Conditions: Carcinoma, Basal Cell
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 138
Healthy volunteers: no

Brief summary:
The primary objective is to estimate the objective response rate (ORR) for metastatic Basal Cell Carcinoma (BCC) (group 1) and for unresectable locally advanced BCC (group 2) when treated with cemiplimab as a monotherapy

Detailed description:

Arms:
arm 1: Administration of cemiplimab in accordance with protocol dosing regimen arm 2: Administration of cemiplimab in accordance with protocol dosing regimen

Interventions: intervention 1: cemiplimab
Intervention descriptions: intervention 1: Regimen as per protocol

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol 
R2810-ONC-1620 Amendment 4 
Regeneron Pharmaceuticals, Inc. 
Page 1 of 133 
CONFIDENTIAL 
IND Number:  127100 
EudraCT Number:  2016-003122-16 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A PHASE 2 STUDY OF REGN2810, A FULLY HUMAN MONOCLONAL 
ANTIBODY TO PROGRAMMED DEATH-1, IN PATIENTS WITH 
ADVANCED BASAL CELL CARCINOMA WHO EXPERIENCED 
PROGRESSION OF DISEASE ON HEDGEHOG PATHWAY INHIBITOR 
THERAPY, OR WERE INTOLERANT OF PRIOR HEDGEHOG 
PATHWAY INHIBITOR THERAPY 
Compound: 
Cemiplimab (REGN2810 [anti-PD-1 mAb]) 
Clinical Phase: 
2 
Protocol Number: 
R2810-ONC-1620 
Protocol Version: 
R2810-ONC-1620 Amendment 4  
Amendment 4 Date of Issue 
See appended electronic signature page 
Amendment 3 Date of Issue 
03 Jul 2017 
Amendment 2 Date of Issue 
23 Mar 2017 
Amendment 1 Date of Issue: 
28 Nov 2016 
Original Date of Issue: 
10 Nov 2016 
Scientific/Medical Monitor: 
Executive Director, Clinical Sciences, 
Oncology 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
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NCT03132636


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Regeneron Pharmaceuticals, Inc. 
Page 2 of 133 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 4 
The following table outlines the changes made to the protocol and the affected sections: 
Changes 
Sections Changed 
Clarified the details of the timing of the data 
cut for the primary analysis for Group 2.  
Added an interim analysis for Group 1. 
Clinical Study Protocol Synopsis: Statistical 
Plan  
Section 5.2 Planned Interim Analysis 
Section 10 Statistical Plan  
Section 10.5 Interim Analysis (section added) 
Clarified that patients are only eligible for 
retreatment if they experience disease 
progression during the follow-up period 
without any intervening systemic anticancer 
therapy. 
Section 8.1.5 Retreatment 
Posttreatment follow-up was extended for an 
additional 1 year, for a total of approximately 
1.5 years after completion of the treatment at 
the end of extended follow-up (unless the 
patient enters retreatment).  
Table 6 Schedule of Events for Follow-Up 
(After 9 Cycles of Treatment) 
Section 8.1.4 Follow-Up 
Neutralizing antibody analysis was included. 
Section 4.4 Anti-Drug Antibody Variables 
Section 10.3.4 Anti-Drug Antibody Analysis 
Set 
Removed exclusion of patients with allergy or 
hypersensitivity to doxycycline or tetracycline 
as these are not utilized in the current 
manufacturing process. 
Section 6.2.2 Exclusion Criteria, #10 
Exclusion criterion relating to pregnancy and 
birth control in women of childbearing 
potential (WOCBP) and their partners was 
revised in accordance with Clinical Trial 
Facilitation Group (CTFG) guidance. 
Section 6.2.2 Exclusion Criteria, #19 
Modifications for consistency and clarity, and 
administrative updates. 
Section 1.2 Cemiplimab, an Anti-PD-1 
Monoclonal Antibody 
Section 7.3.2.1 Immune-Related Adverse 
Events 
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CONFIDENTIAL 
Section 8.1.1 Footnotes for the Schedule of 
Events for Treatment Cycles 1 – 5 (9-Week 
Cycles) – Table 4, Footnotes #2, #3, #7, #8, 
#16   
Table 5 Schedule of Events for Cycle 6 – 9 
(12-Week Cycles) 
Section 8.1.2 Footnotes for the Schedule of 
Events for Treatment Cycles 6 – 9 (12-Week 
Cycles) – Table 5, Footnotes #2, #5, #11 
Table 6 Schedule of Events for Follow-up 
(After 9 Cycles of Treatment) 
Section 8.1.3 Footnotes for the Schedule of 
Events for Follow-up (After 9 Cycles of 
Treatment) – Table 6, Footnotes #1, #13 
(footnote added)  
Section 8.2.2 Efficacy Procedures 
Section 8.2.3.3 Electrocardiogram 
Section 8.2.4.2 Anti-Drug Antibodies 
Measurements and Samples 
Section 10.3.1 Full Analysis Set 
Section 10.3.2 Efficacy Analysis Set (section 
deleted) 
Section 10.4.5.1 Adverse Events 
Appendix 7  
Removed withdrawal volumes for consistency 
across the program, and updated storage 
conditions. 
Section 7.1  Investigational and Reference 
Treatments 
Administrative change 
Title page: Scientific/Medical Monitor 
REGN2810 will be referred by its generic 
name, cemiplimab, for consistency 
throughout the program.  
Throughout 
Correction of typographical, grammatical, and 
formatting errors. 
Throughout 
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CONFIDENTIAL 
Amendment 3 
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 REGN2810 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 REGN2810 
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 REGN2810. 
Section 6.2.2 Exclusion Criteria #20 
Additional safety guidance language added 
for the management of patients developing 
stomatitis or mucositis 
Section 7.3.2 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 9.4.3 Other Events that Require 
Accelerated Reporting to Sponsor 
 
 
 
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CONFIDENTIAL 
Amendment 2  
The purpose of the amendment is to revise the protocol based on regulatory agency advice and the 
internal program review by the sponsor. 
The changes to the protocol and the affected sections are highlighted below. 
Changes 
Sections Changed  
The dose of REGN2810 has been changed 
from 250 mg Q3W to 350 mg Q3W to 
achieve greater consistency in exposure 
with the 3 mg/kg Q2W dose used in the 
FIH study.  The dose selection is 
supported by modeling of exposure. 
Clinical Study Protocol Synopsis: Study Design, 
Treatments 
Section 3.2.3 Rationale for Dose Selection 
Section 5.1 Study Description and Duration 
Section 5.1.2 End of Study Definition 
Section 7.1 Investigational and Reference 
Treatments 
Section 7.3.1 Dose Modification 
Table 4 Schedule of Events for Treatment  
Cycles 1 - 5 (9-Week Cycles) 
Table 5 Schedule of Events for Cycles 6 – 9 
(12-Week Cycles) 
Section 8.1.5 Retreatment 
Updated length of treatment period to 
9 cycles 
Added additional information regarding 
timing of tumor assessments 
Clinical Study Protocol Synopsis: Study Design 
Clinical Study Protocol Synopsis: Study Duration 
Clinical Study Protocol Synopsis: Treatments  
Section 5.1 Study Description and Duration 
Table 4 Schedule of Events for Treatment  
Cycles 1 - 5 (9-Week Cycles) 
Table 5 Schedule of Events for Cycles 6 – 9 
(12-Week Cycles) 
Table 6 Schedule of Events for Follow-up (After 
9 Cycles of Treatment) 
Section 8.1.1 Footnotes for the Schedule of 
Events for Treatment Cycles 1 – 5 (9-Week 
Cycles) 
Section 8.1.2 Footnotes for the Schedule of 
Events for Treatment Cycles 6 – 9 (12-Week 
Cycles) 
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CONFIDENTIAL 
Changes 
Sections Changed  
Section 8.1.3 Footnotes for the Schedule of 
Events for Follow-up (After 9 Cycles of 
Treatment) 
Section 8.1.5 Retreatment  
Section 8.2.2 Efficacy Procedures 
Appendix 1 Response Evaluation Criteria in 
Solid Tumors:  RECIST Guideline (Version 1.1) 
Appendix 7 REGN2810 Pharmacokinetic 
Sampling and Assessment Schedule 
Clarification of primary endpoints 
Clinical Study Protocol Synopsis: Endpoints 
Section 4.2.1 Primary Endpoints 
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CONFIDENTIAL 
Changes 
Sections Changed  
Removed “Total number of patients 
whose response in the ADA assay is 
positive at any time”  
Section 4.4 Anti-Drug Antibody Variables 
Removed additional information regarding 
Group 1 and 2 from interim analysis 
Section 5.2 Planned Interim Analysis 
Updates responsibilities of the Central 
Review Committee 
Section 5.3.3 Central Review Committee 
Changed ≥ to ≤ regarding CPK elevation 
Section 6.2.1 Inclusion Criteria # 8 
Clarification of procedure that can be 
completed before informed consent 
Section 6.2.1 Inclusion Criteria #14 
Updated exclusion for receipt of live 
vaccines 
Section 6.2.2 Exclusion Criteria Added exclusion 
criteria #18: Receipt of live vaccines (including 
attenuated) within 30 days of first study treatment 
Updated information on the effective 
methods of birth control 
Section 6.2.2 Exclusion Criteria #19 
Updated the concentration of study drug 
withdrawable from each vial containing 
study drug 
Section 7.1 Investigational and Reference 
Treatments 
Updated dose levels for dose reduction 
Table 1 Dose Reduction 
Revised definition of resolution of 
immune-related adverse events as 
improvement to ≤ grade 1 and steroid dose 
≤12 mg/day oral prednisone (≤10 mg/day 
methylprednisolone) or equivalent. 
Section 7.3.2.1 Immune-Related Adverse Events 
Updated reasons for permanent 
discontinuation of study drug 
Section 7.3.2.2 Reasons for Permanent 
Discontinuation of Study Drug 
Added that patients cannot receive live 
vaccines during the study 
Section 7.7.1 Prohibited Medications and 
Procedures 
The protocol was revised to include 
coagulation samples (aPTT, INR) at end 
of study which were inadvertently left out 
of the previous version.   
Table 4 Schedule of Events for Treatment Cycles 
1-5 (9–Week Cycles) 
Table 5 Schedule of Events for Cycle 6 – 9  
(12–Week Cycles) 
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CONFIDENTIAL 
Changes 
Sections Changed  
The timing of tumor response assessments 
has been revised.  In weeks 1 - 45, 
response assessments are performed every 
9 weeks to align with 9-week cycles 
(cycles 1-5).  In weeks 46 - 93, response 
assessments are performed every 12 
weeks to align with 12-week cycles 
(cycles 6-9).  This revised schedule of 
response assessments will allow for more 
precise estimates of durability of response.  
Immunogenicity sample collection has 
been added on cycle 1/day 43 prior to 
dosing to detect early onset of anti-drug 
antibodies to REGN2810. 
Table 5 Schedule of Events for Cycle 6 – 9  
(12–Week Cycles)  
Section 8.2 Study Procedures  
Section 8.2.2 Efficacy Procedures 
Appendix 1 Response Evaluation Criteria in 
Solid Tumors: RECIST Guideline (Version 1.1)  
Appendix 2 Clinical and Composite Response 
Criteria for Patients with Locally Advanced BCC 
Clarification regarding treatment cycles 
Update on when urine pregnancy test will 
be conducted 
Update on when ADA samples will be 
collected  
Update on when PK samples will be 
collected 
Clarification regarding visual reminder on 
Table 4 for end-of-cycle tumor 
assessments 
Added “X” for day 22 regarding digital 
medical photography 
Clarification for Skindex-16 translation 
Section 8.1.1 Footnotes for the Schedule of 
Events for Treatment Cycles 1 - 5 (9-Week 
Cycles), #1, #2, #3, #13, #15, #16, #19, #20, and 
#21 
Added footnotes for Table 5 
Section 8.1.2 Footnotes for the Schedule of 
Events Table 5 for Treatment Cycles 6 – 9 (12-
Week Cycles) 
Added information regarding AESI 
Section 8.1.5 Retreatment  
Section 8.2.4.2 Anti-Drug Antibody 
Measurements and Samples 
Added section to define end of study 
Section 8.1.7 End of Study Definition 
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CONFIDENTIAL 
Changes 
Sections Changed  
Clarification regarding method of 
measurement for target lesion 
Section 8.2.2 Efficacy Procedures 
Clarification on when patients will be 
monitored and vital signs will be recorded 
during cycle 1 
Section 8.2.3.1 Vital Signs 
Removed note that ECG is to be recorded 
in triplicate 
Section 8.2.3.3 Electrocardiogram 
Removal of “site” from local laboratory 
Section 8.2.3.5 Coagulation Tests 
Clarification on test names that can be 
found in laboratory manual 
Section 8.2.3.6 Laboratory Testing 
Updated section for determining whether 
an abnormal objective test finding should 
be reported as an AE 
Section 9.4.5 Abnormal Laboratory, Vital Signs, 
or Electrocardiogram Results 
The protocol was revised to state that all 
patients should be followed for a 
minimum of 6 months from onset of 
response for the analysis of duration of 
response.  Additionally, an updated 
analysis of response duration will be 
performed after all responding patients 
have been followed for a minimum of 12 
months from onset of response. 
Section 0 Statistical Plan 
For the analysis of overall response rate in 
Group 1, the statistical plan was revised so 
that the lower bound of the 95% 
confidence interval would exclude a 
clinically insignificant ORR of 15% if the 
null hypothesis is rejected. 
Clinical Study Protocol Synopsis: Statistical Plan  
Section 10.2 Justification of Sample Size 
Table 7 The 95% Binomial Exact Confidence 
Intervals for Observed ORR in Group 1 Given a 
Sample Size of 50 Patients (Based on 85% 
Power) 
Section 10.4.3.1 Primary Efficacy Analysis 
Removed language regarding multiple 
testing with Group 1 
Section 10.4.3.3 Multiplicity Considerations  
Adding “lack of response” category for 
analysis of patients with stable disease 
Section 10.4.4.1 Subgroup Analysis  
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CONFIDENTIAL 
Changes 
Sections Changed  
Updated the analysis of ADA data 
Section 10.4.7 Analysis of Anti-Drug Antibody 
Data 
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CONFIDENTIAL 
Changes 
Sections Changed  
Removed patient initials from patient 
identification number in regards to how 
the patients can be identified 
Section 14.3 Patient Confidentiality and Data 
Protection 
Added “and designee” regarding who will 
schedule central review 
Added clarification that a “Central Review 
Committee” will review the results of 
radiology scans, photographs, and clinical 
tumor biopsies that were already 
independently reviewed 
In Appendix 2, the Table on “Composite 
Response Criteria” has been revised to 
anticipate the possibility of “NA” (not 
applicable) for imaging assessments in 
some patients. 
Appendix 2 Clinical and Composite Response 
Criteria for Patients with Locally Advanced BCC 
Updated criteria for lesion size for number 
of biopsies 
Appendix 4 Guidelines for Biopsies for Locally 
Advanced BCC 
Minor editorial changes for clarification, 
consistency, and correction of self-evident 
inadvertent omissions 
Section 3.1 Hypothesis 
Section 6.1 Number of Patients Planned  
Section 6.2.1 Inclusion Criteria #15 
Section 7.1 Investigational and Reference 
Treatments 
Section 7.7 Concomitant Medications and 
Procedures 
Section 8.1 Schedule of Events 
Table 6 Schedule of Events for Follow-up (After 
9 Cycles of Treatment) 
Section 8.1.1 Footnotes for the Schedule of 
Events Table 4 for Treatment Cycles 1 - 5 (9-
Week Cycles)  
Section 8.1.4 Follow-up 
Section 8.2.1 Procedures Performed Only at the 
Screening/Baseline Visit 
Section 8.2.5 Biomarker Procedures 
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CONFIDENTIAL 
Changes 
Sections Changed  
Section 10.4.4.2 Quality of Life and Skindex-16 
Analysis  
Section 10.7 Statistical Considerations 
Surrounding the Premature Termination of a 
Study 
Section 21 References 
Deleted Appendix 3 EORTC-QLQ-C30 
Deleted Appendix 10 SKINDEX-16 
Amendment 1 (28 Nov 2016) 
The purposes of this amendment are to: 
 Note regional laboratory testing for bicarbonate 
 Add a window for the duration of the REGN2810 infusion 
 Update the contraception language in the exclusion criteria 
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CONFIDENTIAL 
TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................20
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................25
1.
INTRODUCTION ......................................................................................................28
1.1.
Clinical Characteristics and Current Management of Advanced Basal Cell 
Carcinoma ...................................................................................................................28
1.2.
Cemiplimab, an Anti-PD-1 Monoclonal Antibody ....................................................29
2.
STUDY OBJECTIVES ..............................................................................................31
2.1.
Primary Objective .......................................................................................................31
2.2.
Secondary Objectives .................................................................................................31
2.3.
Exploratory Objectives (Group 2 only) ......................................................................31
3.
HYPOTHESIS AND RATIONALE ..........................................................................32
3.1.
Hypothesis ..................................................................................................................32
3.2.
Rationale .....................................................................................................................32
3.2.1.
Rationale for Clinical Study of Cemiplimab in Advanced BCC ................................32
3.2.2.
Rationale for Study Design .........................................................................................32
3.2.3.
Rationale for Dose Selection ......................................................................................33
4.
STUDY VARIABLES................................................................................................34
4.1.
Demographic and Baseline Characteristics ................................................................34
4.2.
Primary and Secondary Endpoints..............................................................................34
4.2.1.
Primary Endpoint ........................................................................................................34
4.2.2.
Secondary Endpoints ..................................................................................................34
4.2.3.
Exploratory Endpoints ................................................................................................35
4.3.
Pharmacokinetic Variables .........................................................................................35
4.4.
Anti-Drug Antibody Variables ...................................................................................35
5.
STUDY DESIGN .......................................................................................................37
5.1.
Study Description and Duration .................................................................................37
5.1.1.
Study Groups ..............................................................................................................37
5.1.2.
End of Study Definition ..............................................................................................38
5.2.
Planned Interim Analysis ............................................................................................38
5.3.
Study Committees .......................................................................................................38
5.3.1.
Independent Data Monitoring Committee ..................................................................38
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5.3.2. 
Study Steering Committee ..........................................................................................38 
5.3.3. 
Central Review Committee .........................................................................................38 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............39 
6.1. 
Number of Patients Planned .......................................................................................39 
6.2. 
Study Population .........................................................................................................39 
6.2.1. 
Inclusion Criteria ........................................................................................................39 
6.2.2. 
Exclusion Criteria .......................................................................................................42 
6.3. 
Premature Withdrawal from the Study .......................................................................45 
6.4. 
Replacement of Patients .............................................................................................45 
7. 
STUDY TREATMENTS............................................................................................45 
7.1. 
Investigational and Reference Treatments ..................................................................45 
7.2. 
Pretreatment(s) ............................................................................................................45 
7.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................46 
7.3.1. 
Dose Modification ......................................................................................................46 
7.3.2. 
Study Treatment Hold or Discontinuation ..................................................................46 
7.3.2.1. 
Immune-Related Adverse Events ...............................................................................48 
7.3.2.2. 
Reasons for Permanent Discontinuation of Study Drug .............................................51 
7.4. 
Management of Acute Reactions ................................................................................51 
7.4.1. 
Acute Infusion Reactions ............................................................................................51 
7.4.1.1. 
Interruption of the Infusion .........................................................................................52 
7.4.1.2. 
Termination of the Infusion ........................................................................................53 
7.5. 
Method of Treatment Assignment ..............................................................................53 
7.5.1. 
Blinding ......................................................................................................................53 
7.6. 
Treatment Logistics and Accountability .....................................................................53 
7.6.1. 
Packaging, Labeling, and Storage ..............................................................................53 
7.6.2. 
Supply and Disposition of Treatments .......................................................................53 
7.6.3. 
Treatment Accountability ...........................................................................................54 
7.6.4. 
Treatment Compliance ................................................................................................54 
7.7. 
Concomitant Medications and Procedures .................................................................54 
7.7.1. 
Prohibited Medications and Procedures .....................................................................54 
7.7.2. 
Surgery ........................................................................................................................55 
7.7.3. 
Radiation Therapy ......................................................................................................55 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................55 
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8.1. 
Schedule of Events .....................................................................................................55 
8.1.1. 
Footnotes for the Schedule of Events for Treatment Cycles 1 – 5 (9-Week 
Cycles) – Table 4 ........................................................................................................57 
8.1.2. 
Footnotes for the Schedule of Events for Treatment Cycles 6 – 9 (12-Week 
Cycles) – Table 5 ........................................................................................................61 
8.1.3. 
Footnotes for the Schedule of Events for Follow-up (After 9 Cycles of 
Treatment) – Table 6 ..................................................................................................65 
8.1.4. 
Follow-up ....................................................................................................................67 
8.1.5. 
Retreatment .................................................................................................................67 
8.1.6. 
Unscheduled Visits .....................................................................................................67 
8.1.7. 
End of Study Definition ..............................................................................................68 
8.2. 
Study Procedures ........................................................................................................68 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................68 
8.2.2. 
Efficacy Procedures ....................................................................................................69 
8.2.3. 
Safety Procedures .......................................................................................................70 
8.2.3.1. 
Vital Signs ..................................................................................................................70 
8.2.3.2. 
Physical Examination .................................................................................................71 
8.2.3.3. 
Electrocardiogram .......................................................................................................71 
8.2.3.4. 
Immune Safety Assays ...............................................................................................71 
8.2.3.5. 
Coagulation Tests .......................................................................................................71 
8.2.3.6. 
Laboratory Testing ......................................................................................................72 
8.2.4. 
Pharmacokinetic and Anti-Drug Antibody Procedures ..............................................73 
8.2.4.1. 
Drug Concentration Measurements and Samples .......................................................73 
8.2.4.2. 
Anti-Drug Antibody Measurements and Samples ......................................................73 
8.2.5. 
Biomarker Procedures ................................................................................................73 
8.2.5.1. 
Biomarker Measurements and Samples ......................................................................73 
8.2.5.2. 
Tumor Biomarker Procedures.....................................................................................73 
 
