
21. 
INVESTIGATOR’S AGREEMENT ........................................................................138 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................185 
 
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LIST OF TABLES 
Table 1: 
Systemic Therapy for Advanced Cutaneous Squamous Cell Carcinoma ....................43 
Table 2: 
General Guidelines for Management of Treatment-Related Adverse Events ............64 
Table 3: 
Study Schedule (Screening and Treatment) for Groups 1 and 2 ................................74 
Table 4: 
Study Schedule (Screening and Treatment) for Group 3 ............................................77 
Table 5: 
Study Schedule (Screening and Treatment) for Group 4 ............................................80 
Table 6: 
Study Schedule (Screening and Treatment) for Group 5 (SC Cemiplimab 
First Dose) ..................................................................................................................83 
Table 7: 
Study Schedule (Screening and Treatment) for Group 6 ............................................86 
Table 8: 
Study Schedule for Group 6 Patients Who  Opt for Subcutaneous Dosing 
 ..................89 
Table 9: 
 Follow-Up (After Cycle 12 for Groups 1, 2, and 6 Patients; After Cycle 6 
for Groups 3 through 5 Patients) ................................................................................92 
Table 10: The 95% Binomial Exact Confidence Intervals for Observed ORR in 
Group 1 and Group 3 Given a Sample Size of 50 Patients (Based on 
85% Power) ..............................................................................................................116 
Table 11: The 95% Binomial Exact Confidence Intervals for Observed ORR in 
Group 2 Given a Sample Size of 72 Patients (Based on 90% Power) ......................116 
Table 12: The 95% Binomial Exact Confidence Intervals for Observed ORR in 
Group 4 Given a Sample Size of 60 Patients (Based on 92% Power) ......................117 
Table 13: The 95% Binomial Exact Confidence Intervals for Observed ORR in 
Group 6 Given a Sample Size of 167 Patients ..........................................................118 
Table 14: Power Analysis for PD-L1 Biomarkers from Tumor Biopsies ................................123 
Table 15: Alpha Spending for Analysis of ORR on Group 6 Patients .....................................124 
Table 16: Intercurrent Events for Analysis of ORR per Central Review and 
Investigator Assessment ...........................................................................................178 
Table 17: Intercurrent Events for Analysis of DOR per Central Review and 
Investigator Assessment ...........................................................................................179 
Table 18: Intercurrent Events for Analysis of PFS per Central Review and Investigator 
Assessment ...............................................................................................................180 
Table 19: Intercurrent Events for Analysis of OS per Central Review and Investigator 
Assessment ...............................................................................................................181 
Table 20: Frequency of Intercurrent Events in Group 1, 2, and 3 in the Primary 
Analysis ....................................................................................................................181 
Table 21: The Binomial Exact Confidence Intervals for Observed ORR in Metastatic 
CSCC Patients at Final Analysis (N=133)................................................................183 
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Table 22: The Binomial Exact Confidence Intervals for Observed ORR in Locally 
Advanced CSCC Patients at Final Analysis (N=34) ................................................183 
Table 23: The Binomial Exact Confidence Intervals for Observed ORR in Advanced 
CSCC Patients at Interim Analysis of Group 6 (N=84) ...........................................184 
Table 24: The Binomial Exact Confidence Intervals for Observed ORR in Metastatic 
CSCC Patients at Interim Analysis (N=64) ..............................................................184 
Table 25: The Binomial Exact Confidence Intervals for Observed ORR in Locally 
Advanced CSCC Patients at Interim Analysis (N=20) .............................................184 
 
LIST OF APPENDICES 
APPENDIX 1. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS: 
RECIST GUIDELINE (VERSION 1.1) ...........................................................139 
APPENDIX 2. COMPOSITE RESPONSE CRITERIA FOR PATIENTS WITH 
LOCALLY ADVANCED CSCC .....................................................................144 
APPENDIX 3. CEMIPLIMAB PHARMACOKINETIC SAMPLING AND 
ASSESSMENT SCHEDULE ...........................................................................149 
APPENDIX 4. RECOMMENDED DOSE MODIFICATION OR 
DISCONTINUATION AND SUPPORTIVE CARE GUIDELINES 
FOR SPECIFIC STUDY DRUG-RELATED ADVERSE EVENTS ...............153 
APPENDIX 5. 
.........169 
APPENDIX 6. 
 ...............................................172 
APPENDIX 7. EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS ...........................................................................................................175 
APPENDIX 8. FACTORS TO CONSIDER IN ASSESSING THE RELATIONSHIP 
OF AES TO CEMIPLIMAB OR STUDY CONDUCT. ..................................176 
APPENDIX 9. ADAPTED EUROPEAN ORGANIZATION FOR RESEARCH AND 
TREATEMENT OF CANCER POSITRON-EMISSION 
TOMOGRAPHY CRITERIA (FOR GROUP 4) ..............................................177 
APPENDIX 10. STATISTICAL ANALYSES ...........................................................................178 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
Definition of Term 
ADA 
Anti-drug antibody 
ADL 
Activities of Daily Living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANA 
Antinuclear antibody 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time  
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration–time curve 
BAL 
Bronchoalveolar lavage 
BCC 
Basal cell carcinoma 
BOR 
Best overall response 
BUN 
Blood urea nitrogen 
CR 
Complete response 
CRC 
Central Review Committee 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CRP  
C-reactive protein 
CSCC 
Cutaneous squamous cell carcinoma 
CT 
Computed tomography 
ctDNA 
Circulating tumor DNA 
CTLA-4 
Cytotoxic T-lymphocyte antigen 4  
DOR 
Duration of Response 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EORTC 
European Organisation for Research and Treatment of Cancer 
EORTC QLQ-
C30 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 
EOS 
End of study 
FAS 
Full analysis set 
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Abbreviations 
Definition of Term 
FDG-PET 
18F-fluorodeoxyglucose positron emission tomography 
FIH 
First-in-human 
FFPE 
Formalin-fixed, paraffin-embedded 
GCP 
Good clinical practice 
GITR 
Glucocorticoid-induced TNFR family related gene 
GnRH 
Gonadotropin-releasing hormone 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HNSCC 
Head and neck squamous cell carcinoma 
HPV 
Human papillomavirus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
INR 
International Normalized Ratio 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
irRC 
Immune-related response criteria 
ISR 
Injection site reaction 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
LAG-3 
Lymphocyte activation gene-3 
LD 
Longest diameter 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LLOQ 
Lower limit of quantification 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NCCN 
The National Comprehensive Cancer Network 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NSCLC 
Non–small-cell lung cancer 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed death-1 (receptor) 
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Abbreviations 
Definition of Term 
PD-L1, PD-L2 
Programmed death ligand 1, programmed death ligand 2 
PET 
Positron-emission tomography 
PFS 
Progression-free survival 
PI 3-K 
phosphatidylinositol 3-kinase 
PK 
Pharmacokinetic 
PR 
Partial response 
PT 
Preferred term 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks  
Q4W 
Every 4 weeks 
Q6W 
Every 6 weeks 
RCC 
Renal cell cancer  
RECIST 
Response Evaluation Criteria in Solid Tumors 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RF 
Rheumatoid factor 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Systems (software) 
SC 
Subcutaneous 
SOC 
System organ class 
SSC 
Study Steering Committee 
TEAE 
Treatment-emergent adverse event 
TIL 
Tumor-infiltrating lymphocytes 
TMB 
Tumor mutation burden 
TSH 
Thyroid-stimulating hormone 
US 
United States 
WBC 
White blood cell 
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1. 
INTRODUCTION AND RATIONALE 
1.1. 
Introduction 
Cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy in the United 
States (US), with approximately 186,000 to 420,000 individuals diagnosed with CSCC each year 
(Karia 2013).  Precise incidence and mortality measurements are not available because these 
cancers are not included in the Surveillance, Epidemiology, and End Results (SEER) database.  A 
review of other national databases indicates that incidence of non-melanoma skin cancers, mostly 
basal cell carcinoma (BCC) and CSCC, approximately doubled between 1994 and 2006 in the 
context of an aging population (Rogers 2010).  Most CSCC patients have a favorable prognosis, 
but annual mortality is approximately 3,900 to 8,800 deaths in the US (Karia 2013).  Risk factors 
for CSCC include UV exposure, advanced age, and immunosuppression (Alam 2001, 
Madan 2010).  Although the vast majority of individuals with diagnosis of CSCC or BCC have a 
very favorable prognosis, CSCC has a greater propensity for aggressive recurrences than BCC.  
Individuals diagnosed with CSCC, unlike those diagnosed with BCC, have an increased mortality 
compared with age-matched controls (Rees 2015). 
In the American Joint Committee on Cancer 7th Edition Staging System, tumor size less than or 
greater than 2 cm is a key distinction between stage 1 and 2, and selected risk factors are also 
incorporated in the staging (Farasat 2011).  Stage 3 designates CSCC with involvement of a single 
lymph node ≤3cm, and stage 4 includes patients with a broad range of locally invasive tumors 
and/or distant metastatic disease (Farasat 2011).  Limitations of this staging system include 
heterogeneity of outcomes in stage I and II tumors; alternative risk-adapted staging has been 
proposed but not externally validated (Karia 2014).  
Surgical resection is the centerpiece of clinical management of CSCC.  The primary goal is 
complete resection of cancer, and acceptable cosmetic outcome is a secondary goal (Madan 2010).  
The choice of surgical intervention is influenced by a number of factors, including size and 
histology of the tumor, expertise of the local clinical team, and comorbidities of the patient.  
Factors associated with poor prognosis in CSCC include tumor size >2 cm, tumor depth >2mm, 
perineural invasion, host immunosuppression, and recurrent lesions (Madan 2010, 
Schmults 2013). 
Efficacy for radiation therapy for CSCC has been described in the adjuvant setting in a large 
retrospective study of 167 patients with nodal involvement who underwent surgical resection.  
Patients undergoing post-operative radiation therapy had a lower rate of locoregional recurrence 
compared to those who underwent surgery only (20% vs. 43%), and superior 5-year overall 
survival (OS) (73% vs. 54%) of CSCC (Veness 2005).  In a small prospective phase 1 study of 
15 CSCC patients who received post-operative radiation (60 to 66 Gy for 6 weeks) with concurrent 
erlotinib, the 2-year OS was 65% (Heath 2013). 
For the small percentage of patients who develop unresectable locally recurrent or metastatic 
disease, treatment options are limited.  A phase 2 prospective study of 14 patients with unresectable 
or inoperable CSCC treated with platinum based-chemoradiation, reported in abstract form only, 
found that OS at 3 years was 54% (Nottage 2012).  In a single institution retrospective case series 
of 12 patients with unresectable CSCC that were treated with radiation therapy (median dose 60 Gy 
in 30 fractions) and concurrent cetuximab, median OS was 8 months (Samstein 2014).  Durable 
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disease control was achieved in some patients, and this retrospective study also reviewed other 
reports of CSCC treated with chemoradiotherapy (case reports, case series) in the literature, in 
which some patients experienced long term disease control (Samstein 2014).  These results 
underscore that for patients with unresectable advanced CSCC, the malignancy is a life-threatening 
condition, but some patients may achieve durable disease control with radiation-based therapy.  As 
such, radiation-based therapy is appropriately considered for some patients with unresectable 
CSCC. 
Regarding systemic therapies, there have been single-arm studies that often contained 
heterogeneous groups of CSCC patients with different stages of disease, but none of these studies 
clearly demonstrated therapeutic advantage (Maubec 2011, Nakamura 2013).  As a result, there is 
a dearth of data to guide clinical decision-making for oncologists who take care of patients with 
advanced CSCC.  The National Comprehensive Cancer Network (NCCN) guidelines do not 
provide firm recommendations.  Cisplatin monotherapy, cisplatin plus 5-fluororucacil (5-FU), and 
cetuximab are discussed only as “possible options,” and participation in clinical trials is 
recommended with the caveat that such trials are scarce (Bichakjian 2015).  One factor that has 
prevented the adoption of a standard-of-care for advanced CSCC is the lack of an adequate 
demonstration of safety of any regimen for this patient population.  Two frequently-cited studies 
of cisplatin + 5-FU-based chemotherapy enrolled 14 and 7 advanced CSCC patients, respectively, 
and therefore were unable to provide a meaningful safety assessment (Sadek 1990, Khansur 1991).  
A more comprehensive description of the safety profile of cisplatin + 5-FU was obtained in a large 
randomized clinical trial for a different patient population, head and neck squamous cell carcinoma 
(HNSCC).  Among 215 patients with a median age of 57 years who were treated with cisplatin + 
5-FU for advanced HNSCC, 76% experienced Grade 3 or 4 toxicities.  Given that CSCC occurs 
in an older patient population (Gray 1997, Diffey 2005, Karia 2014), the lack of optimization of 
dose and schedule of cisplatin and 5-FU for older individuals is a practical limitation to the clinical 
use of these regimens in CSCC.  Advanced age increases the probability of requirement for dose 
reduction in the first cycle of chemotherapy among patients with advanced solid tumors 
(Gajra 2015).  As such, platinum and/or 5-FU-based chemotherapy is not an attractive option for 
many CSCC patients due to safety and tolerability concerns associated with advanced age. 
Targeting of the epidermal growth factor receptor (EGFR) in CSCC has been explored by several 
groups. In a phase 2 study of cetuximab monotherapy for patients with unresectable squamous cell 
carcinoma of the skin, median age was 79 years (Maubec 2011).  The observed response rate was 
28% (10/36 patients), median progression-free survival (PFS) was 4.1 months, and median OS 
was 8.1 months (Maubec 2011).  A phase 2 study of panitumumab enrolled 16 patients with 
advanced CSCC that was deemed incurable; 2 patients had metastatic disease (Foote 2014). 
Overall response rate (ORR) was 31% (95% CI: 11-59%).  These studies of EGFR-targeting 
monoclonal antibodies (mAbs) share some of the same limitations of the studies of cytotoxic 
chemotherapy that were noted above, including small sample size and lack of demonstration of 
benefit in quality of life. 
A review of the published literature for systemic therapy for CSCC demonstrates that response 
rates appear to be associated with extent of disease. Table 1 includes only studies with a least 
20 evaluable patients with advanced CSCC.  Response rates for locally advanced (primary site) 
tumors are generally higher than response rates for tumors that have metastasized to regional 
lymph nodes or distant visceral sites.  As such, in prospective clinical research for patients with 
advanced CSCC, it is appropriate to evaluate patients with locally advanced CSCC as a distinct 
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Additional Background for Amendment 6:  Designs for new Groups 4 and 5 will encompass all 
advanced CSCC (defined as either metastatic [nodal or distant] CSCC or locally advanced CSCC 
that is not appropriate for surgery) as one entity.  
Additional Background for Amendment 7:  As was done in Groups 4 and 5, Group 6 will be 
open to all advanced CSCC patients.  The intent of Group 6 is to provide additional efficacy and 
safety data for 
 IV for patients with advanced CSCC. 
Additional Background for Amendment 9: Based on pilot experience in Group 5 (n=9), a single 
SC dose was shown to be  well tolerated. The bioavailability of a single dose of cemiplimab SC 
was approximately 83% in Group 5 (Regeneron, data on file). Based on the desirability of 
improving patient convenience factors for treatment, and our initial experience in Group 5, it is 
appropriate to explore repeat doses of cemiplimab SC. Protocol Amendment 9 will offer 
approximately 18 patients in Group 6 who have completed ≥27 weeks of IV cemiplimab treatment 
(which corresponds to the first 3 tumor assessments on treatment)  the option to receive subsequent 
doses 
 
 
Additional patients may be offered one of these options as available.   
1.2. 
Rationale 
1.2.1. 
Rationale for Dose Selection 
For Groups 1 and 2:  In the Dose Escalation portion of the FIH study of cemiplimab (R2810-
ONC-1423), no dose-limiting toxicities were observed.  The dose escalation portion of the study 
established that cemiplimab 3 mg/kg every 2 weeks (Q2W) intravenously (IV) administered over 
30 minutes (±10 minutes) is the recommended monotherapy dosing regimen for the agent in 
further studies for advanced cancer patients (Papadopoulos ASCO 2016 Annual Meeting, Abstract 
3024).  
For Groups 3 and 6:  This cemiplimab dose of 350 mg Q3W was chosen for Group 3 based on 
the safety and preliminary anti-tumor activity observed in the ongoing FIH study R2810-ONC-
1423 (NCT02383212), and was supported by modeling of cemiplimab exposure in serum based 
on data collected in the FIH study.  Simulations of cemiplimab exposure in 1000 patients using 
population pharmacokinetic (PK) analyses indicated that: 1) the variability in cemiplimab 
exposure (CV%) was similar with body weight adjusted as compared to fixed doses; therefore, 
supporting the fixed dose selection, and 2) that a 350 mg Q3W dose resulted in similar 
(≤20% difference) Ctrough, AUC12W and Cmax as compared to a 3 mg/kg Q2W dose used in the FIH 
study.  These cemiplimab concentrations exceed those observed at the 1 mg/kg Q2W dose and 
demonstrated clinical efficacy in the FIH study.  At the 350 mg Q3W dose, Ctrough values at steady 
state generally exceed concentrations of approximately 5 to 20 mg/L, above which (based on 
animal data) saturation of PD-1 target occupancy is expected to occur.  Therefore, cemiplimab 
 is being proposed in Group 3 and also in Group 6, and in new phase 2 and phase 3 
studies across the cemiplimab program.   
Text added for implementation of Protocol Amendment 9 (PA9):Based on pilot experience in 
Group 5, a single SC dose was well tolerated and the bioavailability of cemiplimab 350 mg Q3W 
SC was approximately 83%. For this reason, it is appropriate to explore 
 of cemiplimab 
SC, as summarized at the end of this section (Group 6 Option for SC Cemiplimab).  
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For Group 4 (cemiplimab IV Q4W):  Cemiplimab IV regimen every 4 weeks (Q4W) will be 
assessed in Group 4.  The dose of 600 mg IV Q4W is supported by modeling of cemiplimab 
exposure in serum and by observed data with other doses and schedules in this study and the FIH 
study of cemiplimab R2810-ONC-1423.  While a 500 mg IV Q4W dose is predicted to provide 
similar cemiplimab exposure (AUC12W) to that of a 3 mg/kg IV Q2W dose, a slightly higher dose 
is proposed to achieve cemiplimab trough concentrations (Ctrough) during the Q4W dosing that 
remain between those observed at 3 mg/kg IV Q2W and at 350 mg IV Q3W.  Based on this 
approach, a dosing regimen of 600 mg IV Q4W was selected, that is predicted to result in a steady 
state Ctrough value of 59 mg/L, while Cmax and AUC12W would be slightly higher, by about 51% for 
Cmax and about 29% for AUC12W, than observed at a 350 mg IV Q3W dose.  Previous data from 
the FIH study R2810-ONC-1423 demonstrate that the safety profile is flat between 3 mg/kg Q2W 
and 10 mg/kg Q2W.  The predicted exposures and Cmax associated with the 600 mg Q4W regimen 
are less than that achieved with the 10 mg/kg Q2W regimen.   
For Group 5 (pilot cohort with 1 dose of cemiplimab SC): A single dose of cemiplimab 438 mg 
SC (actual dose is 437.5 mg), followed by cemiplimab 350 mg IV Q3W will be administered to 
assess the bioavailability of SC cemiplimab and to determine the SC dose regimen to be used in 
the cohort based on population PK approaches.  As an indication, if the SC bioavailability of 
cemiplimab is confirmed to be around 0.7, which is generally the case for mAbs, simulated 
cemiplimab exposure at steady state after cemiplimab 438 mg SC Q3W would be around 54 mg/L 
for Ctrough, 89 mg/L for Cmax and 3036 mg/L*day for AUC12W, compared to 53 mg/L, 157 mg/L 
and 6950 mg/L*d after cemiplimab 350 mg IV Q3W, respectively. 
For Group 6 Option for SC cemiplimab  (at or after 27 weeks): Protocol Amendment 9 will 
provide patients in Group 6 who have completed ≥ 27 weeks of IV cemiplinab treatment the option 
to receive subsequent doses as cemiplimab SC. The timing (≥ 27 weeks) corresponds to the interim 
and primary efficacy analyses for Group 6. PA9 will only be implemented after the data cut for 
the primary analyses, when all patients will have had the opportunity for at least 3 tumor 
assessments (≥ 27 weeks).   
Based on cemiplimab exposure data and SC bioavailability after a single SC dose in Group 5, 
modeling and simulation of cemiplimab concentrations in serum after subcutaneous doses of 
 suggest that cemiplimab Ctrough,ss after 
350 mg Q3W IV will be maintained with any of these SC dosing regimens, while as expected 
Cmax,ss at 
 will be lower (-48%) and at the 
 will be similar 
compared to the 350 mg Q3W IV dose. Upon switching from an IV to a SC therapy, steady state 
exposure will be reached for cemiplimab upon 12 weeks of cemiplimab SC dosing. 
1.2.2. 
Rationale for Study of Cemiplimab in CSCC 
The central role of sun exposure in the pathogenesis of CSCC is evident at the molecular and 
cellular level.  Most somatic mutations in CSCC tumors are C > T transitions, consistent with UV 
damage (Durinck 2011, Pickering 2014, Li 2015).  The total mutation burden of CSCC is 
approximately 30 to 60 per megabase, compared with approximately 13 per megabase in malignant 
melanoma, which is the tumor type with the highest mutation burden in The Cancer Genome Atlas 
(Durinck 2011, Pickering 2014, Li 2015).  Preclinical studies suggest that UV light may also be 
carcinogenic due to incompletely understood immunosuppressive effects (Fisher 1982, 
Moodycliffe 2000), in addition to mutagenicity. 
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Cutaneous squamous cell carcinoma has several clinical and biological factors that suggest that it 
is appropriate for the clinical study of inhibition of the PD-1 immune checkpoint: high mutation 
burden (Pickering 2014), presence of tumor-infiltrating lymphocytes (TILs) (Muhleisen 2009, 
Freeman 2014), association with immunosuppression as a risk factor (Euvrard 2003), evidence of 
direct immunosuppressive effects of UV radiation (Yu 2014), and some clinical efficacy with 
interferon α2a-based treatment (Lippman 1992).  
The presence of high mutation burden appears to be a shared characteristic of other solid tumors 
for which inhibition of the PD-1/PD-L1 axis has been associated with therapeutic efficacy, 
including melanoma, NSCLC, and bladder cancer (Alexandrov 2013).  Among NSCLC patients 
treated with pembrolizumab, emerging clinical data suggest a direct correlation between mutation 
burden and clinical efficacy of PD-1 inhibition (Rizvi 2015).  Preliminary clinical results from a 
phase 2 study of pembrolizumab for patients with advanced solid tumors that are hypermutated 
due to mismatch repair deficiency demonstrates that overall radiographic response rates are 
approximately 60% (Le 2015).  
Libtayo® (cemiplimab) has received marketing authorization and is now approved in the US, EU, 
Canada, and Brazil for the treatment of patients with metastatic CSCC or patients with locally 
advanced CSCC who are not candidates for curative surgery or curative radiation.  In the US and 
EU, cemiplimab is also approved for the treatment of patients with metastatic basal cell carcinoma 
(BCC) or locally advanced BCC, and who were previously treated with a hedgehog pathway 
inhibitor (HHI).  It is also approved for the first-line treatment of patients with metastatic non-
small cell lung cancer (NSCLC) or locally advanced NSCLC that is not a candidate for surgical 
resection or definitive chemoradiation, and whose tumors have high (tumor proportion score [TPS] 
≥50%) PD-L1 expression (with no EGFR, ALK, or ROS1 abberations).  In the US, it is approved 
as cemiplimab-rwlc.   
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
For Groups 1 to 4, the primary objective of this study is to estimate the clinical benefit of 
cemiplimab monotherapy for patients with: metastatic (nodal or distant) CSCC, or unresectable 
locally advanced CSCC.  Group 1 consists of patients with metastatic (nodal or distant) CSCC 
treated with cemiplimab 3 mg/kg IV Q2W.  Group 2 consists of patients with unresectable locally 
advanced CSCC, treated with cemiplimab 3 mg/kg IV Q2W.  Group 3 consists of patients with 
metastatic (nodal or distant) CSCC treated with cemiplimab 350 mg IV Q3W.  Group 4 consists 
of patients with advanced CSCC (metastatic [nodal or distal] or unresectable locally advanced) 
treated with cemiplimab 600 mg IV every 4 weeks (Q4W).  For Group 6, the primary objective is 
to provide additional efficacy and safety data for cemiplimab monotherapy in patients with 
advanced CSCC (metastatic [nodal or distant] or locally advanced) treated with cemiplimab 
350 mg IV Q3W.   
Clinical benefit is measured by ORR according to central review in each group. 
2.2. 
Secondary Objectives 
The secondary objectives for Groups 1 to 4, and Group 6  are: 
• To estimate ORR (see Appendix 1 and Appendix 2) according to investigator review  
• To estimate the duration of response (DOR), PFS, and OS by central and investigator 
review 
• To estimate the complete response (CR) rate by central review 
• To assess the safety and tolerability of cemiplimab  
• To assess the PK of cemiplimab  
• To assess the immunogenicity of cemiplimab 
For Groups 1 to 5 only: 
• To assess the impact of cemiplimab on quality of life using European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC 
QLQ-C30)  
Group 6 only:  To assess relationships between PD-L1 status (by IHC) and efficacy measures 
(ORR, DOR, PFS). 
2.3. 
Exploratory Objectives 
2.3.1. 
Groups 2 and 4 
 
 
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2.3.2. 
Group 5 Only 
Group 5 will be a pilot cohort that enrolls 10 patients with advanced CSCC.  These patients will 
receive 1 dose of cemiplimab 438 mg SC.  Three weeks later, these patients will receive 
cemiplimab 350 mg IV Q3W.  Pharmacokinetic modeling will be conducted from this first dose.  
A larger cohort may be added to further study the dose and schedule of cemiplimab that is 
recommended based on the results of this pilot cohort at a future amendment following approval 
by health authorities. 
 
 
 
 
  
2.3.3. 
Group 6 Only 
 
 
 
 
 
 
2.3.4. 
Group 6 Only – Patients Who Switch to SC Formulation 
Protocol Amendment 9 allows Group 6 patients who have received IV cemiplimab for at least 27 
weeks without experiencing disease progression to switch to SC cemiplimab (optional). This is 
to extend clinical experience with SC cemiplimab, including variability in PK upon repeated SC 
doses and the assessment of local tolerability at the site of SC injection. For these patients, the 
following exploratory objectives will be evaluated:  
 
 
 
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3. 
STUDY DESIGN 
3.1. 
Study Description and Duration 
This is a phase 2, non-randomized, 6-group, multicenter pivotal study evaluating the efficacy and 
safety of cemiplimab in patients with advanced CSCC.  After a screening period of up to 28 days, 
eligible patients will be enrolled into 1 of 6 groups and receive cemiplimab treatment as below.  
Tumor assessments will be made at the end of each treatment cycle.  Extensive safety evaluations 
will occur on day 1 of each cycle; routine safety evaluations will be conducted at each cemiplimab 
dosing visit. 
Groups 1 and 2 patients:  Patients with metastatic CSCC are enrolled in Group 1 and patients with 
unresectable locally advanced CSCC are enrolled in Group 2 to receive up to twelve 56-day (8-
week) treatment cycles for a total of up to 96 weeks of treatment.  Each patient will receive 
cemiplimab 3 mg/kg Q2W.   
Group 3 patients:  This cohort enrolls patients with metastatic CSCC.  Group 3 only begins 
enrollment after completion of enrollment to Group 1.  The dose regimen is 350 mg IV Q3W for 
up to 54 weeks.  
Group 4 patients:  This cohort enrolls patients with advanced CSCC (metastatic [nodal or distant] 
or locally advanced).  Group 4 only begins enrollment after completion of enrollment in Groups 1 
through 3.  The dose regimen is 600 mg IV Q4W for up to 48 weeks.  
Group 5 patients:  This cohort enrolls patients with advanced CSCC.  The regimen is 438 mg SC, 
1 dose, followed in 3 weeks by 350 mg IV Q3W for up to 54 weeks of total treatment.  The first 
3 patients in Group 5 will be dosed on 3 separate days to monitor for injection site reactions (ISRs).  
If zero severe ISRs are observed in the first 3 patients, the rest of the cohort may enroll without 
restrictions on enrollment day (ie, more than 1 patient may initiate treatment on the same day).  If 
1 or greater severe ISR is observed, enrollment will pause.  In that circumstance, resumption of 
enrollment in Group 5 may be permitted after review of all relevant data and consensus between 
the medical monitor and the designated Risk Management lead from the Pharmacovigilance & 
Risk Management department.  The investigators involved in care of these patients may also be 
consulted.  See Section 5.4.3 regarding ISRs.  
Note on enrollment: Prior to the implementation of Group 6, Groups 4 and 5 had completed 
enrollment. 
Group 6 patients:  
 
 
 
 
 
 
  
 
 
 
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Groups 1 through 5: Patients who do not experience progressive disease (PD) at the completion of 
the planned treatment period will enter follow-up for approximately 6 months.  After completion 
of this follow-up period, patients will then enter an extended follow-up period for approximately 
1 additional year with assessments every 4 months (Table 9). Patients in Groups 1 to 5 who 
complete treatment without disease progression and subsequently experience disease progression 
during the follow-up period without any intervening systemic anticancer therapy, are eligible for 
up to 2 years of retreatment with cemiplimab 350 mg IV Q3W. 
Group 6:  
 
  
 
Exploratory biopsies for correlative science purposes:  
 
  
 
 
 
 
 
 
  
3.1.1. 
Study Groups 
3.1.1.1. 
Groups 1 to 4 and Group 6  
There will be 5 study groups for formal hypothesis testing: 
• Group 1: Patients with metastatic CSCC. These patients are required to have CSCC 
metastases.  Group 1 includes patients with both nodal metastatic and distant metastatic 
disease. 
• Group 2: Patients with unresectable locally advanced CSCC.  These patients are 
required to have disease that is considered inoperable or to have medical 
contraindication to surgery or radiation, or have not achieved disease control with these 
treatments (see Section 4.2.1). 
The study populations in Groups 1 and 2 include patients with both unresectable and metastatic 
CSCC, which is conceptually similar to the enrollment of patients with unresectable or metastatic 
melanoma in immunotherapy trials (Larkin 2015).  The decision to analyze separate cohorts for 
patients with locally advanced (Group 2) and metastatic (Group 1) disease is based on a literature 
review of the reported experiences with other systemic therapies in CSCC, which demonstrates 
that response rates for various chemotherapy regimens generally are higher against advanced 
primary tumors that are locally advanced than against tumors that have metastasized to lymph 
nodes or distant visceral organs (Nakamura 2013).  This observation of higher response rates in 
locally advanced versus metastatic patients is also seen in data from studies of Smoothened 
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inhibitors against basal cell carcinoma, the most common non-melanoma skin cancer 
(Sekulic 2012, Migden 2015).  
Note in clarification:  For patients with in-transit metastases (Carucci 2004), if the baseline 
comprehensive work-up confirms that there are no nodal metastases or distant metastases, the 
patient will be deemed to have locally advanced disease and would be enrolled in Group 2.  Patients 
with in-transit metastases are typically managed by a multidisciplinary team (Carucci 2004), and, 
therefore, the multidisciplinary review regarding potential surgery or radiation therapy options that 
is required prior to study enrolment for all Group 2 patients is appropriate for patients with in-
transit metastases.  
• Group 3:  This cohort opens after the completion of enrollment to Group 1 and is for 
patients with metastatic CSCC. As was the case for Group 1 patients, Group 3 patients 
are required to have metastatic disease).  As in Group 1, Group 3 includes patients with 
both nodal metastatic and distant metastatic disease. Group 3 patients receive 
cemiplimab 350 mg IV Q3W for up to 54 weeks (whereas patients in Groups 1 and 2 
received cemiplimab 3 mg/kg IV Q2W for up to 96 weeks).   
• Group 4:  This cohort enrolls patients with advanced CSCC (metastatic [nodal or 
distant] or locally advanced).  Group 4 only begins enrollment after completion of 
enrollment in Groups 1 through 3.  The dose regimen is cemiplimab 600 mg IV Q4W 
for up to 48 weeks.   
• Group 6:  This cohort enrolls patients with advanced CSCC (metastatic [nodal or 
distant] or locally advanced).  The dose regimen is cemiplimab 350 mg IV Q3W for up 
to 108 weeks. After implementation of PA9, patients will be given the option to receive 
subsequent doses of cemiplimab SC. 
 