 
 
 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................75 
9.1. 
Obligations of Investigator .........................................................................................75 
9.2. 
Obligations of Sponsor ...............................................................................................75 
9.3. 
Definitions ..................................................................................................................75 
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9.3.1. 
Adverse Event .............................................................................................................75 
9.3.2. 
Serious Adverse Event ................................................................................................76 
9.3.3. 
Adverse Events of Special Interest .............................................................................76 
9.3.4. 
Infusion Reactions ......................................................................................................77 
9.4. 
Recording and Reporting Adverse Events ..................................................................77 
9.4.1. 
Adverse Events ...........................................................................................................77 
9.4.2. 
Serious Adverse Events ..............................................................................................77 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................78 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................78 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................78 
9.4.6. 
Follow-up ....................................................................................................................79 
9.5. 
Evaluation of Severity and Causality .........................................................................79 
9.5.1. 
Evaluation of Severity ................................................................................................79 
9.5.2. 
Evaluation of Causality ...............................................................................................80 
9.6. 
Safety Monitoring .......................................................................................................80 
9.7. 
Investigator Alert Notification ....................................................................................81 
10. 
STATISTICAL PLAN................................................................................................82 
10.1. 
Statistical Hypothesis ..................................................................................................82 
10.2. 
Justification of Sample Size........................................................................................82 
10.3. 
Analysis Sets ...............................................................................................................84 
10.3.1. 
Full Analysis Set .........................................................................................................84 
10.3.2. 
Safety Analysis Set .....................................................................................................84 
10.3.3. 
Pharmacokinetic Analysis Set ....................................................................................84 
10.3.4. 
Anti-Drug Antibody Analysis Set ..............................................................................85 
10.3.5. 
Biomarker Analysis Set ..............................................................................................85 
10.4. 
Statistical Methods ......................................................................................................85 
10.4.1. 
Patient Disposition ......................................................................................................85 
10.4.2. 
Demography and Baseline Characteristics .................................................................85 
10.4.3. 
Efficacy Analyses .......................................................................................................85 
10.4.3.1. 
Primary Efficacy Analysis ..........................................................................................85 
10.4.3.2. 
Secondary Efficacy Analysis ......................................................................................86 
10.4.3.3. 
Multiplicity Considerations ........................................................................................86 
10.4.4. 
Exploratory Analyses ..................................................................................................86 
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10.4.4.1. 
Subgroup Analyses .....................................................................................................86 
10.4.4.2. 
Quality of Life and Skindex-16 Analysis ...................................................................86 
10.4.5. 
Safety Analysis ...........................................................................................................87 
10.4.5.1. 
Adverse Events ...........................................................................................................87 
10.4.5.2. 
Other Safety ................................................................................................................88 
10.4.5.3. 
Treatment Exposure ....................................................................................................88 
10.4.5.4. 
Treatment Compliance ................................................................................................88 
10.4.6. 
Analysis of Drug Concentration Data .........................................................................88 
10.4.7. 
Analysis of Anti-Drug Antibody Data ........................................................................88 
10.4.8. 
Analysis of Biomarker Data .......................................................................................88 
10.4.8.1. 
Sample Size Justification for Biomarker Measurements in Tumor Tissue 
Biopsies.......................................................................................................................89 
10.5. 
Interim Analysis ..........................................................................................................90 
10.6. 
Additional Statistical Data Handling Conventions .....................................................91 
10.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .........91 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................92 
11.1. 
Data Management .......................................................................................................92 
11.2. 
Electronic Systems ......................................................................................................92 
12. 
STUDY MONITORING ............................................................................................93 
12.1. 
Monitoring of Study Sites ...........................................................................................93 
12.2. 
Source Document Requirements ................................................................................93 
12.3. 
Case Report Form Requirements ................................................................................93 
13. 
AUDITS AND INSPECTIONS .................................................................................94 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................95 
14.1. 
Good Clinical Practice Statement ...............................................................................95 
14.2. 
Informed Consent .......................................................................................................95 
14.3. 
Patient Confidentiality and Data Protection ...............................................................95 
14.4. 
Institutional Review Board/Ethics Committee ...........................................................96 
15. 
PROTOCOL AMENDMENTS ..................................................................................96 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................97 
16.1. 
Premature Termination of the Study ...........................................................................97 
16.2. 
Close-out of a Site ......................................................................................................97 
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17. 
STUDY DOCUMENTATION ...................................................................................98 
17.1. 
Certification of Accuracy of Data ...............................................................................98 
17.2. 
Retention of Records ..................................................................................................98 
18. 
CONFIDENTIALITY ................................................................................................98 
19. 
FINANCING AND INSURANCE .............................................................................98 
20. 
PUBLICATION POLICY ..........................................................................................98 
21. 
REFERENCES ...........................................................................................................99 
22. 
INVESTIGATOR’S AGREEMENT ........................................................................102 
 
LIST OF TABLES 
Table 1: 
Dose Reductions .........................................................................................................46 
Table 2: 
Study Treatment Dose Modifications or Discontinuations ........................................48 
Table 3: 
General Treatment Hold Guidelines for Immune-Related Adverse Events ...............49 
Table 4: 
Schedule of Events for Treatment Cycles 1 - 5 (9–Week Cycles) .............................56 
Table 5: 
Schedule of Events for Cycle 6 – 9 (12–Week Cycles) ..............................................60 
Table 6: 
Schedule of Events for Follow-up (After 9 Cycles of Treatment) .............................63 
Table 7: 
The 95% Binomial Exact Confidence Intervals for Observed ORR in 
Group 1 Given a Sample Size of 50 Patients (Based on 85% Power) ........................83 
Table 8: 
The 95% Binomial Exact Confidence Intervals for Observed ORR in 
Group 2 Given a Sample Size of 80 Patients (Based on 85% Power) ........................84 
Table 9: 
Power Analysis for PD-L1 Biomarkers from Tumor Biopsies ..................................90 
 
LIST OF APPENDICES 
APPENDIX 1: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS: RECIST 
GUIDELINE (VERSION 1.1) .............................................................................103 
APPENDIX 2: CLINICAL AND COMPOSITE RESPONSE CRITERIA FOR 
PATIENTS WITH LOCALLY ADVANCED BCC ...........................................108 
APPENDIX 3: RECOMMENDED DOSE MODIFICATION OR DISCONTINUATION 
AND SUPPORTIVE CARE GUIDELINES FOR SPECIFIC STUDY 
DRUG RELATED ADVERSE EVENTS ...........................................................113 
APPENDIX 4:GUIDELINES FOR BIOPSIES FOR LOCALLY ADVANCED BCC ..............123 
APPENDIX 5:DIGITAL PHOTOGRAPHIC PROCEDURES ..................................................127 
APPENDIX 6:EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS ..............................................................................................................130 
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APPENDIX 7: CEMIPLIMAB PHARMACOKINETIC SAMPLING AND 
ASSESSMENT SCHEDULE ..............................................................................131 
APPENDIX 8: FACTORS TO CONSIDER IN ASSESSING THE RELATIONSHIP OF 
AES TO CEMIPLIMAB OR INFUSION PROCEDURE, STUDY 
PROCEDURE, OR COMBINATION TREATMENT ........................................132 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 2 Study of REGN2810, a Fully Human Monoclonal Antibody to 
Programmed Death-1, in Patients with Advanced Basal Cell Carcinoma Who 
Experienced Progression of Disease on Hedgehog Pathway Inhibitor Therapy, 
or were Intolerant of Prior Hedgehog Pathway Inhibitor Therapy 
Site Locations 
 
Principal Investigator 
Patients will be enrolled at up to approximately 70 sites globally. 
To be determined. 
Objectives 
The primary objective of the study is to estimate the objective response rate 
(ORR) for metastatic basal cell carcinoma (BCC) (Group 1) or unresectable 
locally advanced BCC (Group 2), according to central review, when treated 
with cemiplimab monotherapy in patients who have progressed on Hedgehog 
Pathway Inhibitor (HHI) therapy, or were intolerant of prior HHI therapy. 
The secondary objectives for both Group 1 and Group 2 are to: 
 
Estimate ORR according to investigator review 
 
Estimate the duration of response, progression-free survival (PFS) by 
central and investigator review, and overall survival (OS) 
 
Estimate the complete response (CR) rate by central review 
 
Assess the safety and tolerability of cemiplimab 
 
Assess the pharmacokinetics (PK) of cemiplimab (at select sites only) 
 
Assess the immunogenicity of cemiplimab 
 
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) and Skindex-16 
The exploratory objectives (for Group 2 only) are to explore the 
pharmacodynamic effects of cemiplimab in tumor biopsies obtained at 
baseline, during treatment, and at progression in BCC patients treated with 
cemiplimab, and to assess predictive potential and correlation to clinical 
response for biomarkers of interest including but not limited to: 
 
Tumor RNA expression 
 
Number and distribution of tumor-infiltrating lymphocytes (TILs) (CD8+ 
T cells, CD4+ T cells, T regulatory cells, and tissue permitting, other 
subtypes such as B cells, myeloid-derived cells, natural killer [NK] cells, 
etc.) 
 
Expression levels (mRNA and/or protein) of programmed death 
ligand 1(PD-L1), glucocorticoid-induced TNFR family related gene 
(GITR), and lymphocyte activation gene-3 (LAG-3), and possibly other 
check-point modulators 
 
Mutations in known oncogenes and potential tumor neoantigens 
 
Tumor mutational burden 
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Study Design 
This is a phase 2, non-randomized, 2-group, multi-center study of cemiplimab 
at a 350 mg dose administered intravenously (IV) every 3 weeks (Q3W) in 
patients with advanced BCC who experienced progression of disease on HHI 
therapy or were intolerant of prior HHI therapy. The study will have 2 groups.  
Group 1 is for patients with metastatic BCC. Group 2 is for patients with 
unresectable locally advanced BCC.  All patients will undergo screening 
procedures to determine eligibility within 28 days prior to the initial 
administration of cemiplimab. There is no randomization or placebo control. 
After a screening period of up to 28 days, patients will receive up to 93 weeks 
of treatment. Each patient will receive a 350 mg Q3W dose of cemiplimab IV.  
The infusion time for cemiplimab is approximately 30 minutes (± 10 minutes).  
Tumor assessments will be made at the end of each treatment cycle, 5 
treatment cycles of 9 weeks followed by 4 treatment cycles of 12 weeks).  
Extensive safety evaluations will occur on day 1 of each cycle, with routine 
safety evaluations to be conducted at each cemiplimab dosing visit. 
A patient will receive treatment until the 93-week treatment period is 
complete, or until disease progression (PD), unacceptable toxicity, withdrawal 
of consent, or confirmed CR. Patients with confirmed CR after a minimum of 
48 weeks of treatment may elect to discontinue treatment and continue with 
all relevant study assessments (eg, efficacy assessments).  Patients who 
discontinue study treatment due to PD should return to the clinic 30 days 
(range: 28 days to 42 days) after the last study treatment to complete the 
end-of-study (EOS) assessments.  After the EOS visit, patients with PD should 
be followed for survival status until death, loss to follow up, or study 
termination by the sponsor. 
Study Duration 
After a screening period of up to 28 days, patients will receive up to 93 weeks 
of treatment.  After the end of study visit, there is a follow-up period consisting 
of periods of 28 days.  Patients should be followed for survival status until 
death, loss to follow up, or study termination by the sponsor. 
Population 
 
 
Sample Size: 
Approximately 137 adult patients (53 in Group 1 and 84 in Group 2) are 
expected to be enrolled. 
 
Target Population: 
Patients with metastatic (Group 1) or unresectable locally advanced (Group 2) 
BCC who experienced progression of disease on HHI therapy, or were 
intolerant of prior HHI therapy. 
Treatments 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Cemiplimab at 350 mg administered IV over 30 minutes (± 10 minutes) Q3W 
for up to 93 weeks 
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Endpoints 
 
 
Primary: 
The primary efficacy endpoint for this study is the ORR as determined by 
central review.  The ORR will be assessed separately for patients with 
metastatic BCC (Group 1) or unresectable locally advanced BCC (Group 2): 
 
For patients in Group 1 (metastatic BCC), Response Evaluation Criteria 
in Solid Tumors (RECIST) version 1.1 will be used to determine ORR. 
Clinical response criteria may be used for patients with externally visible 
target lesions if all metastatic lesions are not measurable by RECIST (as 
may occur in patients with bone-only metastases). 
 
For patients in Group 2 (unresectable locally advanced BCC), clinical 
criteria will be used to determine ORR.  Composite response criteria will 
be used for patients with lesions that are measurable by both clinical 
response criteria and RECIST 1.1. 
The secondary endpoints are: 
 
Duration of response 
 
PFS 
 
OS 
 
CR rate 
 
Change in scores of patient-reported outcomes in the EORTC QLQ-C30 
and the Skindex-16 
 
Adverse events (AEs) 
 
Concentrations of cemiplimab in serum  
 
Anti-cemiplimab antibodies 
 
 
 
 
Secondary: 
 
Exploratory: 
The following exploratory analyses are planned: 
 
Associations between tumor non-synonymous mutational burden at 
baseline and efficacy of cemiplimab 
 
Pharmacodynamic changes, comparing baseline and on-treatment 
biopsies: 
o 
Changes in tumor mRNA expression 
o 
Changes in number of TILs (CD8+ T cells, CD4+ T cells, 
T regulatory cells, and tissue permitting, other subtypes such as 
B cells, myeloid-derived cells, NK cells, etc.) and descriptive 
change in distribution of TILs in respect to tumor tissue and stroma 
o 
Change in expression levels (mRNA and/or protein) of PD-L1, 
GITR, and LAG-3, and possibly other check-point modulators 
o 
Change in number and type of genetic mutations in known 
oncogenes and potential tumor neoantigens 
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. 
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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: 
 
Blood samples for PK 
 
Blood samples to assess anti-cemiplimab antibodies 
 
Tumor biopsies 
 
Biomarkers 
 
Quality of life assessments 
Statistical Plan 
In order to describe objective response rate (ORR) and duration of response 
(DOR), the data cut for primary efficacy analysis will allow responding 
patients to be followed from onset of response for at least 6 months.  The 
primary analysis for each group will be statistically independent. 
For Group 1, 50 patients 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 5% if the 
true ORR is 34%.  For Group 2, 80 patients are required to provide at least 
85% power to reject a null hypothesis of an ORR of 20% at a 2-sided 
significance level of 5% if the true ORR is 35%.  Given the sample sizes above, 
the non-clinically meaningful ORR of 15% for Group 1 will be excluded using 
the lower limit of 2-sided 95% confidence interval (CI) if the observed ORR 
is 28.0% or more; ie, the ORR for Group 1 is significantly different from 15%.  
The non-clinically meaningful ORR of 20% for Group 2 will be excluded 
using the lower limit of 95% CI if the observed ORR is 30.0% or more; ie, the 
ORR for Group 2 is significantly different from 20%.  The sample sizes will 
be 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, 
and 84 patients for Group 2, for a total of 137 patients. 
The primary endpoint for efficacy analyses is the ORR as determined by 
RECIST version 1.1 for visceral lesions or by modified WHO criteria for skin 
lesions or by the composite response criteria for patients with both visceral 
and skin lesions.  The ORR assessment for the primary analysis will be 
performed 
by 
an 
independent 
central 
review 
committee. 
The 
investigator-assessed ORR will be considered as a secondary analysis. 
Efficacy analyses of Group 1 and Group 2 will be independent of each other. 
The primary analyses of efficacy for Group 1 and Group 2 are based on the 
exact binomial CI approach, ie, whether or not the lower limit of 2-sided 95% 
CI will exclude a historical control ORR that is not deemed clinically 
meaningful.  The secondary analyses of efficacy as measured by duration of 
response, PFS, and OS will be summarized by median and its 95% CI using 
the Kaplan-Meier method. 
An interim analysis for Group 1 will be performed at the time of the planned 
efficacy analysis for Group 2. 
The quality of life of patients will be repeatedly measured by the 
EORTC QLQ-C30 and Skindex-16 at day 1 of each treatment cycle.  The 
change scores of QLQ-C30 and Skindex-16 will be summarized descriptively 
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at each post-baseline time point.  The summary scores of QLQ-C30 and 
Skindex-16 will also be graphically depicted by longitudinal plots. 
Safety observations and measurements including drug exposure, AEs, 
laboratory data, vital signs, and ECOG performance status will be summarized 
and presented in tables and listings. 
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LIST OF ABBREVIATIONS AND DEFINITIONS 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 
ANA 
Antinuclear antibody 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time  
AST 
Aspartate aminotransferase 
BAL 
Bronchoalveolar lavage 
BAS 
Biomarker analysis set 
BCC 
Basal cell carcinoma 
BUN 
Blood urea nitrogen 
Ceoi 
Concentration at end of infusion 
CI 
Confidence interval 
CK 
Creatine kinase 
CPK 
Creatine phosphokinase 
CR 
Complete response 
CRC 
Central Review Committee 
CRF; eCRF 
Case report form (electronic or paper); electronic case report form 
CRP  
C-reactive protein 
CSCC 
Cutaneous squamous cell carcinoma 
CT 
Computed tomography 
CTLA-4 
Cytotoxic T-lymphocyte antigen 4  
Ctrough 
Pre-infusion concentration 
DLT 
Dose-limiting toxicity 
EAS 
Efficacy analysis set 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 
EOS 
End of study 
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Abbreviation 
Definition of Term 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FDG-PET 
18F-fluorodeoxyglucose positron emission tomography 
FFPE 
Formalin-fixed, paraffin-embedded 
FIH 
First-in-human 
GCP 
Good clinical practice 
GITR 
Glucocorticoid-induced TNFR family related gene 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HHI 
Hedgehog inhibitor 
HIV 
Human immunodeficiency virus 
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 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone releasing system 
IV 
Intravenous(ly) 
IWRS 
Interactive Web Response System 
LAG-3 
Lymphocyte activation gene-3 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NAb 
Neutralizing antibody 
NBCCS 
Nevoid Basal Cell Carcinoma Syndrome 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NK 
Natural killer 
NSCLC 
Non–small-cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
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Abbreviation 
Definition of Term 
PD-1 
Programmed cell death protein 1 (receptor) 
PD-L1, PD-L2 
Programmed cell 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 
PTCH 
Protein patched homologue 
Q2W 
Every 2 weeks 
Q3W 
Every 3 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) 
SEER 
Surveillance, Epidemiology, and End Results 
SMO 
Smoothened (receptor) 
SOC 
System organ class 
SSA 
Anti-Sjögren’s syndrome A antigen antibody (Ro),  
SSB 
Anti-Sjögren’s syndrome B antigen antibody (La) 
SSC 
Study Steering Committee 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
Teff 
Effector T cells 
Teoi 
Time at end of infusion 
TIL 
Tumor-infiltrating lymphocytes 
TLR-7 
Toll-Like Receptor-7 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cell 
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1. 
INTRODUCTION 
1.1. 
Clinical Characteristics and Current Management of Advanced 
Basal Cell Carcinoma 
Basal cell carcinoma (BCC) is the most common malignancy in the United States (US), with an 
estimated incidence of over 3 million, and UV exposure is the major risk factor (Wu 2013).  
Accurate incidence numbers and mortality estimates are not available because the disease is not 
tracked in the Surveillance, Epidemiology, and End Results (SEER) program.  However, data from 
prospective studies suggest that the incidence of BCC in the US has doubled in the last 2 decades 
(Wu 2013).  Basal cell carcinoma incidence also appears to be increasing slightly in European 
Union (EU) nations, with approximately 50 to 90 new patients per 100,000 individuals annually 
in EU countries (Madan 2010). 
The most common clinical subtype is nodular BCC.  Less common clinical subtypes are 
superficial, morphoeic (fibrosing), and fibroepithelial.  Most patients are cured by surgery, but a 
small percentage of patients develop unresectable locally advanced or metastatic disease.  The 
American Joint Committee on Cancer staging system for BCC is the same as that for cutaneous 
squamous cell carcinoma (CSCC), but is felt to be of limited clinical utility in BCC due the lower 
metastatic potential for this disease (Porceddu 2015). 
Virtually all BCCs are characterized by aberrant signaling of the hedgehog signaling pathway, 
most commonly due to sporadic loss-of-function mutation in the gene encoding protein patched 
homologue (PTCH), a tumor suppressor.  A PTCH mutation results in loss of patched-mediated 
inhibition of the G-protein coupled receptor Smoothened (SMO), thereby enhancing downstream 
signaling that results in uncontrolled cellular proliferation (Sekulic 2016).  A small percentage of 
BCCs arise in the context of the autosomal dominant disorder Nevoid Basal Cell Carcinoma 
Syndrome (NBCCS), also known as Gorlin Syndrome, in which patients carry a germline mutation 
in PTCH that results in de-repression of SMO (Athar 2014). 
Recognition of the oncogenic role of SMO in BCC led to the development of vismodegib and 
sonidegib, orally available inhibitors of SMO, generally referred to as Hedgehog Inhibitors (HHIs).  
ERIVANCE was a non-randomized phase 2 study that led to regulatory approval of vismodegib 
in the US, EU, and several other countries, for the treatment of locally advanced and metastatic 
BCC.  Vismodegib yielded objective response rates (ORRs) of 30% and 43% in metastatic and 
unresectable locally advanced BCC, respectively, in the original report (Sekulic 2012).  At the 12-
month update, median durations of response were 7.6 months for metastatic BCC and 9.5 months 
for locally advanced BCC (Sekulic 2015). 
The largest prospective safety experience with vismodegib was the STEVIE (SafeTy Events in 
VIsmodEgib) study, which enrolled BCC patients in 36 countries to receive vismodegib 
150 mg/day (Basset-Seguin 2015).  Among 499 evaluable patients (468 locally advanced, 
31 metastatic), median duration of exposure was 36.4 weeks.  The most common adverse events 
(AEs) were muscle spasms (64%), alopecia (62%), dysgeusia (54%), and weight loss (33%).  Most 
AEs were grade 1 or grade 2, but 22% of patients experienced serious adverse events (SAEs). 
Sonidegib, another orally available HHI, also has received regulatory approval, at the dose of 
200 mg per day, for unresectable locally advanced BCC, based on demonstration of ORR of 43% 
(18 responses among 42 patients) in this population (Migden 2015).  The most common AEs at 
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the approved dose were muscle spasms (49%), alopecia (43%), and dysgeusia (38%).  For BCC 
patients who progress on vismodegib, subsequent treatment with sonidegib appears to be inactive 
(Danial 2016).  There is no approved agent for BCC in patients who experienced progression of 
disease on HHI therapy, or who are intolerant of prior HHI therapy. 
1.2. 
Cemiplimab, an Anti-PD-1 Monoclonal Antibody 
Under chronic stimulation, T cells lose proliferative and effector function capacity, often due to 
signal down-modulation via the increased expression of proteins such as programmed cell death 
protein 1 (PD-1), an inhibitory checkpoint receptor of the CD28 receptor family.  Binding of 
programmed cell death ligand (PD-L1 or PD-L2), which can be expressed on tumor cells or other 
immune cells, to PD-1 imparts an inhibitory signal to the T cell, thus down modulating the 
anti-tumor T-cell response. 
The largest clinical experiences with PD-1 inhibition are with the monoclonal antibodies 
nivolumab and pembrolizumab.  Blockade of the PD-1 is an effective and well tolerated approach 
to stimulating the immune response, and has achieved therapeutic advantage against various 
human cancers, including melanoma, renal cell cancer (RCC), and non-small cell lung cancer 
(NSCLC) (Postow 2015).  Inhibition of PD-1 can be associated with a wide range of immune-
related AEs, including pneumonitis, dermatologic toxicities (including rash, pruritus, and vitiligo), 
nephritis, hepatitis, diarrhea, colitis, ocular toxicities (including uveitis), endocrine disorders 
(including hypophysitis, thyroid dysfunction, and diabetes), and neurologic toxicities (Spain 
2016). 
Cemiplimab is a high-affinity, fully human, hinge-stabilized IgG4P antibody directed to the PD-1 
receptor that potently blocks the interaction of PD-1with its ligands, PD-L1 and PD-L2.  In 
syngeneic tumor models in immunocompetent mice humanized for PD-1, the antitumor activity of 
cemiplimab delivered as a monotherapy against a mouse colon adenocarcinoma tumor line is 
similar to that observed with the anti-PD-1 monoclonal antibodies pembrolizumab and nivolumab 
generated in-house, based on the publicly available genetic sequences (unpublished data). 
The first-in-human (FIH) protocol of cemiplimab (R2810-ONC-1423; NCT02383212) evaluates 
the safety of cemiplimab as monotherapy at different dose levels and in combination with selected 
other anti-tumor agents that may augment the potency and durability of an anti-tumor immune 
response.  The initial clinical experience with dose escalation cohorts (n = 60 patients) indicates 
that cemiplimab has generally been well tolerated (Papadopoulos 2016).  There were no dose-
limiting toxicities (DLTs) in the dose escalation cohorts.  The most common treatment-related AEs 
were fatigue (n=17 [28.3%]), arthralgia (n=7 [11.7%]), and nausea (n=7 [11.7%]).  Eight 
treatment-related AEs of grade ≥3 were observed:  anemia in 2 cases (3.3%), and 1 (1.7%) case 
each of lymphopenia, elevated alanine aminotransferase (ALT), elevated aspartate 
aminotransferase (AST), and cognitive disorder with anti-HuD associated paraneoplastic 
encephalomyelitis.  Objective responses were observed in 18% of patients, including 1 patient with 
metastatic BCC (see Section 3.2.1).  The phase 1 experience supports a 3 mg/kg cemiplimab 
intravenously (IV) every 2 weeks as dose for further study (see Section 3.2.3). 
Libtayo® (cemiplimab) has received marketing authorization and is now approved in the 
United States (US), Europe, Canada, and Brazil for the treatment of patients with metastatic 
cutaneous squamous cell carcinoma or patients with locally advanced cutaneous squamous cell 
carcinoma who are not candidates for curative surgery or curative radiation. In the US, it is 
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approved as cemiplimab-rwlc.The Investigator’s Brochure provides further details of nonclinical 
pharmacology and antitumor activity of cemiplimab. 
 