 
  
 
 Group 6 patients who 
switch to SC dosing must:  
− Have completed ≥27 weeks of study treatment and completed ≥3 tumor 
assessments on treatment, without disease progression 
− Patients may switch to SC dosing  on Day 1 of next cycle, after completing 
Cycle 3 through Cycle 11 of IV dosing.   Switching to SC dosing prior to 
completion of Cycle 3 of  IV dosing is not permitted. Switching to SC 
cemiplimab after starting Cycle 11 Day 1 of IV dosing is not permitted.  
Switching to SC dosing mid-cycle is not permitted in any cycle.  
− Note: It is possible that study treatment doses may be missed in clinical studies 
for a variety of reasons.  For patients who miss doses in Cycles 1-3, the 
minimum IV exposure requirement is 7 doses (of 9 planned in Cycles 1-3) 
without disease progression prior to switching to SC cemiplimab. 
− Have provided written informed consent to switch to cemiplimab SC  
− Patients may sign the consent for SC dosing at-or-after the Cycle 3/Day 22 visit 
(ahead of the C4D1 visit). The investigator must confirm there has not been 
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disease progression at the end-of-cycle tumor assessment before the patient 
commences SC dosing. 
− Have not missed ≥2 doses of IV cemiplimab therapy during the first 27 weeks. 
(Patients who have missed multiple IV doses may not be able to adhere to the SC 
schedule of events). 
In view of the visit windows that are permitted in the protocol, “27 weeks” is understood to mean 
approximately 27 weeks in accordance with the visit windows for tumor assessments. Patients may 
switch earlier than 27 weeks only if 3 on-treatment tumor assessments have been completed per 
protocol specified windows. 
In general, Group 6 patients who switch to SC dosing will stay on SC dosing for the duration of 
the study. If circumstances arise in which the investigator believes that it is in the best interest of 
the patient to return to IV dosing (ie, a patient who experiences severe injection site reactions with 
SC dosing), the medical monitor must be notified before the patient resumes cemiplimab 350 mg 
IV Q3W  dosing. 
Group 6 patients who do not take the option to switch to SC dosing may continue IV dosing, 
provided that the usual criteria for continued treatment in this study are met. 
3.1.1.2. 
Group 5 (Pilot Study) 
There will be 1 pilot study group: 
• Group 5: This 10-patient pilot cohort opens after the completion of enrollment to 
Group 3 and is for patients with advanced CSCC (defined as either metastatic CSCC 
or locally advanced) who will receive 1 dose of cemiplimab 438 mg SC.  Subsequently, 
patients will receive Q3W dosing of cemiplimab 350 mg IV for up to 54 weeks.  
Group 5 completed enrollment prior to the implementation of Amendment 7. 
3.1.1.3. 
Considerations Regarding Prior Idelalisib 
Idelalisib was exclusionary for patients enrolled into Groups 1 to 3 under Amendments 4 and 5.  
With the implementation of Amendment 6, patients with prior treatment with idelalisib are not 
excluded from enrolling into Groups 4, 5, or 6.  In tumor types in which cemiplimab has high 
efficacy (such as CSCC) and for which other treatment options are limited, in the event that a 
patient had prior idelalisib, the decision on whether to treat with cemiplimab merits an 
individualized risk:benefit assessment by the treating physician in discussion with the patient.  See 
the Investigator’s Brochure for further details of the safety events in lymphoma patients receiving 
prior idelalisib.   
3.1.2. 
End of Study Definition 
The end of study for Groups 1 to 5 is approximately 1.5 years after completion of the treatment at 
the end of extended follow-up (unless the patient enters retreatment, per Section 6.2.2).  For Group 
6, end of study is approximately 6 months after completion of the follow-up period.  The schedules 
of events for each group define when end of study would be after they enter retreatment (see 
Section 6.1).   
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3.2. 
Planned Interim Analysis 
Interim Analysis for Group 2: 
At the time of the planned efficacy analysis for Group 1 (6 months after last patient, first dose), an 
interim analysis of Group 2 patients will be performed in order to assess the risks and benefits of 
cemiplimab in unresectable locally advanced CSCC.  This analysis will be restricted to Group 2 
patients with potential for adequate follow-up, defined as patients who have the opportunity to 
receive approximately 9 months of study treatment at the time of the interim analysis.  This 
analysis will provide an ORR (with 95% confidence interval) for Group 2 patients with adequate 
follow-up.  
Interim Analysis for Group 6: 
An interim analysis of Group 6 patients will be performed after the first 50% of patients have had 
the opportunity to be followed up for a minimum of 28 weeks (27 weeks for 3 tumor assessments 
+ 1-week assessment window) or have reached the end of study.  
For additional details, please see Section 9.7. 
3.3. 
Study Committees 
3.3.1. 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) composed of members who are independent 
from the sponsor and the study sites will be established to monitor patient safety by conducting 
formal reviews of accumulated safety data. 
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, per IDMC 
charter.   
3.3.2. 
Study Steering Committee  
A Study Steering Committee (SSC) will be appointed by Regeneron Pharmaceuticals, Inc. 
(Regeneron), comprising approximately 3 to 7 investigators participating in the trial and 
Regeneron representatives from the study team.  The SSC will ensure transparent management of 
the study according to the protocol through recommending and approving modifications as 
circumstances require.  The SSC will review protocol amendments as appropriate.  Together with 
the study team, the SSC will also develop recommendations for publications of study results 
including authorship rules.  The details of the role of the steering committee will be defined in a 
steering committee charter. 
3.3.3. 
Independent Review Committees  
Three Independent Review Committees will be established to assess the primary endpoint of 
response rate by central review: independent radiologic response assessment committee, 
independent photographic response assessment committee, and independent composite response 
assessment committee.  Committee members will follow charters that are established for each of 
these committees.  
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4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
4.1. 
Number of Patients Planned 
Up to 433 adult patients (Group 1, 53 patients planned [actual enrolled, 59]; Group 2, 76 patients 
planned [actual enrolled, 78]; Group 3, 53 patients planned [actual enrolled, 56]; Group 4, 
63 patients planned (actual enrollment, 63 patients); Group 5, 10 patients planned (actual 
enrollment, 9 patients); Group 6, 167 patients are expected to be enrolled at approximately up to 
100 sites globally.  
4.2. 
Study Population 
The study will include eligible patients with metastatic (nodal and/or distant) CSCC (Groups 1 
and 3) and unresectable locally advanced CSCC (Group 2).  Group 3 for metastatic CSCC opens 
only after enrollment to Group 1 is complete.  Groups 4, 5, and 6 enroll patients with advanced 
CSCC, a term that encompasses both metastatic (nodal or distant) CSCC and locally advanced 
CSCC.  See Section 3.1 for rules regarding when enrollment to Groups 4 and 5 can occur. 
4.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Histologically confirmed diagnosis of invasive CSCC.  
Notes on tumor primary site: Patients for whom the primary site of squamous cell 
carcinoma was the dry red lip (vermillion) are not eligible.  Patients with tumors arising on 
the cutaneous hairbearing (non-glabrous) lip with extension onto dry red lip (vermillion) 
may be eligible after communication with and approval from medical monitor.  Patients 
for whom the primary site of squamous cell carcinoma was the anogenital area (penis, 
scrotum, and perianal region) are not eligible.  Patients for whom the primary site is nose 
are only eligible if the investigator is able to establish unambiguously that the primary site 
was skin, not nasal mucosa with outward extension to skin. 
Notes on tumor histology: Patients with mixed histologies (eg, sarcomatoid, 
adenosquamous) generally will not be eligible.  Patients with mixed histology in which the 
predominant histology is invasive CSCC (with only a minimal component of mixed 
histology) may be eligible, after communication with and approval from medical monitor. 
2. At least 1 lesion that is measurable by study criteria.  
If a previously radiated lesion is to be followed as a target lesion, progression must be 
confirmed by biopsy after radiation therapy.  Previously radiated lesions may be followed 
as non-target lesions if there is at least 1 other measurable target lesion.  
For patients with metastatic (nodal or distant) CSCC:   
There must be at least 1 baseline measurable lesion ≥10 mm in maximal diameter (1.5 cm 
for lymph nodes) according to Response Evaluation Criteria in Solid Tumors (RECIST) 
1.1 criteria (Appendix 1; Eisenhauer 2009)  
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Note: In the case of patients with metastatic disease that does not meet target lesion criteria 
by RECIST 1.1 (eg, bone only lesions, perineural disease; Appendix 1) and with externally 
visible CSCC target lesion(s), Appendix 2 may be used, in which bi-dimensional 
measurements are required (at baseline, perpendicular diameters must both be ≥10 mm).  
The patient would then be enrolled with the plan to measure externally visible target 
lesion(s) by photography with bi-dimensional measurements; the metastatic lesions that 
are not measurable by RECIST 1.1 criteria would be followed as non-target lesions on 
scans. 
For patients with locally advanced CSCC:   
There must be at least 1 measurable baseline lesion in which the longest diameter (LD) and 
the perpendicular diameter are both ≥10 mm if followed by digital medical photography 
(see Appendix 2).  Non-measurable disease for Group 2 is defined as either 
unidimensionally measurable lesions, tumors with margins that are not clearly defined, or 
lesions with maximum perpendicular diameters less than 10 mm.  Patients without 
measurable disease at baseline are not eligible for the study. 
3. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (ECOG PS 1 
definition: Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work; Appendix 7). 
Note: Patients with ECOG PS >1 are ineligible. 
4. ≥18 years old 
5. Hepatic function: 
a. Total bilirubin ≤1.5 x upper limit of normal (ULN; if liver metastases ≤3 x ULN). 
Patients with Gilbert’s Disease and total bilirubin up to 3 x ULN may be eligible after 
communication with and approval from the medical monitor. 
b. Transaminases ≤3 x ULN (or ≤5.0 x ULN, if liver metastases) 
c. Alkaline phosphatase (ALP) ≤2.5 x ULN (or ≤5.0 x ULN, if liver or bone metastases) 
Note for patients with hepatic metastases:  If transaminase levels (AST and/or ALT) are 
>3 x but ≤5 x ULN, total bilirubin must be ≤1.5 x ULN.  If total bilirubin is >1.5 x but ≤3 x 
ULN, both transaminases (AST and ALT) must be ≤3 x ULN. 
6. Renal function: Serum creatinine ≤1.5 x ULN or estimated creatinine clearance (CrCl) 
>30 mL/min 
7. Bone marrow function: 
a. Hemoglobin ≥9.0 g/dL 
b. Absolute neutrophil count (ANC) ≥1.5 x 109/L 
c. Platelet count ≥75 x 109/L 
8. Ability to provide signed informed consent 
9. Ability and willingness to comply with scheduled visits, treatment plans, laboratory tests, 
and other study-related procedures 
10. Anticipated life expectancy >12 weeks 
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11. Patients with locally advanced CSCC:   
Surgery must be deemed contraindicated in the opinion of a Mohs dermatologic surgeon, 
a head and neck surgeon, or plastic surgeon.  A copy of the surgeon’s consultation note 
from a clinical visit within 60 days of enrollment must be submitted. 
Acceptable contraindications in the surgeon’s note include: 
• CSCC that has recurred in the same location after 2 or more surgical procedures and 
curative resection is deemed unlikely 
• CSCCs with significant local invasion that precludes complete resection  
• CSCCs in anatomically challenging locations for which surgery may result in severe 
disfigurement or dysfunction (eg, removal of all or part of a facial structure, such as 
nose, ear, or eye; or requirement for limb amputation) 
• Other conditions deemed to be contraindicating for surgery must be discussed with the 
medical monitor before enrolling the patient. 
12. Patients with locally advanced CSCC:   
Patients must be deemed as not appropriate for radiation therapy.  Specifically, patients 
must meet at least 1 of the following criteria:  
a. A patient previously received radiation therapy for CSCC, such that further radiation 
therapy would exceed the threshold of acceptable cumulative dose, per the radiation 
oncologist.  A copy of the radiation oncologist’s consultation note, from a clinical visit 
within 60 days of enrollment, must be submitted. 
b. Judgment of radiation oncologist that such tumor is unlikely to respond to therapy.  A 
copy of the radiation oncologist’s consultation note, from a clinical visit within 60 days 
of enrollment, must be submitted. 
c. A clinic note from the investigator indicating that an individualized benefit:risk 
assessment was performed by a multidisciplinary team (consisting of, at minimum, a 
radiation oncologist AND EITHER a medical oncologist with expertise in cutaneous 
malignancies OR a dermato-oncologist, OR a head and neck surgeon) within 60 days 
prior to enrollment in the proposed study, and the radiation therapy was deemed to be 
contraindicated.  
Acceptable contraindications to radiation therapy in the investigator’s note for patients who 
have not received any prior radiation include: 
• CSCCs in anatomically challenging locations for which radiation therapy would be 
associated with unacceptable toxicity risk in the context of the patient’s overall medical 
condition in the opinion of the multidisciplinary team (eg, a neck tumor for which 
radiation therapy would result in potential need for a percutaneous gastrostomy tube).  
A copy of the investigator’s consultation note documenting the multidisciplinary 
assessment must be submitted. 
• Other conditions deemed to be contraindicating for radiation therapy must be discussed 
with the medical monitor before enrolling the patient. 
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13. Groups 1 to 5: All patients in either group must consent to provide archived or newly 
obtained tumor material (either formalin-fixed, paraffin-embedded [FFPE] block or 
10 unstained or stained slides) for central pathology review for confirmation of diagnosis 
of CSCC.  This material must be confirmed as received by the central lab prior to 
enrollment. 
14. Group 2 (locally advanced CSCC patients) and Group 4 (locally advanced CSCC patients 
and metastatic CSCC patients) only: Patients must consent to undergo biopsies of CSCC 
lesions at baseline, cycle 1 day 29 (±3 business days), at time of tumor progression, and at 
other time points that may be clinically indicated in the opinion of the investigator. 
15.  For patients with locally advanced CSCC:  An investigator note which states that the 
natural history of the patient’s advanced CSCC would likely be life-threatening within 
3 years with currently available management options outside of a clinical trial or 
cemiplimab. 
16. Group 6: Patients must consent to undergo biopsies of CSCC lesions at baseline (and at 
time of tumor progression, if possible), unless the investigator communicates to the 
medical monitor that there is unacceptable safety risk associated with tumor biopsy in a 
particular patient, and at other time points that may be clinically indicated in the opinion 
of the investigator. 
4.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Ongoing or recent (within 5 years) evidence of significant autoimmune disease that 
required treatment with systemic immunosuppressive treatments, which may suggest risk 
for immune-related adverse events (irAEs).  The following are not exclusionary: vitiligo, 
childhood asthma that has resolved, type 1 diabetes, residual hypothyroidism that required 
only hormone replacement, or psoriasis that does not require systemic treatment. 
2. Prior treatment with an agent that blocks the PD-1/PD-L1 pathway. 
3. Prior treatment with other immune modulating agents that was (a) within fewer than 
4 weeks (28 days) prior to the first dose of cemiplimab, or (b) associated with immune-
mediated adverse events that were ≥ grade 1 within 90 days prior to the first dose of 
cemiplimab, or (c) associated with toxicity that resulted in discontinuation of the immune-
modulating agent.  Examples of immune modulating agents include therapeutic anti-cancer 
vaccines, cytokine treatments (other than G-CSF or erythropoietin), or agents that target 
cytotoxic T-lymphocyte antigen 4 (CTLA-4), 4-1BB (CD137), PI 3-K-delta, or OX-40. 
4. Untreated brain metastasis(es) that may be considered active. (Note: patients with brain 
involvement of CSCC due to direct extension of invading tumor, rather than metastasis, 
may be allowed to enroll if they do not require greater than 10 mg prednisone daily, after 
discussion and approval of the medical monitor).  Patients with previously treated brain 
metastases may participate provided that the lesion(s) is (are) stable (without evidence of 
progression for at least 6 weeks on imaging obtained in the screening period), and there is 
no evidence of new or enlarging brain metastases, and the patient does not require any 
immunosuppressive doses of systemic corticosteroids for management of brain 
metastasis(es) within 4 weeks of first dose of cemiplimab. 
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5. Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within 
4 weeks prior to the first dose of cemiplimab. 
Note: Patients who require brief course of steroids (eg, as prophylaxis for imaging studies 
due to hypersensitivity to contrast agents) are not excluded. 
6. Active infection requiring therapy, including infection with human immunodeficiency 
virus, or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). 
7. History of non-infectious pneumonitis within the last 5 years.  If pneumonitis was purely 
infectious in etiology, enrolling on protocol may be allowed after discussion with medical 
monitor.  
8. Grade ≥3 hypercalcemia at time of enrollment 
9. Any systemic anticancer treatment (chemotherapy, targeted systemic therapy, 
photodynamic therapy), investigational or standard of care, within 30 days of the initial 
administration of cemiplimab or planned to occur during the study period (patients 
receiving bisphosphonates or denosumab are not excluded), radiation therapy within 
14 days of initial administration of cemiplimab or planned to occur during the study period. 
Note: For patients with multiple CSCCs at baseline that are not designated by the 
investigator as target lesions, treatment of these non-target CSCCs with surgery may be 
permitted but must be discussed with the medical monitor prior to any surgical procedure. 
10. History of documented allergic reactions or acute hypersensitivity reaction attributed to 
antibody treatments. 
11. Patients with allergy or hypersensitivity to cemiplimab or to any of the excipients must be 
excluded.   
12. Breast feeding 
13. Positive serum pregnancy test (a false positive pregnancy test, if demonstrated by serial 
measurements and negative ultrasound, will not be exclusionary, upon communication 
with and approval from the medical monitor). 
14. Concurrent malignancy other than CSCC and/or history of malignancy other than CSCC 
within 3 years of date of first planned dose of cemiplimab, except for tumors with 
negligible risk of metastasis or death, such as adequately treated BCC of the skin, 
carcinoma in situ of the cervix, or ductal carcinoma in situ of the breast, or low-risk early 
stage prostate adenocarcinoma (T1-T2aN0M0 and Gleason score ≤6 and PSA ≤10 ng/mL) 
for which the management plan is active surveillance, or prostate adenocarcinoma with 
biochemical-only recurrence with documented PSA doubling time of >12 months for 
which the management plan is active surveillance (D’Amico 2005, Pham 2016). Patients 
with hematologic malignancies (eg, chronic lymphocytic leukemia, CLL) are excluded. 
15. Any acute or chronic psychiatric problems that, in the opinion of the investigator, make the 
patient ineligible for participation. 
16. Continued sexual activity in men or women of childbearing potential (WOCBP)* who are 
unwilling to practice highly effective contraception prior to the initial dose/start of the first 
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treatment, during the study, and for at least 6 months after the last dose. Highly effective 
contraceptive measures include:  
a. 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  
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS);  
c. bilateral tubal ligation  
d. vasectomized partner (provided that the male vasectomized partner is the sole sexual 
partner of the WOCBP study participant and that the vasectomized partner has obtained 
medical assessment of surgical success for the procedure)  
e. and/or sexual abstinence†,‡.  
* 
WOCBP are defined as women who are fertile following menarche until becoming 
postmenopausal, unless permanently sterile.  Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy.  However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a 
postmenopausal state. The above definitions are according to Clinical Trial Facilitation 
Group (CTFG) guidance. 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 
drugs.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
‡ 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are 
not acceptable methods of contraception.  Female condom and male condom should 
not be used together. 
17. Patients with a history of solid organ transplant (patients with prior corneal transplant(s) 
may be allowed to enroll after discussion with and approval from the medical monitor). 
18. Prior treatment with a BRAF inhibitor 
19. Any medical co-morbidity, physical examination finding, or metabolic dysfunction, or 
clinical laboratory abnormality that, in the opinion of the investigator, renders the patient 
unsuitable for participation in a clinical trial due to high safety risks and/or potential to 
affect interpretation of results of the study. 
Note in clarification: The investigator must contact the sponsor’s medical monitor 
regarding any patients that the investigator feels cannot provide the required baseline tumor 
biopsies.  
20. Inability to undergo any contrast-enhanced radiologic response assessment. 
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Notes regarding imaging options: A patient who is unable to undergo CT with iodinated 
contrast (eg, due to contrast allergy) would not be excluded if his/her disease can be 
measured by MRI with gadolinium.  A patient who is unable to undergo MRI with 
gadolinium would not be excluded if his/her disease can be measured by CT scan with 
contrast. 
Note regarding locally advanced CSCC patients only: In selected cases, a locally 
advanced CSCC patient who is unable to undergo any contrast enhanced radiographic 
imaging (neither CT with iodinated contrast nor MRI with gadolinium) may be eligible if 
the patient’s disease can be comprehensively assessed with digital medical photography, 
after communication with and approval from medical monitor. 
4.3. 
Premature Withdrawal from the Study or from Study Treatment 
4.3.1. 
Reasons for Premature Withdrawal or Discontinuation of Study Treatment 
A patient has the right to voluntarily discontinue study treatment or withdraw from the study at 
any time, for any reason, and without repercussion. 
The investigator and sponsor have the right to discontinue a patient from study treatment or 
withdraw a patient from the study at any time. 
Reasons for discontinuation of study treatment or withdrawal from the study may include, but are 
not limited to: 
• Patient withdrawal of consent at any time 
• Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety if he or she continues in the study or continues treatment with study 
drug 
• The investigator or sponsor determines it is in the best interest of the patient 
• Patient noncompliance (eg, not complying with protocol required visits, assessments, 
and dosing instructions) 
• Pregnancy 
4.3.2. 
Discontinuation of Study Treatment 
A patient who permanently discontinues study treatment will be followed as detailed in 
Section 6.2.2. 
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4.3.3. 
Withdrawal from Study Participation 
During the treatment period and follow-up period, a patient who withdraws consent to continue 
participation in the study will not be followed for any reason after consent has been withdrawn.  
An excessive rate of withdrawals would render the study uninterpretable; therefore, unnecessary 
withdrawal of patients should be avoided. 
4.4. 
Replacement of Patients 
Patients prematurely discontinued from the study who had received at least 1 treatment with 
Cemiplimab will not be replaced. 
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5. 
STUDY TREATMENTS 
5.1. 
Investigational Treatment 
Cemiplimab will be supplied as a liquid in sterile, single-use vials.  Each vial of cemiplimab will 
contain a concentration of 50 mg/mL (for IV infusion), or a concentration of 175 mg/mL (for SC 
injection).  
Instructions on dose preparation are provided in the pharmacy manual. 
Cemiplimab will be administered in an outpatient setting as an approximately 30-minute 
(±10 minutes) IV infusion.  Longer infusion durations are acceptable if interruption is required or 
if patient had a previous infusion reaction during a prior treatment.  Group 1 and Group 2 patient’s 
dose will depend on individual body weight.  The dose of cemiplimab must be adjusted each cycle 
for changes in body weight of ≥10%.  Dose adjustments for changes in body weight of <10% will 
be at the discretion of the investigator.  Groups 3 to 6 will receive a fixed dose of cemiplimab.   
SC administration:  Group 5 will receive 1 fixed dose of SC cemiplimab followed by fixed doses 
of IV cemiplimab. For Group 6 patients who switch to cemiplimab 
, each dose 
will be administered as a single SC injection (2 mL). For Group 6 patients assigned to receive 
cemiplimab 
, each dose will be administered as 
 
 (2 mL) each. Administer SC injection into thigh or abdomen, except 2 inches (5 cm) from 
the navel.  The site of injection will be recorded in the case report form (CRF).  Do not inject 
cemiplimab in tender, damaged, bruised or scarred skin.  Cemiplimab should not be directly 
injected into the tumor.  
5.2. 
Pretreatments 
Appropriate premedication for study treatments may be administered at the investigator’s 
discretion as per usual clinical practice and in accordance with institutional guidelines.  No 
premedications are to be administered for the first dose of cemiplimab. 
5.3. 
Dose Modification and Study Drug Discontinuation Rules 
5.3.1. 
Dose Modification 
For Groups 1 and 2, the planned dose and schedule is cemiplimab 3 mg/kg IV over approximately 
30 minutes (±10 minutes) every 14 days.  For Groups 3 and 6, the planned dose and schedule is 
cemiplimab 350 mg IV over approximately 30 minutes (±10 minutes) every 21 days.  For Group 4, 
the planned dose and schedule is cemiplimab 600 mg IV over approximately 30 minutes 
(±10 minutes) every 28 days.  For Group 5, the planned dose and schedule is 1 dose of cemiplimab 
438 mg SC.  After this, Group 5 patients will receive cemiplimab 350 mg IV over approximately 
30 minutes (±10 minutes) every 21 days.  
Patients will generally remain on the assigned dosage of cemiplimab throughout the course of 
study treatment.  Dose reduction of cemiplimab may be allowed (Groups 1 through 3), based on 
the guidelines below, and only after discussion and agreement between the investigator and 
sponsor.   
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Groups 4, 5, and 6:  In view of understanding that optimal toxicity management for this class of 
agents is dose interruption/dose delay and supportive measures (ie, immunosuppressive doses of 
steroids and/or other immunosuppressant or hormone replacement therapy), dose reductions are 
not part of the AE management plan for Groups 4, 5, and 6.   
5.3.2. 
General Guidance for Management of Adverse Events  
This subsection provides general guidance of treatment-related AEs that are not specifically 
addressed in guidelines for management of irAEs (Appendix 4) or in management of acute 
infusion reactions (Section 5.4).  In the event of discrepancy between this section and a section 
that provides for detailed guidance (ie, Appendix 4), the section that provides the more detailed 
guidance will supersede the general guidance in this section. 
Note in clarification on scheduling after missed visits/assessments: The general approach 
regarding missed treatments of cemiplimab (eg, due to AEs or other reasons) is “time marches 
on.”  Missed doses of cemiplimab will not be made up, unless missed doses occur ≤3 calendar 
days from the scheduled date. Study visits cannot be performed outside of the scheduled visit.  As 
such, if a patient misses a dose by more than 3 days for any reason, the next dose would be at the 
subsequent scheduled dose (which could be given 3 days early if need be).  If an investigator deems 
that re-scheduling a missed dose of cemiplimab outside of the 3-day window is in the best interest 
of the patient, this should be discussed with the medical monitor. 
Holding of treatment due to an AE or a missed visit if a patient is hospitalized is not a violation.  
If a patient is able to come in for a study visit according to the visit schedule but does not receive 
cemiplimab the visit should be entered into the database.  The protocol assessments required at the 
visit (ie, labs, physical exam) should still be completed as far as possible and the data entered at 
the appropriate visit in the electronic CRF.  If the patient is not able to come in for a study visit, 
according to the study schedule, the visit should be skipped. 
Table 2: 
General Guidelines for Management of Treatment-Related Adverse Events 
Toxicity 
Grade 
Hold Treatment 
Restarting Criteria 
 
Hematological Toxicity (other 
than grade 3 thrombocytopenia for 
longer than 7 days or associated 
with 
bleeding, 
or 
Grade 4 
thrombocytopenia.) 
1, 2, 3 
No 
N/A 
 
 
4 
Yes 
Toxicity 
resolves 
to 
grade ≤1 or baseline 
 
Grade 3 
thrombocytopenia 
for 
longer than 7 days or associated 
with bleeding 
3 
Yes 
Toxicity 
resolves 
to 
grade ≤1 or baseline 
 
Grade 4 thrombocytopenia 
4 
Yes 
Discontinue permanently 
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Toxicity 
Grade 
Hold Treatment 
Restarting Criteria 
 
Nonhematological Toxicity 
1 
No 
N/A 
 
Note: Exceptions to be treated as 
for Grade 1 toxicity: 
 
2 
Consider withholding for 
persistent symptoms 
Toxicity 
resolves 
to 
grade ≤1 
• 
Grade 2 alopecia 
• 
Grade 2 fatigue 
• 
Clinically insignificant 
lab abnormality not 
meeting AE criteria 
3 
Yes 
Toxicity resolves to  
grade ≤1 
 
4 
Discontinue permanently 
Discontinue permanently  
N/A = not applicable 
5.3.2.1. 
Identification of Immune-Related Adverse Events 
Investigators must be extremely vigilant and be ready to intervene early in the management of 
irAEs, as the onset of symptoms of irAEs (eg, pneumonitis) may be subtle.  An irAE can occur at 
any time during treatment or several months after the last dose of treatment.  All AEs of unknown 
etiology associated with drug 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. 
Based on the established safety profile of cemiplimab and other antibodies targeting the PD-1/PD-
L1 axis, working case definitions are provided in the Investigator’s Brochure to help investigators 
distinguish irAEs from non-immune AEs commonly associated with PD-1 inhibition 
(Naidoo, 2015) (Weber, 2015).  This is not exhaustive of all possible irAEs.  Clinical presentations 
of less common irAEs, including neurologic, musculoskeletal, cardiac, renal, and ocular events 
(Hoffman, 2016)(Zimmer, 2016), should be reviewed in patients with concerning presentations. 
The case definitions in the Investigator’s Brochure have not been validated and are intended only 
as guidance for investigators to help distinguish irAEs from non-immune AEs.  These definitions 
may evolve as clinical experience increases with cemiplimab and other antibodies targeting the 
PD-1/PD-L1 axis.  Investigators’ clinical judgment may include other factors when determining 
immune relatedness.  
5.3.2.2. 
Management of Immune-Related Adverse Events 
Adverse events that meet the criteria for irAEs, as noted above in the Investigator’s Brochure, 
should be reported as irAEs in the case report form (CRF).  If AEs corresponding to the common 
terms for irAEs are attributed as NOT related to cemiplimab by the investigator, additional 
information should be provided to substantiate an alternative attribution (eg, infectious diarrhea).   
If not provided at the outset, this information may be requested by immediate edit checks or in 
subsequent queries.  The sponsor may request additional information for any AE that is of a type 
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known to be potentially immune-related (eg, rash, colitis, elevated transaminases, endocrine 
events), but is deemed not an irAE by the investigatorAny grade 3 or greater irAE should be 
reported as an adverse event of special interest (AESI).  
The following general principles apply to management of irAEs, unless otherwise specified in 
Appendix 4: 
Grade 1:  Continue study treatment with close monitoring and provide symptomatic management   
Grade 2:  Consider withholding study treatment 
Grade 3:  Withhold study treatment 
Grade 4:  Discontinue study treatment 
If cemiplimab is held for ≤ grade 3 irAE, consider resuming when symptoms and/or laboratory 
values revert to baseline or ≤ grade 1 after corticosteroid taper (typically, to ≤10 mg/day 
prednisone or equivalent).  
Permanently discontinue study treatment for: 
• Recurrent grade 3 irAEs 
• Grade ≥3 or recurrent Grade 2 Pneumonitis  
• Grade ≥3 Hepatitis with AST/ALT >5×ULN or total bilirubin >3×ULN  
• Grade ≥3 Nephritis with renal dysfunction 
• Grade ≥3 Uveitis 
• Grade ≥3 Neurologic toxicity 
• Grade ≥3 Myocarditis or pericarditis 
• Grade ≥3 Infusion related reaction 
• Confirmed SJS,TEN or DRESS 
• Grade ≥3 or recurrent Grade 2 events in patients previously treated with idelalisib 
• Grade 2 or 3 irAEs persistent for ≥12 weeks after the last study treatment (excluding 
endocrinopathies) 
• Requirement for ≥10 mg per day prednisone or equivalent lasting ≥12 weeks after the 
last study treatment 
Further guidance regarding management of selected irAEs is provided in Appendix 4.  Additional 
information about the safety profile of cemiplimab is in the Investigators Brochure and in the 
cemiplimab prescribing information.  Expert consensus guidelines regarding characterization and 
management of less common immune-related adverse events (irAEs) are also available 
(Brahmer, 2018)(Haanen, 2017)(Puzanov, 2017)(Thompson, 2018) (Thompson, 2020).  The 
management considerations provided here should not supersede clinical judgment in the setting of 
an individual patient.  The investigator may choose to hold study treatment at his/her clinical 
judgment regarding the safety of an individual patient, even if hold criteria are not formally met 
per protocol. 
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5.3.3. 
Discontinuation of Study Treatment 
Patients who permanently discontinue from study treatment and who do not withdraw from the 
study will be asked to complete the EOS assessments per Table 3 through Table 8, and then 
continue post-treatment follow-up visits per Table 9 until diseas recurrence to assure tht data for 
the primary endpoint of the study is captured. 
5.3.4. 
Reasons for Permanent Discontinuation of Study Treatment 
Study treatment will be permanently stopped in the event of: 
• Evidence of pregnancy 
• Severe allergic reactions considered related to study drug 
• An infusion reaction of grade ≥3 severity during or directly following infusion 
• Patient withdraws consent at any time 
• Unacceptable toxicity 
• The investigator or sponsor determines it is in the best interest of the patient 
• Disease recurrence, unless patient meets criteria for Part 2 of study and opts for 
subsequent cemiplimab treatment. 
• Treatment delay of ≥84 consecutive days from the last dose of study drug due to 
toxicity 
• Any AEs that meet criteria for permanent discontinuation described in Appendix 4. 
• Any medical condition that may jeopardize the patient’s safety if he/she continues 
with study treatment in the opinion of the investigator or sponsor 
• Patient noncompliance (eg, not complying with protocol required visits, assessments, 
and dosing instructions) 
5.3.4.1. 
Reasons for Temporary Discontinuation of Study Drug 
Study treatment may be temporarily stopped due to events that meet the criteria for treatment 
interruption described in Section 5.4.1 and Appendix 4. 
5.4. 
Management of Infusion/Allergic/Hypersensitivity Reactions 
Acute infusion reactions are defined as any AE that occurs during the infusion or within 2 hours 
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 reported as AEs (Section 7.2.1) and graded according to the NCI-CTCAE version 4.03 grading 
scale (Section 7.3.1). 
In the event of an infusion reaction of grade 3 or greater severity during or directly following 
cemiplimab or infusion, dosing should be stopped, and the patient must be permanently 
discontinued from cemiplimab or treatment.  
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5.4.1. 
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 ≤ grade 2 during 
infusion, the infusion should be interrupted or infusion rate reduced. For those 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. 
5.4.2. 
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 
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• 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 
termination of the IV infusion 
*Consider anaphylaxis if the following is observed (Sampson, 2006):  acute onset of an illness 
(minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g., generalized 
hives, pruritus or ﬂushing, swollen lips-tongue-uvula) AND AT LEAST 1 OF THE FOLLOWING  
• respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
• reduced blood pressure or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence) 
5.4.3. 
Injection Site Reactions  
Acute ISRs are defined as any AE that occurs during the injection or at any time until the end of 
the following day (in the absence of an alternative explanation).  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. 
Injection site reactions should be reported in the CRF and graded as per the criteria below: 
The severity of ISRs will be graded according to the following scale 
(semi-colon indicates “or” within description of grade): 
1. Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of 
erythema or induration that does not interfere with activity. 
2. Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or 
interferes with activity; discomfort with movement; 5.1 cm to 10 cm erythema or 
induration or induration that interferes with activity. 
3. Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily activity; 
significant discomfort at rest; >10 cm erythema or induration; prevents daily activity; 
requires ER visit or hospitalization; necrosis or exfoliative dermatitis. 
5.5. 
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 Web Response System (IWRS) manual. 
Eligible patients will be enrolled sequentially as confirmed and tracked by the sponsor, until each 
group is filled per protocol criteria.  Details on treatment assignment can be found in the IWRS 
manual. 
Patients were enrolled in Group 3 only after enrollment in Group 1 was complete.  
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Patients were enrolled in Group 4 only after enrollment in Groups 2 and 3 were complete.  
With the implementation of Group 6 in Amendment 7, Group 4 will be closed to enrollment (even 
if Group 4 is not yet fully enrolled). 
See Section 3.1 for rules regarding enrollment in Groups 4 and 5.  
5.5.1. 
Blinding 
This is an open-label study; no blinding will be employed. 
5.6. 
Treatment Logistics and Accountability 
5.6.1. 
Packaging, Labeling, and Storage 
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 of cemiplimab will contain a concentration of 
50 mg/mL (for all IV infusions), and a concentration of 175 mg/mL (for SC injection).  
Cemiplimab will be refrigerated at the site at a temperature of 2º to 8ºC, and refrigerator 
temperature will be logged daily.  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.  Detailed preparation and administration instructions will be provided to the sites 
in the pharmacy manual. 
5.6.2. 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2º to 8ºC 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 documentation 
by the site monitor, all opened and unopened study drug will be destroyed or returned to the 
sponsor or designee. 
5.6.3. 
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; photocopies must be provided to the sponsor at the conclusion of the study. 
5.6.4. 
Treatment Compliance 
Cemiplimab will be administered at the study site and recorded on the electronic CRF.  All dosing 
records for each patient will be kept by the site.  All drug compliance records must be kept current 
and must be made available for inspection by the sponsor and regulatory agency inspectors. 
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5.7. 
Concomitant Medications and Procedures 
5.7.1. 
Concomitant Medications 
Any treatment administered from the time of informed consent until 30 days after the last study 
treatment will be considered concomitant treatment.  This includes medications and other therapies 
for which administration started before the study and will continue during the study, as well as any 
therapies started in the follow-up period (approximately 6 months [Table 9]) to treat a study-drug–
related AE.  All concomitant treatments must be recorded in the study CRF with the generic name, 
dose, dose unit, frequency, indication, and start/stop date, as appropriate. 
5.7.2. 
Prohibited Medications and Concomitant Treatments 
While participating in this study, a patient may not receive any standard or investigational agent 
for treatment of a tumor other than cemiplimab as mono therapy.  After communication with the 
sponsor, focal palliative treatment (eg, radiation) would be allowed for local control of a 
tumor once a patient has completed 24 weeks of study treatment.  Any other medication which 
is considered necessary for the patient’s welfare, and which is not expected to interfere with the 
evaluation of the study drug, may be given at the discretion of the investigator. 
Patients using immunosuppressive doses (>10 mg per day of prednisone or equivalent) of systemic 
corticosteroids other than for corticosteroid replacement will not be eligible for the study.  It is 
recommended that patients do not receive systemic corticosteroids such as hydrocortisone, 
prednisone, prednisolone (Solu-Medrol®) or dexamethasone (Decadron®) 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 if >10 mg/day prednisone 
equivalents.  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. 
Note: Bisphosphonates and denosumab are not prohibited. 
5.7.3. 
Surgery 
For patients with locally advanced target lesions that are considered unresectable at baseline but 
are subsequently deemed resectable during the course of the study due to tumor response to 
cemiplimab, curative intent surgery may be allowed but must be discussed with the medical 
monitor prior to any surgical procedure.  (This statement does not apply to patients in emergency 
life-threatening situations that require immediate surgery).  Patients with inoperable CSCC at 
baseline who are rendered operable with clear margins will be deemed to have experienced PR. 
If during the course of the study a patient develops new cutaneous lesions that are suspected to be 
a non-melanoma skin cancer other than CSCC (eg, BCC), removal of the lesion and continued 
treatment on study may be allowed after discussion with the medical monitor. 
5.7.4. 
Radiation Therapy  
Radiation therapy is not part of the study regimen. Patients for whom radiation therapy is planned 
are not eligible.  If during the course of the study, a patient develops a symptomatic lesion for 
which palliative radiation therapy is deemed appropriate by the investigator, this will be deemed 
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PD and generally the patient would be removed from study.  Palliative radiation therapy may be 
allowed in certain circumstances in patients who have been on study for at least 24 weeks (see 
Section 5.7.2).  Such cases must be discussed with the medical monitor prior to any radiation 
therapy if the investigator feels that restarting cemiplimab after radiation is in the best interest of 
the patient.  The patient will be deemed to have experienced disease progression if radiation 
therapy is instituted but will be followed for OS. 
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6. 
STUDY SCHEDULE AND VISIT DESCRIPTIONS 
6.1. 
Study Schedule 
Study assessments and procedures are presented by study period and visit in Table 3 for Groups 1 
and 2; Table 4 for patients in Group 3; Table 5 for patients in Group 4; Table 6 for patients in 
Group 5; Table 7 for patients in Group 6; and Table 8 for patients in Group 6 receiving SC dosing.  
Table 9 presents study assessments and procedures for all groups during the follow-up period.  
Study visits can be scheduled so as not to fall on weekends or holidays, after discussion and 
approval by the Sponsor.  
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms.  
Examples of such mechanisms may include, but are not limited to, any of the following:  phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff.  Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted. All 
temporary mechanisms utilized, and deviations from planned study procedures in response to 
COVID-19 are to be documented as being related to COVID-19 and will remain in effect only for 
the duration of the public health emergency. 
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h. Brain MRI with gadolinium is required at screening if not performed in the prior 60 days. Brain scans during the treatment and follow-up periods are required if 
there is a prior history of lesions present at screening or as clinically indicated. A brain CT with iodinated contrast may be performed if an MRI with gadolinium 
is contraindicated. 
i. Hematology includes: WBC count, 3-cell differential (ANC, monocyte count, lymphocyte count), hemoglobin, and platelet count.  Samples may be collected 
≤72 hours prior to study treatment.  
j. Chemistry includes: sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphorous, glucose, albumin, creatinine, blood urea nitrogen (BUN), 
ALT, AST, total bilirubin, alkaline phosphatase (ALP), uric acid, and LDH. Samples may be collected ≤72 hours prior to study treatment. 
k. Predose β-HCG (serum) at screening up to 72 hours prior to first administration. Subsequent pregnancy tests may be urine β-HCG. Serum pregnancy test and 
urine pregnancy test are requirements for women of child bearing potential only. 
l. Urinalysis: glucose, blood, pH, specific gravity, ketones, and spot urine protein. Samples may be collected ≤72 hours prior to study treatment. 
m. ADA samples are collected prior to treatment on day 1 of cycles 1, 3, and 5.  
n. Blood samples for PK will be collected at pre-infusion and end of infusion on days 1, 15, 29, and 43 of cycle 1, on day 1 of cycles 2 through 6, 7, 9, and 11. The 
final PK sample will be collected either at the EOS visit (for patients who discontinue treatment due to progression or toxicity during cycles 1 through 12) or at 
the follow-up visit 1 in Table 9 (for patients who complete cycles 1 through 12).  See Appendix 3 for details on PK collection schedule.  
o. 
 