 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to estimate the ORR for metastatic BCC (Group 1) or 
unresectable locally advanced BCC (Group 2), according to central review, when treated with 
cemiplimab monotherapy in patients who have progressed on HHI therapy, or were intolerant of 
prior HHI therapy (see Appendix 1 and Appendix 2). 
2.2. 
Secondary Objectives 
The secondary objectives for both Group 1 and Group 2 are to: 
 Estimate ORR (see Appendix 1 and Appendix 2) according to investigator review 
 Estimate the duration of response, progression-free survival (PFS) by central and 
investigator review, and overall survival (OS) 
 Estimate the complete response (CR) rate by central review 
 Assess the safety and tolerability of cemiplimab 
 Assess the pharmacokinetics (PK) of cemiplimab (at select sites only) 
 Assess the immunogenicity of cemiplimab 
 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) and Skindex-16 
2.3. 
Exploratory Objectives (Group 2 only) 
The exploratory objectives (for Group 2 only) are to explore the pharmacodynamic effects of 
cemiplimab in tumor biopsies obtained at baseline, during treatment, and at progression in BCC 
patients treated with cemiplimab, and to assess predictive potential and correlation to clinical 
response for biomarkers of interest including but not limited to: 
 Tumor RNA expression 
 Number and distribution of tumor-infiltrating lymphocytes (TILs) (CD8+ T cells, 
CD4+ T cells, T regulatory cells, and tissue permitting, other subtypes such as 
B cells, myeloid-derived cells, natural killer [NK] cells, etc.) 
 Expression levels (mRNA and/or protein) of programmed death ligand 1(PD-L1), 
glucocorticoid-induced TNFR family related gene (GITR), and lymphocyte activation 
gene-3 (LAG-3), and possibly other check-point modulators 
 Mutations in known oncogenes and potential tumor neoantigens 
 Tumor mutational burden 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypothesis 
Basal cell carcinomas have a high mutational burden that encodes neoantigens for presentation to 
effector T (Teff) cells.  Therefore, Teff cell responses against BCC will be unleashed by blockade 
of the PD-1 checkpoint with cemiplimab, achieving high ORR. 
3.2. 
Rationale 
3.2.1. 
Rationale for Clinical Study of Cemiplimab in Advanced BCC 
Several lines of evidence suggest that inhibition of the PD-1 checkpoint could be clinically 
advantageous for patients with advanced BCC.  First, the mutational burden in BCC is among the 
highest of any human malignancy (Jayaraman 2014, Chalmers 2016, Bonilla 2016).  Tumor types 
with high mutational burden are generally more responsive to PD-1 blockade than tumors with 
low mutational burden, and this is thought to be due to generation of neoantigens that can be 
recognized by Teff (Le 2015, McGranahan 2016, Rizvi 2015).  Second, solid organ transplant 
patients have an approximately 10-fold increased risk of BCC, suggesting that immune 
surveillance is relevant in this disease (Euvrard 2003).  Third, other immune modulators have 
activity against BCC.  The Toll-Like Receptor-7 (TLR-7) agonist imiquimod is an approved 
therapy for superficial BCC (Gollnick 2008).  There is a case report of a BCC response to 
ipilimumab, an inhibitor of cytotoxic T-lymphocyte associated protein 4 (Mohan 2016).  In a 
recent case report, disease stabilization of a previously progressing metastatic BCC was achieved 
with off-label administration of pembrolizumab (Winkler 2016). 
In the ongoing FIH study of cemiplimab, a confirmed partial response (PR) has been observed in 
a patient with vismodegib-refractory metastatic BCC.  The patient is a 66-year-old woman who 
had previously received vismodegib from September 2014 until February 2015.  She began 
treatment with 10 mg/kg cemiplimab on 3 Aug 2015.  Response assessments after cycles 1 and 2 
showed stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, but 
with gradual regression.  The tumor measurements had further decreased to -37% compared with 
baseline (unconfirmed PR) at the end of cycle 3, and met the criteria for PR (confirmed) at the end 
of cycle 4.  The patient has tolerated treatment well and continues on therapy as of the date of issue 
of this protocol. 
3.2.2. 
Rationale for Study Design 
Because there is no standard of care for BCC patients who experienced progression of disease on 
HHI therapy, or are intolerant of prior HHI therapy, and metastatic and locally advanced disease 
are relatively rare, it has been acceptable to assess efficacy with non-randomized single-arm 
studies.  Non-randomized studies without control arms, in which primary endpoints were ORR, 
were accepted by both the US Food and Drug Administration (FDA) and the European Medicines 
Agency (EMA) in the approvals of vismodegib and sonidegib for advanced BCC in the 
ERIVANCE (Migden 2015) and BOLT (Sekulic 2012) studies, respectively.  Objective response 
rate is the primary endpoint in ERIVANCE, BOLT, R2810-ONC-1540 (a phase 2 study of 
cemiplimab in patients with advanced CSCC) (NCT02760498, EudraCT 2016-000105-36), and in 
the current study protocol. 
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Tumor biopsies will be obtained at baseline and during treatment for patients with locally advanced 
tumors to inform an understanding of mechanisms of response and resistance to tumor treatment. 
The study populations in this study include patients with both metastatic (Group 1) and 
unresectable locally advanced (Group 2) BCC (see Section 5.1.1).  The decision to analyze 
separate groups of patients with metastatic and unresectable locally advanced disease is based on 
the observation of higher response rates in locally advanced versus metastatic disease seen in data 
from studies of SMO inhibitors against BCC (Sekulic 2012, Migden 2015).  This observation was 
also seen in 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). 
The rationale for including patients who are intolerant of HHIs is that such patients are unlikely to 
have a high probability of objective response if re-challenged with HHI.  In the routine clinical 
practice setting of the STEVIE study, the median time to response was 2.7 months, whereas the 
median times to onset of muscle spasms and dysgeusia were 2.8 and 6.5 months, respectively 
(Basset-Seguin 2015).  Because objective response tends to occur before onset of AEs, it is 
unlikely that patients who interrupt HHI due to AEs will experience objective response upon 
re-challenge.  Consistent with the prediction that intermittent dosing of HHIs is unlikely to increase 
markedly the efficacy of this class of drugs, there was no obvious signal of enhanced efficacy in 
preliminary data from a phase 2 study (MIKIE) that compares 2 intermittent dosing regimens of 
vismodegib in locally advanced BCC (Rogers 2015). 
3.2.3. 
Rationale for Dose Selection 
In the ongoing FIH study, the 3 mg/kg every 2 weeks (Q2W) intravenous (IV) dose has shown 
anti-tumor activity and acceptable safety in the FIH study, including in NSCLC patients; efficacy 
was also observed at 1 mg/kg Q2W.  As many standard chemotherapy treatments for NSCLC are 
dosed on an every 3-week (Q3W) schedule, the clinical development strategy of cemiplimab 
coalesced around a Q3W treatment interval.  The ongoing clinical development of cemiplimab 
also seeks to incorporate a flat dosing paradigm.  As such, a Q3W flat dose regimen has been 
selected that is expected to provide a similar clinical efficacy and safety profile to that observed 
for the 3mg/kg Q2W regimen.  
A flat IV cemiplimab dose of 350 mg Q3W was selected, based on population PK modeling and 
simulation, as it is expected to provide exposure that closely replicates that observed in patients 
(mean weight - 80 kg) for the 3 mg/kg Q2W IV regimen in the ongoing FIH study 
R2810-ONC-1423 (NCT02383212).  Simulations of cemiplimab exposure in 1000 patients using 
population PK analyses indicated that: 1) a 350 mg Q3W dose in patients resulted in similar (≤20% 
difference) Ctrough, AUC12W, and Cmax, as compared to the 3 mg/kg Q2W dose in the FIH patient 
population (mean weight - 80 kg), and exceeded those observed at the 1 mg/kg Q2W dose; and 2) 
the variability in cemiplimab exposure (CV%) was similar for body-weight adjusted doses as 
compared to flat doses.  Given the similar predicted exposure for 350 mg Q3W when compared to 
the 3 mg/kg Q2W regimen, a similar efficacy/safety profile is also expected.  Therefore, the 
350 mg Q3W IV dose of cemiplimab is being proposed for new studies in patients with NSCLC, 
and across the cemiplimab program. 
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4. 
STUDY VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height), disease 
characteristics including medical history, and medication history for each patient. 
4.2. 
Primary and Secondary Endpoints 
4.2.1. 
Primary Endpoint 
The primary efficacy endpoint for this study is the ORR as determined by central review.  The 
ORR will be assessed separately for patients with metastatic BCC (Group 1) or unresectable 
locally advanced BCC (Group 2): 
 For patients in Group 1 (metastatic BCC), RECIST version 1.1 (Eisenhauer 2009) 
(Appendix 1) generally will be used to determine ORR.  Clinical 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 in Group 2 (unresectable locally advanced BCC), clinical response criteria 
(Appendix 2) will be used to determine ORR.  Composite response criteria (Appendix 2) 
will be used for patients who have both target lesions measurable by clinical response 
criteria and by RECIST 1.1.   
 Patients who are deemed not evaluable by RECIST version 1.1 (Group 1; Appendix 1) or 
by the composite response criteria (Group 2; Appendix 2) will be considered as not 
reaching PR/CR for ORR. 
4.2.2. 
Secondary Endpoints 
The secondary endpoints are: 
 Duration of response 
 PFS 
 OS 
 CR rate 
 Change in scores of patient-reported outcomes in the EORTC QLQ-C30 and the 
Skindex-16 
 AEs 
 Concentrations of cemiplimab in serum (at select sites) 
 Anti-cemiplimab antibodies 
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4.2.3. 
Exploratory Endpoints 
The following exploratory analyses are planned: 
 Associations between tumor non-synonymous mutational burden at baseline and efficacy 
of cemiplimab 
 Pharmacodynamic changes, comparing baseline and on-treatment biopsies: 
 Changes in tumor mRNA expression 
 Changes in number of TILs (CD8+ T cells, CD4+ T cells, T regulatory cells, and 
tissue permitting, other subtypes such as B cells, myeloid-derived cells, NK cells, 
etc.) and descriptive change in distribution of TILs in respect to tumor tissue and 
stroma 
 Change in expression levels (mRNA and/or protein) of PD-L1, GITR, and LAG-3, 
and possibly other check-point modulators 
 Change in number and type of genetic mutations in known oncogenes and potential 
tumor neoantigens 
4.3. 
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 
 Ctrough – pre-infusion concentration 
 teoi – time of end of infusion 
4.4. 
Anti-Drug Antibody Variables 
Anti-drug antibody (ADA) variables include status (negative),titer, and neutralizing antibody 
(NAb) status as follows: 
 Pre-existing immunoreactivity – defined either as a positive ADA assay response at 
baseline with all posttreatment ADA assay results negative, or a positive assay response 
at baseline with all posttreatment ADA assay responses <9-fold over baseline titer levels 
 Treatment-emergent ADA response is defined as any posttreatment positive ADA assay 
response when baseline ADA assay results are negative. 
 Treatment-boosted ADA response is defined as any posttreatment ADA response that is 
≥9-fold over baseline titer levels when baseline is positive in the ADA assay. 
 Titer values (by category) 
 Low (titer <1,000) 
 Moderate (1,000≤ titer ≤10,000) 
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 High (titer >10,000) 
 NAb status for samples that are positive in the ADA assay. 
 