p. 
 
  
 
 
 
q. The same method (CT with iodinated contrast or MRI with gadolinium) and/or digital medical photography used at baseline should be used throughout the study. 
For patients with locally advanced CSCC, guidelines for digital photography are provided in Appendix 6. Imaging requirements differ for patients in Group 1 
and Group 2; see Sections 6.3.1 and 6.3.2 for further details. On day 29, photos only for Group 2 patients need to be done.  The intent of the photography is to 
show locations of the biopsies; formal response assessments are not planned for day 29 photos. 
r. Concomitant medication recording will be done at the start of each cycle, at a minimum. Concomitant medications should be recorded from the date of signing 
the ICF through follow-up visit 1 (posttreatment; Table 9). 
s. Adverse event recording will be ongoing throughout the course of the study, using NCI-CTCAE v4.03. See Section 7.2.  
t. (1) The EOS visit is for patients who experience PD requiring study discontinuation in cycles 1 through 12.  This visit should occur 30 days (allowed window: 
21 to 42 days) after the last dose of cemiplimab.  The only posttreatment assessment that can occur outside of this timeframe is the posttreatment biopsy (required 
in Group 2) that can be obtained at any time within 28 days of last dose of cemiplimab. (2) Patients who complete the required events in Table 3 (excluding the 
EOS visit) with any status other than PD (eg, CR, PR, or SD), or who discontinue treatment during cycles 1 through 12 for any reason other than PD, should go 
on to complete the assessments in Table 9 (unless not possible, due to factors such as clinical decline or withdrawal of consent).  These patients do not need to 
complete the EOS visit at end of cycle 12 as they will be assessed per Table 9.  After treatment and follow-up are completed or patients prematurely discontinue 
treatment and follow-up, patients will be followed quarterly for survival and tumor treatment status, if available. 
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k. Predose β-HCG (serum) at screening up to 72 hours prior to first administration.  Subsequent pregnancy tests may be urine β-HCG. Serum pregnancy test and 
urine pregnancy test are requirements for women of child bearing potential only. 
l. Urinalysis: glucose, blood, pH, specific gravity, ketones, and spot urine protein.  Samples may be collected ≤72 hours prior to study treatment. 
m. ADA samples are collected prior to treatment on day 1 of cycles 1, 3, and 5.  ADA samples are not collected if a patient enters retreatment. 
n. Blood samples for PK will be collected at pre-infusion and end of infusion on days 1, 22, and 43 of cycle 1, and on day 1 of cycles 2 through 6.  The final PK 
sample will be collected either at the EOS visit (for patients who discontinue treatment due to progression or toxicity during cycles 1 through 6) or at the follow-
up visit 1 in Table 9 (for patients who complete cycles 1 through 6). See Appendix 3 for details on PK collection schedule.  
o. 
 
p. The same method (CT with iodinated contrast or MRI with gadolinium) and/or digital medical photography used at baseline should be used throughout the study. 
See Sections 6.3.1 and 6.3.2 for further details regarding imaging requirements for Group 3.  
q. Concomitant medication recording will be done at the start of each cycle, at a minimum. Concomitant medications should be recorded from the date of signing 
the ICF through follow-up visit 1 (posttreatment; Table 9).   
r. Adverse event recording will be ongoing throughout the course of the study, using NCI-CTCAE v4.03. See Section 7.2.  
s. (1) The EOS visit is for patients who experience PD requiring study discontinuation in cycles 1 through 6.  This visit should occur 30 days (allowed window: 
21 to 42 days) after the last dose of cemiplimab. (2) Patients who complete the required events in Table 4 (excluding the EOS visit) with any status other than 
PD (eg, CR, PR, or SD), or who discontinue treatment during cycles 1 to 6 for any reason other than PD, should go on to complete the assessments in Table 9 
(unless not possible, due to factors such as clinical decline or withdrawal of consent).  These patients do not need to complete the EOS visit at end of cycle 6 as 
they will be assessed per Table 9.  After treatment and follow-up are completed or patients prematurely discontinue treatment and follow-up, patients will be 
followed quarterly for survival and tumor treatment status, if available. 
t. For all patients who enter retreatment, the duration of retreatment will be up to 108 weeks. 
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i. Hematology includes: WBC count, 3-cell differential (ANC, monocyte count, lymphocyte count), hemoglobin, and platelet count. Samples may be collected 
≤72 hours prior to study treatment.  
j. Chemistry includes: sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphorous, glucose, albumin, creatinine, blood urea nitrogen (BUN), 
ALT, AST, total bilirubin, alkaline phosphatase (ALP), uric acid, and LDH. Samples may be collected ≤72 hours prior to study treatment. 
k. Predose β-HCG (serum) at screening up to 72 hours prior to first administration. Subsequent pregnancy tests may be urine β-HCG.  Serum pregnancy test and 
urine pregnancy test are requirements for women of child bearing potential only. 
l. Urinalysis: glucose, blood, pH, specific gravity, ketones, and spot urine protein. Samples may be collected ≤72 hours prior to study treatment. 
m. ADA samples are collected prior to treatment on day 1 of cycles 1, 3, and 5.  
n. Blood samples for PK will be collected at pre-infusion and end of infusion.  The final PK sample will be collected either at the EOS visit (for patients who 
discontinue treatment due to disease progression or during cycles 1 through 6), or at the follow-up visit 1 in Table 9 (for patients who complete cycles 1 through 
6).  See Appendix 3 for details on PK collection schedule. 
o. 
 
p. The same method (CT with iodinated contrast or MRI with gadolinium) and/or digital medical photography used at baseline should be used throughout the study.  
See Sections 6.3.1 and 6.3.2 for further details regarding imaging requirements.  
q. Concomitant medication recording will be done at the start of each cycle, at a minimum. Concomitant medications should be recorded from the date of signing 
the ICF through follow-up visit 1 (posttreatment, Table 9). 
r. Adverse event recording will be ongoing throughout the course of the study, using NCI-CTCAE v4.03. See Section 7.2.  
s.  (1) The EOS visit is for patients who experience PD requiring study discontinuation in cycles 1 through 6. This visit should occur 30 days (allowed window: 
21 to 42 days) after the last dose of cemiplimab. (2) Patients who complete the required events in Table 5 (excluding the EOS visit) with any status other than 
PD (eg, CR, PR, or SD), or who discontinue treatment during cycles 1 to 6 for any reason other than PD, should go on to complete the assessments in Table 9 
(unless not possible, due to factors such as clinical decline or withdrawal of consent). These patients do not need to complete the EOS visit at end of cycle 6 as 
they will be assessed per Table 9. After treatment and follow-up are completed or patients prematurely discontinue treatment and follow-up, patients will be 
followed quarterly for survival and tumor treatment status, if available. 
t. For Group 4 patients who enter retreatment, refer to Table 4.  
u. [18F]-FDG PET-CT is once at screening and then at 6-month intervals:  screening, end week 24 (cycle 3) and end week 48 (cycle 6).  For patients who complete 
[18F]-FDG PET-CT at end of cycle 6, it does not need to be repeated at the EOS visit.  The [18F]-FDG PET-CT requirements will not apply to patients enrolled 
at sites in Germany. 
v. 
 
 
  
  
 
w. Optional serum ctDNA samples will collected at cycles 1, 3, and 5 and disease progression. 
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h. Brain MRI with gadolinium is required at screening if not performed in the prior 60 days. Brain scans during the treatment and follow-up periods are required if 
there is a prior history of lesions present at screening or as clinically indicated. A brain CT with iodinated contrast may be performed if an MRI with gadolinium 
is contraindicated. 
i. Hematology includes: WBC count, 3-cell differential (ANC, monocyte count, lymphocyte count), hemoglobin, and platelet count. Samples may be collected 
≤72 hours prior to study treatment.  
j. Chemistry includes: sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphorous, glucose, albumin, creatinine, blood urea nitrogen (BUN), 
ALT, AST, total bilirubin, alkaline phosphatase (ALP), uric acid, and LDH. Samples may be collected ≤72 hours prior to study treatment. 
k. Predose β-HCG (serum) at screening up to 72 hours prior to first administration. Subsequent pregnancy tests may be urine β-HCG.  Serum pregnancy test and 
urine pregnancy test are requirements for women of child bearing potential only. 
l. Urinalysis: glucose, blood, pH, specific gravity, ketones, and spot urine protein. Samples may be collected ≤72 hours prior to study treatment. 
m. ADA samples are collected prior to treatment on day 1 of cycles 1, 3, and 5.  
n. Blood samples for PK will be collected at predose and at multiple time points after the single SC dose (C1D1) and after the first IV dose (C1D22) to assess the 
SC bioavailability of cemiplimab. See Appendix 3 for details on PK collection schedule. 
o. 
 
p. The same method (CT with iodinated contrast or MRI with gadolinium) and/or digital medical photography used at baseline should be used throughout the study.  
See Sections 6.3.1 and 6.3.2 for further details regarding imaging requirements for Group 3.  
q. Concomitant medication recording will be done at the start of each cycle, at a minimum.  Concomitant medications should be recorded from the date of signing 
the ICF through follow-up visit 1 (posttreatment, Table 9).   
r. Adverse event recording will be ongoing throughout the course of the study, using NCI-CTCAE v4.03.  See Section 7.2.  
s.  (1) The EOS visit is for patients who experience PD requiring study discontinuation in cycles 1 through 6. This visit should occur 30 days (allowed window: 
21 to 42 days) after the last dose of cemiplimab. (2) Patients who complete the required events in Table 6  (excluding the EOS visit) with any status other than 
PD (eg, CR, PR, or SD), or who discontinue treatment during cycles 1 to 6 for any reason other than PD, should go on to complete the assessments in Table 9 
(unless not possible, due to factors such as clinical decline or withdrawal of consent). These patients do not need to complete the EOS visit at end of cycle 6 as 
they will be assessed per Table 9.  After treatment and follow-up are completed or patients prematurely discontinue treatment and follow-up, patients will be 
followed quarterly for survival and tumor treatment status, if available. 
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Table 7: 
Study Schedule (Screening and Treatment) for Group 6  
Study Procedure 
Screening 
Cycle 1 
Cycles 2 – 12a 
End of Study 
Visit Days 
–28 to –1 
1 
22±3 
43±3 
63±3 
1
b 
22±
3 
43±
3 
63±
3 
30 days after last dose of 
cemiplimab
s 
Clinical Assessments and Study Treatment 
Informed Consent
c 
X 
 
 
 
 
 
 
 
 
 
Genomics Substudy Informed Consent (optional) 
X 
 
 
 
 
 
 
 
 
 
Medical/Oncology History 
X 
 
 
 
 
 
 
 
 
 
Complete Physical Examination and ECOG PS
d 
X 
X 
 
 
 
X 
 
 
 
X 
Physical Examination, Limited
e 
 
 
X 
X 
 
 
X 
X 
 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
Vital Signs and Weight
f 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Brain MRI (optional)
g 
X 
 
 
 
 
 
 
 
 
 
Cemiplimab 350 mg IV Q3W  
 
X 
X 
X 
 
X 
X 
X 
 
 
Laboratory Tests 
Hematology
h and Blood Chemistry
i 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Serum HCG ≤72 Hour Predose
j 
X 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
 
 
X 
X 
 
X 
X 
X 
 
X 
Urinalysis
k 
X 
 
 
 
 
 
 
 
 
X 
aPTT; INR 
 
X 
 
 
 
 
 
 
 
 
HBV, HCV, HIV 
X 
 
 
 
 
 
 
 
 
 
Immune Safety and PK Blood Samples 
TSH (local laboratory)  
 
X 
 
 
 
X 
 
 
 
X 
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Study Procedure 
Screening 
Cycle 1 
Cycles 2 – 12a 
End of Study 
Visit Days 
–28 to –1 
1 
22±3 
43±3 
63±3 
1
b 
22±
3 
43±
3 
63±
3 
30 days after last dose of 
cemiplimab
s 
ADA
l 
 
X 
 
 
 
X 
 
 
 
X 
Cemiplimab PK/Drug Conc.
m 
 
X 
X 
 
 
X 
 
 
 
X 
Pathology and Research Samples 
Baseline Tumor Biopsy
n 
X 
 
 
 
 
 
 
 
 
 
Response Imaging and other assessments 
ADA=anti-drug antibody; AE=adverse event; aPTT=activated partial thromboplastin time; CT=computed tomography; ECG=electrocardiogram; ECOG 
PS=Eastern Cooperative Oncology Group Performance Status; EOS=end of study; HCG=human chorionic gonadotropin; INR=International Normalized Ratio; 
MRI=magnetic resonance imaging; TSH=thyroid-stimulating hormone; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus 
a. The maximum number of treatment cycles is 12 (planned 108 weeks total). 
b. Should occur at least 60 days from day 1 of previous cycle, and no sooner than 18 days after the previous dose. 
c. Informed consent must be provided before the initiation of screening procedures and must be obtained within 45 days prior to cycle1/day1.  All screening 
assessments must be performed within 28 days prior to cycle 1, day 1.  Assessments performed as part of standard of care that fall within the screening 
window but before informed consent is obtained may be used for screening and need not be repeated for enrollment eligibility. Note: Patients who opt to 
switch to SC dosing after 27 weeks may sign the ICF for SC dosing at-or-after the C3D22 visit. 
d. Complete physical examination includes head and neck, lungs, heart, abdomen, lymph nodes, extremities, and skin. A brief neurologic examination should also 
be performed.  The exam may be performed ≤72 hours prior to study treatment.  Complete physical exam must be accompanied by assessment and 
documentation of ECOG Performance Status.  
e. Limited physical exam includes lungs, heart, abdomen, and skin. 
f. Vital signs include temperature, resting blood pressure, pulse, and respiration.  Vital signs will be assessed and documented prior to the cemiplimab infusion, 
and then approximately 15 minutes after the completion of the cemiplimab infusion.  The allowable window for each specified time point is ±10 minutes. 
g. Brain MRI with gadolinium is required at screening only if the investigator feels that there is clinical suspicion of brain metastases.  Brain scans during the 
treatment and follow-up periods are required if there is a prior history of lesions present at screening or as clinically indicated.  A brain CT with iodinated 
contrast may be performed if an MRI with gadolinium is contraindicated. 
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Table 8: 
Study Schedule for Group 6 Patients Who  Opt for Subcutaneous Dosing
 
  After 27 Weeks of IV Dosing 
Study Procedure 
 
 
Cycle 1-SCa 
Subsequent SC Cyclesb 
 
Visit Days 
1 
8e 
22±3 
43±3 
64±3 
85±3 
1
c 
22±3 
43±3 
64±3 
85±3 
30 days after last dose 
of SC cemiplimab s 
Clinical Assessments and Study 
Treatment 
  
Informed Consent for SC dosing
d 
X
d 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination 
and ECOG PS
f 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Physical Examination, Limitedg 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
Vital Signs and Weighth 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
Laboratory Tests 
 
Hematology j and Blood Chemistry k 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
Urine Pregnancy Test l 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
Urinalysis m 
X 
 
 
 
 
 
 
 
 
 
 
X 
Immune Safety and PK Samples 
 
TSH (local laboratory)  
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
Cemiplimab PK/Drug Conc 
See Appendix 3 
ADAn 
X 
 
 
 
 
 
Xn 
 
 
 
 
 
Response Imaging and other Assessments 
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Study Procedure 
 
 
Cycle 1-SCa 
Subsequent SC Cyclesb 
 
Visit Days 
1 
8e 
22±3 
43±3 
64±3 
85±3 
1
c 
22±3 
43±3 
64±3 
85±3 
30 days after last dose 
of SC cemiplimab s 
Adverse Events r 
← continuous monitoring→ 
ADA=anti-drug antibody; AE=adverse event;  CT=computed tomography; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group 
Performance Status; EOS=end of study; HCG=human chorionic gonadotropin;MRI=magnetic resonance imaging; TSH=thyroid-stimulating hormone; - 
a. Cycles are denoted with the suffix “SC” (ie, 1-SC, 2-SC etc) and are 12-week cycles. SC therapy can only begin at the start of a new cycle (not mid-cycle).  
b. Patients will continue SC therapy to complete planned 108 weeks of total cemiplimab therapy (IV + SC combined), or until disease progression or unacceptable 
toxicity (For patients who initiate SC therapy after completing an even number of IV cycles, total planned duration of therapy would be 111 weeks).  The 
maximum number of SC cycles would be 7 (Cycle 1-SC through 7-SC) for patients who begin SC therapy after completing 3 cycles of IV cemiplimab. 
c. For patients receiving Q3W SC cemiplimab, this should occur at least 60 days from day 1 of previous cycle, and no sooner than 18 days after the previous dose.  
d. Patient may sign consent for SC dosing at any time during the final IV cycle. 
e. The Day 8 visit in the first SC cycle is a PK-only visit for all patients who opt for SC cemiplimab. There is no Day 8 visit for subsequent SC cycles. See 
Appendix 3 . 
f.  Complete physical examination includes head and neck, lungs, heart, abdomen, lymph nodes, extremities, and skin. A brief neurologic examination should also 
be performed.  Exam should also include examination of site of SC injection to ensure local tolerability. The exam may be performed ≤72 hours prior to study 
treatment.  Complete physical exam must be accompanied by assessment and documentation of ECOG Performance Status.   
g. Limited physical exam includes lungs, heart, abdomen, and skin. 
h. Vital signs include temperature, resting blood pressure, pulse, and respiration.  Vital signs will be assessed and documented prior to the cemiplimab SC 
infusion, and then approximately 15 minutes after the completion of the cemiplimab SC injection(s).  The allowable window for each specified time point is 
±10 minutes. 
 
 
  
j. Hematology includes: WBC count, 3-cell differential (ANC, monocyte count, lymphocyte count), hemoglobin, and platelet count.  Samples may be collected 
≤72 hours prior to study treatment.  
k. Chemistry includes: sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphorous, glucose, albumin, creatinine, blood urea nitrogen (BUN), 
ALT, AST, total bilirubin, alkaline phosphatase (ALP), uric acid, and LDH.  Samples may be collected ≤72 hours prior to study treatment. 
l. Pregnancy tests should be urine β-HCG, but serum serum β-HCG is also acceptable.  Pregnancy tests are requirements for WOCBP only.   
m. Urinalysis: glucose, blood, pH, specific gravity, ketones, and spot urine protein.   
n. ADA samples will be collected at pre-dose on cycle 1 day1, cycle 3 day 1 and FU4 visit (Table 9).  
 
 
 
 
 
 
   
 
 
  
r. Adverse event recording will be ongoing throughout the course of the study. 
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s. The EOS visit should occur 30 days (allowed window: 21 to 42 days) after the last dose of cemiplimab for patients who experience disease progression or 
withdraw consent.  For patients who discontinue treatment for reason other than disease progression or withdrawal of consent, they should enter post-treatment 
follow up.      See  final footnote in  Table 9 that specifies  required duration of follow-up for patients who enter post-treatment follow up after SC dosing. 
 
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k. After treatment and follow-up are completed or patients prematurely discontinue treatment and follow-up, patients will be followed quarterly for survival and tumor treatment 
status, if available.  See Section 6.2.2. 
l. In Groups 1 to 5, patients who do not experience PD will be followed for an additional 1 year with assessments every 4months.  Patients in Group 6 will complete 6 months of 
follow-up (follow-up Visits 1 to 7 only) and will not go into extended follow-up after the 6-month follow-up is completed. 
m. For Group 6 patients who opt to switch to SC dosing and complete the Schedule of Events in Table 8, the only required follow up visits are Follow up visits 1-4. The last visit 
for these patients will be follow up 4, which provides sufficient long term safety follow up (> 105 days) after last dose of SC cemiplimab.  These patients will not enter survival 
follow up.  
n. ADA collection at follow up visit 3 is only for Group 6 patients who switch to SC cemiplimab. 
 
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6.2. 
Study Follow-Up and Treatment Discontinuation 
6.2.1. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule as specified in Table 4 through  
Table 9. Unscheduled visits may be necessary to repeat testing following abnormal laboratory 
results, for follow-up of AEs, or for any other reason, as warranted. 
6.2.2. 
Follow-up 
Patients who discontinue study treatment due to PD should return to the clinic 30 days (range: 
21 to 42 days) after the last study treatment to complete the EOS assessments indicated in Table 4 
through  Table 9.  After the EOS visit, patients should be followed for survival status until death, 
loss to follow-up, or study termination by the sponsor.  
For all patients in Group 2, tumor biopsies (Appendix 5) should be obtained at time of 
progression, whether progression occurs in cycles 1 through 12 or during follow-up (after 
cycle 12). 
Patients who discontinue study treatment due to reasons other than PD (eg, toxicity, confirmed CR 
after 48 weeks) should enter the follow-up schedule in  Table 9.  (Note in clarification: Any 
patients who completed the posttreatment Table 9 follow-up period of 6 months from previous 
amendments without disease progression will be asked to remain in follow-up.  Such patients will 
be re-consented and asked to return approximately every 4 months (±14 days) for 1 additional year 
to complete the extended follow-up assessments in  Table 9.) 
For patients in Groups 1 or 2 who complete 12 cycles of treatment or for patients in Groups  3, 4, 
or 5 who complete 6 cycles of treatment without disease progression and subsequently experience 
disease progression during the follow-up period in  Table 9 without any intervening systemic 
anticancer therapy, resumption of treatment with cemiplimab 350 mg IV Q3W will be allowed.  
Prior to resumption of cemiplimab treatment, patients must be re-consented and repeat all 
screening activities (with the exception of providing new archived pathology material, or research 
biopsies), and the investigator must confirm that the patient still meets all eligibility criteria (other 
than the exclusion regarding prior treatment with anti-PD-1).  Such patients will resume 
cemiplimab 350 mg IV Q3W for up to 108 weeks (maximum 12 retreatment cycles).  The 
retreatment visit schedule will follow the study schedule in Table 4.  ADA samples will not be 
collected during retreatment.  Patients in Group 5 who enter retreatment will not receive an 
additional dose of cemiplimab SC.  For any patients who enter retreatment, the following are not 
required during retreatment:  PK samples, research blood samples, and research tumor biopsies 
(exploratory tumor biopsies in Groups 2and 4).  Note: Patients enrolled in Group 6 are not eligible 
for retreatment. 
After treatment, retreatment, and follow-up are completed or if patients prematurely discontinue 
from treatment, patients in Groups 1 to 5 will receive extended follow-up every 4 months for 1 year 
as per  Table 9.  After this time, patients will be followed quarterly for survival and tumor treatment 
status, if available, until death.  Survival follow-up status may be determined at clinic visits or via 
telephone contact with the patient, a family member of the patient, or the physician.  Patients from 
Group 6 who discontinue cemiplimab early (before completing 108 weeks of treatment) for 
reasons other than disease progression will enter follow-up. 
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6.3. 
Study Procedures 
6.3.1. 
Procedures Required Only at the Screening/Baseline Visit 
The following procedures will be performed at screening for the purpose of determining study 
eligibility or characterizing the baseline population: 
• Serum β-HCG (result must be ≤72 hours before first dose). 
• HBV, HCV, and HIV screening.  The required serologies are:  hepatitis B surface 
antigen, hepatitis C antibody test (if positive, obtain hepatitis C RNA PCR to rule out 
active infection), HIV-1 and HIV-2 serum antibody 
• Documentation of pathologic confirmation of CSCC by a pathologist at the study site 
(see Section 4.2.1, Inclusion Criterion 1).  The pathology report that documents the 
diagnosis of CSCC should be from the most recent biopsy that documented CSCC.  
Pathology material (FFPE block or 10 unstained slides from the sample in the submitted 
pathology report) must be provided to the sponsor prior to enrollment. 
• Group 2 only: Baseline/screening research biopsy is required (see Appendix 5 for 
guidelines). This baseline biopsy is intended for exploratory assessments but will only 
be used for this purpose after central pathology confirmation of diagnosis of CSCC is 
obtained on archived material.  If the archived material is not sufficient for 
confirmation of diagnosis of CSCC by central review, baseline biopsy material will be 
used for central pathologic confirmation; remaining baseline tumor material can only 
be used for exploratory assessments after central pathology confirmation of diagnosis 
of CSCC has been established. 
• Group 4 and 6: Baseline/screening research biopsy is required for these patients 
(see Appendix 5 for guidelines).  In patients without externally accessible lesions, 
CT-guided biopsies are required.  If the investigator determines that biopsy would 
create an unacceptable safety risk for the patient or cannot be performed without 
interfering with measurement of target lesions, the biopsy requirement may be waived 
for an individual patient after communication with the medical monitor. 
• Brain MRI (except Group 6): Brain MRI is required at screening if not performed in 
the prior 60 days. Brain scans during the treatment and follow-up periods are required 
if there is a prior history of lesions present at screening or as clinically indicated.  A 
brain CT may be performed if an MRI is contraindicated. 
• For patients with metastatic CSCC – Baseline imaging should include all known 
target lesions.  Baseline scans must evaluate extent of disease, including imaging of 
chest, abdomen, and pelvis.  This may be accomplished with CT chest, abdomen, and 
pelvis with contrast, or CT chest with contrast and MRI abdomen/pelvis with 
gadolinium.  The imaging modality for metastatic lesions may be either CT with 
iodinated contrast or MRI with gadolinium, per investigator discretion.  MRI with 
gadolinium is generally preferred for bone lesions, perineural lesions, abdomen, pelvis, 
extremity, and head and neck.  CT with contrast is generally preferred for chest.  For 
Group 1 patients who also have externally visible lesions, digital medical photography 
will be used, and these lesions generally will be followed as non-target lesions.  Note: 
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In the case of a patient with metastatic disease that is not measurable by RECIST 
criteria (eg, bone only lesions, perineural disease) and with externally visible CSCC 
target lesions, digital medical photography may be used to follow the externally visible 
lesions as target lesions.  
• Groups 2, 4, 5, and 6 – 
 
 
 
 
  Baseline radiologic assessment will also include CT chest, 
preferably with contrast (if CT chest identifies a metastatic lesion, the patient should 
be assigned to Group 1 if open for enrollment, Group 3, if open for enrollment, or 
Group 6).  For patients with locally advanced CSCC with deeply invasive target lesions 
that are not externally visible, baseline assessment should include photography of 
overlying normal appearing skin because this baseline image may provide useful 
clinical context for independent central review. 
6.3.2. 
Efficacy Procedures 
For patients with disease that can be measured radiologically according to RECIST 1.1 criteria 
(Appendix 1; Eisenhauer 2009), a CT or MRI for tumor assessment will be performed as detailed 
in Table 3 through  Table 9.  The choice of whether the imaging is by CT or MRI is an investigator 
decision, but preferred imaging choices are provided in Section 6.3.1.  Once the choice of CT scan 
or MRI has been made, subsequent assessments should be made using the same modality whenever 
possible.  For patients whose CSCC lesions are evaluable on the skin, composite response criteria 
(Appendix 2) should be used on the same schedule (every 8 weeks for Groups 1 and 2, every 
9 weeks for Group 3), in combination with radiologic imaging if appropriate. 
• For patients with metastatic CSCC: Whole-body imaging, as performed at the 
baseline assessment, is strongly recommended at each response assessment.  At a 
minimum, all radiologically measurable target lesions (RECIST 1.1) should be imaged 
at each response assessment.  The same radiologic imaging modality should be used at 
each response assessment.  Additionally, radiologic imaging of anatomic area of 
externally visible target lesions should be performed at each response assessment (MRI 
with gadolinium is preferred for all anatomic sites except lung).  Externally visible 
CSCC lesions noted at baseline should be photographed at each response assessment 
(Appendix 6), and will generally be deemed non-target.  New externally visible lesions 
that are clinically suspicious for malignancy should be photographed (Appendix 6) and 
biopsied.  Note:  In the case of patients with metastatic disease that is not measurable 
by RECIST criteria (eg, bone only lesions, perineural disease) and with externally 
visible CSCC target lesions, digital medical photography may be used to follow the 
externally visible lesions as target lesions.  
• Groups 2, 4, 5, and 6: 
 
  
 
  
 
 
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• Group 4 (if metastatic): Whole-body imaging with 18F-FDG-PET at baseline and at 
6-month intervals. These will be evaluated by EORTC PET Criteria (Appendix 9). The 
18F-FDG-PET requirements will not apply to patients enrolled at sites in Germany.  
• Group 6 (if metastatic): 
 
 
 