 
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5. 
STUDY DESIGN 
5.1. 
Study Description and Duration 
This is a phase 2, non-randomized, 2-group, multi-center study of cemiplimab at a 350 mg dose 
administered IV Q3W in patients with advanced BCC who experienced progression of disease on 
HHI therapy, or were intolerant of prior HHI therapy.  The study will have 2 groups. Group 1 is 
for patients with metastatic BCC.  Group 2 is for patients with unresectable locally advanced BCC. 
All patients will undergo screening procedures to determine eligibility within 28 days prior to the 
initial administration of cemiplimab.  There is no randomization or placebo control. 
After a screening period of up to 28 days, patients will receive 5 treatment cycles of 9 weeks 
followed by 4 treatment cycles of 12 weeks for up to 93 weeks of treatment.  Each patient will 
receive a 350 mg dose of cemiplimab IV Q3W.  The infusion time for cemiplimab is approximately 
30 minutes (± 10 minutes).  Tumor assessments will be made at the end of each treatment cycle (5 
treatment cycles of 9 weeks followed by 4 treatment cycles of 12 weeks). Extensive safety 
evaluations will occur on day 1 of each cycle, with routine safety evaluations to be conducted at 
each cemiplimab dosing visit. 
A patient will receive treatment until the 93-week treatment period is complete, or until disease 
progression (PD), unacceptable toxicity, withdrawal of consent, or confirmed CR.  Patients with 
confirmed CR after a minimum of 48 weeks of treatment may elect to discontinue treatment and 
continue with all relevant study assessments (eg, efficacy assessments).  Patients who discontinue 
study treatment due to PD should return to the clinic 30 days (range: 28 days to 42 days) after the 
last study treatment to complete the end-of-study (EOS) assessments.  After the EOS visit, patients 
with PD should be followed for survival status until death, loss to follow up, or study termination 
by the sponsor. 
5.1.1. 
Study Groups 
There will be 2 study groups: 
 Group 1:  Patients with metastatic BCC.  These patients are required to have 
histologic confirmation of distant BCC metastases (eg, lung, liver, bone, or lymph 
node).  Group 1 includes patients with both nodal metastatic and distant metastatic 
disease. 
 Group 2:  Patients with unresectable locally advanced BCC.  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 6.2.1). 
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, then 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, which is required prior to study enrollment for all Group 2 patients, is appropriate 
for patients with in-transit metastases. 
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5.1.2. 
End of Study Definition 
The end of the study will occur when the last patient to enter retreatment (per Section 8.1.5) 
completes the retreatment plus safety follow-up for 5 half-lives (105 days). 
5.2. 
Planned Interim Analysis 
Interim Analysis for Group 1: 
At the time of the planned efficacy analysis for Group 2 (approximately 57 weeks after last patient, 
first dose), an interim analysis of Group 1 patients will be performed in order to assess the risks 
and benefits of cemiplimab in metastatic BCC.  This analysis will be restricted to Group 1 patients 
with potential for adequate follow-up, defined as patients who have the opportunity to be followed 
approximately 57 weeks at the time of the interim analysis. This analysis will provide an ORR 
(with 95% confidence interval) for Group 1 patients with adequate follow-up.  
For additional details, please see Section 10.5.  
5.3. 
Study Committees 
5.3.1. 
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 would 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 the IDMC 
charter. 
5.3.2. 
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. 
5.3.3. 
Central Review Committee 
To assess the primary endpoint of response rate, the processes for the independent reviews and the 
central reviews will be appropriately described in the charter documents. 
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6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
Up to approximately 137 adult patients (53 in Group 1 and 84 in Group 2) are expected to be 
enrolled at up to approximately 70 sites globally.  The large number of sites is due to the rarity of 
patients with metastatic or unresectable locally advanced BCC. 
6.2. 
Study Population 
Patients with metastatic (Group 1) or unresectable locally advanced (Group 2) BCC who 
experienced progression of disease on HHI therapy, or were intolerant of prior HHI therapy. 
6.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Histologically confirmed diagnosis of invasive BCC 
Note for clarification:  The following are acceptable histologic subtypes of BCC:  
nodular, morpheaform, metatypical, superficial, micronodular, infiltrative, mixed, 
basosquamous, keratotic, desmoplastic 
2. Patients must be deemed unlikely to benefit from further therapy with an HHI due to any 
of the following: 
a. Prior progression of disease on HHI therapy, or 
b. Intolerance of prior HHI therapy defined as: 
(i) 
any Grade 3 or 4 AE deemed related to HHI 
(ii) 
Or any of the following HHI-related events in patients with at least 3 months 
of exposure to HHI therapy (exclusive of treatment breaks): 
 Grade 2 muscle spasms or myalgias (iia) 
 Grade 2 dysgeusia or anorexia, if accompanied by ≥Grade 1 weight loss 
(iib) 
 Grade 2 nausea or diarrhea despite medical management or (iic) 
c. No better than a stable disease after 9 months on HHI therapy (exclusive of treatment 
breaks) 
3. 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. 
Group 1:  At baseline, there must be at least 1 measurable lesion ≥10 mm in maximal 
diameter (1.5 cm in short axis for lymph nodes) according to RECIST 1.1 criteria 
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Group 2:  At baseline, there must be at least 1 measurable baseline lesion in which the 
longest diameter and the perpendicular diameter are both ≥10 mm if measured by digital 
medical photography.  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 <10 mm.  Patients without measurable 
disease at baseline are not eligible for the study. 
Note in clarification:  In the case of a Group 1 patient 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 BCC 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 in Group 1 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. 
In the case of a Group 2 patient with a deeply invasive lesion that the investigator deems 
is best measured by magnetic resonance imaging (MRI) or computed tomography (CT), 
measurement for that target lesion will be done according to RECIST 1.1 criteria 
(Appendix 1).  The requirement for a lesion to be measurable by RECIST 1.1 is that it 
must be ≥10 mm in longest dimension. 
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 
5. At least 18 years old 
6. Hepatic function: 
a. Total bilirubin ≤1.5x upper limit of normal (ULN) (or ≤3x ULN, if liver metastases).  
Patients with Gilbert’s Disease and total bilirubin up to 3x ULN may be eligible after 
communication with and approval from the medical monitor 
b. Transaminases ≤3x ULN (or ≤5x ULN, if liver metastases) 
c. Alkaline phosphatase (ALP) ≤2.5x ULN (or ≤5x ULN, if liver or bone metastases) 
Note for patients with hepatic metastases who wish to enroll in Group 1:  If 
transaminase levels (AST and/or ALT) are >3x but ≤5x ULN, total bilirubin must be 
≤1.5x ULN.  If total bilirubin is >1.5x but ≤3x ULN, both transaminases (AST and ALT) 
must be ≤3x ULN. 
7. Renal function:  Serum creatinine ≤2x ULN or estimated creatinine clearance 
>35 mL/min (according the method of Cockcroft and Gault) 
8. Creatine phosphokinase (CPK) (also known as CK [creatine kinase]) elevation ≤ grade 2 
9. 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 
10. Anticipated life expectancy >12 weeks 
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11. 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 BCC.  This 
material must be confirmed as received by the central laboratory prior to enrollment. 
12. Group 2 only (unresectable locally advanced BCC):  Patients must consent to undergo 
biopsies of externally visible BCC lesions at baseline, cycle 1 day 22 (±3 business days), 
at time of tumor progression, and at other time points that may be clinically indicated in 
the opinion of the investigator 
13. Willing and able to comply with clinic visits and study-related procedures 
14. Provide signed informed consent prior to any screening procedures (with the exception of 
brain MRI which is allowed to be obtained within 60 days of enrollment).  
15. Group 2 only:  Patients in Group 2 must be deemed to have unresectable disease.  
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 
(surgeon may be site PI) from a clinical visit within 60 days of enrollment must be 
submitted.  
Acceptable contraindications in the surgeon’s note include: 
a. BCC that has recurred in the same location after 2 or more surgical procedures and 
curative resection is deemed unlikely 
b. BCCs with significant local invasion that precludes complete resection 
c. BCCs 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. 
16. Group 2 Only:  Patients in Group 2 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 BCC, 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:  
BCCs in anatomically challenging locations for which radiation therapy would be 
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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. 
6.2.2. 
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 systemic immune-modulating agents within fewer than 28 days 
prior to the first dose of cemiplimab.  Examples of immune-modulating agents include 
therapeutic vaccines, cytokine treatments, or agents that target cytotoxic T-lymphocyte 
antigen 4 (CTLA-4), 4-1BB (CD137), or OX-40. 
Note in clarification:  Prior treatment with imiquimod or other topical or intralesional 
immune modulators will not be exclusionary 
4. Untreated brain metastasis(es) that may be considered active.  (Note: patients with brain 
involvement of BCC due to direct extension of invading tumor, rather than metastasis, 
may be allowed to enroll if they do not require >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 patients do not require any 
immunosuppressive doses of systemic corticosteroids for management of brain 
metastasis(es) within 28 days of the first dose of cemiplimab. 
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 courses of steroids (eg, as prophylaxis for imaging 
studies due to hypersensitivity to contrast agents) are not excluded 
6. Active infection requiring therapy, including positive tests for human immunodeficiency 
virus (HIV)-1 or HIV-2 serum antibody, hepatitis B virus (HBV), or hepatitis C virus 
(HCV) 
7. History of pneumonitis within the last 5 years 
8. Any anticancer treatment other than radiation therapy (chemotherapy, targeted systemic 
therapy, imiquimod, photodynamic therapy), investigational or standard of care, within 
30 days of the initial administration of cemiplimab or planned to occur during the study 
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period (patients receiving bisphosphonates or denosumab allowed because these are not 
considered anticancer treatments in this protocol) 
Notes:  (a) For patients with multiple BCCs at baseline that are not designated by the 
investigator as target lesions, treatment of these non-target BCCs with surgery may be 
permitted but must be discussed with the medical monitor prior to any surgical procedure.  
(b) Patients are excluded if they receive any radiation therapy within ≤14 days of the 
initial administration of cemiplimab or planned to occur during the study period. 
9. History of documented allergic reactions or acute hypersensitivity reaction attributed to 
antibody treatments 
10. Patients with allergy or hypersensitivity to cemiplimab or to any of the excipients must be 
excluded.  . 
11. Concurrent malignancy other than BCC and/or history of malignancy other than BCC 
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 CSCC 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-T2a N0M0 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) are excluded. 
12. Any acute or chronic psychiatric problems that, in the opinion of the investigator, make 
the patient ineligible for participation 
13. Patients with a history of solid organ transplant (patients with prior corneal transplants 
may be allowed to enroll after discussion with and approval from the medical monitor) 
14. 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:  For Group 2 patients, the investigator must contact the sponsor’s 
medical monitor regarding any patients who the investigator feels cannot provide the 
required baseline tumor biopsies. 
15. Inability to undergo any contrast-enhanced radiologic response assessment 
Note 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 Group 2 patients:  In selected cases, a patient in Group 2 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 
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comprehensively assessed with digital medical photography, after communication with 
and approval from the medical monitor. 
Note in clarification: For Group 2 patients, the investigator must contact the Sponsor's 
medical monitor regarding any patients that the investigator feels cannot provide the 
required baseline biopsies. 
16. Breastfeeding 
17. 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) 
18. Receipt of live vaccines (including attenuated) within 30 days of first study treatment 
19. Women of childbearing potential (WOCBP)*, or sexually active men, who are unwilling 
to practice highly effective contraception prior to the initial dose/start of the first treatment, 
during the study, and for at least 6 months after the last dose.  Highly effective 
contraceptive measures include:  
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 
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not acceptable methods of contraception.  Female condom and male condom should 
not be used together. 
 
20. Prior treatment with idelalisib 
6.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures).  An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patients who are withdrawn prematurely from the study will be asked to complete study 
assessments, as described in Section 8.1.4. 
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. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 7.3.2. 
6.4. 
Replacement of Patients 
Patients prematurely discontinued from the study will not be replaced. 
7. 
STUDY TREATMENTS 
7.1. 
Investigational and Reference Treatments 
Open-label cemiplimab will be supplied as a liquid in sterile, single-use -vials.  Each vial will 
contain cemiplimab at a concentration of 50 mg/mL. Instructions on dose preparation are provided 
in the pharmacy manual. 
Open-label cemiplimab will be administered in an outpatient setting as an IV infusion over 
approximately 30 minutes (± 10 minutes).  Each patient’s dose will be administered as a dose of 
350 mg Q3W (dose is not weight based, dosing in this study is a flat dose).  
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. 
7.2. 
Pretreatment(s) 
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. 
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7.3. 
Dose Modification and Study Treatment Discontinuation Rules 
7.3.1. 
Dose Modification 
The planned dose and schedule is a 350 mg dose of cemiplimab IV over approximately 30 minutes 
(± 10 minutes) Q3W.  Patients will generally remain on the assigned dosage of cemiplimab 
throughout the course of study treatment.  Dose reduction of cemiplimab may be allowed following 
temporary discontinuation of study drug, based on the guidelines below, and only after discussion 
and agreement between the investigator and sponsor. 
7.3.2. 
Study Treatment Hold or Discontinuation 
Patients who permanently discontinue from study drug and who do not withdraw from the study 
should continue follow-up in the study without additional treatment until progression of disease, 
completion of all study assessments, or closure of the study (Section 6.3). 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 6.3. 
Adverse events are to be reported according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03.  Patients who experience 
grade ≥3 treatment-related toxicity (excluding laboratory abnormalities that are considered 
clinically insignificant) that is not otherwise specified in the protocol will be required to 
temporarily discontinue treatment with cemiplimab.  Such patients may be considered for 
resumption of treatment once the toxicity resolves to grade 1 or baseline, or when the toxicity is 
stable and manageable through supportive/medical therapy (eg, grade 3 hypertension that can be 
controlled with the addition of a second anti-hypertensive agent). 
Upon occurrence of a study treatment-related event at any time in the study, resumption of 
treatment after resolution or stabilization of the condition is allowed at the discretion of the 
investigator and sponsor if resuming treatment is thought to be in the best interest of the patient, 
with the exception of the following categories: 
 Patients with events that require cemiplimab to be discontinued for more than 
84 consecutive days from the previous dose 
 Patients with grade ≥2 uveitis will generally be discontinued from study treatment, 
unless there is resolution to grade ≤1 as outlined in Appendix 3 AND discussion with 
and approval by the medical monitor.  All patients with grade ≥3 uveitis will be 
permanently discontinued from study treatment. 
After other AEs, resumption of treatment may be at the initial dose level, or at 1 dose level reduced, 
based upon the discretion of the investigator and the sponsor (Table 1). 
Table 1: 
Dose Reductions 
Dose Level 
Reduction Order 
Dose 
Dose Level -1 
First dose reduction 
120 mg cemiplimab Q3W 
Dose Level -2 
Second dose reduction 
60 mg cemiplimab Q3W 
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A patient who requires dose reduction below dose level -2 will be permanently discontinued from 
the study. 
Guidelines for study treatment temporary discontinuations, including delays and interruptions, and 
permanent discontinuations for toxicity are outlined in Table 2. 
Any patient currently receiving cemiplimab who was previously treated with a 
phosphatidylinositol 3-kinase (PI 3-K) inhibitor and who develops stomatitis or mucositis should 
temporarily suspend study treatment.  If this or any other immune-related AE occurs among these 
patients, the sponsor should be informed as soon as possible to discuss further management of the 
patient.  An irAE of any grade in a patient previously treated with a PI 3-K inhibitor should be 
reported as an adverse event of special interest (AESI). 
 
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Table 2: 
Study Treatment Dose Modifications or Discontinuations 
Toxicity 
Grade 
Hold 
Treatment? 
Restarting 
Criteria 
Restarting 
Dose/Schedule 
Discontinuation 
Criteria 
Hematological Toxicity 
(other than grade 3 
thrombocytopenia greater 
than 7 days or associated 
with bleeding) 
1, 2, 3 
No 
N/A 
N/A 
N/A 
 
4 
Yes 
Toxicity 
resolves to 
grade ≤1 or 
baseline 
Decrease cemiplimab 
dosage to the next lower 
dosing level (see 
Table 1) 
Toxicity does not 
resolve within 84 days 
of last infusion 
Permanent 
discontinuation should 
be considered for any 
severe or life-
threatening event 
Grade 3 thrombocytopenia 
greater than 7 days or 
associated with bleeding 
3 
Yes 
Toxicity 
resolves to 
grade ≤1 or 
baseline 
Decrease cemiplimab 
dosage to the next lower 
dosing level (see 
Table 1) 
Toxicity does not 
resolve within 84 days 
of last infusion 
Permanent 
discontinuation should 
be considered for any 
severe or life-
threatening event 
Nonhematological Toxicity 
1 
No 
N/A 
N/A 
N/A 
Note: Exceptions to be treated 
as for Grade 1 toxicity: 
 