 
To account for the possibility of unconventional immune responses, immune-related response 
criteria (irRC) (Nishino 2013) can inform the decision regarding whether to continue treatment for 
an individual patient if the investigator believes it is in the best clinical interest of the patient, after 
discussion and approval from the medical monitor.  Reasons for any such decision to treat 
beyond the protocol definitions of progression must be documented in the CRFs.  However, 
irRC are currently deemed a surrogate endpoint (Postow 2015), and irRC data are not included in 
the primary endpoint of this study.  Any patient who experiences best response (PR or CR) after 
initial progression (per Appendix 1 or Appendix 2, as appropriate) in the context of continued 
treatment (according to principles of irRC in after sponsor approval) will not have that best 
response (partial or complete) counted towards the primary endpoint of this study. 
Patients with metastatic CSCC will generally be followed by RECIST 1.1 criteria (Appendix 1).  
It is possible that some patients may also have externally visible lesions that are measurable by 
digital medical photography.  Generally, it will be clinically appropriate to follow these externally 
visible lesions as non-targets.  However, patients with externally visible lesions that are deemed 
clinically significant by the investigator, the clinical and composite response criteria in Appendix 2 
may be used in selected cases.  However, it is anticipated that most patients in Groups 1 and 3 (and 
most metastatic patients in Groups 4, 5, and 6) will be followed by RECIST 1.1 only.  
For Group 2, response assessment is according to the clinical and composite response criteria in 
Appendix 2. 
For externally visible lesions that are indeterminate-appearing regarding presence of CSCC, see 
Appendix 5 for guidelines on tumor biopsies.  Annotation of tumor measurements and biopsies 
should adhere to the guidelines in Appendix 5.  If annotation of the full perimeter of a lesion is 
deemed not clinically appropriate by the investigator (eg, an ulcerated lesion), the priority 
annotation will be the axes delimiters.  The perimeter of the lesion should be annotated as fully as 
possible without causing undue discomfort to the patient. 
All radiology, photography, and biopsy results will be independently reviewed.  A blinded central 
review committee will be formed to determine overall response based on the integration of these 
modalities.  For Group 5, central review of photographs and radiologic images may be performed. 
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6.3.3. 
Safety Procedures 
6.3.3.1. 
Vital Signs 
Vital signs, including temperature, resting blood pressure, pulse, and respiration, will be collected 
at time points according to Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, and  Table 9. 
Note: blood pressure should be measured after the patient has been resting quietly for at least 
5 minutes. 
At cycle 1 day 1 and on all subsequent treatment days, vital signs will be collected prior to infusion, 
and approximately 15 minutes after the completion of the infusion.  The allowable window for 
each specified time point is ±10 minutes. 
6.3.3.2. 
Physical Examination 
A thorough complete or limited physical examination will be performed at visits specified in 
Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, and Table 9. 
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 will include examination of head and neck, lungs, heart, abdomen, 
lymph nodes, extremities, and skin.  A brief neurologic examination also should be performed. 
Complete physical exam must be accompanied by assessment and documentation of 
ECOG Performance Status (Appendix 7). 
Limited physical examination will include lungs, heart, abdomen, and skin. 
Group 5 patients only: any local ISRs will be described in the CRF, as appropriate (Section 5.4.3 
and Section 7.2.1). 
6.3.3.3. 
Electrocardiogram 
A standard 12-lead ECG will be performed at time points according to Table 3, Table 4, Table 5, 
Table 6, Table 7, and Table 8. 
The patient should be relaxed and in a recumbent or semi-recumbent position at least 5 minutes 
before recording an ECG. The ECG strips or reports will be retained with the source.  The ECG 
will be reviewed by the investigator (paper or electronic tracing) and will be available for 
comparison with subsequent ECGs by the investigator.  The following will be recorded on the 
CRF: 
• PR Interval (msec) 
• QRS Interval (msec) 
• QT Interval (msec) 
• Heart Rate (BPM; recorded from the ventricular rate). 
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. 
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6.3.3.4. 
Immune Safety Assays 
Immune safety assays consist of rheumatoid factor (RF), TSH, C-reactive protein (CRP), and 
antinuclear antibody (ANA) titer and pattern (for Group 6, only TSH is required). 
If, during the course of the study, a 4-fold or greater increase from baseline in RF or ANA or 
abnormal levels of TSH or CRP are observed, the following tests may also be performed: anti-
DNA antibody, anti-Sjögren’s syndrome A antigen (SSA) antibody (Ro), anti-Sjögren’s syndrome 
B antigen (SSB) antibody (La), antithyroglobulin antibody, anti-LKM antibody, antiphospholipid 
antibody, anti-islet cell antibody, antineutrophil cytoplasm antibody, C3, C4, CH50. 
6.3.3.5. 
Immunoglobulin Levels 
Serum IgG, IgM, and IgE will be measured at timepoints according to Table 3, Table 4, Table 5, 
and Table 6 (no immunoglobulin levels are collected for Group 6). 
Coagulation Tests 
Activated partial thromboplastin time (aPTT) and International Normalized Ratio (INR) will be 
analyzed by the site’s local laboratory. 
6.3.3.6. 
Laboratory Testing 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by the site’s 
local laboratory. 
Detailed instructions for blood sample collection are in the laboratory manual provided to study 
sites. 
Samples for laboratory testing will be collected at time points according to Table 3, Table 4, 
Table 5, Table 6, Table 7, Table 8, and Table 9. 
Tests will include: 
Blood Chemistry 
Sodium 
Phosphorus 
ALT 
Potassium 
Glucose 
AST 
Chloride 
Albumin 
Total bilirubin 
Bicarbonate* 
Creatinine 
Alkaline phosphatase (ALP) 
Calcium 
Blood urea nitrogen (BUN)** 
Lactate dehydrogenase (LDH) 
Magnesium 
Uric acid 
 
Hematology 
Hemoglobin 
Differential (absolute, percent if absolute not performed): 
WBCs 
 
Neutrophils 
Platelet count 
 
Lymphocytes 
 
 
Monocytes 
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Urinalysis 
Glucose 
pH 
Ketones 
Blood 
Specific gravity 
Spot urine protein 
*At ex-US centers where the bicarbonate test is not performed as part of the routine chemistry panel, it may be 
omitted. 
**At ex-US centers where Urea assay is performed instead of Blood Urea Nitrogen (Urea), the Urea assay will be 
acceptable. 
Abnormal Laboratory Values and Laboratory Adverse Events 
• All laboratory values must be reviewed by the investigator or authorized designee. 
• Significantly abnormal tests 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 7.2.5. 
6.3.4. 
Pharmacokinetic and Antibody Procedures 
6.3.4.1. 
Drug Concentration Measurements and Samples 
Cemiplimab PK parameters after IV administration will be determined by measuring cemiplimab 
concentrations in serum samples using a validated assay at visits and time points indicated in, 
Table 3, Table 4, Table 5, Table 6, Table 7, and Table 8 (as listed in Appendix 3).  Actual time of 
each blood draw must be recorded. “Predose” is defined as before the start of the first cemiplimab 
infusion.  Predose samples may be collected ≤72 hours prior to day 1 dosing.  Subsequent sampling 
times for drug concentrations will be based on the cemiplimab dosing time that precedes the 
sampling collection.  Pre-infusion is defined as before the start of the cemiplimab infusion and 
“0 hour” is defined as immediately (within 10 minutes) after the end of the cemiplimab infusion. 
For cemiplimab SC administration, the ‘pre-infusion PK sample’ refers to the PK sample before 
the SC injection (for patients receiving 
, the sample should be taken 
prior to the first of series of 3 injections).  
Any unused samples collected for drug concentration measurements may be used for exploratory 
biomarker research or to investigate unexpected AEs. 
Cemiplimab PK parameters and absolute bioavailability by SC route will be determined by 
measuring cemiplimab concentrations in serum samples from patients in Group 5 after a single SC 
dose (C1D1) (time points are indicated in Appendix 3).  Actual dosing time and time of each blood 
draw must be recorded.  Predose samples may be collected ≤72 hours prior to day 1 dosing.  
Subsequent sampling times for drug concentration will be based on the cemiplimab dosing time 
that precedes the sampling collection.  Pre-infusion is defined as before the start of the 
cemiplimab infusion and “0 hour” is defined as immediately (within 10 minutes) after the end of 
the cemiplimab infusion. For SC administration PK sample should be collected immediately before 
the SC injection, then at time points indicated in Appendix 3 over first dosing interval.  
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Subsequently, trough samples from patients receiving SC should be taken immediately prior to 
dosing. 
6.3.4.2. 
Anti-Drug Antibody Measurements and Samples 
Samples for ADA assessment will be collected prior to dosing at time points listed in Table 3, 
Table 4, Table 5, Table 6, Table 7, Table 8, and Table 9. 
Any unused samples collected for ADA assessment may be used for exploratory biomarker 
research or to investigate unexpected AEs. 
6.3.5. 
Biomarker Measurements and Samples 
Speculated 
pharmacodynamic, 
predictive, 
and 
prognostic 
biomarkers 
related 
to 
cemiplimab treatment exposure, clinical activity, or underlying disease will be investigated in 
tumor biopsy tissue collected at baseline, after treatment with cemiplimab, and at progression, if 
available.  Correlative analyses between these biomarkers and clinical response to cemiplimab and 
disease progression may elucidate molecular mechanisms of action of cemiplimab and may 
identify biomarkers for patient stratification in future studies.  Additional biomarker analysis may 
be performed (tissue permitting) to gain better understanding of the tumor microenvironment and 
immune milieu.  Biomarker results will be reported separately from the clinical study report.  
 
 
 
6.3.5.1. 
Tumor Biomarker Procedures 
For patients with locally advanced CSCC, tumor biopsies will be collected per the timepoints and 
methodology in Appendix 5. 
 
 
  
  
 
 
 
 
  
 
 
 
 
Main exploratory potential biomarkers of interest include, but are not limited to: 
 
 
 
  
 
 
 
 
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6.3.5.2. 
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.  Blood for genomic DNA extraction 
should be collected on day 1/baseline (predose) but may be collected at any study visit.  Patients 
are not required to participate in the genomics sub-study in order to enroll in the primary study. 
 
  
 
  
 
 
 
 
 
  
 
  
 
 
6.3.6. 
Groups 3, 4, and 5 Only: Guidance Regarding Patients Who Wish to Continue 
Treatment Beyond Planned Treatment Period 
The intent of Groups 3, 4, and 5 is that patients who have completed planned treatment (54 weeks 
in Groups 3 and 5, and 48 weeks in Group 4) without PD will enter posttreatment follow-up.  The 
potential risks and benefits of continued treatment beyond planned treatment duration are not 
known, but risks may include cumulative toxicities with cytotoxic chemotherapy and late immune-
related toxicities with PD-1 inhibition.  The planned treatment for the patient's assigned group, 
with an option for retreatment as set forth in Section 6.2.2 must be discussed with Groups 3, 4, and 
5 patients during the informed consent process. 
Some patients who are experiencing clinical benefit may be hesitant to stop treatment at 54 weeks.  
It is important that study teams remind patients of the treatment duration as they approach the 
completion of the planned treatment period.  Patients who are experiencing durable responses or 
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stable disease (>6 months) should be reminded that study treatment ends (at 54 weeks for Groups 3 
and 5, and 48 weeks for Group 4), with a plan for follow-up and potential retreatment in the event 
of PD. 
Patients are strongly encouraged to adhere to the study plan.  However, it is anticipated that some 
Group 3, 4, and 5 patients who have experienced clinical benefit may be unwilling to discontinue 
treatment at the completion of the planned treatment period for the group.  In such cases, the 
investigator will contact the medical monitor.  Patients who have not experienced PD and who are 
unwilling to stop study treatment will be allowed to continue study treatment if the investigator 
deems that there are not unacceptable safety risks with continued treatment, after notification of 
medical monitor.  After completion of the planned treatment period for the group, such patients 
may continue on the same dose and schedule of study treatment (cemiplimab 350 mg IV Q3W for 
Groups 3 and 5, cemiplimab 600 mg IV Q4W for Group 4), unless there has been dose reduction.  
Patients with dose reduction would only be treated at the reduced dose. 
For Group 3:  The schedule of events will follow Table 4 but cycles will be counted as 7 through 
12 (instead of 1 through 6).  The patient will not repeat screening assessments before beginning 
cycle 7.   
For Groups 4 and 5:  The schedule of events will follow Table 5 and Table 6 but cycles will be 
counted as 7 through 12 (instead of 1 through 6).  The patient will not repeat screening assessments 
before beginning cycle 7.   
The following assessments are not required during cycles 7 through 12:  PK samples, research 
blood samples, and research tumor biopsies (exploratory tumor biopsies in Group 4). 
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7. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
7.1. 
Definitions 
7.1.1. 
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 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 7.2. 
NCI-CTCAE version 4.03 terms should be used. 
7.1.2. 
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), within 30 days of 
last dose of cemiplimab 
• 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. 
Hospitalization or prolongation of existing hospitalization due to the progression of 
underlying malignancy will not be considered an SAE, if it is clearly consistent with 
the typical progression pattern of the underlying cancer. 
• 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 
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may require intervention to prevent 1 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 an SAE in this study. 
Serious adverse events must be reported as directed in Section 7.2. 
7.1.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical interest 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 
trial sponsor to other parties (eg, regulators) might also be warranted (Section 7.2.3). 
7.2. 
Recording and Reporting Adverse Events 
7.2.1. 
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 (5 half-lives) 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 electronic CRF: 
• SAEs 
• Nonserious AEs associated with a protocol-mandated intervention (eg, AEs related to 
an invasive procedure such as a biopsy) 
(Other AEs that occur prior to first treatment should be reported on the medical history CRF.) 
All AEs after initiation of study treatment and until 105 days (5 half-lives) after the last study 
treatment, regardless of relationship to study treatment, will be reported on the AE electronic CRF.  
Additionally, any SAE or other AE of concern that the investigator believes may be related to 
study treatment and that occurs later than 105 days (5 half-lives) after last study treatment should 
be reported. 
Information on follow-up for AEs is provided in Section 7.2.6.  Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 7.2.5. 
Group 5 patients and Group 6 patients who opt to receive SC dosing only: any local ISRs will be 
reported as AEs in the CRF, as appropriate. 
7.2.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study treatment must be reported to 
the sponsor (or designee) within 24 hours.  Refer to the safety reporting guidelines for the 
procedure to be followed. 
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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 the investigator is informed of an SAE that occurs more than 105 days (5 half-lives) 
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 a treatment-related 
SAE until the event is considered resolved or chronic and/or stable. 
7.2.3. 
Other Events that Require Accelerated Reporting to the 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 
patient or female partner of a male patient, during the study or within 105 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 must be reported as an SAE.  Outcomes for all 
pregnancies should be reported to the sponsor. 
Adverse Events of Special Interest: 
An AESI must be reported within 24 hours of identification.  Adverse events of special interest for 
this study include: 
• Grade 2 or greater infusion-related reactions 
• Grade 2 or greater allergic/hypersensitivity reactions 
• Grade 3 or higher irAEs 
• Grade 3 or greater ISR for the SC route 
• An irAE of any grade in a patient previously treated with a PI 3-K inhibitor 
Note: An irAE 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 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. 
Refer to the safety reporting guidelines for the reporting procedures to be followed. 
If any SAE or unusual AE is judged related to study treatment, and as possible and practical, obtain 
a blood sample from the patient to permit measurement of plasma drug levels. 
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7.2.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from study treatment or from the study must be reported 
to the sponsor’s medical monitor within 30 days. 
Refer to the safety reporting guidelines for the procedures to be followed. 
7.2.5. 
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 
• 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), and/or 
• the test result leads to discontinuation from the study, significant additional 
concomitant medication, 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 7.3.1. 
7.2.6. 
Follow-up 
Information for any nonserious AE that starts during the treatment period or within 105 days 
(5 half-lives) after last 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 adverse event information will be collected until the event is considered resolved or 
chronic and/or stable. 
7.3. 
Evaluation of Severity and Causality 
7.3.1. 
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 ADL*.  
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3 (Severe): 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**. 
4 (Life–threatening): 
Life-threatening consequences; urgent intervention indicated. 
5 (Death): 
Death related to AE 
* Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc. 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
The grading criteria for ISRs in Section 5.4.3 are different than NCI-CTCAE version 4.03 grading 
of ISRs, because the criteria in Section 5.4.3 are more descriptive of potential local reactions to 
this class of drug.  
7.3.2. 
Evaluation of Causality 
Relationship of AEs 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 
The investigator should justify the causality assessment of each reported SAE. 
Appendix 8 lists factors to consider in assessing the relationship of AEs to cemiplimab. 
Relationship of Adverse Events to Study Conduct: 
The relationship of AEs or SAEs 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 or SAE 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 or SAEs to study conduct is 
provided in Appendix 8. 
The investigator should justify the causality assessment of each SAE. 
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7.4. 
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.  The study monitor 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. 
7.5. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial 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, and has a reasonable suspected causal relationship to the medicinal/study drug). 
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8. 
STUDY VARIABLES AND ENDPOINTS 
8.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height), disease 
characteristics including medical history, cancer stage (Edge 2010), and medication history for 
each patient. 
8.2. 
Primary and Secondary Endpoints 
8.2.1. 
Primary Efficacy Endpoints 
The primary efficacy endpoint for this study is ORR according to central review during the 
12 treatment cycles (Groups 1, 2, and 6), or 6 treatment cycles (Groups 3 and 4).  Overall response 
rate will be assessed separately for patients with metastatic CSCC or locally advanced CSCC: 
• For patients with metastatic disease, RECIST version 1.1 will be used to determine 
ORR (Eisenhauer 2009) (Appendix 1).  Patients in which all response assessments are 
performed on radiologic scans according to RECIST 1.1, the determination of the 
independent radiologic response assessment committee will serve as the central 
response assessment.  Clinical or composite response criteria (Appendix 2) may be 
used for patients with externally visible target lesions, if all metastatic lesions are not 
measurable by RECIST (such as may occur in patients with bone-only metastases). 
• For patients with unresectable locally advanced disease, clinical response criteria 
(Appendix 1) will be used to determine ORR, for externally visible tumor(s) use bi-
dimensional measurements according to World Health Organization (WHO) criteria.  
Composite response criteria will be used for patients who have both target lesions 
measurable by clinical response criteria and by RECIST 1.1 to determine ORR 
(Appendix 2).  In patients achieving a CR, tumor biopsies will be used in the final 
determination of complete versus PR.  
Patients who are deemed not evaluable (NE) by RECIST version 1.1 (Groups 1, 3, 4, and 6; 
Appendix 1) or inevaluable by the clinical or composite response criteria (Group 2; Appendix 2) 
will be considered as not reaching PR/CR for ORR.  ORR will be calculated from time of 
enrollment. 
8.2.2. 
Secondary Endpoints 
The secondary efficacy endpoints are: 
• ORR for Groups 1 through 6 by investigator assessments: 
− For patients with metastatic CSCC in which all response assessments are performed 
on radiologic scans according to RECIST 1.1, the term “composite response 
assessment” is not applicable.  The investigator’s response assessment for such 
patients will be RECIST 1.1 assessment. 
− For patients with locally advanced CSCC in which all response assessments are 
performed on photographs according to Clinical Response Criteria for Externally 
Visible Tumors (in Appendix 2), the term “composite response assessment” is not 
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applicable.  The investigator’s response assessment for such patients will be 
according to Clinical Response Criteria for Externally Visible Tumors. 
− For patients in which target lesion response assessments are performed with both 
scans (according to RECIST 1.1) and photographs (according to Clinical Response 
Criteria for Externally Visible Tumors), the investigator’s response assessment will 
be according to Composite Response Criteria (in Appendix 3). 
• DOR – measured from the time measurement criteria are first met for CR/PR, 
whichever is recorded first, until the first date of recurrent or progressive disease or 
death due to any cause in patients with best overall response (BOR) of CR or PR  
• PFS – measured from time of enrollment until the first date of recurrent or progressive 
disease, or death due to any cause  
• OS – measured from time of enrollment until death due to any cause  
• CR rate 
• Change in scores of patient-reported outcomes on EORTC QLQ-C30 (except Group 6) 
• AEs  
• Cemiplimab concentrations in serum (Appendix 3) 
• Anti-drug antibodies (ADA) 
• For Group 6 only:  To assess relationships between PD-L1 status (by IHC) and 
efficacy measures (ORR, DOR, PFS). 
8.2.3. 
Exploratory Endpoints 
The following exploratory analyses are planned: 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
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8.2.4. 
Pharmacokinetic Variables 
Serum concentration of cemiplimab will be assessed at multiple time points throughout the study 
treatment and follow-up periods, and the PK will be analyzed. 
Pharmacokinetic variables may include, but are not limited to, the following: 
• Ceoi – concentration at end-of-infusion (IV) 
• Cmax – peak concentration (SC) 
• Ctrough – pre-infusion concentration 
• teoi – time of end-of-infusion 
• tmax – time to peak concentration (SC) 
• AUC3w – area under the plasma concentration-time curve after the first SC or IV dose 
• F – Absolute bioavailability after SC administration 
8.3. 
Anti-Drug Antibody Variables 
Regeneron plans to evaluate the impact of the immunogenicity of cemiplimab. 
Anti-drug antibody variables include ADA status and titer as follows: 
• Treatment emergent – defined as any positive postdose ADA assay response when 
baseline results are negative 
• Treatment boosted – defined as any postdose ADA response that is at least 9-fold over 
baseline titer levels 
• Titer values (Titer value category): 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000) 
The relationship between immunogenicity and PK of cemiplimab may be assessed, as appropriate.  
8.4. 
Exploratory Biomarker Variables – Group 6  
Exploratory pharmacodynamic and biomarker variables for Group 6 include: 
 
  
 
  
 
 
  
 
  
 
   
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9. 
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 SAP will be issued before the database is locked. 
Analysis variables are listed in Section 8. 
9.1. 
Statistical Hypothesis 
For the primary endpoint of ORR, the following null hypothesis and alternative will be tested for 
Groups 1, 2, 3, 4, and 6, respectively. 
Group 1: H0: ORR = 15% vs. H1: ORR ≠ 15% 
Group 2: H0: ORR = 25% vs. H1: ORR ≠ 25% 
Group 3: H0: ORR = 15% vs. H1: ORR ≠ 15% 
Group 4: H0: ORR = 20% vs. H1: ORR ≠ 20% 
Group 6: H0: ORR: = 28% vs. H1: ORR ≠ 28% 
9.2. 
Justification of Sample Size 
Patients will be enrolled into 6 separate groups.  A single-stage exact binomial design is adopted 
for Groups 1, 2, 3, 4, and 6 respectively, for the primary endpoint of ORR.  After completion of 
enrollment in Group 1, up to 53 additional patients with metastatic CSCC will be enrolled in 
Group 3.  Group 4 will begin enrollment after completion of enrollment in Groups 1 through 3.  
Published clinical studies for CSCC patients have had relatively small sample sizes and often 
include a wide range of disease stages (Nakamura 2013).  Clinical studies of CSCC patients have 
been predominantly composed of patients with locally advanced disease (primary site).  The 
NCCN guidelines for CSCC, cisplatin monotherapy, cisplatin plus 5-FU, and cetuximab are 
described as “possible options” (Bichakjian 2015).  In the only study of cisplatin-based therapy 
for advanced CSCC reported in the last 15 years, the ORR was 34% (Shin 2002).  Cetuximab 
yielded a response rate of 28% in a phase 2 study for patients with advanced CSCC (Maubec 2011).  
Most patients in these studies had locoregionally advanced disease.  There hasn’t been a 
publication of a clinical study specifically for patients with metastatic CSCC.  The aggregate 
experience of patients enrolled in trials of systemic therapy indicates that a clinically meaningful 
ORR for an investigational agent would be >15% for patients with metastatic disease or >25% for 
patients with unresectable locally/regionally advanced CSCC (Khansur 1991, Lippman 1992, 
Nakamura 2013, Shin 2002).   
Group 4 enrolls patients with advanced CSCC (metastatic or locally advanced).  The clinically 
meaningful ORR would range from 15% to 25% for patients with advanced CSCC.  Assuming 
equal number of patients with metastatic CSCC or locally advanced CSCC, the clinically 
meaningful ORR would be >20% for patients with advanced CSCC. (Note: With protocol 
Amendment 7, enrollment will begin for Group 6 and enrollment for Group 4 will close even if it 
is not fully enrolled.  If statistical hypothesis testing for Group 4 is not possible due to incomplete 
enrollment, descriptive statistics will be used for Group 4). 
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Hence, the sample sizes for Group 1 through 4 were selected such that the lower limit of the 95% 
confidence intervals of the estimated ORRs will be clinically meaningful.  The non-clinically 
meaningful ORR of 15% for Group 1 and Group 3 (evaluated independently) will be excluded 
using the lower limit of 95% CI if the observed ORR is 28.0% or more; ie, the ORR for Group 1 
and/or Group 3 (evaluated independently) is significantly different from 15%.  The non-clinically 
meaningful ORR of 25% for Group 2 will be excluded using the lower limit of 95% CI if the 
observed ORR is 36.1% or more (ie, the ORR for Group 2 is significantly different from 25%).  
The non-clinically meaningful ORR of 20% for Group 4 will be excluded using the lower limit of 
95% confidence interval if the observed ORR is 31.7% or more; ie, the ORR for Group 4 is 
significantly different from 20%.  In addition, if the observed ORR for Group 4  is 26.7% or 38.3% 
or more, the ORR for Group 4  is significantly different from 15% or 25% respectively, using the 
lower limit of the 95% confidence intervals (see Table 10, Table 11, and Table 12).  
Group 6 enrolls patients with advanced CSCC (metastatic or locally advanced).  The statistical 
design for Group 6 will be capable of demonstrating a point estimate of ORR (per independent 
central review) in which the lower bound of the 95% confidence interval excludes the highest 
centrally reviewed ORR in the literature for any prospective study of systemic anticancer treatment 
(other than cemiplimab) that enrolled at least 30 patients.  Most previous studies of advanced 
CSCC used investigator-based assessments of ORR (William 2017, Gold 2018, Shin 2002, 
Lippman 1992, Khansur 1991, Sadek 1990, Cartei 2000) and therefore do not serve as comparators 
for ORR per independent central review in Study 1540.  Additionally, some studies did not report 
results according to intention-to-treat (Shin 2002, Lippman 1992, Sadek 1990).   However, the 
phase 2 study of cetuximab (N = 36 patients) in advanced CSCC did report ORR of 28% per 
independent radiology review (Maubec 2011).  As such, 28% is the highest reported ORR in any 
study in advanced CSCC patients that used independent radiology review and enrolled at least 
30 patients.  The statistical plan for Group 6 is capable of testing for an ORR (per independent 
central review) that excludes 28% at the lower bound of the 95% confidence interval.  
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Table 10: 
The 95% Binomial Exact Confidence Intervals for Observed ORR in 
Group 1 and Group 3 Given a Sample Size of 50 Patients (Based on 
85% Power) 
Number of Responders 
Observed ORR 
95%CI – lower 
95% CI – upper 
7 
0.14 
0.058 
0.267 
8 
0.16 
0.072 
0.291 
9 
0.18 
0.086 
0.314 
10 
0.20 
0.100 
0.337 
11 
0.22 
0.115 
0.360 
12 
0.24 
0.131 
0.382 
13 
0.26 
0.146 
0.403 
14 
0.28 
0.162 
0.425 
15 
0.30 
0.179 
0.446 
16 
0.32 
0.195 
0.467 
17 
0.34 
0.212 
0.488 
Table 11: 
The 95% Binomial Exact Confidence Intervals for Observed ORR in 
Group 2 Given a Sample Size of 72 Patients (Based on 90% Power) 
Number of Responders 
Observed ORR 
95%CI – lower 
95% CI – upper 
18 
0.250 
0.155 
0.366 
19 
0.264 
0.167 
0.381 
20 
0.278 
0.179 
0.396 
21 
0.292 
0.190 
0.411 
22 
0.306 
0.202 
0.425 
23 
0.319 
0.214 
0.440 
24 
0.333 
0.227 
0.454 
25 
0.347 
0.239 
0.469 
26 
0.361 
0.251 
0.483 
27 
0.375 
0.264 
0.497 
28 
0.389 
0.276 
0.511 
29 
0.403 
0.289 
0.525 
30 
0.417 
0.302 
0.539 
31 
0.431 
0.314 
0.553 
32 
0.444 
0.327 
0.566 
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Table 12: 
The 95% Binomial Exact Confidence Intervals for Observed ORR in 
Group 4 Given a Sample Size of 60 Patients (Based on 92% Power) 
Number of Responders 
Observed ORR 
95%CI – lower 
95% CI – upper 
16 
0.267 
0.161 
0.397 
19 
0.317 
0.203 
0.450 
23 
0.383 
0.261 
0.518 
26 
0.433 
0.306 
0.568 
For Groups 1 and 3, 50 patients (in each group) will be required to provide at least 85% power to 
reject a null hypothesis of an ORR of 15% at a 2-sided significance level of no more than 5% if 
the true ORR is 34%.  For Group 2, 72 patients will be required to provide at least 90% power to 
reject a null hypothesis of an ORR of 25% at a 2-sided significance level of no more than 5% if 
the true ORR is 44%.  For Group 4, 60 patients with advanced CSCC will be required to provide 
at least 92% power to reject a null hypothesis of an ORR of 20% at a 2-sided significance level of 
no more than 5% if the true ORR is 40%.  In addition, for Group 4, 60 patients with advanced 
CSCC will provide at least 93% or 87% power to reject a null hypothesis of an ORR of 15% or 
25% at a 2-sided significance level of no more than 5% if true ORR is 35% or 45% respectively.  
The sample sizes will be further increased by 5% to account for patients who withdraw prematurely 
from the study.  Hence, the total planned sample sizes will be 53 patients (actual enrolled 59) for 
Group 1, 76 patients (actual enrolled 78) for Group 2, 53 patients (actual enrolled 56) in Group 3, 
and 63 patients for Group 4. 
Group 5 is a pilot cohort to obtain initial clinical and PK experience among patients who receive 
a single dose of cemiplimab SC, with a sample size of 10 patients for PK analysis.  
The sample size for Group 6 was selected such that the lower limit of the 95% confidence interval 
of the estimated ORR excludes the highest independently-reviewed ORR to date in any prospective 
study of anticancer systemic therapy for advanced CSCC that enrolled at least 30 patients.   
For Group 6, 150 patients will be required to provide at least 85% power to reject a null hypothesis 
of an ORR of 28% at a 2-sided significance level of no more than 5% if the true ORR is 40%.  The 
sample size will be further increased by 10% to account for patients who withdraw prematurely 
from the study.  Hence, the total planned sample size will be approximately 167 patients for 
Group 6.  The ORR of 28% for Group 6 will be excluded using the lower limit of 95% exact CI if 
the observed ORR is 35.3% or more, ie, the ORR for Group 6 is significantly different from 28% 
(Table 13). 
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Table 13: 
The 95% Binomial Exact Confidence Intervals for Observed ORR in 
Group 6 Given a Sample Size of 167 Patients  
Number of Responders 
Observed ORR 
95%CI – lower 
95% CI – upper 
56 
33.5% 
26.4% 
41.2% 
57 
34.1% 
27.0% 
41.9% 
58 
34.7% 
27.5% 
42.5% 
59 
35.3% 
28.1% 
43.1% 
60 
35.9% 
28.7% 
43.7% 
61 
36.5% 
29.2% 
44.3% 
62 
37.1% 
29.8% 
44.9% 
In Group 6, enrollment of metastatic CSCC patients will be capped at 133 patients to allow for at 
least 34 patients with locally advanced CSCC to be enrolled.  This mirrors the real-world 
distribution of metastatic (80%) and locally advanced (20%) patients with CSCC described in 
retrospective study of advanced CSCC in the US Oncology Network (Cowey, manuscript in 
preparation).  Appendix 10 presents reference tables for Group 6 subgroup analyses.  However, 
the primary analysis for Group 6 is based on all advanced CSCC patients, both metastatic and 
locally advanced.  These subgroup analyses are descriptive only. 
9.3. 
Analysis Sets 
9.3.1. 
Full Analysis Set  
The full analysis set (FAS) includes all patients who have passed screening and deemed to be 
eligible for this study.  All efficacy endpoints will be analyzed using FAS. 
9.3.2. 
Safety Analysis Set  
The safety analysis set (SAF) includes all enrolled patients who received any study drug for each 
group. Treatment compliance/administration and all clinical safety variables will be analyzed or 
summarized using the SAF. 
9.3.3. 
Pharmacokinetic Analysis Set 
The PK analysis set for cemiplimab will include all patients who had received cemiplimab/ and 
had at least 1 qualified (non-missing) postbaseline measurement of cemiplimab concentration in 
serum. 
9.3.4. 
Anti-drug Antibody Set  
The ADA population for cemiplimab includes all treated patients who had at least 1 postdose ADA 
result for cemiplimab. 
9.3.5. 
Biomarker Analysis Set 
The biomarker analysis set (BAS) includes all treated patients who had at least 1 sample assayed. 
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9.4. 
Patient Disposition 
The following will be provided by group and overall: 
• The number of screened patients  
• The number of patients included in the FAS and the SAF 
• The number of patients who discontinued study participation, and the reasons for 
discontinuation from the study 
• The number of patients who discontinued treatment, and the reasons for treatment 
discontinuation 
9.5. 
Statistical Methods 
In general, the descriptive summary for continuous data will include the number of observations 
(n), mean, standard deviation (SD), median, minimum and maximum.  In addition, 25% percentile 
and 75% percentile will also be provided. 
The descriptive summary for categorical data will include counts (n) and percentages calculated 
in each group.  The denominator will be determined by the analysis population used for the 
summary.  Non-evaluable outcome or missing data will be handled based on the data handling 
strategy. 
The descriptive summary for time-to-event data will include the median time-to-event and its 
95% confidence intervals using the Kaplan-Meier method.  
9.5.1. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively for each group by 
extent of prior therapy (no prior systemic therapy versus having received any prior systemic 
therapy). 
9.5.2. 
Efficacy Analyses 
The primary endpoint for efficacy analyses is the ORR, by central review.  For Group 1 and 
Group 3 patients in which all response assessments are done by RECIST 1.1 (Eisenhauer 2009) 
analysis of radiologic scans, the independent radiology review is the central review.  For Group 2 
patients (and some Group 1 and Group 3 patients), response assessments include photos and 
radiologic scans, and the independent composite review committee will serve as the central review.   
The primary analyses of efficacy are based on the binomial exact confidence interval approach, ie, 
whether the lower limit of 95% confidence interval will exclude a historical control ORR that is 
not deemed clinically meaningful.  The 95% binomial exact confidence intervals using Clopper-
Pearson method (Clopper 1934) for observed ORRs are listed for Groups 1 and 3 (Table 10), 
Group 2 (Table 11), Group 4 (Table 12), and Group 6 (Table 13).  
The investigator-assessed ORR will be considered as a secondary analysis.  Patients who are 
deemed as not evaluable according to RECIST 1.1 or inevaluable by the composite efficacy criteria 
will be considered as not reaching PR/CR for ORR (see Section 6.3.2 ). 
The secondary efficacy endpoints as measured by DOR, PFS, and OS will be summarized by 
median and its 95% confidence interval by the Kaplan-Meier method. 
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The CR rate will be summarized descriptively with 95% confidence interval.  Absence of residual 
CSCC in patients with locally advanced CSCC achieving a clinical response to cemiplimab, as 
measured by central review, will be summarized descriptively. 
On an exploratory basis, efficacy data between different groups may be described. Such analyses 
should be performed so that each group has a similar amount of follow up (for example, at time of 
primary analysis, which is pre-specified as last patient first dose (LPFD) plus approximately 6 
months for each group.) 
Amendment 9: For Group 6 patients who opt to switch to  SC cemiplimab, efficacy data per central 
review will be censored at the first SC dose.  Because Group 6 patients are only allowed to switch 
to SC cemiplimab after completing at least 27 weeks on study (3 tumor assessments after baseline), 
which is the pre-specified timepoint for primary efficacy analyses in Group 6, switching to SC 
dosing will have no impact on the primary efficacy analysis for Group 6. 
9.5.3. 
Exploratory Analyses 
 
 
 
 
 
 
 
  
 
 
 
9.5.4. 
Safety Analysis 
Safety observations and measurements including drug exposure, AEs, laboratory data, vital signs, 
and ECOG performance status will be summarized and presented in tables. 
9.5.4.1. 
Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The on-treatment period is defined as the day from first dose of study drug to 105 days 
after the last dose of study drug or to follow-up visit, whichever is longer. 
• The posttreatment period is defined as the time after follow-up visit 1. 
Treatment-emergent adverse events (TEAEs) are defined as those not present at baseline or 
represent the exacerbation of a condition present at baseline during the on-treatment period or 
within 105 days after the last study dose. 
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Analysis 
All AEs reported in this study will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®).  
Summaries of all TEAEs by group will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity (NCI-CTCAE, version 4.03 grade), presented by SOC and PT 
• TEAEs by outcome 
• TEAEs by relationship to experimental treatment (related, not related), presented by 
SOC and PT 
Deaths and other SAEs will be listed and summarized by group. 
Events of NCI-CTCAE Grade 3 and Grade 4 severity will be summarized by group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by group.  
9.5.4.2. 
Other Safety 
Vital Signs 
Vital signs (temperature, pulse, 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 number and percentage of patients with NCI-CTCAE 
Grade 3 or Grade 4 lab values will be summarized by lab test and by group. 
9.5.4.3. 
Treatment Exposure 
Duration of exposure, number of dose administered, and dose intensity will be summarized by 
group. Dose intensity will be calculated by dividing actual dose by body weight for cemiplimab. 
9.5.4.4. 
Treatment Compliance 
Patients will be administered IV study drug and treatment compliance will be defined in detail in 
the SAP and summarized by group. 
9.5.5. 
Analysis of Drug Concentration Data 
9.5.5.1. 
Descriptive Analysis of Drug Concentrations 
Summaries of study drug concentrations will be presented by nominal time point (ie, the time 
points specified in the protocol) and group. 
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9.5.6. 
Analysis of Anti-Drug Antibody Data 
Formation of ADA will be assessed in individual patients and per treatment group as follows: 
• Possible correlation between changes in PK profile and the presence/absence of anti-
cemiplimab antibodies will be evaluated to identify a potential impact of anti-
cemiplimab antibodies on drug exposure. 
• Possible correlation between AEs and the presence/absence of anti-cemiplimab 
antibodies may be evaluated to identify a potential impact of anti-cemiplimab and/or 
antibodies on the incidence of Grade 3 and 4 AEs, atypical AEs, and SAEs. 
Cases of ADA positivity will be listed and summarized as appropriate. 
9.5.7. 
Analysis of Biomarker Data 
Biomarker data will be analyzed using standard scientific methods and summarized by descriptive 
statistics and plot.  Comparative analysis of biomarker data with parent study may be performed 
using paired t-test or nonparametric Wilcoxon signed rank test or Chi-square test.  Correlative 
analysis with clinical response may be performed using correlation coefficient, box plot and scatter 
plot, and basic regression models.  Both comparative analysis and correlative analysis will be 
exploratory in nature and will be described in a separate report. 
9.5.7.1. 
Sample Size Justification for Biomarker Measurements in Tumor Tissue 
Biopsies 
Although many biomarkers may be assayed in tumor biopsy tissues, CD274 (PD-L1) was selected 
to illustrate the power analysis as an example.  PD-L1 expression level, as defined by percent 
tumor cells with membranous staining by immunohistochemistry, was reported to be associated 
with clinical activity of Nivolumab (Borghaei 2015).  The prevalence of PD-L1 expression levels 
≥1%, ≥5%, ≥10% were 53%, 41%, and 37%, respectively, and the ORRs were reported as 9% vs. 
31%, 10% vs. 36%, 11% vs. 37% for each categorization of PD-L1 expression level, respectively.  
In the following power analysis, the following variations are considered (Table 14):  
1. Actual number of tumor biopsy obtained and deemed evaluable are 60, 50, or 40. 
2. The PD-L1 expression level categorization results in PD-L1 negative / positive ratio as 1:1 
or 3:2. 
3. Objective response rates of 10% (PD-L1 negative) vs. 30% (PD-L1 positive) results an 
odds ratio of 3.857 and 10% (PD-L1 negative) vs. 25% (PD-L1 positive) results an odds 
ratio of 3.0 
The power analysis was based on the one-sided Chi-square test with type I error of 20% due to the 
exploratory nature of biomarker analysis, performed in nQuery Advisor 7.0 (Elashoff, 2007).  The 
power may be overestimated for some configurations as the large sample approximation may not 
be adequate for a Chi-square test with small sample sizes. 
In summary, requiring each patient enrolled in this study to provide tumor biopsy provides 
moderate power for exploratory biomarker analysis.  
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Table 14: 
Power Analysis for PD-L1 Biomarkers from Tumor Biopsies 
Number of 
PD-L1 
Tumor Response 
Tumor Biopsies 
Neg/Pos 
Odds Ratio 
Power (%) 
60 
1:1 
3.857 
87 
3.0 
75 
50 
1:1 
3.857 
83 
3.0 
71 
40 
1:1 
3.857 
77 
3.0 
66 
60 
3:2 
3.857 
86 
3.0 
75 
50 
3:2 
3.857 
82 
3.0 
70 
40 
3:2 
3.857 
76 
3.0 
65 
9.6. 
Multiplicity Considerations 
Adjustments to the significance level for the purposes of multiple testing are not applicable for this 
study.  Statistical analyses for Group 1 and Group 2 will be conducted and reported separately; ie, 
efficacy results and clinical conclusions from Group 1 will not affect those of Group 2, and vice 
versa.  Therefore, statistical control of overall type I error for the whole study is not planned.   
Group 3 is a 53-patient cohort that opens after Group 1 completes enrollment.  Efficacy results and 
clinical conclusions from Group 3 will not affect those of Group 1 or Group 2.  Efficacy results 
and clinical conclusions from Group 1 or Group 2 will not affect those of Group 3.   
Groups 4 and 5 are added in protocol amendment after the completion of enrollment in Groups 1 
through 3 (See Section 3.1).  Efficacy results and clinical conclusions from Group 4 will not affect 
those of the other groups.  Group 5 is a 10-patient pilot cohort to explore SC cemiplimab. Efficacy 
results and clinical conclusions from Group 5 will not affect those of the other groups.  
Group 6 is added to provide additional efficacy and safety for cemiplimab monotherapy in patients 
with advanced CSCC (metastatic or unresectable locally advanced) treated with cemiplimab 
350 mg IV Q3W and fulfill the regulatory requirements associated with conditional approval of 
cemiplimab in Europe.  Efficacy results and clinical conclusions from Group 6 will not affect those 
of the other groups.  
9.7. 
Interim Analysis 
Interim Analysis for Group 2  
For regions where, alpha spending is not required:  For this planned interim analysis, the ORR and 
associated 95% confidence interval will be summarized.  As the primary objective of this the 
interim analysis is point estimation on ORR and characterizing the precision of point estimation, 
there is no hypothesis testing associated with this interim analysis.  Also, no decisions will be made 
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regarding study conduct associated with the interim analysis.  Therefore, Type I error adjustment 
is not applicable for this planned interim analysis. 
For regions where, alpha spending is required:  For this interim analysis on Group 2 patients, 2-
sided alpha of 0.0001 will be allocated for interim analysis, and 2-sided alpha of 0.0499 will be 
preserved for the final analysis.  Correspondingly, for the interim analysis of the primary endpoint 
of ORR in Group 2 patients, the precision of ORR will be estimated by adjusted and 2-sided 
99.99% exact confidence interval.  The un-adjusted and 2-sided 95% exact confidence interval 
will also be reported at the time of interim analysis.  At the time of the final analysis for Group 2 
patients, both adjusted 95.01% and un-adjusted 95% exact confidence interval will be reported. 
For other efficacy endpoints in Group 2 patients, only 2-sided 95% exact confidence interval will 
be presented both at the interim and at the final analysis. 
Interim Analysis for Group 6  
Per sample size calculation, 167 patients are planned for Group 6.  The EMA requires alpha 
spending correction for the interim analysis.  An interim analysis of Group 6 patients will be 
performed after the first 50% of patients have had the opportunity to be followed up for a minimum 
of 28 weeks (27 weeks for 3 tumor assessments + 1-week assessment window) or have reached 
the end of study.  The interim analysis will include a minimum of 20 locally advanced CSCC 
patients.  If 20 locally advanced patients are not yet enrolled in the set of the first 84 patients 
enrolled in Group 6, the interim analysis will be performed after 20 locally advanced CSCC 
patients have been enrolled and have had the opportunity to be followed for at least 28 weeks.  All 
patients enrolled in Group 6 who have had the opportunity to be followed for at least 28 weeks 
will be included in the interim analysis. 
For regions where alpha spending is not required:  For this planned interim analysis, the ORR and 
associated 95% confidence interval will be summarized.  As the primary objective of this the 
interim analysis is point estimation on ORR and characterizing the precision of point estimation, 
there is no hypothesis testing associated with this interim analysis.  Therefore, Type I error 
adjustment is not applicable for this planned interim analysis. 
For regions where alpha spending is required:  The overall type I error rate for analyses of the 
primary endpoint of ORR is controlled at a 2-sided alpha of 0.05 using the O’Brien-Fleming 
spending function.  Table 15 demonstrates the bound and boundary properties for ORR hypothesis 
testing at interim and final analyses, assuming interim analysis was performed at 50% of 
enrollment. The table will be updated using the actual number of patients included in the interim 
and final ORR analysis.  
Table 15: 
Alpha Spending for Analysis of ORR on Group 6 Patients 
Analysis 
 
Value 
Interim Analysisa 
 
Z 
2.9626 
α (2-sideda) 
0.0031 
Final Analysis 
 
Z 
1.9686 
α (2-sided) 
0.0490 
a As a 2-sided test is used at interim, the superiority or futility of cemiplimab treatment will be claimed if the 
statistical boundary is crossed. 
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For the interim analysis of ORR, the precision of ORR will be estimated by adjusted 2-sided 
99.69% exact confidence interval.  The un-adjusted 2-sided 95% exact confidence interval will 
also be reported at the time of interim analysis.  At the time of the final analysis, both adjusted 
95.10% and un-adjusted 95% exact confidence interval will be reported. The confidence level will 
be updated using the actual number of patients included in the interim and final ORR analysis. 
For other efficacy endpoints in Group 6 patients, only 2-sided 95% confidence interval will be 
presented both at the interim and at the final analysis. 
9.8. 
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 the missing data 
• 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 medication 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 
medication date, then the start date by the study medication intake date will be imputed, 
otherwise, the missing day or month by the first day or the first month will be imputed. 
• Patients who are deemed NE by RECIST version 1.1 (Group 1; Appendix 1) or 
inevaluable by the composite response criteria (Group 2; Appendix 2) will be 
considered as not reaching PR/CR for ORR.  Their disease progression will be censored 
at the date of baseline tumor assessment + 1 day.  DOR and PFS will be censored at 
the last tumor assessment date for patients without disease progression. 
• Missing data in quality of life analysis will be presented as missing in changes scores. 
Visit windows: 
• Assessments taken outside of protocol allowable windows will be displayed according 
to the case report form (CRF) assessment recorded by the investigator. 
9.9. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
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 15.1. 
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10. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
10.1. 
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 /surgical history) will be done using 
internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with electronic data capture (EDC) tool.  User training 
must be documented before the user is granted access to the EDC system. 
10.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• EDC system – data capture 
• Statistical Analysis Systems (SAS) (Software)– statistical review, analysis and 
reporting 
• Pharmacovigilance safety database  
• IWRS 
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11. 
STUDY MONITORING 
11.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization [CRO] monitor) will visit 
each site prior to enrollment of the first patient, and periodically during the study.  In accordance 
with ICH guidelines, the monitor will compare the CRF entries with the appropriate source 
documents.  Additional review may include, but is not limited to, patient ICFs, documentation of 
patient recruitment and follow-up, AEs, SAEs, and concomitant therapy; as well as records of 
study drug dispensing, compliance, and accountability.  A copy of the drug dispensing log must 
be provided to the sponsor upon request. 
11.2. 
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 CRF (throughout this protocol, 
CRF refers to either a paper CRF or an eCRF).  Case report forms and source documents must be 
available at all times for inspection by authorized representatives of the sponsor and regulatory 
authorities. 
11.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs by 
trained site personnel.  A CRF 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 CRF page 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 CRF will be entered in the CRF by the investigator or an authorized designee.  
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the system.  For corrections made via data queries, a reason for any alteration must 
be provided. 
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12. 
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, CRFs, 
medical records, correspondence, ICFs, Institutional Review Board (IRB)/Ethics Committee (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 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. 
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
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. 
13.2. 
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 or EC.  A copy of the IRB- or 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 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. 
13.3. 
Patient 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 a patient identification number, only, 
on CRFs 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. 
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13.4. 
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 patients, 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. 
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14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design or operation of the protocol or ICF without 
an IRB/EC-approved amendment. 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-
OUT OF A SITE 
15.1. 
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. 
15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
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. 
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16. 
STUDY DOCUMENTATION 
16.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRFs must be signed 
by the investigator.  This certification form accompanies each set of CRFs.  The signed form will 
be provided to the sponsor with the final set of CRFs for each patient. 
16.2. 
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. 
17. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
18. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
19. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 
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21. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Phase 2 Study of REGN2810, a Fully Human Monoclonal 
Antibody to Programmed Death-1 (PD-1), in Patients with Advanced Cutaneous Squamous Cell 
Carcinoma, and agree to abide by all 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. 
RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS: RECIST GUIDELINE (VERSION 1.1) 
This appendix applies to all patients with metastatic disease that can be evaluated by RECIST 
criteria.  They should receive response assessments according to the treatment schedule of their 
cohort.  
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (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. 
Selection of Lesions 
• Measurable disease: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm 
(≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical 
exam. All tumor measurements must be recorded in millimeters (or decimal fractions 
of centimeters). 
Note:  
• 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. 
• Non-measurable disease: All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥ 10 to 
<15 mm [≥1 to <1.5 cm] 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 or MRI), are considered as non-measurable. 
Note: 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. 
• Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 
5 lesions in total, representative of all involved organs, should be identified as target 
lesions and 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, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. A sum of the diameters (longest for 
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non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. 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 any measurable 
lesions over and above the 5 target lesions 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.  
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 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 (eg, skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter 
as assessed using calipers (eg, skin nodules). In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
• Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung. However, CT is preferable.  
• Conventional CT and MRI: This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If 
CT scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situation. 
• 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 measuring cancer lesions 
over time. Note, however, that the PET portion of the CT introduces additional data 
which 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. Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date and, because they are operator 
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dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT or MRI is advised.  If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
• Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine relapse in 
trials where recurrence following complete response (CR) or surgical resection is an 
endpoint. 
• Tumor markers: Tumor markers alone cannot be used to assess response. If markers 
are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
• Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (eg, residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease 
• FDG-PET:  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 
PD 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 PD. If the positive FDG-PET at follow-up is not confirmed as a new 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 PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
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. 
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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. 
Response Criteria 
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 (0.5 cm). (Note: the appearance 
of one or more new lesions is also considered progressions). 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
Evaluation of Non-Target Lesions 
• Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm 
[<1 cm] short axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
• 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 (PD): 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 Principal Investigator). 
Evaluation of Overall Response Criteria 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria. Revised Response Evaluation 
Criteria in Solid Tumors (RECIST) Version 1.1 (Eisenhauer 2009) are summarized in the table:  
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Response According to Revised Response Evaluation Criteria in Solid Tumors 
(Version 1.1) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Requireda 
CR 
CR 
No 
CR 
>4 weeks confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
>4 weeks confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not evaluated 
No 
SD 
Documented at least once 
>4 weeks from baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease. 
a In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as PD. 
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APPENDIX 2. 
COMPOSITE RESPONSE CRITERIA FOR PATIENTS 
WITH LOCALLY ADVANCED CSCC 
These criteria are designed primarily for patients whose target lesions will be evaluated by bi-
dimensional digital medical photography. This appendix also provides composite response criteria 
for disease that is measurable by both clinical response criteria and RECIST 1.1. 
These patients will be followed by digital medical photography. They will also undergo radiologic 
imaging (typically, MRI with gadolinium) at baseline, and this will also be performed serially at 
each response assessment unless the investigator deems that baseline radiologic imaging was 
uninformative.  Radiologic imaging (preferably, MRI with gadolinium) will be essential in the 
evaluation of tumors that have subdermal components that cannot be adequately assessed by digital 
medical photography.  See protocol Section 6.3.1 and 6.3.2 for further information on imaging 
requirements.  
Response assessments to be performed depends on the group and their stage of 
treatment/retreatment/follow-up.  Standardized digital photographs of the externally visible 
component of all target lesions must be obtained at baseline and at the time of each subsequent 
tumor assessment.  
  
Investigators will also provide a clinical description of the externally visible target lesion(s) at 
baseline and at each tumor assessment, as well as comments on any changes in the lesion(s) since 
the previous assessment. 
SPECIAL ISSUES FOR EXTERNALLY VISIBLE TUMORS: 
1. Anatomic Defects 
Regarding tumor around a surgical cavity/anatomic defect (eg, rhinectomey), such lesions should 
be considered non-measurable unless there is a nodular lesion measuring ≥10 mm in maximal bi-
dimensional perpendicular diameters. The surgical cavity or anatomic defect should not be 
considered in measuring the lesion.  
2. Indeterminate-Appearing Tissue  
If there is uncertainty about whether a given lesion or area of a lesion represents malignancy versus 
benign process (eg, scarring, fibrosis), biopsies should be obtained. Indeterminate-appearing areas 
(eg, scarring, fibrosis) are included in the tumor measurements unless biopsies are obtained to 
establish benign status. 
To reduce risk of sample error, biopsy of only a single area on the tumor is not allowed. Biopsy of 
at least two separate areas of the lesion are required when biopsy is indicated. Each biopsy will be 
performed in a pairwise manner (approximately adjacent) so that there will be one sample for local 
review and one for central review for each biopsy, as per Appendix 5.  
As such, when the decision is made to perform biopsy, at least 4 biopsy samples are obtained 
(biopsy of two separate areas, with two biopsies in each area: one for central, one for local from 
each area).  Biopsy samples will not be bisected or split in half for local and central review; rather, 
separate adjacent samples will be obtained.  See Appendix 5 for biopsy details. 
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Note on timeline for finalization of measurement/response assessment: Generally, baseline 
disease measurements and response assessments should be completed on the day of the visit at 
which digital medical photography was performed. However, for visits in which tumor biopsies 
are performed, it is understood that the local pathology report may not be available for up to 
5 business days after the biopsy.  
When biopsies are performed to distinguish between benign versus malignant tissue, the annotated 
photograph for that visit should clearly indicate the region of the tumor that was biopsied to 
distinguish benign versus malignant tissue. Within one week of the date of biopsies, the 
investigator should finalize the tumor measurements for that visit with the benefit of the local 
pathology report.  
For circumstances in which the intent of the biopsy is to distinguish between disease stability and 
response, it is not necessary to hold study treatment while the local pathology report is pending. 
For circumstances in which the biopsy, if positive, would result in discontinuation of study 
treatment due to progression, treatment should be held until biopsy results are finalized and 
progression has been ruled out.  
3) Local Versus Central Review 
An independent photographic review committee, with access to de-identified digital medical 
photography results and biopsy results, will provide response assessments as required by the 
sponsor to address study objectives (Section 2). Independent photographic reviews will be 
scheduled by the sponsor in coordination with vendor but will not be “real-time.” Clinical 
management decisions generally will be as per investigator response assessments and local 
pathology review. In the unlikely event that independent review yields major differences with the 
local response assessment that could have implications for the ongoing management of an active 
patient on study, the situation will be discussed between the sponsor and the investigator in order 
to determine patient management. 
4) Confirmation of Responses 
After any objective response, confirmatory digital photography (and radiologic imaging, if 
performed as part of the initial response assessment) will be obtained at least 4 weeks following 
initial documentation of objective response.  
For any complete responses observed in digital medical photography of externally visible target 
lesions, confirmatory biopsies are required to establish status of complete response. 
5) For all Patients being followed with Externally Visible Tumors 
Patients with metastatic CSCC will generally be followed by RECIST 1.1 criteria (Appendix 1). 
It is possible that some patients in may also have externally visible lesions that are measurable by 
digital medical photography. In such circumstances, the externally visible lesions generally will 
be followed as non-target lesions. The exception to this rule would be a patient with externally 
visible lesions in whom the only M1 lesions are not measurable by RECIST (eg, a patient with 
bone-only metastases), in which case the externally visible lesions (lesion size ≥10 mm in baseline 
dimensional perpendicular axes) would be target lesions and followed as per clinical response 
criteria in this appendix, and the non-measurable metastatic lesions (eg, bone metastases) would 
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be followed as non-target lesions. For any target lesions that are measured by digital medical 
photography, measurements will be bi-dimensional. 
6) Patients with unresectable locally advanced CSCC with Deeply Invasive Tumors 
Regarding patients with unresectable locally advanced CSCC, tumor measurements for these 
patients will generally be performed with digital medical photography (bi-dimensional 
measurements).  However, some patients may have deeply invasive target lesions in which tumor 
measurements can better be obtained with cross-sectional imaging (eg, MRI with gadolinium or 
CT with contrast).  For any target lesions that are measured by cross-sectional imaging (MRI 
gadolinium or CT with contrast), measurements will unidimensional according to RECIST 1.1. 
Clinical Response Criteria for Externally Visible Tumors (for Groups 2, 4, 5, and 6 
patients with locally advanced CSCC, and selected Groups 1, 3, 4, 5, and 6 patients in which 
target lesions are followed by digital medical photography) 
A. Externally Visible Tumor Dimension 
The externally visible component of target lesion(s) will be measured using bi-dimensional WHO 
criteria as the sum of the products (of individual target lesions) in the longest dimension and 
perpendicular second longest dimension at each tumor assessment and will be documented using 
  
 
 
 
. 
Clinical response criteria for externally visible tumor(s) require bi-dimensional measurements 
according to WHO criteria (reference), and are as follows: 
• Complete response of externally visible disease (vCR): all target lesion(s) and non-
target lesion(s) no longer visible, maintained for at least 4 weeks.  Documentation of 
vCR requires confirmation by biopsies of site(s) of externally visible target lesion(s) 
with histologic confirmation of no residual malignancy, per central pathology review 
(Appendix 5).  In the absence of such histologic confirmation, a patient cannot be 
deemed to have experienced vCR and the best response would be partial response. 
• Partial response of externally visible disease (vPR): decrease of 50% (WHO criteria) 
or greater in the sum the products of perpendicular longest dimensions of target 
lesion(s), maintained for at least 4 weeks 
• Stable externally visible disease (vSD): not meeting criteria for vCR, vPR, or 
progressive disease  
• Progression of visible disease (vPD): increase of ≥ 25% (WHO criteria) in the sum of 
the products of perpendicular longest dimensions of target lesion(s). In rare cases, 
unequivocal progression of a non-target lesion may be accepted as vPD. 
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B. New Lesions 
A new cutaneous lesion consistent with CSCC will be considered as cPD if the lesion is ≥10 mm 
in both maximal perpendicular diameters and can be clearly documented as not being previously 
present, unless it is confirmed on biopsy not to be consistent with CSCC.  If a new cutaneous 
lesion is not biopsied or if the histology is inconclusive, it should be considered CSCC and deemed 
cPD.  
Overall Clinical Responses For Locally Advanced CSCC Lesions that are Measured by 
Digital Medical Photography 
Externally Visible Tumor 
Dimensiona 
New Lesionsa 
Clinical Response 
vCR 
No 
cCRb,c 
vPR 
No 
cPRd 
vSD 
No 
cSDe 
vPD 
Yes or No 
cPDf 
Any 
Yes 
cPDf 
a See above for definitions 
b Clinical Complete Response 
c Negative biopsy showing no residual malignant cells is required for any lesion be deemed cCR 
d Clinical Partial Response 
e Clinical Stable Disease 
f Clinical Progression of Disease 
Composite Response Criteria 
These criteria are for patients who have locally advanced or metastatic CSCC (any Group) that is 
measurable by BOTH clinical response criteria by digital medical photography and RECIST 1.1 
using radiologic imaging.  The “Clinical Response” column in this table will be based on the 
results of the “Clinical Response” (far-right) column of the table above.  RECIST 1.1 
response is according to Appendix 1.  The determinations of the Independent Composite 
Response Committee will serve as the central reviews for these patients. 
Clinical Response 
(Digital Medical 
Photography) 
RECIST 1.1 Response 
(Radiology) 
Composite (Overall): 
Clinical + RECIST 
Response 
cCR 
CR or NAa 
CR 
NA 
CR 
CR 
cCR 
PR or SD 
PR 
cPR 
CR, PR, or SD, or NA 
PR 
NA 
PR 
PR 
cSD 
CR or PR 
PR 
cSD 
SD or NA 
SD 
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Clinical Response 
(Digital Medical 
Photography) 
RECIST 1.1 Response 
(Radiology) 
Composite (Overall): 
Clinical + RECIST 
Response 
NA 
SD 
SD 
cPD 
Any 
PD 
Any 
PD 
PD 
a  NA indicates “Not applicable” (eg, because the assessment was not done). 
In addition, if all previously inoperable target lesions are rendered operable with clear margins 
obtained at the time of surgery, this will be considered a PR. If the investigator deems a previously 
unresectable lesion to be potentially resectable due to response to cemiplimab, the Medical 
Monitor should be consulted prior to any surgical procedure being performed. A decision will be 
rendered by the sponsor as to whether the planned surgical intervention is compatible with study 
requirements. (This statement does not apply to patients in emergency life-threatening situations 
that require immediate surgery).  
C. Ulcerated Lesions 
This section only pertains to target lesions that have extensive ulceration at baseline that prevents 
measurement by the above methods in this appendix.  Response criteria are as follows: 
• Complete response:  re-epithelialization of the entire baseline area of ulceration of 
target lesion(s), maintained over at least 4 weeks. 
• Partial response:  there are no criteria for partial response 
• Stable disease:  not meeting criteria for complete response or progressive disease 
• Progressive disease:  new ulceration of target lesion(s) not related to (ie, in a location 
separate from) tissue biopsy or other known trauma, persistent without evidence of 
healing for at least 2 weeks 
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APPENDIX 3. 
CEMIPLIMAB PHARMACOKINETIC SAMPLING AND 
ASSESSMENT SCHEDULE 
For Groups 1 and 2: 
Study Visit 
PK Sampling Time* 
Cycle 1, day 1 
• 
Preinfusion 
• 
Within 10 minutes after end of infusion 
Cycle 1: day 15 ± 3, day 29 ± 3, day 43 ± 3 
• 
Preinfusion 
• 
Within 10 min after end of infusion 
Cycles 2–6: day 1 
• 
Preinfusion 
• 
Within 10 min after end of infusion 
Cycles 7, 9, 11: day 1 
• 
Preinfusion 
• 
Within 10 min after end of infusion 
End of study (if progression during cycles 1-
12) or Follow-up Visits 1, 2, 3 4, and 7 
Anytime during the visit 
*All actual PK dosing times and PK sampling times should be recorded 
For Group 3: 
Study Visit 
PK Sampling Time* 
Cycle 1, day 1 
• 
Preinfusion 
• 
Within 10 minutes after end of infusion 
Cycle 1: day 22 ± 3, day 43 ± 3 
• 
Preinfusion 
• 
Within 10 min after end of infusion 
Cycles 2-6: day 1 
• 
Preinfusion 
• 
Within 10 min after end of infusion 
End of study (if progression during cycles 1-6) 
or Follow-up Visits 1, 2, 3, 4, and 7 
Anytime during the visit 
*All actual PK dosing times and PK sampling times should be recorded 
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For Group 4: 
Study Visit 
PK Sampling Time * 
Cycle 1, day 1 
• 
Preinfusion  
• 
Within 10 minutes after end of infusion  
Cycle 1: day 29 ± 3 
• 
Preinfusion  
• 
Within 10 min after end of infusion  
Cycles 2-6: day 1 
• 
Preinfusion  
• 
Within 10 min after end of infusion  
End of study (if progression during cycles 1-
6) or Follow-up Visits 1, 2, 3, 4, and 7 
Anytime during the visit 
*All actual PK dosing times and PK sampling times should be recorded 
For Group 5: 
Study Visit 
PK Sampling Time* 
Cycle 1: day 1 (SC dose) 
Predose (SC dose) 
Cycle 1: day 4 ± 1  
• 
Any time  
Cycle 1: day 6 ± 1 
• 
Any time  
Cycle 1: day 8 ± 1 
• 
Any time 
Cycle 1 day 14 ± 3 
• 
Any time 
Cycle 1: day 22 (First IV dose) 
Preinfusion (IV dose) 
• 
Within 10 min after end of infusion 
Cycle 1: day 25 ± 1 
• 
Any time  
Cycle 1: day 29 ± 1 
• 
Any time 
Cycle 1: day 35 ± 1 
• 
Any time 
Cycle 1: day 43 ± 3 
• 
Preinfusion 
• 
Within 10 min after end of infusion 
Cycles 2-6: day 1 
• 
Preinfusion 
• 
Within 10 min after end of infusion 
End of study (if progression during cycles 1-
6) or Follow-up Visits 1, 2, 3, 4, and 7  
Anytime during the visit 
*All actual PK dosing times and PK sampling times should be recorded 
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For Group 6 Patients who Remain on 350 mg Q3W IV Dosing: 
Study Visit 
PK Sampling Time * 
Cycle 1: day 1 
• 
Preinfusion  
• 
Within 10 minutes after end of infusion  
Cycle 1: day 22 ±3 
• 
Preinfusion   
Cycle 3: day 1 
• 
Preinfusion  
• 
Within 10 min after end of infusion  
Cycle 5 and 9: day 1 
• 
Preinfusion 
End of study (if progression during cycles 1-
12) or Follow-up Visits 1, 2, 3, 4, and 7 
Anytime during the visit 
*All actual PK dosing times and PK sampling times should be recorded 
For Group 6 Patients Receiving 
 Tumor 
Assessment 
Study Visit IV to SC Q3W Switch 
PK Sampling Time 
Cycle 1 SC: Day 1  
Predose (SC Injection) 
Cycle 1 SC: Day 8 ± 1 
Any Time 
Cycle 1 SC: Day 22± 3 
Predose (SC Injection) 
Cycle 1 SC: Day 43± 3 
Predose (SC Injection) 
Cycle 1 SC: Day 64± 3 
Predose (SC Injection) 
Cycle 2 SC: Day 1 
Predose (SC Injection) 
Cycle 2 SC: Day 43± 3 
Predose (SC Injection) 
Cycle 3 SC and subsequent cycles Day 1 
Predose (SC Injection) 
Cycle 3SC and beyond: Day 43± 3 
Predose (SC Injection) 
FU4 
Any Time 
12-week Cycles for Q3W SC and Q6W SC Dosing 
 
 
 
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For Group 6 Patients Receiving 
 Tumor Assessment 
Study Visit IV to SC Q6W Switch 
PK Sampling Time 
Cycle 1 SC: Day 1  
Predose (SC Injection) 
Cycle 1 SC: Day 8 ± 1 
Any Time 
Cycle 1 SC: Day 43± 3 
Predose (SC Injection) 
Cycle 2 SC: Day 1 
Predose (SC Injection) 
Cycle 2 SC: Day 43± 3 
Predose (SC Injection) 
Cycle 3 SC and beyond Day 1 
Predose (SC Injection) 
Cycle 3SC and beyond: Day 43± 3 
Predose (SC Injection) 
FU4 
Any Time 
9-week Cycles for Q3W SC and Q6W SC Dosing 
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APPENDIX 4. 
RECOMMENDED DOSE MODIFICATION OR 
DISCONTINUATION AND SUPPORTIVE CARE 
GUIDELINES FOR SPECIFIC STUDY DRUG-RELATED 
ADVERSE EVENTS 
Select immune-related adverse events (irAEs) and their management are described in this 
appendix. The following general principles apply to management of irAEs, if they are not 
otherwise specifically described in this appendix: 
Grade 1: Continue study treatment with close monitoring and provide symptomatic 
management.  
Grade 2: Consider withholding study treatment 
Grade 3: Withhold study treatment 
Grade 4: Discontinue study treatment. 
 
Temporary hold and resumption. Except as described for select irAEs, if cemiplimab is withheld 
for grade ≤3 irAE, consider resuming cemiplimab when the irAE improves to baseline or grade 1 
after corticosteroid taper to ≤10 mg/day prednisone or equivalent.  
Permanent discontinuation. Except as described for select irAEs, give an initial dose of 1 to 
2 mg/kg/day prednisone or equivalent followed by a taper and permanently discontinue study 
treatment for: 
• Grade 4 adverse reactions (excluding endocrinopathies) 
• Recurrent grade 3 irAEs 
• Grade 2 or 3 irAEs persisting for ≥12 weeks after the last study treatment  
• Requirement for ≥10 mg per day prednisone or equivalent lasting ≥12 weeks after the 
last study treatment. 
For additional guidance to that provided here, please refer to regional irAE management guidelines 
such as those provided by NCCN or ESMO. In countries where cemiplimab has a marketing 
authorisation the local product information may be consulted. Note that local and regional 
treatment guidelines and cemiplimab product information may be updated periodically and the 
latest version should always be reviewed. 
 