Grade 2 alopecia 
 
Grade 2 fatigue 
 
Clinically 
insignificant lab 
abnormality not 
meeting AE 
criteria 
2 
Consider 
withholding 
for persistent 
symptoms 
Toxicity 
resolves to 
grade 0–1 
or baseline 
Clinical AE resolves 
within 4 weeks: Same 
dose and schedule  
Clinical AE does not 
resolve within 4 weeks: 
May decrease 
cemiplimab dosage to 
the next lower dosing 
level (see Table 1) 
Toxicity does not 
resolve within 84 days 
of last infusion 
3 
Yes 
Toxicity 
resolves to 
grade 0–1 
or baseline 
Decrease cemiplimab 
dosage to the next lower 
dosing level (see 
Table 1) 
Toxicity does not 
resolve within 84 days 
of last infusion 
4 
Yes 
N/A 
N/A 
Patient must be 
discontinued 
AE=adverse event, N/A=not applicable 
For additional information regarding AEs with a potential for irAEs, reference Table 3 and Appendix 3. 
7.3.2.1. 
Immune-Related Adverse Events 
Case report forms (CRFs) for this study are designed to capture AEs that may be suggestive of 
potential irAEs.  Attribution of AEs in the CRFs will require not only the investigator’s assessment 
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regarding whether or not the AE was related to cemiplimab, but also whether or not the AE was 
an irAE.  Please see the CRF completion guidelines for information about attribution of irAEs. 
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 or endocrinopathies) may be subtle.  
Detailed guidance of management of irAEs is provided in Appendix 3.  In the event of irAEs that 
are not addressed in Appendix 3, general guidance is provided in Table 3.  The recommendations 
in Table 3 and Appendix 3 should be seen as guidelines, and the treating physician should exercise 
clinical judgment based on the symptoms and condition of the individual patient. 
Table 3: 
General Treatment Hold Guidelines for Immune-Related Adverse Events 
Severity 
Withhold/Discontinue 
Treatment? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold treatment 
Consider systemic corticosteroids in addition to appropriate 
symptomatic treatment 
Grade 3  
Grade 4 
Withhold treatment 
Discontinue if unable to reduce 
corticosteroid dose to <10 mg 
per day prednisone equivalent 
within 12 weeks of toxicity 
Systemic corticosteroids are indicated in addition to appropriate 
symptomatic treatment. May utilize 1 to 2 mg/kg prednisone or 
equivalent per day. 
Steroid taper should be considered once symptoms improve to 
Grade 1 or less and tapered over at least 4 weeks. 
For any severe (Grade 3-4) irAE, if symptoms worsen or do not 
improve on adequate corticosteroids within 48 to 72 hours, 
consider adding additional immunosuppressive agents (to be 
selected from agents such as infliximab, cyclophosphamide, 
cyclosporine, mycophenolate mofetil).  Referral of the patient to a 
specialized unit for assessment and treatment should be 
considered. 
Note: These recommendations should be seen as guidelines, and the treating physician should exercise clinical 
judgment based on the symptoms and condition of the individual patient. 
Note regarding irAEs: For any AE that is of a type known to be potentially immune-related (eg, rash, colitis, 
elevated transaminases, endocrine), but is deemed not to be an irAE by the investigator, the sponsor may request 
additional information. 
Based on the emerging safety profile of cemiplimab and other antibodies targeting the PD-1/PD-L1 
axis (Weber 2015, Naidoo 2015), the following working case definitions are provided to help 
investigators distinguish irAEs from non-immune AEs.  These case definitions pertain to the more 
commonly reported irAEs associated with PD-1 inhibition (Weber 2015, Naidoo 2015), and is not 
exhaustive of all possible irAEs.  Clinical presentations of less common irAEs, including 
neurologic, musculoskeletal, cardiac, renal, and ocular events (Zimmer 2016, Hofmann 2016), 
should be reviewed in patients with concerning presentations. 
The case definitions below have not been validated, and are intended only as guidance for 
investigators to help distinguish irAEs from non-immune AEs.  Investigators’ clinical judgment 
may include other factors when determining immune-relatedness.  The case definitions for irAEs 
may evolve as clinical experience increases with cemiplimab and other antibodies targeting the 
PD-1/PD-L1 axis. 
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a. Immune-related rash:  Skin examination demonstrates a rash that is usually 
maculopapular, but other presentations may occur, including papulopustular, follicular, or 
urticarial dermatitis.  Consider dermatologic consultation and biopsy for atypical 
presentations.   Exclude other cause such as virally-induced rash or contact dermatitis. 
b. Immune-related diarrhea/colitis:  These events are on a continuum, with diarrhea 
defined as increased stool frequency, and colitis involves abdominal pain and/or 
radiologic evidence of colonic inflammation (Naidoo 2015).  Onset at 4 to 6 weeks 
is common (Weber 2015).  A CT scan usually demonstrates diffuse colitis 
(Tirumani 2015).  Exclude clostridium dificile or other infectious etiologies and exclude 
laxative misuse. 
c. Immune-related hepatitis:  Laboratory studies are notable for elevated ALT and/or AST 
that is usually asymptomatic.  Viral or other drug-induced hepatitis is excluded.  Exclude 
alcohol-related liver toxicity.  If clinically appropriate, consider radiologic imaging to 
exclude malignant causes.  If clinically appropriate, exclude worsening of underlying 
cirrhosis. 
d. Immune-related hypothyroidism:  Laboratory studies are notable for elevated TSH 
associated with low serum free thyroxine (free T4).  If elevated TSH is detected, it is 
recommended that free T4 level also be tested.  Elevated TSH with low free T4 
establishes the diagnosis of hypothyroidism.  Hypothyroidism may be asymptomatic or 
associated with symptoms such as fatigue, constipation, cold intolerance, dry skin, weight 
gain, and/or bradycardia.  Exclude other causes of hypothyroidism, such as prior 
radiation therapy to the neck.  In patients with prior history of hypothyroidism, exclude 
noncompliance with thyroid replacement medication. 
e. Immune-related hyperthyroidism:  Hyperthyroidism should be managed with standard 
antithyroid pharmacotherapy, and consultation with an endocrinologist is recommended. 
f. Immune-related pneumonitis: Pneumonitis, defined as inflammation of the lung 
parenchyma, may present as shortness of breath, cough, fever, and/or chest pain.  Median 
time from start of anti-PD-1 therapy to onset of pneumonitis is 2.6 months 
(Nishino 2016), but delayed onset of pneumonitis has been reported.  The most common 
radiologic pattern on CT chest has been described as cryptogenic organizing pneumonia 
(COP), but other radiographic patterns may occur (Nishino 2016).  If performed, biopsy 
may demonstrate lymphocyte-predominant interstitial pneumonitis with areas of 
organizing pneumonia (Nishino 2016).  Exclude infectious causes of pneumonitis. 
Case report forms for irAEs must capture: 
 Date of onset and date of resolution.  Resolution is defined as improvement to 
≤ grade 1 and steroid dose ≤12 mg/day oral prednisone (≤10 mg/day 
methylprednisolone) or equivalent. 
 Treatment administered, including specific drugs and doses, duration of 
immunosuppressive therapy, and if any additional interventions (biopsies, surgical or 
medical procedures) were required 
 Information on dose modifications (eg, date when dose was modified, date dosing 
was resumed and if reaction occurred with re-challenge) 
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7.3.2.2. 
Reasons for Permanent Discontinuation of Study Drug 
Reasons for permanent discontinuation of study drug may include, but are not limited to: 
 An infusion reaction of grade ≥3 severity during or directly following cemiplimab 
infusion 
 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 
 Patients with confirmed disease progression  
 Patient noncompliance (eg, not complying with protocol required visits, assessments, 
and dosing instructions) 
 Pregnancy 
7.4. 
Management of Acute Reactions 
7.4.1. 
Acute Infusion 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 infusion 
reactions must be available for immediate use.  All infusion reactions must be reported as AEs (as 
defined in Section 9.4.1) and graded using the grading scales as instructed in Section 9.5.1. 
In the event of an infusion reaction of Grade 3 or greater severity during or directly following 
cemiplimab infusion, dosing should be stopped and the patient must be permanently discontinued 
from cemiplimab treatment. 
To assist investigators in identifying cemiplimab-related infusion reactions, the following case 
definition is provided: 
 Typical symptoms may include fever, chills, rigors, skin flushing, dyspnea, back pain, 
abdominal pain, and nausea 
 Reason why the event is deemed immune-related 
 Infusion reactions usually occur either during the infusion or within  2 hours after the 
infusion is completed 
 Vital signs may be notable for hypotension and/or tachycardia 
The investigator’s clinical judgment may include other factors when evaluating a possible 
cemiplimab-related infusion reaction.  For example, rarely, an infusion reaction may occur up to 
24 hours after initiation of the infusion. 
Case report forms must capture start and stop time of the event, signs and symptoms, and 
management interventions (medications, interruption of infusion, rate reduction). 
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7.4.1.1. 
Interruption of the Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
 cough 
 rigors/chills 
 rash, pruritus (itching) 
 urticaria (hives, welts, wheals) 
 diaphoresis (sweating) 
 hypotension 
 dyspnea (shortness of breath) 
 vomiting 
 flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of the 
original rate. 
If investigators feel there is a medical need for treatment or discontinuation of the infusion other 
than described above, they should use clinical judgment to provide the appropriate response 
according to typical clinical practice. 
For patients who experience infusion-related hypersensitivity reactions that are less than grade 3 
and who plan to continue treatment, premedication will be required for retreatment. 
For grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated), the following prophylactic medications are recommended for future infusions:  
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 mg 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 mg 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. 
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7.4.1.2. 
Termination of the Infusion 
The infusion should be terminated and NOT restarted if any of the following AEs occur: 
 anaphylaxis 
 laryngeal/pharyngeal edema 
 severe bronchospasm 
 chest pain 
 seizure 
 severe hypotension 
 other neurological symptoms (confusion, loss of consciousness, paresthesia, 
paralysis, etc.) 
 any other symptom or sign that, in the opinion of the investigator, warrants 
discontinuation of the infusion 
7.5. 
Method of Treatment Assignment 
Each patient who signs the informed consent form (ICF) will be assigned a patient number and 
tracked centrally as described in the Interactive 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. 
7.5.1. 
Blinding 
This is an open-label study; no blinding will be employed. 
7.6. 
Treatment Logistics and Accountability 
7.6.1. 
Packaging, Labeling, and Storage 
Open-label study drug will display the product lot number on the label. 
Study drug will be stored at the site at a temperature of 2º to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
7.6.2. 
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. 
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7.6.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug.  These records 
should contain the dates, quantity, and study medication 
 dispensed to each patient, 
 returned from each patient (if applicable), and 
 disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
7.6.4. 
Treatment Compliance 
Cemiplimab will be administered at the study site and recorded on the electronic case report form 
(eCRF).  All dosing records for each patient will be kept by the site.  All drug compliance records 
must be kept current and made available for inspection by the sponsor and regulatory agency 
inspectors. 
7.7. 
Concomitant Medications and 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 follow-up period (approximately 6 months) 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. 
7.7.1. 
Prohibited Medications and Procedures 
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.  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.  Patients must not receive live vaccines 
during the study and up to 5 half-lives after the last dose of study drug.  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. 
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Note: Bisphosphonates and denosumab are not prohibited. 
7.7.2. 
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 BCC 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 BCC (eg, CSCC), removal of the lesion and continued 
treatment on study may be allowed after discussion with the medical monitor. 
7.7.3. 
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 
PD and generally the patient would be removed form study.  Palliative radiation therapy may be 
allowed in certain circumstances in patients who have been on study for at least 24 weeks (see 
Section 7.7.1).  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. 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events 
Study assessments and procedures in the treatment periods are presented in Table 4 and Table 5. 
Study assessments and procedures in the follow-up period are presented in Table 6.  Study visits 
can be scheduled so as not to fall on weekends or holidays, after discussion and approval by the 
Sponsor. 
 
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Table 4: 
Schedule of Events for Treatment Cycles 1 - 5 (9–Week Cycles) 
Study Procedure 
Screening 
Cycle 1 
Cycles 2-51 
End of Study 
Visit Days 
–28 to –1 
1 
22± 
3 
43± 
3 
64±3 
1
2 
22±3 
43±3 
64±3 
30 days after last dose 
cemiplimab 3 
Clinical Assessments and Study Treatment 
Informed Consent4 
X4 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Medical/Oncology History 
X 
 
 
 
 
 
 
 
 
 
Complete Physical Examination, Neurological Exam, 
and ECOG PS5 
X 
X 
 
 
 
X 
 
 
 
X 
Physical Examination (Limited)6 
 
 
X 
X 
 
 
X 
X 
 
 
12-Lead ECG7 
X 
X 
 
 
 
X 
 
 
 
X 
Vital Signs and Weight8 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Brain MRI9 
X 
 
 
 
 
 
 
 
 
 
350 mg cemiplimab Q3W IV 
 
X 
X 
X 
 
X 
X 
X 
  
 
Laboratory Tests 
Hematology10 and Blood Chemistry11 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Serum HCG ≤72 Hour Predose12 
X 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
X13 
 
X 
Urinalysis14 
X 
X 
 
 
 
X 
 
 
 
X 
aPTT; INR 
 
X 
 
 
 
 
 
 
 
X 
HBV, HCV, HIV 
X 
 
 
 
 
 
 
 
 
 
Immune Safety and PK Blood Samples 
RF and ANA 
 
X 
 
 
 
X 
 
 
 
X 
TSH and CRP 
 
X 
 
 
 
X 
 
 
 
X 
ADA15 
 
X15 
 
X 
 
X15 
 
 
 
X 
Cemiplimab PK/Drug Conc16 
 
X 
X 
X 
 
X 
 
 
 
X 
Pathology and Exploratory Biomarker Research Samples 
Archived tissue for histological confirmation of BCC17 
X 
 
 
 
 
 
 
 
 
 
Tumor biopsies for Group 218 
X 
 
X 
 
 
 
 
 
 
 
  
 
X 
 
 
 
 
 
 
 
 
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Study Procedure 
Screening 
Cycle 1 
Cycles 2-51 
End of Study 
Visit Days 
–28 to –1 
1 
22± 
3 
43± 
3 
64±3 
1
2 
22±3 
43±3 
64±3 
30 days after last dose 
cemiplimab 3 
Response Imaging and Other Assessments 
CT/MRI and/or digital photography19 
X 
 
X20 
 
X 
 
 
 
X 
X 
EORTC QLQ-C30, Skindex-1621 
 
X 
 
 
 
X 
 
 
 
X 
Concomitant medications22 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events23 
← continuous monitoring→ 
8.1.1. 
Footnotes for the Schedule of Events for Treatment Cycles 1 – 5 (9-Week Cycles) – Table 4  
ADA=anti-drug antibody; AE=adverse event; ANA=antinuclear antibody; ECOG PS=Eastern Cooperative Oncology Group 
Performance Status; EOS=end of study; HBV=hepatitis B virus; HCG=human chorionic gonadotropin; HCV=hepatitis C virus; 
HIV=human immunodeficiency virus; INR=International Normalized Ratio; MRI=magnetic resonance imaging; RF= rheumatoid 
factor; TSH=thyroid-stimulating hormone 
1. There are 5 treatment cycles of 9 weeks in this table, followed by 4 treatment cycles of 12 weeks in the subsequent table.  The 
maximum number of treatment cycles is 9 (planned 93 weeks total).   
2. Should occur at least 59 days from day 1 of previous cycle, and no sooner than 18 days after the previous dose. 
(1) The EOS visit is for patients who experience PD requiring study discontinuation in cycles 1 through 5.  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 4 and Table 5 (excluding the EOS visit) with any status other than PD 
(eg, CR, PR, or SD) will go on to complete the assessments for follow up in Table 6. 
3. Patients who do not experience PD do not need to complete the EOS visit at end of cycle 9.  Patients will be followed quarterly 
for survival and tumor treatment status, if available. 
4. Informed consent must be provided before the initiation of screening procedures, and must be obtained within 45 days prior to 
cycle1/day 1.  All screening assessments must be performed within 28 days prior to cycle 1/day 1 (with exception for brain 
MRI according to footnote 9, as per below).  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. 
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5. 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. 
6. Limited physical exam includes lungs, heart, abdomen, and skin. 
7. A 12-lead ECG should be recorded at screening, and 30 minutes (±10 minutes) after end of infusion at day 1 visits during 
cycle 1 and cycle 3, and at end of study.  The patient should be relaxed and in a recumbent or semi-recumbent position at least 
5 minutes before recording an ECG.   
8. 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 (±10 minutes) after the completion of the cemiplimab 
infusion. Refer to Section 8.2.3.1 for more information. 
9. 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. 
10. Hematology samples may be collected ≤72 hours prior to study treatment.  Refer to Section 8.2.3.6 for the hematology panel. 
11. Chemistry samples may be collected ≤72 hours prior to study treatment.  Refer to Section 8.2.3.6 for the chemistry panel. 
12. 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. 
13. Urine pregnancy test should be done cycle 1 day 43, cycle 2 day 22, cycle 3 days 1 and 43, cycle 4 day 22, cycle 5 day 1. 
14. Urinalysis samples may be collected ≤72 hours prior to study treatment.  Refer to Section 8.2.3.6 for the urinalysis panel. 
15. ADA samples are collected prior to treatment on day 1 and day 43 of cycle 1, and prior to treatment on day 1 of cycles 3 and 5.  
For patients who complete cycles 1 through 5 and begin follow-up, an ADA sample is collected at end of study (30 days after 
last dose). 
16. Blood samples for PK will be collected at pre-infusion and at end-of-infusion (within 10 minutes after the end of infusion) on 
days 1, 22, and 43 cycle 1, and on day 1 of cycles 2 through 5.  For patients who discontinue treatment during cycles 1 through 
5, a PK sample is collected 30 days after last dose of study drug.   
17. Section 8.2.1 provides the requirements for documentation of histologic confirmation of diagnosis of BCC. 
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18. For Group 2 patients only:  Exploratory tumor biopsies (paired) are required at baseline and on cycle 1 day 22 (±3 business 
days), and at progression (see Appendix 5).  Optional tumor biopsies (paired “Response Biopsies”) should be performed at any 
response assessment in which there is indeterminate-appearing skin regarding malignant versus benign status (see Appendix 
5).  Tumor biopsies should also be collected for histologic confirmation of complete response in any patient for whom the 
clinical impression is complete response, as well as at progression.  Biopsied lesions must be annotated and photographed as 
per Appendix 6. 
19. 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.  Imaging requirements differ for patients in Group 1 and Group 2, and are provided in 
Section 8.2.2.  For the day 22 exploratory tumor biopsy for Group 2 patients, the purpose of the photography is to demonstrate 
the location of the biopsy.  Formal response assessment is not planned for the day 22 photo.  In Table 4, the rows for day 64 
are intended as visual reminders for end-of-cycle tumor assessments.  cemiplimab treatment occurs on day 1 of the subsequent 
cycle. 
20. The “X” for day 22 in cycle 1 pertains to digital medical photography of Group 2 patients (not Group 1) who undergo 
Exploratory Biopsies on day 22.  The day 22 photos are annotated to demonstrate biopsy locations, and are not intended for 
tumor response assessments.  Scheduled tumor response assessments during cycles 1 to 5 are every 9 weeks. 
21. If the Skindex-16 translation is not available for a specific language this can be omitted.  
22. Concomitant medication recording will be done at every visit. 
23. Adverse event recording will be ongoing throughout the course of the study, using NCI-CTCAE v4.03. 
 