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Recommended Adverse Event Management for Colitis/Diarrhea 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
• Colitis: 
Asymptomatic; clinical or 
diagnostic observations 
only; intervention not 
indicated 
• Diarrhea: Increase of <4 
stools per day over 
baseline; mild increase in 
ostomy output compared 
to baseline 
• No change  
 
• Treat symptomatically (loperamide, oral hydration, 
electrolyte substitution and ADA colitis diet)  
• Consider consultation with gastroenterologist for 
prolonged symptoms  
• If symptoms are persistent, consider endoscopic 
evaluation 
• If persists for >2 weeks, treat as grade 2  
 
 
 
• All attempts 
should be 
made to rule 
out other 
causes such as 
metastatic 
disease, 
bacterial or 
parasitic 
infection, or 
viral 
gastroenteritis 
Grade 2 
• Colitis: Abdominal pain; 
mucus or blood in stool 
• Diarrhea: Increase of 4 
to 6 stools per day over 
baseline; moderate 
increase in ostomy output 
compared to baseline; 
limiting instrumental 
ADL 
• Withhold study treatment 
until colitis or diarrhea 
improves and remains at 
grade 0 to 1 after 
corticosteroid taper to ≤10 
mg/day prednisone or 
equivalent 
• Treat symptomatically (loperamide, oral hydration, 
electrolyte substitution and ADA colitis diet) 
• Consultation with gastroenterologist  
• Consider colonoscopy ± 
esophagogastroduodenoscopy (EGD), or endoscopy  
• Consider stool evaluation to rule out infectious 
etiology 
• Consider stool inflammatory marker evaluation (ie, 
lactoferrin and calprotectin) to differentiate 
functional vs. inflammatory diarrhea 
• Consider abdominal and pelvic CT with contrast 
• Treatment with systemic corticosteroids (1 to 
2 mg/kg/day prednisone or equivalent) until 
resolution to grade ≤1 and taper over at least a 
month 
• If no improvement within 2 to 3 days, treat as grade 
3 
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CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 3 
• Colitis: Severe 
abdominal pain; 
peritoneal signs 
• Diarrhea: Increase of ≥7 
stools per day over 
baseline; hospitalization 
indicated; severe increase 
in ostomy output 
compared to baseline; 
limiting selfcare ADL 
• Withhold study treatment 
until colitis or diarrhea 
improves and remains at  
grade 0 to 1 after 
corticosteroid taper to ≤10 
mg/day prednisone or 
equivalent 
• Permanently discontinue 
study treatment if patient 
develops a second episode 
of grade 3 colitis or diarrhea 
upon re-challenge 
 
• Treat symptomatically (loperamide, oral hydration, 
electrolyte substitution and ADA colitis diet) 
• Consultation with gastroenterologist  
• Consider colonoscopy ± 
esophagogastroduodenoscopy (EGD), or endoscopy  
• Consider stool evaluation to rule out infectious 
etiology 
• Consider stool inflammatory marker evaluation (ie, 
lactoferrin and calprotectin) to differentiate 
functional vs. inflammatory diarrhea 
• Consider abdominal and pelvic CT with contrast 
• Inpatient care for close monitoring and supportive 
care 
• Treatment with systemic corticosteroids (1 to 2 
mg/kg/day prednisone or equivalent) until resolution 
to grade ≤1 and taper over at least 1 month 
• If no improvement with corticosteroid within 2 to 3 
days, consider additional immunosuppressive 
therapy ie, mycophenolate 0.5 to 1g BID, infliximab 
5 mg/kg IV  
Grade 4 or Recurrent 
Grade 3 
• Colitis: Life-threatening 
consequences: urgent 
intervention indicated 
• Diarrhea: Life-
threatening 
consequences; urgent 
intervention indicated 
• Permanently discontinue 
study treatment 
 
• Same as above 
• Consider lower GI endoscopy if symptoms are 
refractory despite treatment or there is concern of 
new infections 
 
 
 
 
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Recommended Adverse Events Management for Dermatologic Toxicities 
Immune-related skin toxicities include maculopapular rash, dermatitis, rash generalized, dermatitis bullous, drug eruption, erythema, 
rash erythematous, rash macular, rash pruritic, and skin reaction. Guidance here is provided for maculopapular rash. For other 
immune-related skin toxicities, see expert consensus guidelines cited in Section 5.3.2.2.  
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
or 
Grade 2 lasting 1 
week or less 
• No change  
 
• Treatment with mild to moderate potency topical steroids  
• Treatment with oral antihistamine 
• All attempts should 
be made to rule out 
other causes such as 
metastatic disease, 
infection, contact 
dermatitis, effect of 
another drug, or a 
skin condition linked 
to another systemic 
disease 
 
 
 
Grade 2 lasting 
longer than 1 week 
or 
Grade 3 
or 
Suspected Stevens-
Johnson syndrome 
(SJS), toxic 
epidermal 
necrolysis (TEN) or 
Drug rash with 
eosinophilia and 
systemic symptoms 
(DRESS) 
• Withhold study 
treatment until skin 
reaction improves 
and remains at 
grade 0 to 1 after 
corticosteroid taper 
to ≤10 mg/day 
prednisone or 
equivalent 
• Consider consultation with dermatologist and skin biopsy for 
diagnosis of bullous dermatitis 
• Treatment with systemic corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) until resolution to ≤ grade 1 and 
taper over at least one month 
• Consider treatment with medium to high potency topical 
steroids  
• Treatment with oral antihistamine 
Grade 4 
or 
Confirmed SJS,  
TEN, or DRESS 
• Permanently 
discontinue study 
treatment  
• Consultation with dermatologist and skin biopsy 
• Treatment with high potency topical steroids and with 
systemic corticosteroids (1 to 2 mg/kg/day prednisone or 
equivalent) until resolution to ≤ grade 1 and taper over at 
least one month 
 
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Immune-Mediated Skin 
Adverse Reactions or other 
Immune-Related Adverse 
Reactions in Patients with 
Prior Treatment with 
Idelalisib 
CTCAE v5.0 Grade  
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
• No change 
• Treatment as clinically indicated 
• All attempts should 
be made to rule out 
other causes such as 
metastatic disease, 
infection, contact 
dermatitis, effect of 
another drug, or a 
skin condition 
linked to another 
systemic disease 
 
 
 
Grade 2 
• Withhold study treatment until 
skin reaction or other 
immune-related adverse 
reaction improves and remains 
at grade 0 to 1 after 
corticosteroid taper to ≤10 
mg/day prednisone or 
equivalent 
• Consider consultation with dermatologist 
and skin biopsy for diagnosis of bullous 
dermatitis 
• Immediate symptom management, 
including systemic corticosteroids (1 to 2 
mg/kg/day prednisone or equivalent) until 
resolution to ≤ grade 1 and taper over at 
least one month 
• Consider treatment with medium to high 
potency topical steroids and/or oral 
antihistamine for skin reactions  
Grade 3 or 4 (excluding 
endocrinopathies) 
or  
Recurrent Grade 2 
• Permanently discontinue 
study treatment  
• Consultation with dermatologist and skin 
biopsy for skin reactions 
• Treatment with high potency topical 
steroids if skin reaction 
• Treatment with systemic corticosteroids (1 
to 2 mg/kg/day prednisone or equivalent) 
until resolution to ≤ grade 1 and taper over 
at least one month 
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Recommended Adverse Events Management for Endocrine Events: Hypothyroidism 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
 
• No change  
 
• Monitor thyroid function more frequently (every 3 to 6 
weeks) until resolution to baseline 
• There should be low index of suspicion for immune-related 
endocrinopathy including checking TSH, T4, cortisol and 
adrenocorticotropic hormone levels if clinically appropriate 
• Immune-related 
endocrinopathies can 
have subtle and wide-
ranging presentations. 
Please refer to expert 
panel consensus 
guidance documents 
for further guidance 
• All attempts should 
be made to rule out 
other causes such as 
brain metastases, 
sepsis, and/or 
infection 
 
Grade 2 
 
• Withhold study 
treatment if 
clinically necessary 
• Consult with endocrinologist and provide supportive care per 
institutional guidelines 
• Replacement of thyroid hormone as indicated 
Grade 3 or 4 
• Withhold study 
treatment until 
hypothyroidism 
improves and 
remains at grade 0 
to 1 or is otherwise 
clinically stable 
• Consult with endocrinologist and provide supportive care per 
institutional guidelines 
• Replacement of thyroid hormone as indicated 
 
 
 
 
 
 
 
 
 
 
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Recommended Adverse Events Management for Endocrine Events: Hyperthyroidism 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
 
• No change  
 
• Monitor thyroid function more frequently (every 2 to 3 
weeks) until resolution to baseline 
• There should be low index of suspicion for immune-related 
endocrinopathy including checking TSH, T4, cortisol and 
adrenocorticotropic hormone levels if clinically appropriate 
• Immune-related 
endocrinopathies can 
have subtle and wide-
ranging presentations. 
Please refer to expert 
panel consensus 
guidance documents 
for further guidance 
• All attempts should 
be made to rule out 
other causes such as 
brain metastases, 
sepsis, and/or 
infection 
 
Grade 2 
 
• Withhold study 
treatment if 
clinically necessary 
• Same as above 
• Consult with endocrinologist and provide supportive care per 
institutional guidelines 
• Consider -blocker for symptomatic relief 
• For persistent hyperthyroidism (> 6weeks), consider work up 
for Graves disease and refer to endocrinology for Graves 
disease 
Grade 3 or 4 
• Withhold study 
treatment until 
hyperthyroidism 
improves and 
remains at grade 0 
to 1 or is otherwise 
clinically stable 
• Same as above 
• For severe symptoms, inpatient care and consider systemic 
corticosteroids treatment (1 to 2 mg/kg/day prednisone or 
equivalent) until resolution to ≤ grade 1 and taper over 1-2 
weeks in consultation with endocrinology 
• Consider use of saturated solution of potassium idodide 
(SSKI) or thioanmide 
 
 
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Recommended Adverse Events Management for Endocrine Events: Hypophysitis or Adrenal Insufficiency 
CTCAE v5 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
 
• No change  
 
• There should be low index of suspicion for 
immune-related endocrinopathy including 
checking TSH, T4, cortisol and 
adrenocorticotropic hormone levels if clinically 
appropriate 
• Immune related 
endocrinopathies can 
have subtle and wide-
ranging presentations. 
Please refer to expert 
panel consensus 
guidance documents 
for further guidance 
• All attempts should 
be made to rule out 
other causes such as 
brain metastases, 
sepsis, and/or 
infection 
 
Grades 2 to 4 
• Withhold study treatment 
until hypophysitis or adrenal 
insufficiency improves and 
remains at grade 0 to 1 after 
corticosteroid taper to ≤10 
mg/day prednisone or 
equivalent or is otherwise 
clinically stable 
• Consult with endocrinologist and provide 
supportive care per institutional guidelines 
• Initial dose of 1 to 2 mg/kg/day prednisone or 
equivalent followed by a taper 
• Replacement of relevant hormone(s) as indicated 
 
 
 
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Recommended Adverse Events Management for Endocrine Events: Type I Diabetes Mellitus 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
 
• No change  
 
• Monitor glucose level more frequently until 
resolution to baseline 
• There should be low index of suspicion for 
immune-related endocrinopathy including 
checking TSH, T4, cortisol and 
adrenocorticotropic hormone levels if clinically 
appropriate 
 
• Immune related 
endocrinopathies can 
have subtle and wide-
ranging presentations. 
Please refer to expert 
panel consensus 
guidance documents 
for further guidance 
• All attempts should 
be made to rule out 
other causes such as 
brain metastases, 
sepsis, and/or 
infection 
 
Grade 2 
• Withhold study treatment if 
clinically necessary until 
glucose control is obtained 
• Same as above 
• Consult with endocrinologist and provide 
supportive care per institutional guidelines 
 
Grade 3 or 4 
(hyperglycemia) 
• Withhold study treatment 
until diabetes mellitus returns 
to grade 0 to 1 or is otherwise 
clinically stable 
• Consult with endocrinologist and provide 
supportive care per institutional guidelines 
• Initiate treatment with anti-hyperglycemics as 
clinically indicated 
 
 
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Recommended Adverse Events Management for Hepatitis 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
 
• No change 
• Monitor liver function tests (LFT) more frequently until 
resolution to baseline values 
• All attempts should 
be made to rule out 
other causes such as 
metastatic disease, 
progressive liver 
disease, viral 
hepatitis, alternative 
drug toxicity, 
infectious causes 
and/or myositis  
 
 
 
Grade 2 with: 
Elevated ALT & 
AST >3 and ≤5x 
ULN  
Or total bilirubin 
>1.5x and ≤3x ULN 
 
• Withhold study 
treatment until 
hepatitis improves 
and remains at 
grade 0 to 1 after 
corticosteroid taper 
to ≤10 mg/day 
prednisone or 
equivalent or 
returns to baseline 
AST or ALT after 
completion of 
corticosteroid taper 
• Monitor liver function tests (LFT) more frequently until 
resolution to baseline values 
• Consider appropriate consultation with hepatologist and liver 
biopsy to establish etiology of hepatic injury, if necessary 
• Consider inpatient monitoring for patients with ALT/AST 
>8x ULN and or elevated total bilirubin >3x ULN 
• Treatment with systemic corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) until resolution to ≤ grade 1 and 
taper over at least 1 month 
• If no improvement within 3 days after initiation of systemic 
steroids, consider additional immunosuppressive therapy ie, 
mycophenolate mofetil 0.5 to 1 g BID 
• Several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased 
Grade 3 or 4 with: 
Elevated ALT & 
AST >5x ULN 
or total bilirubin ˃3x 
ULN 
 
• Permanently 
discontinue study 
treatment 
• Same as above 
 
 
 
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Recommended Adverse Events Management for Neurotoxicity 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
 
• No change  
• Closely monitor the patient 
• If worsening, treat as grade 2 or 3 to 4, as clinically 
appropriate 
• If immune-mediated 
encephalitis is 
suspected, consider 
radiologic assessment 
and, if possible, CSF 
assessment for auto-
immune antibodies 
Grade 2 
• Withhold study 
treatment until 
improves and 
remains at grade 0 
to 1 after 
corticosteroid taper 
to ≤10 mg/day 
prednisone or 
equivalent 
• Treat symptoms per local guidelines, eg 0.5 to 1 mg/kg/day 
methylprednisolone IV or PO equivalent 
• If worsening, treat as grades 3 to 4 
• Consider neurology consult 
Grade 3 or 4 
 
• Permanently 
discontinue study 
treatment  
• Neurology consult required 
• Treat symptoms per local guidelines AND give 1 to 2 
mg/kg/day methylprednisolone IV 
• If improves to grade 2: taper with corticosteroids over at least 
4 weeks 
• Consider adding prophylactic antibiotics for opportunistic 
infections 
• If worsening or atypical presentation, consider IVIG or other 
immunosuppressive therapies per local guidelines 
 
 
 
 
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Recommended Adverse Events Management for Pneumonitis 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
Asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated 
• Consider 
withholding study 
treatment 
• Monitor symptoms every 2 to 3 days 
• Consider consultation with pulmonologist 
• Consider chest imaging (chest CT or chest x-ray) followed by 
serial imaging at least every 3 weeks to monitor resolution or 
progression 
• May resume study treatment upon improvement or 
resolution. If no improvement, treat as grade 2 
• All attempts should 
be made to rule out 
other causes such as 
metastatic disease, 
bacterial or viral 
infection  
Grade 2 
Symptomatic; 
medical intervention 
indicated; limiting 
instrumental ADL 
• Withhold study 
treatment until 
pneumonitis 
improves and 
remains at grade 0-
1 after 
corticosteroid taper 
to ≤10 mg/day 
prednisone or 
equivalent 
• Permanently 
discontinue study 
treatment if patient 
develops a second 
episode of ≥ grade 
2 pneumonitis upon 
re-challenge 
• Monitor symptoms daily; consider hospitalization 
• Consider consultation with pulmonologist 
• Consider chest imaging (chest CT or chest x-ray) followed by 
serial imaging at least every 3 weeks to monitor resolution or 
progression 
• Consider bronchoscopy with bronchoalveolar lavage (BAL) 
to rule out infection and malignant lung infiltration 
• Consider pulmonary function tests and laboratory work up 
for infections 
• Treatment with systemic corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) until resolution to ≤ grade 1 and 
taper over at least a month 
• If symptoms do not improve within 48 to 72 hours of 
corticosteroid treatment, treat as grade 3 
• Consider empiric antibiotics if infection has not yet been 
fully excluded 
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CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 3 or 4 or 
Recurrent Grade 2 
 
Grade 3: 
Severe symptoms; 
limiting selfcare 
ADL; oxygen 
indicated 
 
Grade 4: 
Life-threatening 
respiratory 
compromise; urgent 
intervention 
indicated (eg, 
tracheotomy or 
intubation) 
 
• Permanently 
discontinue study 
treatment 
 
• Inpatient care 
• Consultation with pulmonologist and infectious disease 
specialties 
• Treatment with systemic corticosteroids (2 to 4 mg/kg/day 
prednisone or equivalent) until resolution to ≤ grade 1 and 
taper over at least 6 weeks 
• If symptoms do not improve within 48 to 72 hours of 
corticosteroid treatment, consider additional 
immunosuppressive treatment ie, mycophenolate mofetil 1 to 
1.5 g BID, infliximab 5 mg/kg IV 
• If symptoms worsen during steroid reduction, initiate a re-
tapering of steroids starting at a higher dose of 80 or 100 mg 
followed by a more prolonged taper 
• Consider bronchoscopy with bronchoalveolar lavage (BAL) 
to rule out infection and malignant lung infiltration 
• Empiric antibiotics if infection has not yet been fully 
excluded 
• Consider adding prophylactic antibiotics for opportunistic 
infections 
 
 
 
 
 
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Recommended Adverse Events Management for Renal Events 
Immune-Mediated 
Nephritis with 
renal dysfunction 
 CTCAE v5 Grade  
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
 
• No change  
• Provide symptomatic treatment.  
• Monitor creatinine weekly; when it returns to baseline, 
resume routine creatinine monitoring per protocol 
• All attempts should 
be made to rule out 
other causes such as 
obstructive uropathy, 
progression of 
disease, or injury to 
other chemotherapy 
agents 
 
 
  
 
 
Grade 2 
Blood creatine 
increased > 1.5 – 
3.0 X baseline or 
ULN or 
 
• Withhold study 
treatment until 
nephritis improves 
and remains at 
grade 0-1 after 
corticosteroid taper 
to ≤10 mg/day 
prednisone or 
equivalent 
• Consultation with nephrologist 
• Treatment with systemic corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) until resolution to ≤ grade 1 and 
taper over at least a month 
• Consider prophylactic antibiotics for opportunistic infections 
• Consider renal biopsy 
• If elevations persist >7 days or worsen, treat as severe AE 
Grade 3  
Blood creatinine 
increased > 3.0 X 
baseline or > 3.0 – 
6.0 x ULN 
 
Grade 4 
Blood creatine 
increased > 6.0 X 
ULN 
• Permanently 
discontinue study 
treatment 
• Consultation with nephrologist in consideration of ultrasound 
and/or biopsy as appropriate 
• Consider inpatient care and monitor creatinine daily 
• Treatment with systemic corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) until resolution to ≤ grade 1 and 
taper over at least a month 
• If no improvement within 7 days after initiation of systemic 
steroids, consider additional immunosuppressive therapy ie, 
mycophenolate mofetil 0.5 to 1 g BID  
 
 
 
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Recommended Adverse Events Management for Uveitis 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 
 
 
• No change 
• Consultation with ophthalmologist within 1 week 
• Treatment with artificial tears 
• All attempts should 
be made to rule out 
other causes such as 
metastatic disease, 
infection, or other 
ocular disease 
(eg, glaucoma or 
cataracts) 
Grade 2 
 
• Withhold study treatment  
• Urgent consultation with ophthalmologist 
• Treatment with topical/periocular/intravitreal 
corticosteroids and/or systemic corticosteroids 
guided by ophthalmologist  
• May resume study treatment if resolved to ≤ grade 1 
and systemic steroid is reduced to ≤10 mg. 
Topical/ocular steroids are permitted during study 
treatment 
Grade 3 or 4 
• Permanently discontinue 
study treatment  
• Same as above 
• If severe or refractory to steroid treatment, consider 
infliximab 
 
 
 
 
 
 
 
 
 
 
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Recommended Adverse Events Management for Myocarditis or Pericarditis 
CTCAE v5.0 Grade 
Study Treatment 
Management 
Action & Supportive Care Guidelines 
Diagnostic 
Considerations 
Grade 1 - 2 
Grade 2 
 
• Consider withholding study 
treatment 
• Immediate consultation with cardiologist 
• Inpatient care 
• Consider ECG, telemetry monitoring, cardiac MRI 
• Consider cardiac biomarker assessment (creatine 
kinase and troponin) or inflammatory biomarkers 
(ESR, CRP, WBC count, etc) 
• May offer immediate transfer to a coronary care 
unit for patient with elevated troponin or 
conduction abnormalities 
• Treatment with systemic corticosteroids (1 to 
2 mg/kg/day prednisone or equivalent) initiated 
rapidly (oral or IV depending on symptoms) until 
resolution to baseline and taper over 4-6 weeks 
• Manage cardiac symptoms according to American 
College of Cardiology (ACC)/AHA guidelines and 
with guidance from cardiology 
 
• All attempts should 
be made to rule out 
other causes such as 
metastatic disease 
and viral infection 
Grade 3 - 4 
  
• Permanently discontinue 
study treatment  
 
• Same as above 
• Consider 1 g methylprednisolone pulse dose 
• If severe or refractory to steroid treatment, consider 
additional immunosuppressive agents 
 
 
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APPENDIX 7. 
EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
Grade 
Description 
0 
Fully active; able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature; eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; Up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair 50% or more of waking hours 
4 
Completed disabled. Cannot carry on any selfcare. Totally confined to bed or chair. 
5 
Dead 
Source: Oken 1982 
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APPENDIX 8. 
FACTORS TO CONSIDER IN ASSESSING THE 
RELATIONSHIP OF AES TO CEMIPLIMAB OR STUDY 
CONDUCT. 
Is there a reasonable possibility that the event may have been caused by the study drugs or infusion 
procedure, study procedure, or concomitant treatment? 
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 cemiplimab, study procedure, or combination treatment 
• do not reappear or worsen when dosing with cemiplimab, study procedure, or 
combination treatment is resumed 
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 cemiplimab  
• resolve or improve after discontinuation of cemiplimab study procedure, or 
combination treatment 
• reappear or worsen when dosing with cemiplimab study procedure, or combination 
treatment is resumed 
• are known to be a response to cemiplimab or the infusion procedure, study procedure, 
or combination treatment based upon pre-clinical data or prior clinical data 
NOTE: This list is not exhaustive. 
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APPENDIX 9. 
ADAPTED EUROPEAN ORGANIZATION FOR 
RESEARCH AND TREATEMENT OF CANCER 
POSITRON-EMISSION TOMOGRAPHY CRITERIA 
(FOR GROUP 4) 
Reporting of results of [18F]-FDG measurements is adapted from EORTC 1999 Criteria 
(Young 1999). 
1. Progressive metabolic disease to be classified as an increase in [18F]-FDG tumour SUV of 
greater than 25% within the tumour region defined on the baseline scan, visible increase in the 
extent of [18F]-FDG tumour uptake or the appearance of new [18F]-FDG uptake in metastatic 
lesions. 
2. Stable metabolic disease would be classified as an increase in tumour [18F]-FDG SUV of less 
than 25% or a decrease of less than 15% and no visible increase in extent of [18F]-FDG tumour 
uptake (>20% in the longest dimension). 
3. Partial metabolic response would be classified as a reduction of a minimum of 25% in tumour 
[18F]-FDG SUV after one cycle of chemotherapy, and greater than 25% after more than one 
treatment cycle. Reporting would need to be accompanied by adequate and disclosed 
reproducibility measurements from each centre. An empirical 25% was found to be a useful cutoff 
point, but there is a need for a reproducibility analysis to determine the appropriate cutoffs for 
statistical significance. A reduction in the extent of the tumour [18F]-FDG uptake is not a 
requirement for partial metabolic response. 
4. Complete metabolic response would be complete resolution of [18F]-FDG uptake within the 
tumour volume so that it was indistinguishable from surrounding normal tissue. 
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APPENDIX 10. STATISTICAL ANALYSES 
ESTIMANDS 
For Group 6 primary analysis, the statistical methods for the primary and secondary endpoints will 
be consistent with that which was done for Groups 1 to 3.  This will facilitate a meaningful 
comparison of Group 6 with the previous groups.  Additional statistical analyses will also be 
performed, including sensitivity analyses for DOR and PFS assuming informative censoring for 
intercurrent event. 
Attributes for ORR per Central Review and Investigator Assessment  
1. The study population is defined as CSCC patients who are enrolled on the protocol.  
2. The endpoint is ORR, defined as the proportion of patients with BOR of CR or PR.  ORR 
per central review is the primary endpoint, and ORR per investigator assessment is a 
secondary endpoint. 
3. Intercurrent events and how to account for these events are described in Table 16. 
4. Estimated ORR will be provided, along with the 2-sided 95% exact binomial confidence 
interval using the Clopper-Pearson method. 
Table 16: 
Intercurrent Events for Analysis of ORR per Central Review and 
Investigator Assessment 
Intercurrent events 
Rules of imputing data in primary analysis 
Initiation of palliative radiation 
therapy 
Patient will be considered to have PD at time of initiation of 
radiation (Section 5.7.4 of protocol). 
Surgical removal of target 
lesion 
BOR will be considered as PR if no prior PD is observed 
(Section 5.7.3 of protocol). 
Unconventional responses (eg, 
a patient first experience PD 
and then CR or PR) 
BOR will be considered as PD. 
No evaluable postbaseline 
tumor assessment 
BOR will be deemed NE. Patient with BOR of NE will be 
included in the ORR analysis as a non-responder.  
A sensitivity analysis will be performed for ORR where the intercurrent events of “initiation of 
palliative radiation therapy” and “surgical removal of target lesion” will be ignored.  Patients with 
unconventional responses will be considered as responders.  Patients with BOR of NE will be 
excluded from this analysis. 
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Attributes for DOR per Central Review and Investigator Assessment 
1. The study population is defined as CSCC patients who are enrolled on the protocol and had 
a CR/PR response.  
2. The endpoint is DOR, measured from the time measurement criteria are first met for CR/PR 
(whichever is first recorded) until the first date of recurrent or progressive disease or death 
due to any cause in patients with BOR of CR or PR.  
3. Intercurrent events and how to account for these events are described in Table 17. 
4. DOR will be summarized by median and its 95% confidence interval by the Kaplan-Meier 
method. 
Table 17: 
Intercurrent Events for Analysis of DOR per Central Review and 
Investigator Assessment 
Intercurrent events 
Rules of imputing data in 
primary analysis 
Sensitivity analysis 
Initiation of radiation 
therapy 
Patient will be considered to have 
PD at time of initiation of radiation. 
 
Surgical removal of 
target lesion 
DOR will be censored at time of 
surgery if no prior PD or death is 
observed. 
 
No evaluable post-
baseline tumor 
assessment 
(BOR=NE) 
Patient will be deemed as a non-
responder and will not be included 
in the DOR analysis. 
 
Lost to follow-up 
Or 
Discontinuation of 
study in patients with 
BOR of CR or PR 
DOR will be censored at last valid 
tumor assessment if no PD or death 
is observed. 
If a patient discontinued study 
due to PD or AE, this patient 
will be considered to have DOR 
event on the end of study date. * 
A sensitivity analysis will be performed for DOR where the intercurrent events of “initiation of 
palliative radiation therapy” and “surgical removal of target lesion” will be ignored.  Patients with 
unconventional responses will be included in this analysis where DOR is measured from time of 
first response to first PD after the response or death, whichever is earlier.  The analysis will only 
include patients with BOR of CR or PR.  DOR for patients who don’t have PD or death will be 
censored at last valid tumor assessment. 
Attributes for PFS per Central Review and Investigator Assessment  
1. The study population is defined as CSCC patients who are enrolled on the protocol.  
2. The endpoint is PFS, measured from time of enrollment until the first date of recurrent or 
progressive disease, or death due to any cause.  
3. Intercurrent events and how to account for these events are described in Table 18.  
4. PFS will be summarized by median and its 95% confidence interval by the Kaplan-Meier 
method. 
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Table 18: 
Intercurrent Events for Analysis of PFS per Central Review and Investigator 
Assessment 
Intercurrent 
events 
Rules of imputing data after 
intercurrent events for primary 
analysis 
Sensitivity analysis  
Initiation of 
radiation therapy 
Patient will be considered to have PD at 
time of initiation of radiation. 
 
Unconventional 
responses (eg, a 
patient first 
experience PD 
and then CR or 
PR) 
Patient will be considered to have PD at 
time of first PD.  
 
No evaluable 
post-baseline 
tumor assessment 
due to early death 
The date of death will be the event date 
of PFS.   
 
No evaluable 
post-baseline 
tumor assessment 
due to reasons 
other than death 
Patient will be censored on treatment 
start date.  
If a patient discontinued study due to 
PD or AE, this patient will be 
considered to have PFS event on the 
end of study date.* 
Lost to follow-up 
Or 
Discontinuation 
of study after at 
least 1 evaluable 
post-baseline 
tumor assessment 
PFS will be censored at last valid tumor 
assessment. 
If a patient discontinued study due to 
PD or AE, this patient will be 
considered to have PFS event on the 
end of study date.* 
A sensitivity analysis will be performed for PFS where the intercurrent events of “initiation of 
palliative radiation therapy” will be ignored.  PFS for patients with unconventional responses will 
be measured from time of first dose to first PD after the response or death, whichever is earlier.  
PFS for patients who don’t have PD or death will be censored at last valid tumor assessment (or 
study day 1 if there is no valid postbaseline tumor assessment). 
Attributes for OS 
1. The study population is defined as CSCC patients who are enrolled on the protocol.  
2. The endpoint is OS, measured from time of enrollment until death due to any cause.  
3. Intercurrent events and how to account for these events are described in Table 19.  
4. OS will be summarized by median and its 95% confidence interval by the Kaplan-Meier 
method. 
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Table 19: 
Intercurrent Events for Analysis of OS per Central Review and Investigator 
Assessment 
Intercurrent 
events 
Rules of imputing data after 
intercurrent events in the 
primary analysis 
New sensitivity analysis  
New anticancer 
therapy added 
OS will be censored at last known 
alive date if there is no death event.  
OS will be censored at the first date 
of a subsequent anticancer therapy is 
taken. 
Lost to survival 
follow-up 
OS will be censored at last known 
alive date.  
If a patient was lost to survival 
follow-up, this patient will be 
considered to have death event on 
last known alive date+1. * 
*All analyses for Group 6 are the same as those in Groups 1 to 3, except for additional sensitivity analyses denoted 
by asterisk. 
The primary analysis of OS ignored the intercurrent events of “new anticancer therapy added” and 
“lost to survival follow-up”.  OS for patients who are alive will be censored on last known alive 
date.  No additional sensitivity analysis will be performed for OS. 
For Group 6, the rates of intercurrent events are expected to be similar to those observed in 
Groups 1 to 3.  Frequencies of these events in Groups 1 to 3 are presented in Table 20. 
Table 20: 
Frequency of Intercurrent Events in Group 1, 2, and 3 in the Primary 
Analysis 
Intercurrent event 
Endpoint 
Group 1 
(N=59) 
Group 2 
(N=78) 
Group 3 
(N=56) 
Initiation of radiation therapy 
ORR, DOR, 
PFS 
0 
0 
0 
Surgical removal of target lesion 
ORR, DOR  
 1 (1.7%) 
0 
0 
Unconventional response 
ORR, DOR, 
PFS 
0 
2 (2.6%) 
0 
No evaluable post-baseline tumor assessment 
(BOR=NE) 
ORR, DOR 
7 (11.9%) 
7 (9.0%) 
6 (10.7%)  
Due to early death 
PFS 
3 (5.1%) 
1 (1.3%) 
3 (5.4%) 
Due to reasons other than death 
PFS 
4 (6.8%) 
6 (7.7%) 
3 (5.4%) 
Lost to follow-up or Discontinuation of study in 
patients with BOR of CR or PR 
DOR 
1 (1.7%) 
11 (14.1%) 
1 (1.8%) 
Due to AE or PD  
DOR 
1 (1.7%) 
1 (1.3%) 
0 
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Intercurrent event 
Endpoint 
Group 1 
(N=59) 
Group 2 
(N=78) 
Group 3 
(N=56) 
Lost to follow-up or Discontinuation of study after at 
least one evaluable post-baseline tumor assessment 
PFS 
15 (25.4%) 
35 (44.9%) 
19 (33.9%) 
Due to AE or PD  
PFS 
12 (20.3%) 
14 (17.9%) 
14 (25.0%) 
New anti-cancer therapy added 
OS 
8 (13.6%) 
5 (6.4%) 
8 (14.3%) 
Lost to survival follow up  
OS 
6 (10.2%) 
33 (42.3%) 
13 (23.2%) 
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SUBGROUP ANALYSES – METASTATIC AND LOCALLY ADVANCED 
CSCC PATIENTS AT FINAL ANALYSIS 
Table 21 and Table 22 provide the 95% confidence intervals for observed ORRs for the 
2 subgroups of Group 6: metastatic and locally advanced CSCC separately.  The primary analysis 
for Group 6 is based on all advanced CSCC patients, both metastatic and locally advanced.  These 
subgroup analyses are descriptive only.  
Table 21: 
The Binomial Exact Confidence Intervals for Observed ORR in Metastatic 
CSCC Patients at Final Analysis (N=133) 
Number of Responders 
ORR (N=133) 
95% CI (%) 
47 
35.3% 
(27.3, 44.1) 
48 
36.1% 
(27.9, 44.9) 
49 
36.8% 
(28.6, 45.6) 
50 
37.6% 
(29.3, 46.4) 
51 
38.3% 
(30.1, 47.2) 
52 
39.1% 
(30.8, 47.9) 
53 
39.8% 
(31.5, 48.7) 
54 
40.6% 
(32.2, 49.5) 
55 
41.4% 
(32.9, 50.2) 
56 
42.1% 
(33.6, 51.0) 
57 
42.9% 
(34.3, 51.7) 
58 
43.6% 
(35.0, 52.5) 
59 
44.4% 
(35.8, 53.2) 
60 
45.1% 
(36.5, 54.0) 
 
Table 22: 
The Binomial Exact Confidence Intervals for Observed ORR in Locally 
Advanced CSCC Patients at Final Analysis (N=34) 
Number of Responders 
ORR (N=34) 
95% CI (%) 
11 
32.4% 
(17.4, 50.5) 
12 
35.3% 
(19.7, 53.5) 
13 
38.2% 
(22.2, 56.4) 
14 
41.2% 
(24.6, 59.3) 
15 
44.1% 
(27.2, 62.1) 
Table 23, Table 24, and Table 25 provide the 95% confidence intervals for observed ORRs at 
interim analysis for the advanced CSCC patients and 2 subgroups of Group 6: metastatic and 
locally advanced CSCC separately.  The interim analysis for Group 6 is based on all advanced 
CSCC patients in the Group 6 interim analysis.  Subgroup analyses are descriptive. 
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CONFIDENTIAL 
Table 23: 
The Binomial Exact Confidence Intervals for Observed ORR in Advanced 
CSCC Patients at Interim Analysis of Group 6 (N=84) 
Number of 
Responders 
ORR (N=84) 
99.69% CI (%) 
95% CI (%) 
30 
35.7% 
(21.2, 52.4) 
(25.6, 46.9) 
31 
36.9% 
(22.2, 53.6) 
(26.6, 48.1) 
32 
38.1% 
(23.2, 54.8) 
(27.7, 49.3) 
33 
39.3% 
(24.2, 56.0) 
(28.8, 50.5) 
34 
40.5% 
(25.2, 57.1) 
(29.9, 51.7) 
35 
41.7% 
(26.3, 58.3) 
(31.0, 52.9) 
36 
42.9% 
(27.3, 59.5) 
(32.1, 54.1) 
37 
44.0% 
(28.4, 60.6) 
(33.2, 55.3) 
 
Table 24: 
The Binomial Exact Confidence Intervals for Observed ORR in Metastatic 
CSCC Patients at Interim Analysis (N=64) 
Number of Responders 
ORR (N=64) 
95% CI (%) 
23 
35.9% 
(24.3, 48.9) 
24 
37.5% 
(25.7, 50.5) 
25 
39.1% 
(27.1, 52.1) 
26 
40.6% 
(28.5, 53.6) 
27 
42.2% 
(29.9, 55.2) 
28 
43.8% 
(31.4, 56.7) 
29 
45.3% 
(32.8, 58.3) 
 
Table 25: 
The Binomial Exact Confidence Intervals for Observed ORR in Locally 
Advanced CSCC Patients at Interim Analysis (N=20) 
Number of Responders 
ORR (N=20) 
95% CI (%) 
6 
30% 
(11.9, 54.3) 
7 
35% 
(15.4, 59.2) 
8 
40% 
(19.1, 63.9) 
9 
45% 
(23.1, 68.5) 
 
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CONFIDENTIAL 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this protocol accurately describes the conduct of the study. 
Study Title: 
A Phase 2 Study of REGN2810, a Fully Human Monoclonal Antibody to 
Programmed Death-1 (PD-1), in Patients with Advanced Cutaneous Squamous Cell Carcinoma  
 
Protocol Number: R2810-ONC-1540 
Protocol Version: R2810-ONC-1540 Amendment 9 
 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director: 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison: 
 
 
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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Signature Page for VV-RIM-00165169 v2.0
Signature Page for VV-RIM-00165169 v2.0 Approved
ESig Approval
09-Sep-2021 00:58:33 GMT+0000
ESig Approval
09-Sep-2021 12:35:22 GMT+0000
ESig Approval
09-Sep-2021 14:40:24 GMT+0000
ESig Approval
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
REGENERON CONFIDENTIAL 
Page 1 of 41 
STATISTICAL ANALYSIS PLAN 
VERSION 6.0 FINAL 
Title: 
A Phase II Study of REGN2810, A Fully Human Monoclonal 
Antibody to Programmed Death-1 (PD-1), in Patients with 
Advanced Cutaneous Squamous Cell Carcinoma 
Compound: 
Cemiplimab [REGN2810 (anit-PD-1 mAb)] 
Protocol Number: 
R2810-ONC-1540 
Clinical Phase: 
Phase 2 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
 
Version/Date: 
Version 6.0 / October 27, 2023 
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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. 
 
 
See appended electronic signature page 
 
 
 
 
 
See appended electronic signature page 
 
 
 
 
 
See appended electronic signature page 
 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................9 
1.1. 
Background/Rationale ..................................................................................................9 
1.1.1. 
Background ...................................................................................................................9 
1.1.2. 
Rationale .......................................................................................................................9 
1.2. 
Study Objectives ...........................................................................................................9 
1.2.1. 
Primary Objectives .......................................................................................................9 
1.2.2. 
Secondary Objectives .................................................................................................10 
1.2.3. 
Exploratory Objective .................................................................................................10 
1.2.3.1. 
Groups 2 and 4 ............................................................................................................10 
1.2.3.2. 
Group 5 Only ..............................................................................................................11 
1.2.3.3. 
Group 6 Only ..............................................................................................................11 
1.2.3.4. 
Group 6 Only – Patients Who Switch to SC Formulation ..........................................11 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................11 
1.2.5. 
Revision History for SAP Amendments .....................................................................12 
2. 
INVESTIGATION PLAN ..........................................................................................13 
2.1. 
Study Design ...............................................................................................................13 
2.2. 
Sample Size and Power Considerations .....................................................................13 
2.3. 
Study Plan ...................................................................................................................14 
3. 
ANALYSIS POPULATIONS ....................................................................................16 
3.1. 
Full Analysis Set (FAS) ..............................................................................................16 
3.2. 
Safety Analysis Set (SAF) ..........................................................................................16 
3.3. 
Pharmacokinetic Analysis Set ....................................................................................16 
3.4. 
Anti-drug Antibody Set ..............................................................................................16 
3.5. 
Biomarker Analysis Set ..............................................................................................16 
4. 
ANALYSIS VARIABLES .........................................................................................17 
4.1. 
Demographic and Baseline Characteristics ................................................................17 
4.2. 
Medical History ..........................................................................................................17 
4.3. 
Pre-Treatment / Concomitant Medication ..................................................................17 
4.4. 
Rescue Medication/Prohibited Medication .................................................................18 
4.5. 
Efficacy Variable ........................................................................................................18 
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4.5.1. 
Primary Efficacy Variable ..........................................................................................18 
4.5.2. 
Secondary Efficacy Variables .....................................................................................19 
4.5.3. 
Exploratory Efficacy Variable ....................................................................................20 
4.5.4. 
Exploratory Biomarker Variables ...............................................................................20 
4.6. 
Safety Variables ..........................................................................................................20 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................20 
4.6.2. 
Adverse Events of Special Interest .............................................................................22 
4.6.3. 
Laboratory Safety Variables .......................................................................................22 
4.6.4. 
Vital Signs ..................................................................................................................22 
4.6.5. 
12-Lead Electrocardiography (ECG) ..........................................................................23 
4.6.6. 
Physical Examination Variables .................................................................................23 
4.7. 
Pharmacokinetic Variables and Immunogenicity Variables (ADA) ..........................23 
5. 
STATISTICAL METHODS .......................................................................................24 
5.1. 
Demographics and Baseline Characteristics ...............................................................24 
5.2. 
Medical History ..........................................................................................................24 
5.3. 
Prior/Concomitant Medications ..................................................................................24 
5.4. 
Subject Disposition .....................................................................................................25 
5.5. 
Protocol Deviation ......................................................................................................25 
5.6. 
Measurement of Compliance ......................................................................................25 
5.7. 
Exposure to Investigational Product ...........................................................................25 
5.8. 
Analyses of Efficacy Variables ..................................................................................26 
5.8.1. 
Analysis of Primary Efficacy Variable .......................................................................26 
5.8.2. 
Analysis of Secondary Efficacy Variables .................................................................27 
5.8.3. 
Analysis of Quality of Life Variables .........................................................................28 
5.8.4. 
Analysis of Exploratory Efficacy Variable .................................................................28 
5.8.5. 
Subgroup Efficacy Analysis .......................................................................................28 
5.9. 
Analysis of Safety Data ..............................................................................................28 
5.9.1. 
Adverse Events ...........................................................................................................29 
5.9.2. 
Clinical Laboratory Measurements.............................................................................30 
5.9.3. 
Analysis of Vital Signs ...............................................................................................31 
5.9.4. 
Analysis of 12-Lead ECG ...........................................................................................31 
5.9.5. 
Physical Exams ...........................................................................................................31 
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5.10. 
Analysis of Pharmacokinetic and Immunogenicity Data ...........................................31 
5.10.1. 
Analysis of Pharmacokinetic Data ..............................................................................31 
5.10.2. 
Analysis of Anti-Drug Antibody Data ........................................................................32 
5.10.3. 
Analysis of Neutralizing Antibody (NAb) Data .........................................................34 
5.10.4. 
Analysis of Exploratory Biomarker Data ...................................................................34 
6. 
DATA CONVENTIONS ............................................................................................35 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................35 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................35 
6.3. 
Data Handling Convention for Missing Data .............................................................35 
6.4. 
Unscheduled Assessments ..........................................................................................35 
7. 
MULTIPLICITY CONSIDERATIONS .....................................................................36 
8. 
INTERIM ANALYSIS ...............................................................................................37 
9. 
SOFTWARE ...............................................................................................................39 
10. 
REFERENCES ...........................................................................................................40 
11. 
APPENDIX.................................................................................................................41 
11.1. 
Summary of Statistical Analyses ................................................................................41 
 
LIST OF TABLES 
Table 1: 
Alpha Spending for Analysis of ORR on Group 6 Patients .......................................38 
Table 2: 
Binomial Exact Confidence Intervals for Observed ORR in Group 6 .......................38 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition of Term 
ADA 
Anti-drug antibody 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
BAS 
Biomarker analysis set 
BCC 
Basal cell carcinoma  
BLA 
Biologics license application 
BMI 
Body mass index 
BOR 
Best overall response 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
CSR 
Clinical study summary 
CR 
Complete response 
CRF 
Case report form  
CSCC 
Cutaneous squamous cell carcinoma  
CT 
Computed tomography 
dDCR 
Durable disease control rate 
DCR 
Disease control rate 
DOR 
Duration of response 
EAS 
Efficacy analysis set 
ECG 
Electrocardiogram 
ECOG 
East Cooperative Oncology Group 
EOS 
End of study 
FAS 
Full analysis set 
GITR 
Glucocorticoid-induced TNFR family related gene 
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Abbreviation 
Definition of Term 
ICH 
International Council for Harmonisation 
IHC 
Immunohistochemistry 
irAE 
Immune-related adverse event 
irRC 
Immune-related response criteria 
IWRS  
Interactive web response system 
LLOQ 
Lower limit of quantification 
LDH 
Lactate dehydrogenase 
MAA 
Marketing authorization application 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging  
mRNA 
Messenger ribonucleic acid 
NCCN 
National Comprehensive Cancer Network 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events  
NE 
Not evaluable  
NSCLC 
Non-small cell lung cancer 
PBMC 
Peripheral blood mononuclear cell 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progression 
PD-1 
Programmed death-1 (receptor) 
PD-L1  
Programmed death ligand 1 
PD-L2 
Programmed death ligand 2 
PET 
Positron-emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PR 
Partial response 
PT 
Preferred term 
RCC 
Renal cell cancer 
RECIST 
Response Evaluation Criteria in Solid Tumors 
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Abbreviation 
Definition of Term 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Systems (software) 
SC 
Subcutaneous 
SD 
Stable disease 
SI 
Standard international 
SOC 
System organ class 
t½ 
Beta-phase terminal half life 
TEAE 
Treatment-emergent adverse event 
TILs 
Tumor-infiltrating lymphocytes 
TMB 
Tumor mutation burden 
TTR 
Time to response 
UV 
Ultraviolet 
WHODD 
World Health Organization drug dictionary 
WBC 
White blood cell 
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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 and statistical 
methods to be used in the analysis of data for R2810-ONC-1540 study. 
This plan may be revised during the study to accommodate protocol amendments and/or to make 
changes to adapt to unexpected issues in study execution and/or data that affect planned 
analyses. The final plan, if revised, will document all changes and be issued prior to database 
lock.  
1.1. 
Background/Rationale 
1.1.1. 
Background 
Cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy in the 
United States. A review of national databases indicates that incidence of non-melanoma skin 
cancers, mostly basal cell carcinoma (BCC) and CSCC, approximately doubled between 1994 
and 2006 in the context of an aging population. Most CSCC patients have a favorable prognosis, 
but annual mortality is approximately 3,900 to 8,800 deaths in the United States. 
Surgical resection is the centerpiece of clinical management of CSCC. Radiation therapy for 
CSCC has also been used in the adjuvant setting. For the small percentage of patients who 
develop unresectable locally recurrent or metastatic disease, treatment options are limited. 
Regarding systemic therapies, there is a dearth of data to guide clinical decision-making for 
oncologists who take care of patients with advanced CSCC. National Comprehensive Cancer 
Network (NCCN) guidelines do not provide firm recommendations.  
Blockade of the PD-1/PD-L1 immune checkpoint pathway is an effective and well tolerated 
approach to stimulate the immune response, and has achieved significant objective responses in 
advanced melanoma, renal cell cancer (RCC), non-small cell lung cancer (NSCLC), and other 
solid tumors. 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. 
1.1.2. 
Rationale 
CSCC has several clinical and biological factors that suggest that it is appropriate for the clinical 
study of inhibition of the PD-1 immune checkpoint: high mutation burden, presence of tumor 
infiltrating lymphocytes (TILs), association with immunosuppression as a risk factor, evidence 
of direct immunosuppressive effects of ultraviolet radiation (UV) which predisposes to CSSC, 
and some clinical efficacy with interferon α2a-based treatment. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
For Groups 1 to 4, the primary objective of this study is to estimate the clinical benefit of 
cemiplimab monotherapy for patients with: metastatic (nodal or distant) CSCC, or unresectable 
locally advanced CSCC. Group 1 consists of patients with metastatic (nodal or distant) CSCC 
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treated with cemiplimab 3 mg/kg IV Q2W. Group 2 consists of patients with unresectable locally 
advanced CSCC, treated with cemiplimab 3 mg/kg IV Q2W. Group 3 consists of patients with 
metastatic (nodal or distant) CSCC treated with cemiplimab 350 mg IV Q3W. Group 4 consists 
of patients with advanced CSCC (metastatic [nodal or distal] or unresectable locally advanced) 
treated with cemiplimab 600 mg IV every 4 weeks (Q4W). For Group 6, the primary objective is 
to provide additional efficacy and safety data for cemiplimab monotherapy in patients with 
advanced CSCC (metastatic [nodal or distant] or locally advanced) treated with cemiplimab 
350 mg IV Q3W. 
Clinical benefit is measured by ORR according to central review in each group. 
1.2.2. 
Secondary Objectives 
The secondary objectives for Groups 1 to 4, and Group 6 are: 
• To estimate ORR according to investigator review 
• To estimate the duration of response (DOR), PFS, and OS by central and investigator 
review 
• To estimate the complete response (CR) rate by central review 
• To assess the safety and tolerability of cemiplimab 
• To assess the PK of cemiplimab 
• To assess the immunogenicity of cemiplimab 
For Groups 1 to 5 only: 
• To assess the impact of cemiplimab on quality of life using European Organization 
for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 
(EORTC QLQ-C30) 
Group 6 only: To assess relationships between PD-L1 status (by IHC) and efficacy measures 
(ORR, DOR, PFS). 
1.2.3. 
Exploratory Objective 
1.2.3.1. 
Groups 2 and 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.2.3.2. 
Group 5 Only 
 
 
 
 
 
 
 
 
 
 
 
1.2.3.3. 
Group 6 Only 
 
 
 
 
 
 
1.2.3.4. 
Group 6 Only – Patients Who Switch to SC Formulation 
Protocol Amendment 9 allows Group 6 patients who have received IV cemiplimab for at least 27 
weeks without experiencing disease progression to switch to SC cemiplimab (optional). This is 
to extend clinical experience with SC cemiplimab, including variability in PK upon repeated SC 
doses and the assessment of local tolerability at the site of SC injection. For these patients, the 
following exploratory objectives will be evaluated: 
 
 
 
 
 
 
 
 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
This study is expected to be a pivotal trial and will be part of the core of the BLA/MAA 
submission. Accordingly, revision to this plan will only be made if deemed necessary to the 
furtherance of the trial objectives. Such revision, if necessary, will be completed prior to the final 
database lock. 
Modifications from the Statistical Section in the protocols are listed below: 
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• Added TTR, DCR, and dDCR as additional analyses. 
• Added a sensitivity analysis of ORR using patients who received at least one dose of 
cemiplimab. 
1.2.5. 
Revision History for SAP Amendments 
This is the sixth version of the SAP, based on the study protocol R2810-ONC-1540 Amendment 
9 dated Sep 9, 2021. 
The changes from SAP v5.0 dated Mar 10, 2021 (based on protocol amendment 7) include the 
addition of exploratory objectives and analysis for Group 6 patients who were allowed to switch 
to subcutaneous (SC) dosing per protocol amendment 9.  
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design 
This is a phase 2, non-randomized, 6-group, multicenter pivotal study evaluating the efficacy and 
safety of cemiplimab in patients with advanced CSCC. After a screening period of up to 28 days, 
eligible patients will be enrolled into 1 of 6 groups and receive cemiplimab treatment as below. 
• Group 1: Patients with metastatic (nodal or distant) CSCC, treated with cemiplimab 
3 mg/kg IV every 2 weeks (Q2W). These patients are required to have histologic 
confirmation of distant CSCC metastases (eg, lung, liver, bone, or lymph node). 
• Group 2: Patients with unresectable locally advanced CSCC, treated with cemiplimab 
3 mg/kg IV Q2W. These patients are required to have diseases that are considered 
inoperable or to have medical contraindication to surgery or radiation or have not 
achieved disease control with these treatments. 
• Group 3: Patients with metastatic (nodal or distant) CSCC, treated with cemiplimab 
350 mg IV every 3 weeks (Q3W) 
• Group 4: Patients with advanced CSCC (metastatic [nodal or distant] or locally 
advanced) treated with cemiplimab 600mg IV every 4 weeks (Q4W). 
• Group 5: Patients with advanced CSCC, treated with 1 dose of cemiplimab 438 mg 
SC followed by cemiplimab 350mg IV Q3W. 
• Group 6: 
 
  
 
 
 
 
 