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Table 5: 
Schedule of Events for Cycle 6 – 9 (12–Week Cycles) 
Study Procedure 
Cycles 6 - 9 
End of Study 
Visit Days 
 
1±31 
22±3 
43±3 
64±3 
85±3 
30 days after last dose 
cemiplimab 2 
Clinical Assessments and Study Treatment 
Complete Physical Examination, Neurological Exam, and ECOG 
PS3 
X 
 
 
 
 
X 
Physical Examination (Limited)4 
 
X 
X 
X 
 
 
12-Lead ECG5 
X 
 
 
 
 
X 
Vital Signs and Weight6 
X 
X 
X 
X 
 
X 
350 mg cemiplimab Q3W IV 
X 
X 
X 
X 
 
 
Laboratory Tests 
Hematology7 and Blood Chemistry8 
X 
X 
X 
X 
 
X 
Pregnancy Test (serum or urine) 
X 
 
X 
 
 
X 
Urinalysis9 
X 
 
X 
 
 
X 
aPTT; INR 
 
 
 
 
 
X 
Immune Safety and PK Blood Samples 
RF and ANA 
X 
 
 
 
 
X 
TSH and CRP 
X 
 
 
 
 
X 
ADA10 
X 
 
 
 
 
X 
Cemiplimab PK/Drug Conc11 
X 
 
 
 
 
X 
Response Imaging and Other Assessments 
CT/MRI and/or digital photography 12,13 
 
 
 
 
X 
X 
EORTC QLQ-C30, Skindex-1614  
X 
 
 
 
 
X 
Concomitant medications15 
X 
X 
X 
X 
X 
X 
Adverse Events16 
← continuous monitoring→ 
 
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8.1.2. 
Footnotes for the Schedule of Events for Treatment Cycles 6 – 9 (12-Week Cycles) – Table 5  
ADA=anti-drug antibody; AE=adverse event; ANA=antinuclear antibody; ECOG PS=Eastern Cooperative Oncology Group 
Performance Status; EOS=end of study; HBV=hepatitis B virus; HCG=human chorionic gonadotropin; HCV=hepatitis C virus; 
HIV=human immunodeficiency virus; INR=International Normalized Ratio; MRI=magnetic resonance imaging; RF= rheumatoid 
factor; TSH=thyroid-stimulating hormone 
1. Should occur at least 59 days from the previous day 1 of cycle 5 (for cycle 6), or 81 days from day 1 of previous cycle (for 
cycles 7 – 9), and no sooner than 18 days after the previous dose. 
(1) The EOS visit is for patients who experience PD requiring study discontinuation in cycles 6 through 9.  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 post treatment 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 4 and Table 5 (excluding the EOS visit) with any status other than PD 
(eg, CR, PR, or SD) will go on to complete the assessments for follow up in Table 6 . 
2. Patients who do not experience PD do not need to complete the EOS visit at end of cycle 9.  Patients will be followed quarterly 
for survival and tumor treatment status, if available 
3. 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. 
4. Limited physical exam includes lungs, heart, abdomen, and skin. 
5. A 12-lead ECG should be recorded at screening, and 30 minutes (±10 minutes) after end of infusion at day 1 visits during 
cycle 6 and cycle 9, and at end of study.  The patient should be relaxed and in a recumbent or semi-recumbent position at least 
5 minutes before recording an ECG.   
6. 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 (±10 minutes) after the completion of the cemiplimab 
infusion. 
7. Hematology samples may be collected ≤72 hours prior to study treatment.  Refer to Section 8.2.3.6 for the hematology panel. 
8. Chemistry samples may be collected ≤72 hours prior to study treatment.  Refer to Section 8.2.3.6 for the chemistry panel. 
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9. Urinalysis samples may be collected ≤72 hours prior to study treatment.  Refer to Section 8.2.3.6 for the urinalysis panel. 
10. ADA samples are collected prior to treatment on day 1 of cycles 6 through 9.  For patients who discontinue treatment during 
cycles 6 through 9, an ADA sample is collected 30 days after last dose of study drug. 
11. Blood samples for PK will be collected on day 1 of cycles 6 through 9 at pre-infusion and at end-of-infusion (within 10 
minutes after the end of infusion).  For patients who discontinue treatment during cycles 6 through 9, a PK sample is collected 
30 days after last dose of study drug.   
12. 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.  Imaging requirements differ for patients in Groups 1 and 2, and are provided in 
Section 8.2.2.  In Table 5, the row for day 85 is intended as a visual reminder for end-of-cycle tumor assessment.  Cemiplimab 
treatment occurs on day 1 of the subsequent cycle.  
13. For Group 2 patients only: Optional tumor biopsies (paired “Response Biopsies”) should be performed at any response 
assessment in which there is indeterminate-appearing skin regarding malignant versus benign status (see Appendix 4).  Tumor 
biopsies should also be collected for histologic confirmation of complete response in any patient for whom the clinical 
impression is complete response, as well as at progression. Biopsied lesions must be annotated and photographed as per 
Appendix 5. 
14. If the Skindex-16 translation is not available for a specific language this can be omitted 
15. Concomitant medication recording will be done at every visit. 
16. Adverse event recording will be ongoing throughout the course of the study, using NCI-CTCAE v4.03. 
 
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Table 6: 
Schedule of Events for Follow-up (After 9 Cycles of Treatment) 
Study Procedure 
Visit 
Follow-up 1 
Follow-up 2 
Follow-up 3 
Follow-up 4 
Follow-up 5 Follow-up 6 
Follow-up 71 
Extended Follow-up 
 
Time point (Day) 
Cycle 9 visit +  
28 ± 7 
days 
  
Follow-up 1 + 
28 ± 7 days 
Follow-up 2 
+ 28 ± 7 days 
Follow-up 3 + 28 ± 7 
Days 
Follow-up 4 
+ 28 ± 7 
days 
Follow-up 5 + 
28 ± 7 
days 
Follow-up 6 + 
28 ± 7 
days 
Every 4 months for 1 
year13 
Complete Physical 
examination and 
neurological exam2 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Status 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Tests 
Hematology4,5 
X 
 
 
 
 
 
 
 
Blood chemistry4,5,6 
X 
 
 
 
 
 
 
 
Urine or serum pregnancy 
test5,7 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis5,8 
X 
 
 
 
 
 
 
 
Immune Safety Assays 
RF5 
X 
ANA5 
X 
TSH5 
X 
CRP5 
X 
PK Drug Conc/ADA 
Sample 
Cemiplimab PK/Drug 
Conc9 
X 
X 
X 
 
ADA sample9 
X 
 
X 
 
Pathology Samples 
Tumor biopsy5 
=========== ============= ===========  At Time of Progression  ===================== 

Tumor Assessments 
CT/MRI 
(chest/abdomen/pelvis) 
And/or digital 
photography10 
 
X 
 
X 
 
 
X 
X 
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Other Clinical 
Assessments 
Concomitant medications11 
X 
 
 
 
 
 
Adverse events12 
===========  
============= ===========  
============  
=========== ============ ==========
 
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8.1.3. 
Footnotes for the Schedule of Events for Follow-up (After 9 Cycles of Treatment) – Table 6 
ADA=anti-drug antibody; AE=adverse event; ANA=antinuclear antibody; CRP=C-reactive protein; CT=computed tomography; 
ECOG=Eastern Cooperative Oncology Group; MRI=magnetic resonance imaging; RF= rheumatoid factor; TSH=thyroid-stimulating 
hormone. 
1. After completion of this schedule of events, patients will be followed quarterly for survival and tumor treatment status, if 
available.   
2. Complete physical examination includes head and neck, lungs, heart, abdomen, lymph nodes, extremities, and skin. A brief 
neurologic examination should also be performed. Complete physical exam must be accompanied by assessment and 
documentation of ECOG Performance Status. 
3. Vital signs include temperature, resting blood pressure, pulse, and respiration. 
4. Refer to Section 8.2.3.6 for the hematology panel. 
5. At time of progression, the EOS tumor biopsy should be obtained for all patients in Group 2. Blood samples for laboratory 
tests (hematology, blood chemistry, urine pregnancy test, urinalysis) and immune safety (RF, ANA, TSH, CRP) are also 
obtained at time of progression (within 28 days of the imaging study that documented progression) according to the EOS 
assessment schedule (Table 4 and Table 5 ).   
6. Refer to Section 8.2.3.6 for the chemistry panel. 
7. Pregnancy tests may be urine β-HCG or serum. 
8. Refer to Section 8.2.3.6 for the urinalysis panel. 
9. Cemiplimab PK samples will be collected at follow-up visits 1, 4, and 7.  ADA samples will be collected at follow-up visits 1 
and 7.  ADA is not required at the EOS visit if it was collected at follow-up visit 1.  PK is not required at the EOS visit if it was 
collected at follow-up visit 1 and follow-up visit 4. 
10. The same method (CT/MRI) and/or digital medical photography used at baseline should be used throughout the study. Scans 
linked to follow-up visits are required only if PD has not been confirmed previously while on study.  CT/MRI imaging will be 
obtained within 14 days prior to the follow-up visit, so that the disease status is known at the time of the visit. Digital medical 
photography may be obtained within 14 days prior to visit, or on the day of the visit, and response status (CR, PR, SD, PR) 
will guide whether the visit is to be treated as a follow-up visit or as the EOS visit. 
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11. Concomitant medications should be recorded from the date of informed consent through 30 days after last dose of study drug.  
Any drug started to treat a study drug-related AE during the follow-up will also be recorded.  In addition, any cancer 
treatments should be recorded from the day of informed consent until 105 days (5 half-lives) after the administration of the last 
dose of cemiplimab.  Any AE assessed as related to study treatment and persisting after 105 days (5 half-lives) post last dose 
should be reported until resolution to baseline or grade ≤1. 
12. Nonserious AE and SAE data will be collected from the day of informed consent until 30 days after the last dose of 
cemiplimab.  Any AE assessed as related to study treatment and persisting after 105 days (5 half-lives) post-last dose should be 
reported until resolution to baseline or grade ≤1. 
13. Patients who do not experience PD will be followed for an additional 1 year with assessments every 4 months. 
 
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8.1.4. 
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 
(same as in Table 5), as appropriate.  After the EOS visit, patients with PD 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 4) should be obtained at time of progression, 
whether progression occurs in cycles 1 through 9 or during follow-up (after cycle 9). 
Patients who discontinue study treatment due to reasons other than PD (eg, toxicity, confirmed CR 
after 45 weeks) should continue follow-up to complete all assessments in Table 6 until PD or 
completion of follow-up visits 1 to 7  and extended follow-up (Table 6).  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. 
 
8.1.5. 
Retreatment 
For patients (Group 1 or Group 2) who complete 9 cycles of treatment without disease progression 
and subsequently experience disease progression during the follow-up period (follow-up visits 1 
through 7 only) without any intervening systemic anticancer therapy, resumption of treatment with 
cemiplimab IV 350 mg Q3W  will be allowed per Table 5 (four 12-week cycles).  Prior to 
resumption of cemiplimab treatment, patients must be re-consented (including resigning informed 
consent) and must repeat all screening activities (with the exception of providing new archived 
pathology material, research biopsies, or brain MRI), 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 Q3W monotherapy treatment for 48 
weeks (maximum 4 retreatment cycles; 12 weeks per cycle), as per the schedule of events in 
Table 5.  However, PK, ADA, research blood samples, and research tumor biopsies (exploratory 
“Tumor Biopsies” for Group 2) are not required for these patients during retreatment. In response 
to AESI like anaphylaxis or hypersensitivity, ADA samples closer to the event may be collected 
and analyzed, based on the judgement of the medical investigator and/or medical monitor. 
After retreatment, patients will be followed quarterly for survival and tumor treatment status, if 
available, until death.  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. 
8.1.6. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted.  
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8.1.7. 
End of Study Definition 
The end of the study will occur when the last patient to enter retreatment (per Section 8.1.5 ) 
completes the retreatment plus safety follow-up for 5 half-lives (105 days).  Regeneron reserves 
the right to terminate this study at any time if safety concerns emerge that warrant study closure. 
8.2. 
Study Procedures 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole 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: hepatitis B surface antigen, hepatitis C positive RNA 
(positive hepatitis C antibody test will require hepatitis C RNA test to rule out active 
infection), HIV-1, or HIV-2 serum antibody 
 Documentation of pathologic confirmation of BCC by a pathologist at the study site (see 
Section 6.2.1, Inclusion Criterion #1).  The pathology report that documents the diagnosis 
of BCC should be from the most recent biopsy that documented BCC. 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 4 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 BCC is 
obtained on archived material.  If the archived material is not sufficient for confirmation 
of diagnosis of BCC 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 BCC has 
been established. 
 Brain MRI, with gadolinium, is required at screening if it has 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 is contraindicated. 
 Group 1 – 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.  Magnetic resonance imaging with gadolinium is generally 
preferred for bone lesions, perineural lesions, abdomen, pelvis, extremity, and head and 
neck.  Computed tomography 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: In the case 
of a Group 1 patient with metastatic disease that is not measurable by RECIST criteria 
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(eg, bone only lesions, perineural disease) and with externally visible BCC target lesions, 
digital medical photography may be used to follow the externally visible lesions as target 
lesions. 
 Group 2 – Externally visible lesions will be followed by digital medical photography.  
Baseline assessments will include radiologic imaging of all target lesions (preferably 
MRI with gadolinium for all anatomic sites except lung, but CT with iodinated contrast 
allowed at any anatomic site, per investigator discretion) to assess for deep invasion.  
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).   
8.2.2. 
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 and Table 5 .  The choice of whether the imaging is by CT or MRI is an investigator decision, 
but preferred imaging choices are provided in Section 8.2.1.  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 BCC lesions are evaluable on the skin, composite response criteria 
(Appendix 2) should be used on the same schedule (every 9 weeks for cycles 1 to 5, every 12 weeks 
for cycles 6 - 9), in combination with radiologic imaging if appropriate. 
 Group 1:  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 BCC lesions noted at baseline should be 
photographed at each response assessment (Appendix 5), and will generally be deemed 
non-target.  New externally visible lesions that are clinically suspicious for malignancy 
should be photographed (Appendix 5) and biopsied.  Note: In the case of a Group 1 patient 
with metastatic disease that is not measurable by RECIST criteria (eg, bone only lesions, 
perineural disease) and with externally visible BCC target lesions, digital medical 
photography may be used to follow the externally visible lesions as target lesions. 
 Group 2: All externally visible BCC lesions should be photographed in a consistent 
manner at each response assessment as described in Appendix 5.  Radiologic imaging (MRI 
with gadolinium preferred) of anatomic area of externally visible target lesions should be 
performed at screening and at each response assessment. For each target lesion, the 
investigator will decide (based on screening imaging) if the radiology (CT or MR) or photo 
will be the most appropriate method to measure that target lesion, and should use the same 
modality to measure that target lesion at baseline and at each assessment. If photo is 
selected to measure a target lesion, imaging (CT or MR) should be obtained to provide 
supplemental information. In cases in which it is the opinion of the investigator that no 
significant added information was provided by baseline radiologic imaging of the lesion 
(beyond the information that was provided by baseline digital medical photography), it is 
allowed to use digital medical photography only (without radiologic imaging) at 
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subsequent response assessments of that lesion, at the discretion of the investigator (or 
vice-versa).  If the investigator opts to discontinue cross-sectional radiologic imaging after 
the baseline assessments and follow the lesion only with digital medical photography (or 
vice-versa), the reason(s) should be captured in the CRF.  
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.  When possible, 
progression should be confirmed.  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. 
In Group 1, patients will generally be followed by RECIST 1.1 criteria (Appendix 1).  It is possible 
that some patients in Group 1 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, for Group 1 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 
Group 1 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.  See Appendix 5 for guidelines on annotation of photos.  If annotation of full 
perimeter of the lesion is deemed not clinically appropriate by the investigator (eg, an ulcerated 
lesion), the priority annotation will be of the axes delimiters. The perimeter of the lesion should 
be annotated as fully as possible without causing undue discomfort to the patient. 
For externally visible lesions that are indeterminate-appearing regarding presence of BCC, see 
Appendix 4 for guidelines on tumor biopsies.   
All radiological scans, photography, and biopsy results will be independently reviewed.  An 
independent central review committee will be formed to determine overall response for each 
patient based on the integration of these modalities. 
8.2.3. 
Safety Procedures 
8.2.3.1. 
Vital Signs 
Vital signs, including temperature, resting blood pressure, pulse, and respiration, will be collected 
at time points according to Table 4, Table 5, and Table 6 . 
Note: blood pressure should be measured after the patient has been resting quietly for at least 
5 minutes. 
At cycle 1 day 1 and cycle 1 day 22, patients will be monitored for 30 minutes after the completion 
of cemiplimab infusion, and vital signs will be recorded at the end of 30 minutes. On all subsequent 
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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. 
8.2.3.2. 
Physical Examination 
A thorough complete or limited physical examination will be performed at visits specified in 
Table 4, Table 5, and Table 6.  Care should be taken to examine and assess any abnormalities that 
may be present, as indicated by the patient’s medical history. 
Complete physical examination 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 6). 
Limited physical examination will include lungs, heart, abdomen, and skin. 
8.2.3.3. 
Electrocardiogram 
A standard 12-lead electrocardiogram (ECG) will be performed at time points according to 
Table 4, Table 5, and Table 6,.  On treatment days, ECG will be collected 30 minutes 
(±10 minutes) after the end of the infusion. 
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 (beats per minute; 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. 
8.2.3.4. 
Immune Safety Assays 
Immune safety assays consist of rheumatoid factor (RF), thyroid-stimulating hormone (TSH), 
C-reactive protein (CRP), and antinuclear antibody (ANA) titer and pattern. 
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. 
8.2.3.5. 
Coagulation Tests 
Activated partial thromboplastin time (aPTT) and International Normalized Ratio (INR) will be 
analyzed by local laboratory. 
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8.2.3.6. 
Laboratory Testing 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by local 
laboratory. 
Detailed instructions for blood sample collection (eg, immune safety assays, ADA, PK, 
 
not routine local labs) are in the laboratory manual provided to 
study sites. 
Samples for laboratory testing will be collected at time points according to Table 4, Table 5, and 
Table 6.  Tests will include: 
Blood Chemistry 
Sodium 
Albumin 
Total bilirubin 
Potassium 
Creatinine 
Alkaline phosphatase 
Chloride 
Blood urea nitrogen (BUN)* 
Glucose 
Bicarbonate** 
Aspartate aminotransferase (AST) 
Creatine phosphokinase (CPK) 
Calcium 
Alanine aminotransferase (ALT) 
 