Although included in the same clinical trial, the statistical analyses of the 6 groups will be 
conducted independently and summarized separately, except for safety data analyses may be 
combined at a later stage when deemed appropriate. 
2.2. 
Sample Size and Power Considerations 
For Group 1 and Group 3, 50 patients (in each group) are required to provide at least 85% power 
to reject a null hypothesis of an ORR of 15% at a 2-sided significance level of no more than 5% 
if the true ORR is 34%. For Group 2, 72 patients are required to provide at least 90% power to 
reject a null hypothesis of an ORR of 25% at a 2-sided significance level of no more than 5% if 
the true ORR is 44%. For Group 4, 60 patients with advanced CSCC will be required to provide 
at least 92% power to reject a null hypothesis of an ORR of 20% at a 2-sided significance level 
of no more than 5% if the true ORR is 40%. In addition, for Group 4, 60 patients with advanced 
CSCC will provide at least 93% or 87% power to reject a null hypothesis of an ORR of 15% or 
25% at a 2-sided significance level of no more than 5% if true ORR is 35% or 45% respectively. 
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Group 5 is a pilot cohort to obtain initial clinical and PK experience among patients who receive 
a single dose of cemiplimab SC, with a sample size of 10 patients for PK analysis. 
The sample size for Group 6 was selected such that the lower limit of the 95% confidence 
interval of the estimated ORR excludes the highest independently-reviewed ORR to date in any 
prospective study of anticancer systemic therapy for advanced CSCC that enrolled at least 
30 patients. For Group 6, 150 patients will be required to provide at least 85% power to reject a 
null hypothesis of an ORR of 28% at a 2-sided significance level of no more than 5% if the true 
ORR is 40%.  
The sample sizes for group 1 through 4 were selected such that the lower limit of the two-sided 
95% confidence interval (CI) of the estimated ORR will be clinically meaningful. The non-
clinically meaningful ORR of 15% for Group 1 and Group 3 (evaluated independently) will be 
excluded using the lower limit of 95% CI if the observed ORR is around 28.0% or more; ie, the 
ORR for Group 1 and/or Group 3 (evaluated independently) is significantly different from 15%. 
The non-clinically meaningful ORR of 25% for Group 2 will be excluded using the lower limit 
of 95% CI if the observed ORR is around 36.1% or more; ie, the ORR for Group 2 is 
significantly different from 25%. An ORR of 20% for Group 4 will be excluded using the lower 
limit of 95% confidence interval if the observed ORR is 31.7% or more; ie, the ORR for Group 4 
is significantly different from 20%. In addition, if the observed ORR for Group 4 is 26.7% or 
38.3% or more, the ORR for Group 4 is significantly different from 15% or 25% respectively, 
using the lower limit of the 95% confidence intervals (see Table 11, Table 12, and Table 13 in 
the protocol). The sample size for Group 6 was selected such that lower limit of the two-sided 
95% CI of the estimated ORR will exclude the highest reported ORR in any study in advanced 
CSCC patients that used independent radiology review and enrolled at least 30 patients. The 
ORR of 28% for Group 6 will be excluded using the lower limit of 95% exact CI if the observed 
ORR is 35.3% or more, ie, the ORR for Group 6 is significantly different from 28% 
(see Table 14 of the protocol). 
For groups 1 through 4, the sample sizes are further increased by 5% to account for patients who 
withdraw prematurely from the study. Hence, the total sample sizes will be 53 patients for Group 
1, 76 patients for Group 2, and 53 patients for Group 3, and 63 patients for Group 4. For Group 
6, the sample size will be further increased by 10% to account for patients who withdraw 
prematurely from the study. Hence, the total planned sample size will be approximately 
167 patients for Group 6. The sample size calculation was based on the exact binomial test using 
nQuery Advisor version 7.0 (Elashoff, 2007). 
2.3. 
Study Plan 
After a screening period of up to 28 days, Group 1 and Group 2 patients will receive up to twelve 
56-day (8-week) treatment cycles for a total of up to 96 weeks of treatment. Each patient will 
receive 3 mg/kg cemiplimab intravenously on days 1, 15±3, 29±3, and 43±3 during each 
treatment cycle. Tumor assessments will be made at the end of each treatment cycle. Extensive 
safety evaluations will occur on day 1 of each cycle; routine safety evaluations will be conducted 
at each cemiplimab dosing visit.  
Group 3 patients will receive up to six 63-day (9-week) treatment cycles for up to 54 weeks of 
treatment. Each patient will receive 350 mg cemiplimab intravenously on days 1, 22±3, and 
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43 ±3 during each treatment cycle. Tumor assessments will be made at the end of each treatment 
cycle.  Extensive safety evaluations will occur on day 1 of each cycle, with routine safety 
evaluations to be conducted at each cemiplimab dosing visit. 
Group 4 patients will receive up to six 56-day (8-week) treatment cycles for up to 48 weeks of 
treatment. Each patient will receive 600 mg cemiplimab intravenously on day 1, 29±3, and 56 ±3 
during each treatment cycle. Tumor assessments will be made at the end of each treatment cycle.  
Extensive safety evaluations will occur on day 1 of each cycle, with routine safety evaluations to 
be conducted at each cemiplimab dosing visit. 
Group 5 patients will receive up to six 63-day (9-week) treatment cycles for up to 54 weeks of 
treatment. Each patient will receive 438 mg cemiplimab SC for the first dose and receive 350 mg 
cemiplimab intravenously on day 22±3, and 43 ±3 in cycle 1 and day 1, 22±3, and 43 ±3 during 
rest of treatment cycles. Tumor assessments will be made at the end of each treatment cycle.  
Extensive safety evaluations will occur on day 1 of each cycle, with routine safety evaluations to 
be conducted at each cemiplimab dosing visit. 
Group 6 patients will receive up to twelve 63-day (9-week) treatment cycles for up to 108 weeks 
of treatment. Each patient will receive 350 mg cemiplimab intravenously on days 1, 22±3, and 
43 ±3 during each treatment cycle. Tumor assessments will be made at the end of each treatment 
cycle.  Extensive safety evaluations will occur on day 1 of each cycle, with routine safety 
evaluations to be conducted at each cemiplimab dosing visit. After implementation of PA9, 
patients will be given the option to receive subsequent doses of cemiplimab SC. The first 12 
patients who opt to switch to SC will receive cemiplimab 
. The next ≥6 patients 
who opt to switch to SC will receive cemiplimab 
. Group 6 patients will have the 
option to switch to SC dosing or to remain on 350 mg Q3W IV dosing. 
A patient will receive treatment until the treatment period (96 weeks in Group 1 and Group 2; 
54 weeks in Group 3; 48 weeks in Group 4; 54 weeks in Group 5; 108 weeks in Group 6) is 
complete, or until disease progression, unacceptable toxicity, withdrawal of consent, or 
confirmed complete response (CR). Group 1 and Group 2 patients with confirmed CR after a 
minimum of 48 weeks of treatment and Group 6 patients with confirmed CR after a minimum 
54 weeks of treatment may elect to discontinue treatment and continue with all relevant study 
assessments (eg, efficacy assessments).  
Groups 1 through 5: Patients in all groups who do not experience progressive disease (PD) will 
be followed for an additional nontreatment period of up to approximately 6 months with scans 
performed every 8-12 weeks. After completion of this follow-up period, patients will then enter 
an extended follow-up period for approximately 1 additional year with assessments every 
4 months. Patients in Groups 1 to 5 who complete treatment without disease progression and 
subsequently experience disease progression during the follow-up period without any intervening 
systemic anticancer therapy, are eligible for up to 2 years of retreatment with cemiplimab 
350 mg IV Q3W. 
Group 6: Patients who do not experience PD at the completion of the planned treatment period 
will enter follow-up for approximately 6 months. There is no extended follow-up for Group 6. 
Patients enrolled in Group 6 are not eligible for retreatment. 
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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), the following population sets will be used 
for statistical analysis. A patient is deemed eligible and enrolled after the patient completes the 
screening process and the investigator deems that the subject is eligible, and the investigator 
orders study drug in interactive web response system (IWRS). At that point, the patient’s status 
in IWRS changes from “in screening” to “enrolled.” A patient is not deemed eligible until he/ 
she is enrolled in IWRS. 
3.1. 
Full Analysis Set (FAS) 
The full analysis set (FAS) includes all patients who have passed screening and deemed to be 
eligible for this study. All efficacy endpoints will be analyzed using FAS. 
3.2. 
Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all enrolled patients who received any study drug for each 
group. Treatment compliance/administration and all clinical safety variables will be analyzed or 
summarized using the SAF. 
3.3. 
Pharmacokinetic Analysis Set 
The PK analysis set for cemiplimab will include all patients who had received cemiplimab/ and 
had at least 1 qualified (non-missing) postbaseline measurement of cemiplimab concentration in 
serum. 
3.4. 
Anti-drug Antibody Set 
The ADA population for cemiplimab includes all treated patients who had at least 1 postdose 
ADA result for cemiplimab. 
3.5. 
Biomarker Analysis Set 
The biomarker analysis set (BAS) includes all treated patients who had at least 1 sample assayed. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristics variables will be summarized: 
• Age at screening in years (quantitative and qualitative variable: <65, ≥65 years) 
• Sex (Male, Female) 
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White and Other) 
• Ethnicity (Hispanic/Latino or not) 
• Weight (kg) 
• Height (cm) 
• Body mass index (BMI) calculated from weight and height: weight (kg) / [height 
(m)]^2 
• ECOG performance status (0, 1) 
• For group 1 and group 3, type metastatic disease (Distant or Nodal only). 
4.2. 
Medical History 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to the latest available version of MedDRA. 
Oncology history: 
• Primary diagnosis 
• Time from initial diagnosis to study entry 
• Histologic grade 
• Cancer stages at initial diagnosis and at screening 
• Prior anticancer systemic therapy 
• Prior radiotherapy 
• Duration of latest anticancer systemic therapy 
4.3. 
Pre-Treatment / Concomitant Medication 
Medications/Procedures will be recorded from the day of informed consent until the end of study 
(EOS) visit. Medications will be coded to the anatomical therapeutic chemical (ATC) level 2 
(therapeutic main group) and ATC level 4 (chemical/therapeutic subgroup), according to the 
latest available version of WHO Drug Dictionary (WHODD). Patients will be counted once in all 
ATC categories linked to the medication. 
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Pre-treatment medications/procedures: medications taken or procedures performed prior to 
administration of the study drug, particularly, prior cancer related surgery, prior cancer related 
radiotherapy, and prior cancer related systemic therapy: chemotherapy, targeted therapy, 
immunotherapy and others.  
Concomitant medications/procedures: any treatment administered from the time of informed 
consent until 30 days after the last study treatment will be considered concomitant treatment. 
This includes medications and other therapies for which administration started before the study 
and will continue during the study, as well as any therapies started in the 6-month follow-up 
period to treat a study drug related AE. All concomitant treatments must be recorded in the study 
case report form (CRF) with the generic name, dose, dose unit, frequency, indication, and 
start/stop date, as appropriate. 
4.4. 
Rescue Medication/Prohibited Medication 
While participating in this study, a patient may not receive any standard or investigational agent 
for treatment of a tumor other than cemiplimab as monotherapy. Any other medication which is 
considered necessary for the patient’s welfare, and which is not expected to interfere with the 
evaluation of the study drug, may be given at the discretion of the investigator. 
Patients using immunosuppressive doses (>10 mg per day of prednisone or equivalent) of 
systemic corticosteroids other than for corticosteroid replacement will not be eligible for the 
study. It is recommended that patients do not receive systemic corticosteroids such as 
hydrocortisone, prednisone, prednisolone (Solu-Medrol®) or dexamethasone (Decadron®) at 
any time throughout the study except in the case of a life-threatening emergency and/or to treat 
an immune-related adverse event (irAE). Physiologic replacement doses of systemic 
corticosteroids are permitted, even if >10 mg/day prednisone equivalents. 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. 
4.5. 
Efficacy Variable 
4.5.1. 
Primary Efficacy Variable 
Overall response is based on central-reviewed evaluation at each time point at which a 
response assessment occurs using the RECIST version 1.1 (Appendix 1 of the protocol) or the 
composite response criteria (Appendix 2 of the protocol).  
Best overall response (BOR) is determined once all the overall response data for the patient are 
known. The best overall response is the best response recorded during the study.  
• Best overall response of CR or PR must be confirmed by consecutive evaluations of 
overall response of CR or PR at time points at least 4 weeks apart. In addition, locally 
advanced CSCC patients followed by digital medical photography require biopsy to 
confirm CR. 
• Best overall response of SD must have met the response SD criteria at least once 
≥39 days (6 weeks*7 days/week -3 days) after start of study treatment. Best overall 
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response of (early) PD does not require confirmation using the RECIST or the 
composite response criteria.  
• The best overall response for patients who do not have any post-baseline tumor 
assessment will be not evaluable (NE). Patients with best overall response of NE will 
be considered as not reaching an objective response of CR or PR. 
Objective response rate (ORR) is determined by the proportion of patients with best overall 
response of CR or PR in the FAS by group.  
4.5.2. 
Secondary Efficacy Variables 
ORR based on investigator-assessed evaluation is also derived from the overall response that is 
based on investigator-assessed evaluation at each time point at which a response assessment 
occurs using the RECIST version 1.1 (Appendix 1 of the protocol) or the composite response 
criteria (Appendix 2 of the protocol).  
Duration of response (DOR) is determined for patients with best overall response of CR or PR. 
Duration of response is measured from the time measurement criteria are first met for CR/PR 
(whichever is first recorded) until the first date of recurrent or progressive disease (radiographic 
or photographic), or death due to any cause. DOR by central-reviewed evaluation is the key 
secondary endpoint. 
Patients who do not have a documented tumor progression or death will be censored at the last 
evaluable tumor assessment.   
Progression-free survival (PFS) is measured from the start of treatment until the first date of 
recurrent or progressive disease (radiographic or photographic), or death due to any cause. 
Patients who do not have a documented tumor progression or death will be censored at the last 
evaluable tumor assessment. If a patient has no post-baseline tumor assessment, the patient will 
be censored at the first treatment date. 
Overall survival (OS) is measured from the start of treatment until death due to any cause. 
Patients who do not have a survival event will be censored at the last date that patient is 
documented to be alive. As many patients may receive subsequent therapy after disease 
progression, a variant of OS will also be defined as censoring patients who do not have a survival 
event at the first date of a subsequent therapy is taken. 
Time to tumor response (TTR) is determined for patients with BOR of CR or PR. TTR is 
measured from the start of treatment until the time measurement criteria are first met for CR/PR 
(whichever is first recorded).   
For all of the above time-to-event variables, the time to event (day) is the date of event/censor   
the date of first study treatment+ 1. 
CR rate is determined by the proportion of patients with best overall response of CR. Patients 
with best overall response of NE will be considered as not reaching an objective response of CR. 
Disease control rate (DCR) is determined by the proportion of patients with BOR of CR, PR, or 
SD.  
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Durable disease control rate (dDCR) is defined as the proportion of patients best overall response 
of CR, PR, or SD without progression for at least 16 weeks (allowing tumor assessment made 
1 week earlier than week 16).   
Patient-reported quality of life is measured by the EORTC QLQ-C30 (Appendix 1 of protocol) 
on day 1 of every cycle (Aaronson, 1993). The global health status/QoL, five functional scales 
(physical, role, cognitive, emotional and social), and three symptom scales (fatigue, pain, nausea 
and vomiting) and a number of single items assessing additional symptom commonly reported 
by cancer patients (dyspnoea, loss of appetite, insomnia, constipation and diarrhoea) and 
perceived financial impact of the disease will be computed using the QLQ-C30 scoring 
procedures (Fayers, 2001). Change scores are defined as change of summary score of EORTC 
QLQ-C30 from day 1 of first treatment cycle. 
4.5.3. 
Exploratory Efficacy Variable 
Group 4 (excluding patients enrolled in Germany): ORR based on 18F-FDG-PET is determined 
by the proportion of patients with best overall response of complete metabolic response (CMR) 
or partial metabolic response (PMR) using EORTC criteria (Appendix 9 of the protocol). 
4.5.4. 
Exploratory Biomarker Variables 
Biomarker variables for exploratory analyses of association with clinical efficacy endpoints may 
include: 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
4.6. 
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. 
4.6.1. 
Adverse Events and Serious 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 (5 half-lives) after 
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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 electronic 
CRF: 
• SAEs 
• Nonserious AEs associated with a protocol-mandated intervention (eg, AEs related to 
an invasive procedure such as a biopsy) 
Other AEs that occur prior to first treatment should be reported on the medical history CRF. 
All AEs after initiation of study treatment and until 105 days (5 half-lives) after the last study 
treatment, regardless of relationship to study treatment, will be reported on the AE electronic 
CRF. Additionally, any SAE or other AE of concern that the investigator believes may be related 
to study treatment and that occurs later than 105 days (5 half-lives) after last study treatment 
should be reported. 
Group 5 patients only: any local ISRs will be reported as AEs in the CRF, as appropriate. 
All adverse events are to be coded to a Preferred Term (PT) and associated primary System 
Organ Class (SOC) according to the latest available version of Medical Dictionary for 
Regulatory Activities (MedDRA). 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. A Serious Adverse Event (SAE) is an AE that is 
classified as serious according to the criteria specified in the protocol. 
The severity of AEs (including test findings classified as AEs) will be graded using the National 
Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. 
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 ADL*.  
• 3 (Severe): Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL**.  
• 4 (Life-threatening): Life-threatening consequences; urgent intervention indicated.  
• 5 (Death): Death related to AE. 
* Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping 
for groceries or clothes, using the telephone, managing money, etc.  
** Self-care ADL refers to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden. 
The relationship of AEs to study drug will be assessed by the investigator and be determined 
based on protocol specified criteria. 
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Laboratory results, vital signs, or ECG abnormalities are to be recorded as AEs if they are 
medically relevant: symptomatic, requiring corrective therapy, leading to treatment 
discontinuation and/or fulfilling a seriousness criterion. 
4.6.2. 
Adverse Events of Special Interest 
An AE of special interest (AESI) must be reported within 24 hours of identification. AEs of 
special interest for this study include: 
• Grade 2 or greater infusion-related reactions 
• Grade 2 or greater allergic/hypersensitivity reactions 
• Grade 3 immune-related toxicities (irAE) 
• Grade 3 or greater ISR for the SC route 
• An irAE of any grade in a patient previously treated with a PI 3-K inhibitor 
Note: An irAE 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 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. 
4.6.3. 
Laboratory Safety Variables 
The clinical laboratory data consists of serum chemistry, hematology, and urinalysis. Clinical 
laboratory values will be converted to standard international (SI) units and grouped by function 
in summary tables. Conventional unit may be provided. Functions are defined as follows: 
Blood Chemistry: Sodium; Phosphorus; Alanine aminotransferase (ALT); Potassium; Glucose; 
Aspartate aminotransferase (AST); Chloride; Albumin; Total bilirubin; Bicarbonate; Creatinine; 
Alkaline phosphatase (ALP); Calcium; Blood urea nitrogen (BUN); Lactate dehydrogenase 
(LDH); Magnesium; Uric acid 
Hematology: Hemoglobin; White blood cells (WBCs); Platelet count; Differential: Neutrophils, 
Lymphocytes, Monocytes 
Urinalysis: Glucose; pH; Ketones; Blood; Specific gravity; Spot urine protein 
Immune safety tests consist of rheumatoid factor (RF), thyroid-stimulating hormone (TSH), C-
reactive protein (CRP), and antinuclear antibody (ANA). 
4.6.4. 
Vital Signs 
Vital signs will be collected according to Table 5, Table 6, Table 7, Table 8, and Table 9 Study 
Schedule of the protocol: 
• Body temperature (°C) 
• Resting systolic blood pressure and diastolic blood pressure (mmHg) 
• Pulse (beats/minute) 
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• Respiratory rate (breaths/minute) 
4.6.5. 
12-Lead Electrocardiography (ECG) 
A standard 12-lead ECG will be performed at time points according to Table 5, Table 6, Table 7, 
Table 8, and Table 9 of the protocol. The ECG is to be recorded in triplicate. The ECG strips or 
reports will be retained with the source. The ECG will be reviewed by the investigator (paper or 
electronic tracing) and will be available for comparison with subsequent ECGs by the 
investigator: 
• PR Interval (msec) 
• QRS Interval (msec) 
• QT Interval (msec) 
• Heart Rate (BPM; recorded from the ventricular rate) 
Corrected QT (QTc) will be calculated from the QT interval and RR by two methods: 
• Bazett's correction = QT/[RR1/2 ] 
• Fredericia's Correction = QT/[RR1/3] 
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. 
4.6.6. 
Physical Examination Variables 
A thorough complete or limited physical examination will be performed at visits specified in 
Table 5, Table 6, Table 7, Table 8, and Table 9 of the protocol. 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 will include examination of 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 lungs, 
heart, abdomen, and skin. 
4.7. 
Pharmacokinetic Variables and Immunogenicity Variables (ADA)  
Serum concentration of cemiplimab will be assessed at multiple time points throughout the study 
treatment and follow-up periods, and descriptive PK variables will include: 
• Ctrough - pre-infusion concentration 
• Ceoi - concentration at end-of-infusion 
• teoi - time of end-of-infusion  
Anti-drug antibody variables include status (positive or negative), titer, NAb status and time-
point/visit. Serum samples for ADA will be collected at the clinic visits specified in the protocol.  
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, minimum, and maximum. In 
addition, 25th percentile and 75th percentile will be provided. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
The denominator will be determined by the analysis population used for the summary.  
For time-to-event variables, median time-to-event (and the survival rate at a fixed time point) 
and its 95% confidence intervals will be summarized by the Kaplan-Meier method. 
Statistical analysis for efficacy will be conducted independently for each group.  
The data cut-off for primary efficacy analysis will be six months after the last patient starts the 
treatment, plus at most three additional months if a tumor response of CR or PR occurring at six 
months need be confirmed. The study will continue for data collection of tumor response, 
duration of response and safety after primary efficacy analysis. The statistical analysis of 
duration of response will be updated after four additional months to allow for sufficient data 
maturation. 
5.1. 
Demographics and Baseline Characteristics 
Patient demographics and baseline characteristics will be summarized by group based on the 
FAS population.  
Assessments made before the first dose of cemiplimab will be used as baseline measurements for 
the purposes of statistical analysis and reporting unless otherwise specified. 
5.2. 
Medical History 
Medical history will be listed which includes SOC, PT, investigator verbatim and start and end 
dates and summarized by SOC and PT. Tables will be sorted by decreasing frequency of SOC 
followed by PT. 
Cancer diagnosis will be listed and summarized by primary cancer diagnosis, histological grade 
and stages.  
Prior cancer related surgery will be listed including type of procedure and date of surgery and 
summarized by prior surgery status. Prior cancer related systemic therapy will be listed including 
systemic therapy type, name of drug and start and end dates and summarized by systemic therapy 
type. Prior cancer related radiotherapy will be listed by site, total dose and start and end dates 
and summarized by prior radiotherapy status. 
5.3. 
Prior/Concomitant Medications  
Prior/concomitant medications will be listed including generic name and ATC levels 2 and 4, 
indication, study day onset (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 date of medication start - date of the first dose+1), the 
study end date (defined similarly as for study onset day), ongoing status, dose, frequency, and 
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route. Number and proportion of subjects taking concomitant medications sorted by decreasing 
frequency of ATC Level 2 and ATC level 4. 
5.4. 
Subject Disposition 
For subject disposition, the following summaries by table will be provided: 
• The total number of screened patients 
• The total number of patients in each analysis set 
• The total number of patients who discontinued the study treatment and the reasons for 
the treatment discontinuation 
• The total number of patients who discontinued the study, and the reasons for the 
study discontinuation 
Listing of patient disposition will include dates of the first and the last cemiplimab 
administration, date of the end of treatment and end of study visits, and reasons for treatment and 
study discontinuation. 
5.5. 
Protocol Deviation 
Protocol deviations will be defined in a separate protocol deviation definition document.  A 
listing of all patients with protocol deviations and the reason of deviation will be provided. The 
major protocol deviation, such as violation of inclusion/exclusion criteria; post-enrollment 
deviations which will impact assessment of efficacy or safety endpoints, will be determined 
before database lock and be summarized by group. 
5.6. 
Measurement of Compliance 
Compliance with cemiplimab treatment will be calculated as follows: 
Treatment Compliance =  
(Number of doses of cemiplimab administered during treatment period) / (Number of 
doses of cemiplimab planned to be administered during period) × 100% 
where temporary dose discontinuation is ignored. 
The percentage of subjects who have <60%, 60-80%, 80-100%, and >100% compliance will be 
summarized for each group. 
5.7. 
Exposure to Investigational Product 
Exposure to cemiplimab will be examined for each subject and the following variables will be 
summarized by group: 
• The total number of study doses administered  
• The total dosage of cemiplimab administered  
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• Duration of treatment exposure (in weeks) calculated as the minimum of  
− [date of last dose - date of first dose + 14 days based on Q2 weekly dosing 
schedule] / 7 for Group 1 and Group 2;  
[date of last dose - date of first dose + 21 days based on Q3 weekly dosing 
schedule] / 7 for Group 3, Group 5, and Group 6; 
[date of last dose - date of first dose + 28 days based on Q4 weekly dosing 
schedule] / 7 for Group 4 
or  
− [date of clinical data cut-off or date of death - date of first dose + 1] / 7 
• The number and percentage of subjects exposed to cemiplimab will be presented by 
specific time points of interest (eg, . 4, 8, 12, 16, 24, 48, 72, 84, 96) for each group. 
• The actual dose intensity (mg/kg/week) = total dose received per kg (mg/kg) / 
duration of treatment exposure (week) for Group 1 and Group 2;  
The actual dose intensity (mg /week) = total dose received (mg) / duration of 
treatment exposure (week) for Group 3, Group 4, Group 5, and Group 6. 
• The relative dose intensity = actual dose intensity / planned dose intensity, 
− Planned dose intensity (mg/kg/week) = planned dose (mg/kg) / 2 for Group 1 and 
Group 2; 
− Planned dose intensity (mg /week) = planned dose (mg) / 3 for Group 3, Group 5, 
and Group 6; 
− Planned dose intensity (mg /week) = planned dose (mg) / 4 for Group 4 
For patients who also receive cemiplimab as re-treatment which starts more than 30 days after 
their last regular cemiplimab treatment, the retreatment dose will not be included in summery of 
on-treatment exposure, instead, they will be listed and summarized if necessary. 
For Group 6 patients who opt to switch to SC cemiplimab, cumulative exposure to cemiplimab 
(IV + SC combined) and exposure to SC or IV alone will be summarized. 
5.8. 
Analyses of Efficacy Variables 
The analysis of efficacy data will be performed based on the FAS. The summary of efficacy 
results will be presented by group. 
5.8.1. 
Analysis of Primary Efficacy Variable 
The ORR according to central review will be summarized by group and the corresponding 2-
sided 95% exact binomial confidence intervals will be derived using the Clopper Pearson method 
(Clopper, 1934). BOR will also be summarized by group. 
The primary analysis of efficacy is based on the exact binomial confidence interval approach of 
ORR.  If the lower limit of 95% confidence interval of observed ORRs excludes 15% for Group 
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1 and Group 3, excludes 25% for Group 2, exclude 20% for Group 4, or exclude 28% for Group 
6, the study treatment is deemed effective for that group, respectively.  
In addition, ORR along with two-sided 95% exact binomial confidence intervals for all patients 
treated with cemiplimab will be presented.   ORR in patients whose CSCC disease has been 
confirmed by central pathology review will also be summarized. 
A sensitivity analysis will be performed for ORR using patients who received at least one dose of 
cemiplimab. 
For Group 6 patients who opt to switch to SC cemiplimab, efficacy data per central review will 
be censored at the first SC dose. Because Group 6 patients are only allowed to switch to SC 
cemiplimab after completing at least 27 weeks on study (3 tumor assessments after baseline), 
which is the pre-specified timepoint for primary efficacy analyses in Group 6, switching to SC 
dosing will have no impact on the primary efficacy analysis for Group 6. 
The primary endpoint of ORR will also be summarized by pooling the objective response 
observed in CSCC patients in this study with object response data of CSCC patients in 
Regeneron study R2810-ONC-1423 to satisfy regulatory requirements from certain regions. 
Details will be provided in separate SAP for integrated efficacy analysis. 
5.8.2. 
Analysis of Secondary Efficacy Variables 
ORR derived from the overall response that is based on investigator-reviewed evaluation will be 
analyzed similarly as primary efficacy variable. 
DOR: The distribution of DOR will be estimated using the Kaplan-Meier method. The median 
DOR along with its 95% CI will be presented by group and Kaplan-Meier estimates with 2-sided 
95% CIs at specific time points (eg, 4, 6, 8, 12, 16, 20 and 24 months) will be summarized. The 
Kaplan-Meier curves will be displayed by group. DOR will also be summarized descriptively by 
range. Number and percentage of patients with DOR at specific time periods of interest (eg, >=4 
months, >=6 months, >=8 months, >=12 months, etc.) will be summarized by group.  
PFS: The distribution of PFS will be estimated using the Kaplan-Meier method. The median PFS 
along with its 95% CI will be presented by group and Kaplan-Meier estimates with 2-sided 95% 
CIs at specific time points (eg, 4, 6, 8, 12, 16, 20 and 24 months) will be summarized. The 
Kaplan-Meier curves will be displayed by group.  
OS: The distribution of OS will be estimated using the Kaplan-Meier method. The median OS 
along with its 95% CI will be presented by group and Kaplan-Meier estimates with 2-sided 95% 
CIs at specific time points (eg, 4, 6, 8, 12, 16, 20 and 24 months) will be summarized. The 
Kaplan-Meier curves will be displayed by group. A variant of OS defined by censoring patients 
at the start date of subsequent therapy will be summarized and displayed by Kaplan-Meier 
approach as a sensitivity analysis. 
TTR will be summarized descriptively by group and at specific time periods of interest (eg, 
<2 months, 2 to 4- months, 4 to 6- months, >=6 months). 
CR rate, DCR and dDCR with 95% confidence interval will be summarized by group using the 
Clopper-Pearson method.  
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Depth of tumor response will be displayed using waterfall plot and spider plot and summarized 
by descriptive statistics. 
For Group 6 patients who opt to switch to SC cemiplimab, ORR, DOR, PFS per investigator 
assessment will be summarized as IV + SC combined period and IV period.  
Absence of residual CSCC in biopsy samples from patients with locally advanced CSCC 
achieving a clinical response to cemiplimab, as measured by independent central pathological 
review, will be summarized descriptively.  
5.8.3. 
Analysis of Quality of Life Variables  
The quality of life of patients will be repeatedly measured by the EORTC QLQ-C30 at the day 1 
of each treatment cycle for Groups 1 to 5. The change scores of each component of QLQ-C30 
will be summarized descriptively at each post-baseline time point. The summary scores of each 
component of QLQ C30 will also be graphically depicted by longitudinal plots. Partial missing 
data in QLQ C30 will be taken care of by the scoring algorithm, no additional imputations will 
be conducted for missing data. 
5.8.4. 
Analysis of Exploratory Efficacy Variable 
ORR according to 18F-FDG-PET using EORTC criteria will be summarized for Group 4 patients 
(excluding patients enrolled in Germany) and the corresponding 2-sided 95% exact binomial 
confidence intervals will be derived using the Clopper-Pearson method. 
5.8.5. 
Subgroup Efficacy Analysis 
Subgroup efficacy analyses will be performed based on the following factors, respectively: 
• gender (Male, Female) 
• age group (<65, ≥65) 
• race (White, Non-white) 
• geographical region (North American, Europe and Rest of World) 
• ECOG (0, 1) 
• Prior systemic anticancer therapy (Yes, No)  
• Prior radiotherapy (Yes, No) 
• For Group 1 and Group 3: Metastatic status (Distant or Nodal only) 
• For Group 4 and Group 6: Advanced CSCC type (mCSCC, laCSCC)  
However, as such analyses may not have enough power for hypothesis tests, the analysis will be 
exploratory in nature. 
5.9. 
Analysis of Safety Data 
The analysis of safety and tolerance will be performed on the SAF, as defined in Section 3.2.  
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The safety analysis will be based on the reported AEs and other safety information (clinical 
laboratory evaluations, vital signs and 12-lead ECG).  The analysis will comprise the basis upon 
which conclusions will be drawn regarding the cemiplimab. The AE of special interest will be 
determined by the list provided by medical monitors. 
Period of observation: The observation period will be divided into three segments: pre-treatment, 
on-treatment and post-treatment. 
• The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The on-treatment period is defined as the day from the first dose of study drug to 
105 days after the last dose of study drug or to follow-up visit, whichever is longer. 
For patients who started cemiplimab as re-treatment more than 30 days after their last 
regular cemiplimab treatment, the on-treatment period ends at the earlier day of 
105 days after the last regular cemiplimab dose or 1 day before their first dose of 
cemiplimab re-treatment. 
• The post-treatment period is defined as the time starting 1 day after the on-treatment 
period. 
Day 1 is the first day of patient receiving cemiplimab treatment, Day –1 is the day before, and 
there is no Day 0. 
The safety analysis will be concentrated on events that occur during on-treatment period. Events 
that occur during post-treatment period, or during cemiplimab re-treatment will be listed and 
summarized if necessary. 
The summary of safety results will be presented by group and combined. 
5.9.1. 
Adverse Events  
The verbatim text, the primary system organ class (SOC), and the preferred term (PT) will be 
displayed in subject listings. Summaries that include frequencies and proportions of patients 
reporting AEs will include the SOCs and the PTs. 
Definitions: 
• Pre-treatment AEs are defined as AEs that developed during the pre-treatment period. 
• Treatment-emergent AEs (TEAEs) are defined as AEs that developed or worsened 
during the on-treatment period and any immune-related AEs that occurs any time 
after the first dose of cemiplimab.  
• Post-treatment AEs are defined as AEs that developed or worsened during the post 
treatment period and are not considered drug related by the investigator. 
The focus of adverse event reporting in the CSR will be on TEAEs. For details on handling 
missing data and partial dates, see Section 6.  
Summaries of AEs will include: TEAEs, Treatment related TEAEs, Serious TEAEs, Treatment-
related Serious TEAEs, AESI, immune-related AEs, and infusion related AEs. For TEAEs, the 
following will be summarized: 
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• The number and proportions of patients reporting at least 1 TEAE, presented by SOC 
and PT 
• TEAEs by severity (CTCAE, version 4.03 grade), presented by SOC and PT 
• TEAEs related to treatment, presented by SOC and PT 
• TEAEs occurring in ≥ 5% patients, presented by PT 
• TEAEs leading to permanent treatment discontinuation, presented by SOC and PT 
• TEAEs leading to death, presented by SOC and PT 
For each TEAE summary presented by SOC and PT, the summary table will be sorted by 
decreasing frequency of SOC and PT. For TEAE summary presented by PT, the summary table 
will be sorted by decreasing frequency of PT. 
The irAEs reported by investigator will be summarized. Additionally, irAEs identified by the 
sponsor will be summarized. All irAEs occurred during the on-treatment and post-treatment 
period will be included. 
For AE listings, the following variables will be displayed:  
• Age/Gender 
• Verbatim Term, SOC, PT 
• AE start date and end date/ongoing (and corresponding study day) 
• AE duration 
• Relationship to study drug: unrelated or related 
• Seriousness (Serious AE or not) 
• National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI 
CTCAE) grade 
• Action taken 
• Treatment for AE 
• Outcome 
Counts will be provided for each patient within each SOC and PT. Percentages will be calculated 
using the number of patients from the SAF in each group. 
For Group 6 patients who opt to switch to SC cemiplimab, AEs that occured during SC 
cemiplimab will be summarized separately. 
Pre-treatment AEs and post-treatment AEs will be listed separately.  
5.9.2. 
Clinical Laboratory Measurements  
Listings of laboratory measurement will include laboratory values, normal ranges, grade 
(if applicable), collection date, and visit/cycle. The numeric lab variables and change from 
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baseline to each visit/cycle will be summarized. Listings of abnormal lab values and clinically 
significant (Yes/No) by patient and visit/cycle will also be constructed.    
Summary tables for worst laboratory values with NCI CTCAE v4.03 all grade and grade ≥ 3 
observed during on-treatment period will be generated. Summary of Shift tables from baseline to 
worst NCI CTCAE v4.03 grade observed during on-treatment period will be generated.  
The shift tables include: 
• Overall and individual Hematologic Test (Hemoglobin, Platelets, WBC) 
• Overall and individual Liver Function Test: (AST, ALT, ALP, Total Bilirubin and 
Albumin) 
• Overall and individual Electrolytes (Sodium, Potassium, Magnesium, Calcium, 
Chloride, Bicarbonate, Phosphorus) 
5.9.3. 
Analysis of Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be listed and 
summarized by Baseline and change from Baseline to each scheduled assessment time with 
descriptive statistics.  
5.9.4. 
Analysis of 12-Lead ECG 
ECG parameters (PR interval, QT interval, QTc interval, QRS interval, Ventricular rate and 
Heart rate) will be listed and summarized by Baseline and change from Baseline to each 
scheduled assessment time with descriptive statistics. 
ECG status (ie, normal, abnormal not clinically significant, and abnormal clinically significant) 
will be reported. Shift tables from baseline to worst post-baseline findings (normal, abnormal not 
clinically significant, and abnormal clinically significant) during on-treatment period will be 
generated.  
5.9.5. 
Physical Exams 
Physical examination findings at baseline as well as post-treatment abnormal findings by body 
system and status (normal, abnormal not clinically significant, and abnormal clinically significant) 
will be listed. Number and proportion of patients with new or worsened physical exam 
abnormalities during on-treatment period will be summarized. 
5.10. 
Analysis of Pharmacokinetic and Immunogenicity Data  
5.10.1. 
Analysis of Pharmacokinetic Data 
Serum concentration of cemiplimab will be assessed at multiple time points throughout the study 
treatment and follow-up periods, and the PK variables will be determined. 
Summaries of study drug concentrations will be presented by nominal time point (ie, the time 
points specified in the protocol) and group. Pharmacokinetic variables, including Ceoi, Ctrough, and 
teoi, will be presented as individual values with descriptive statistics. 
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5.10.2. 
Analysis of Anti-Drug Antibody Data  
The anti-drug antibody variables described in Section 4.7 will be summarized using descriptive 
statistics.  
Immunogenicity will be characterized by ADA responses and titers observed in patients in the 
ADA analysis set. ADA response categories and titer categories are defined as follows: 
ADA response categories:  
• ADA Negative, defined as ADA negative response in the cemiplimab ADA assay at 
all time points, regardless of any missing samples. 
• Pre-existing immunoreactivity, defined as either an ADA positive response in the 
ADA assay at baseline with all post first dose ADA results negative, OR a positive 
response at baseline with all post first dose ADA responses less than 9-fold over 
baseline titer levels.  
• Treatment-emergent response, defined as a positive response in the ADA assay post 
first dose when baseline results are negative or missing. The treatment-emergent 
responses will be further characterized as Persistent, Indeterminate or Transient.   
− Persistent Response – Treatment-emergent ADA positive response with two or 
more consecutive ADA positive sampling time points, separated by at least        
16-week period (based on nominal sampling time), with no ADA negative 
samples in between, regardless of any missing samples. 
− Indeterminate Response –Treatment-emergent ADA positive response with only 
the last collected sample positive in the ADA assay, regardless of any missing 
samples. 
− Transient Response –Treatment-emergent ADA positive response that is not 
considered persistent or indeterminate, regardless of any missing samples. 
• Treatment-boosted response, defined as a positive response in the ADA assay post 
first dose that is greater than or equal to 9-fold over baseline titer levels, when 
baseline results are positive. 
Titer categories (Maximum titer values): 
• Low (titer <1,000) 
• Moderate (1,000 ≤ titer ≤ 10,000) 
• High (titer >10,000) 
The following analysis will be provided: 
• Number (n) and percent (%) of ADA-negative patients (pre-existing 
immunoreactivity or negative in the REGNXXXX ADA assay at all time points) by 
treatment groups 
• Number (n) and percent (%) of treatment-emergent ADA positive patients by 
treatment groups and ADA titer categories 
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− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of transient treatment-emergent ADA positive 
patients 
• Number (n) and percent (%) of treatment-boosted ADA positive patients by treatment 
groups and ADA titer categories 
• Listing of all ADA titer levels will be provided for patients with pre-existing, 
treatment-emergent and treatment-boosted ADA response. 
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Formation of ADA will be assessed in individual patients and per group as follows: 
• Possible relationship between changes in PK profile and treatment-emergent positive 
responses in the ADA assay will be assessed to evaluate a potential impact of anti 
cemiplimab antibodies on drug exposure. 
• Possible relationship between AEs and treatment-emergent positive responses in the 
ADA assay will be assessed to evaluate a potential impact of anti-cemiplimab 
antibodies on the incidence of Grade 3 and 4 AEs, atypical AEs, and SAEs. 
Cases of ADA positivity will be listed and summarized as appropriate. Analysis of ADA data 
will be provided in a separate report. 
5.10.3. 
Analysis of Neutralizing Antibody (NAb) Data 
The absolute occurrence (n) and percent of patients (%) with NAb status in the NAb analysis set 
will be provided by treatment groups.   
5.10.4. 
Analysis of Exploratory Biomarker Data 
Biomarker data will be analyzed using standard scientific methods and summarized by 
descriptive statistics and plots. Comparative analysis of biomarker data with parent study 
(R2810-ONC-1423) may be performed using paired t-test or nonparametric Wilcoxon signed-
rank test or Chi-square test. Correlative analysis with clinical response may be performed using 
correlation coefficient, box plot and scatter plot, and basic regression models. Both comparative 
analysis and correlative analysis will be exploratory in nature and may be provided either as an 
appendix to CSR or in a separate report. 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the Baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of investigational product.  
6.2. 
Data Handling Convention for Efficacy Variables  
Patients who are deemed NE according to RECIST version 1.1. or inevaluable by the composite 
response criteria will be considered as not reaching PR/CR in calculating ORR, i.e. they are not 
considered as responders in the numerator of ORR, but they are counted in the denominator of 
ORR. 
6.3. 
Data Handling Convention for Missing Data 
No missing data imputation is planned in this study unless specified otherwise. 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of patients with missing data 
is presented. 
Medication missing/partial dates 
To determine whether a medication is prior, concomitant or post-treatment medication, the 
missing medication start date is estimated as early as possible up to date of the first study 
treatment, and the missing medication end date is estimated as late as possible. If the medication 
start date is missing, the onset day will not be imputed in medication listings. 
Date of first / last study treatment 
Date of first infusion is the first non-missing start date of dosing filled in the CRF 
“Investigational Product” module. 
If a patient’s date of the last dose is totally missing or unknown, his/her last visit date will be 
substituted. 
6.4. 
Unscheduled Assessments 
Unscheduled visit measurements may be used to provide a measurement for a baseline or 
endpoint value if appropriate according to their definition.  The measurements may also be used 
to determine abnormal laboratory or ECG values. 
The determination of baselines and values at the end of treatment for both efficacy and safety 
variables will be based on scheduled available assessments and unscheduled available 
assessments.  
Extra assessments (laboratory data or vital signs associated with non-protocol clinical visits or 
obtained in the course of investigating or managing adverse events) will be included in listings, 
but not by visit summaries except for the endpoint determination.  If more than one laboratory 
value is available for a given visit, the first observation will be used in summaries and all 
observations will be presented in listings. 
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7. 
MULTIPLICITY CONSIDERATIONS 
Adjustments to the significance level for the purposes of multiple testing are not applicable for 
this study. Statistical analyses of efficacy for each group will be conducted and reported 
separately; ie, efficacy results and clinical conclusions from one Group will not affect those of 
other Groups, and vice versa. Therefore, statistical control of overall type I error for the whole 
study is not planned. There is no multiplicity adjustment for secondary endpoint. 
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8. 
INTERIM ANALYSIS 
Interim analysis for Group 2 
At the time of the planned efficacy analysis for Group 1 (6 months after first dose of last patient), 
an interim analysis of efficacy for Group 2 patients will be performed in order to better assess the 
risks and benefits of cemiplimab in CSCC. This analysis will be restricted to Group 2 patients 
with potential for adequate follow up, defined as patients who have opportunity to receive 
approximately 9 months of study treatment at the time of the interim analysis.  
For regions where alpha spending is not required: For this planned interim analysis, the ORR and 
associated 95% confidence interval will be summarized. As the primary objective of this the 
interim analysis is point estimation on ORR and characterizing the precision of point estimation, 
there is no hypothesis testing associated with this interim analysis. Also, no decisions will be 
made regarding study conduct associated with the interim analysis. Therefore, Type I error 
adjustment is not applicable for this planned interim analysis. 
For regions where alpha spending is required: For this interim analysis on group 2 patients, two-
sided alpha of 0.0001 will be allocated for interim analysis and two-sided alpha of 0.0499 will be 
preserved for the final analysis. Correspondingly, for the interim analysis of primary endpoint of 
ORR in group 2 patients, the precision of ORR will be estimated by adjusted and two-sided 
99.99% exact confidence interval. The un-adjusted and two-sided 95% exact confidence interval 
will also be reported at the time of interim analysis. At the time of the final analysis for group 2 
patients, both adjusted 95.01% and un-adjusted 95% exact confidence interval will be reported. 
For other efficacy endpoints in group 2 patients, only two-sided 95% exact confidence interval 
will be presented both at the interim and at the final analysis. 
Interim analysis for Group 6 
Per sample size calculation, 167 patients are planned for Group 6. An interim analysis of Group 
6 patients will be performed after the first 50% of patients have had the opportunity to be 
followed up for a minimum of 28 weeks (27 weeks for 3 tumor assessments + 1-week 
assessment window) or have reached the end of study. The interim analysis will include a 
minimum of 20 locally advanced CSCC patients. If 20 locally advanced patients are not yet 
enrolled in the set of the first 84 patients enrolled in Group 6, the interim analysis will be 
performed after 20 locally advanced CSCC patients have been enrolled and have had the 
opportunity to be followed for at least 28 weeks. All patients enrolled in Group 6 who have had 
the opportunity to be followed for at least 28 weeks will be included in the interim analysis. 
For regions where alpha spending is not required: For this planned interim analysis, the ORR and 
associated 95% confidence interval will be summarized. As the primary objective of this interim 
analysis is point estimation on ORR and characterizing the precision of point estimation, there is 
no hypothesis testing associated with this interim analysis. Therefore, Type I error adjustment is 
not applicable for this planned interim analysis. 
For regions where alpha spending is required: The overall type I error rate for analyses of the 
primary endpoint of ORR is controlled at a 2-sided alpha of 0.05 using the O’Brien-Fleming 
spending function. Table 1 demonstrates the bound and boundary properties for ORR hypothesis 
testing at interim and final analyses, assuming interim analysis was performed at 50% of 
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enrollment. The table will be updated using the actual number of patients included in the interim 
and final ORR analysis. 
Table 1: 
Alpha Spending for Analysis of ORR on Group 6 Patients 
Analysis 
 
Value 
Interim Analysisa 
Z 
2.9626 
α (2-sideda) 
0.0031 
Final Analysis 
Z 
1.9686 
α (2-sided) 
0.0490 
a As a 2-sided test is used at interim, the superiority or futility of cemiplimab treatment will be claimed if the 
statistical boundary is crossed. 
For the interim analysis of ORR, the precision of ORR will be estimated by adjusted 2-sided 
99.69% exact confidence interval. The un-adjusted 2-sided 95% exact confidence interval will 
also be reported at the time of interim analysis. The ORR of 28% for Group 6 will be excluded 
using the lower limit of 99.69% exact CI if the observed ORR is 44.1% or more (Table 2). 
At the time of the final analysis, both adjusted 95.10% and un-adjusted 95% exact confidence 
interval will be reported. The confidence level will be updated using the actual number of 
patients included in the interim and final ORR analysis. 
For other efficacy endpoints in Group 6 patients, only a 2-sided 95% confidence interval will be 
presented both at the interim and at the final analysis. 
Table 2: 
Binomial Exact Confidence Intervals for Observed ORR in Group 6 
Analysis 
Two-sided 
Exact CI 
N 
Number of 
Responders 
Observed ORR 
Lower 
Bound 
Upper 
Bound 
Interim 
99.69% 
84 
37 
44.1% 
28.4% 
60.6% 
Final 
95.10% 
167 
59 
35.3% 
28.1% 
43.1% 
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9. 
SOFTWARE 
All statistical analyses will be done using SAS Version 9.4 or above. 
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10. 
REFERENCES 
1. Aaronson N.K., Ahmedzai S., Bergman B., et al. (1993) 'The European Organization for 
Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in 
international clinical trials in oncology', J Natl Cancer Inst, 85, 365–376. 
2. Clopper, C. & Pearson, E. S. (1934), 'The use of confidence or fiducial limits illustrated 
in the case of the binomial', Biometrika, 404-413. 
3. Elashoff, J. D. (2007), 'nQuery Advisor Version 7.0 User’s Guide', Statistical Solutions 
Ltd., Los Angeles, CA. 
4. Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf 
of the EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual 
(3rd Edition). Published by: European Organisation for Research and Treatment of 
Cancer, Brussels 2001. 
5. ICH. (1998). ICH Harmonized tripartite guideline: Statistical principles for clinical trials 
(E9). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
                                        VV-RIM-00330503-1.0 Approved - 12 Dec 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R2810-ONC-1540 
Statistical Analysis Plan 
Date: October 27, 2023 
 
REGENERON CONFIDENTIAL 
Page 41 of 41 
11. 
APPENDIX 
11.1. 
Summary of Statistical Analyses 
Efficacy Analysis: 
Endpoint 
Analysis 
Populations 
Primary Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoint 
ORR 
FAS 
Proportion of patients with best overall 
response of CR or PR (central review) 
95% exact binomial 
confidence interval using 
Clopper-Pearson method 
Exact binomial 
test p-value 
Yes 
Yes 
Secondary Endpoints 
ORR 
FAS 
Proportion of patients with best overall 
response of CR or PR (investigator 
review) 
95% exact binomial 
confidence interval using 
Clopper-Pearson method 
Exact binomial 
test p-value 
No 
No 
Duration of 
response 
Patients with 
best overall 
response of 
CR/PR in FAS 
From the time measurement criteria are 
first met for CR/PR (whichever is first 
recorded) until the first date of recurrent 
or progressive disease (radiographic), or 
death due to any cause. 
Kaplan-Meier method and 
descriptive statistics 
No 
Yes 
No 
Progression-free 
survival 
FAS 
From the start of treatment until the first 
date of recurrent or progressive disease 
(radiographic), or death due to any 
cause. 
Kaplan-Meier method 
No 
No 
No 
Overall survival 
FAS 
From the start of treatment until death 
due to any cause. 
Kaplan-Meier method 
No 
No 
No 
Quality of life 
FAS 
Changes scores from day 1 of EORTC-
QLQ-C30 
Descriptive statistics and 
longitudinal plots 
No 
No 
No 
Safety Analyses: 
Endpoint 
Analysis 
Populations 
Primary Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Adverse Events 
SAF 
Percent of patients by system organ class and PT 
Descriptive Statistics 
No 
No 
No 
 
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