 
*At ex-US centers in which a urea assay is performed instead of BUN, the urea assay will be acceptable. 
**At ex-US centers in which the bicarbonate test is not performed as part of the routine blood chemistry panel, it 
may be omitted. 
Hematology 
Hemoglobin 
Differential: 
White blood cells (WBCs) 
 
Neutrophils 
Platelet count 
 
Lymphocytes 
 
 
Monocytes 
Urinalysis 
Glucose 
pH 
Ketones 
Blood 
Specific gravity 
Spot urine protein 
Abnormal Laboratory Values and Laboratory Adverse Events 
 All laboratory values must be reviewed by the investigator or authorized designee. 
 Significantly abnormal test results that occur after start of treatment must be repeated 
to confirm the nature and degree of the abnormality.  When necessary, appropriate 
ancillary investigations should be initiated.  If the abnormality fails to resolve or 
cannot be explained by events or conditions unrelated to the study medication or its 
administration, the medical monitor must be consulted.   
 The clinical significance of an abnormal test value, within the context of the disease 
under study, must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 9.4.5. 
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8.2.4. 
Pharmacokinetic and Anti-Drug Antibody Procedures 
8.2.4.1. 
Drug Concentration Measurements and Samples 
Cemiplimab PK parameters will be determined by measuring cemiplimab concentrations in serum 
samples using a validated assay at visits and time points indicated in Table 4, Table 5, and Table 6, 
and listed in Appendix 7.  The 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 PK sampling times will be based on the cemiplimab 
dosing time that precedes the PK sampling.  Pre-infusion is defined as before the start of the 
cemiplimab infusion and “0 hour” is defined as immediately after the end of the cemiplimab 
infusion. 
 
 
8.2.4.2. 
Anti-Drug Antibody Measurements and Samples 
Samples for ADA assessment will be collected prior to dosing at time points listed in Table 4 and 
Table 5, and at the follow-up time points specified in Table 6.  In response to AESI like 
anaphylaxis or hypersensitivity, ADA samples closer to the event may be collected and analyzed, 
based on the judgement of the medical investigator and/or medical monitor (in treatment, 
follow-up, or retreatment). 
The relationship between immunogenicity and PK of cemiplimab may be assessed, as appropriate.  
 
8.2.5. 
Biomarker Procedures 
Soluble biomarker samples will be collected at time points according to Table 4. 
8.2.5.1. 
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 tissue 
collected at baseline (including archival tumor tissue), after treatment with cemiplimab, and at 
progression, if available.  
 
 
 
 
 Biomarker results will be reported separately from the 
clinical study report. 
8.2.5.2. 
Tumor Biomarker Procedures 
For patients with locally advanced BCC (Group 2), tumor biopsies will be collected per the time 
points and methodology in Appendix 4 and the Laboratory Manual. 
Expression levels (mRNA and/or protein) of PD-L1, GITR, and LAG-3, as well as the number and 
distribution of TILs (defined by lineage markers CD4, CD8, CD25, FoxP3) will be assessed in 
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tumor biopsy samples.  Additional biomarkers may be measured tissue permitting.  Biomarker 
measurements and correlative analyses in respect to clinical response and disease progression will 
be used to explore potential predictive value of these biomarkers. 
Tumor tissue, as well as RNA and DNA isolated from tumor tissue, will be used to assess changes 
in potential pharmacodynamic biomarkers induced by cemiplimab treatment from baseline. 
Main exploratory potential biomarkers of interest include, but are not limited to: 
 Tumor mRNA expression 
 Number and distribution of TILs (CD8+ T cells, CD4+ T cells, T regulatory cells, and 
tissue permitting, other subtypes such as B cells, myeloid-derived cells, NK cells, 
etc.) 
 Expression levels (mRNA and/or protein) of PD-L1 and possibly other check-point 
modulators 
 Mutations in known oncogenes and potential tumor neoantigens 
 Tumor mutational burden 
Additional biomarkers may be measured (for example, exome sequencing, single cell RNA 
analysis, microsatellite instability, T cell clonality) tissue permitting.  Biomarker measurements 
and correlative analyses in respect to clinical response and disease progression will be used to 
explore potential predictive value of these biomarkers. 
Tumor-derived DNA and RNA samples will be double-coded as defined by the International 
Council for Harmonisation (ICH) guideline E15. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB)/Ethics Committee 
(EC) all unanticipated problems involving risks to patients per local IRB/EC requirements.   
9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (suspected unexpected serious 
adverse reaction [SUSAR]), to the health authorities, IECs/IRBs as appropriate, and to the 
investigators.  
Any AE not listed as an expected event in the RSI section of the Investigator’s Brochure will be 
considered as unexpected for regulatory reporting purposes.  Any worsening of or new onset of 
symptoms related to BCC that occur during the screening/washout period prior to study drug 
administration will be considered expected for the underlying disease population and will be 
recorded as AEs/SAEs. 
In addition, the sponsor will report in an expedited manner all SAEs that are unexpected and at 
least reasonably related to the study drug to the health authorities, according to local regulations. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the clinical study report to health authorities and IECs/IRB as appropriate. 
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug.  Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
Progression of underlying malignancy will not be considered an AE if it is clearly consistent with 
the typical progression pattern of the underlying cancer (including time course, affected organs, 
etc.).  Clinical symptoms of progression may be reported as AEs if the symptom cannot 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. 
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If there is any uncertainty about an AE being due only to progression of the underlying malignancy, 
it should be reported as an AE or SAE as outlined in Section 9.3.2. 
9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (eg, a car accident in which a patient is a passenger). 
 Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
 Requires in-patient hospitalization or prolongation of existing hospitalization.  
In-patient hospitalization is defined as admission to a hospital or an emergency room 
for longer than 24 hours.  Prolongation of existing hospitalization is defined as a 
hospital stay that is longer than was originally anticipated for the event, or is 
prolonged due to the development of a new AE as determined by the investigator or 
treating physician. 
 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
 Is a congenital anomaly/birth defect 
 Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse). 
Hospitalization or death due solely to manifestations consistent with typical progression of 
underlying malignancy will not be considered an SAE. 
Criteria for reporting SAEs must be followed for these events.  See Section 9.4 for more 
information on recording and reporting SAEs. 
9.3.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the sponsor’s 
product or program, for which ongoing monitoring and rapid communication by the investigator 
to the sponsor can be appropriate.  Such an event might warrant further investigation in order to 
characterize and understand it.  Depending on the nature of the event, rapid communication by the 
trial sponsor to other parties (eg, regulators) might also be warranted (Section 9.4.3).  
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9.3.4. 
Infusion Reactions 
Infusion reactions are defined as any AE that occurs during the infusion or within 2 hours after the 
infusion is completed.  See Section 7.4.1 for case definition.  All infusion reactions must be 
reported as AEs (defined in Section 9.4.1) and graded using the grading scales as instructed in 
Section 9.5.1. 
9.4. 
Recording and Reporting Adverse Events 
9.4.1. 
Adverse Events 
The investigator (or designee) will seek information on AEs at each patient contact, and record all 
AEs that occur from the time the informed consent is signed until 105 days (5 half-lives) after the 
end of study treatment.  Prior to initiation of study treatment, only the following categories of AEs 
should be reported on the AE CRF: 
 SAEs 
 Non-SAEs 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 CRF. 
Information on follow-up for AEs is provided in Section 9.4.6.  Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours.  Refer to the study reference manual for the procedure to 
be followed. 
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 until 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 chronic and/or stable. 
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9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
Symptomatic Overdose of Study Drug: 
Accidental or intentional overdose of at least 2 times 
the intended dose of study drug within the intended therapeutic window, if 
associated with an AE. 
Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female or female partner of a male, during the study 
or within 105 days (5 half-lives) of the last dose of study drug.  Any complication 
of pregnancy affecting a female study patient or female partner of a male study 
patient, and/or fetus and/or newborn that meets the SAE criteria must be reported 
as an SAE.  Outcome for all pregnancies should be reported to the sponsor. 
Adverse Events of Special Interest: 
AESIs for this study may include: 
 Grade 2 or greater infusion-related reactions 
 Grade 2 or greater allergic/hypersensitivity reactions 
 Grade 3 or greater irAEs 
 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 study manual for the procedures to be followed. 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
medical monitor within 30 days. 
Refer to the study reference manual for the procedures to be followed. 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
 the test result is associated with accompanying symptoms, and/or 
 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)  
 the test result leads to discontinuation from the study, significant additional concomitant 
medication, or other therapy 
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Contact the medical monitor in the event the investigator feels that an abnormal test finding should 
be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE.  Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale outlined 
in Section 9.5.1. 
9.4.6. 
Follow-up 
Information for any non-SAE that starts during the treatment period or within 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 chronic and/or 
stable. 
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
The severity of AEs will be graded according to the following scale: 
The severity of AEs (including test findings classified as AEs) will be graded using the current 
version of the NCI-CTCAE grading system.  Adverse events not listed in the NCI-CTCAE will be 
graded according to the following scale: 
 1 (Mild):  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
 2 (Moderate):  Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental Activities of Daily Living (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 ADLs refer to activities such as preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc. 
** Self-care ADLs refer to activities such as bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not being bedridden. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
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9.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the investigator, and will be a clinical 
decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the study 
drug 
Related: 
There is a reasonable possibility that the event may have been caused by the study 
drug 
A list of factors to consider when assessing the relationship of AEs to study drug is provided in 
Appendix 8. 
The investigator should justify the causality assessment of each SAE. 
Relationship of Adverse Events to Study Conduct: 
The relationship of AEs to study conduct will be assessed by the investigator, and will be a clinical 
decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by study conduct? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by study 
conduct 
Related: 
There is a reasonable possibility that the event may have been caused by study 
conduct 
A list of factors to consider when assessing the relationship of AEs to study conduct is provided 
in Appendix 8. 
The investigator should justify the causality assessment of each SAE. 
9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP).  Any questions or 
concerns should be discussed with the sponsor in a timely fashion.  The sponsor will monitor the 
safety data from across all study sites.  The medical monitor will have primary responsibility for 
the emerging safety profile of the compound, but will be supported by other departments 
(eg, Pharmacovigilance and Risk Management; Biostatistics and Data Management).  Safety 
monitoring will be performed on an ongoing basis (eg, individual review of SAEs) and on a 
periodic cumulative aggregate basis. 
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9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical 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 or this protocol, and has a reasonable suspected causal relationship to the 
medicinal/study drug). 
 
 
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10. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (SAP) for the study.  The SAP may 
be revised during the study to accommodate amendments to the clinical study protocol and to make 
changes to adapt to unexpected issues in study execution and data that may affect the planned 
analyses.  The final SAP will be issued before the database is locked. 
In order to describe ORR and DOR, the data cut for primary efficacy analysis will allow 
responding patients to be followed from onset of response for at least 6 months. Because responses 
may emerge slowly in BCC patients (Falchook 2016), and the primary endpoint results are not 
known prior to data cut, the convention in this study will be that all patients will have the 
opportunity for at least 6 months to develop response.  For primary analysis, the last patient in a 
group will have the opportunity to be followed for approximately 57 weeks, including 27 weeks 
(cycles 1 to 3) for response, plus an additional 30 weeks (cycles 4 to 6) for DOR.  If the last 
patient(s) has early EOS, the timing of data cut will be determined by the enrollment date of the 
last enrolled patient who remains on study (first dose + approximately 57 weeks).    
An updated analysis of the response duration will be performed after all responding patients have 
been followed for a minimum of 12 months from onset of response.  
An interim analysis of Group 1 patients will be performed at the time of the primary analysis for 
Group 2.  For additional details, please see Section 10.5.  
Analysis variables are listed in Section 4. 
10.1. 
Statistical Hypothesis 
For the primary endpoint of ORR, the statistical hypothesis is that cemiplimab-treated patients will 
have an ORR representing a clinically meaningful treatment, with Group 1 and Group 2 evaluated 
independently. 
10.2. 
Justification of Sample Size 
Patients will be enrolled into 2 separate groups according to the stage of disease: metastatic BCC 
(Group 1) or unresectable locally advanced BCC (Group 2).  The benchmarks for clinically 
meaningful response rates of >15% and >20% in metastatic and in unresectable locally advanced 
BCC, respectively, are consistent with published literature for BCC (Sekulic 2012, Migden 2015).  
For Group 1, 50 patients 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 5% if the true ORR is 34%.  For Group 2, 
80 patients are required to provide at least 85% power to reject a null hypothesis of an ORR of 
20% at a 2-sided significance level of 5% if the true ORR is 35%. 
Given the sample sizes above, the nonclinically meaningful ORR of 15% for Group 1 will be 
excluded using the lower limit of 2-sided 95% CI if the observed ORR is 28% or more (see 
Table 7) among 50 patients. The nonclinically meaningful ORR of 20% for Group 2 will be 
excluded using the lower limit of 2-sided 95% CI if the observed ORR is 30.0% or more (see 
Table 8) among 80 patients.  
The sample sizes will be 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 and 84 patients for 
Group 2, for a total of 137 patients. 
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Table 7: 
The 95% Binomial Exact Confidence Intervals for Observed ORR in 
Group 1 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 
It is acknowledged that metastatic BCC is uncommon. For this reason, the following stopping rule 
will be enforced if accrual to Group 1 is insufficient: If accrual to Group 1 is <16 patients in 
6 months, Group 1 will be closed for inability to achieve target accrual. The start of this 6-month 
period will be the date that ninth patient is enrolled in Group 2. 
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Table 8: 
The 95% Binomial Exact Confidence Intervals for Observed ORR in 
Group 2 Given a Sample Size of 80 Patients (Based on 85% Power) 
Number of Responders 
Observed ORR 
95%CI – lower 
95% CI – upper 
16 
0.200 
0.119 
0.304 
17 
0.212 
0.129 
0.318 
18 
0.225 
0.139 
0.332 
19 
0.237 
0.149 
0.346 
20 
0.250 
0.160 
0.359 
21 
0.263 
0.170 
0.373 
22 
0.275 
0.181 
0.386 
23 
0.287 
0.192 
0.400 
24 
0.300 
0.203 
0.413 
25 
0.312 
0.213 
0.426 
26 
0.325 
0.224 
0.439 
27 
0.338 
0.236 
0.452 
28 
0.350 
0.247 
0.465 
10.3. 
Analysis Sets 
A patient is deemed eligible and enrolled after the patient completes the screening process and the 
investigator deems that the patient is eligible, and the investigator orders study drug in the IWRS.  
At that point, the patient’s status in the IWRS changes from “in screening” to “enrolled.”  A patient 
is not deemed eligible until he/ she is enrolled in IWRS. 
10.3.1. 
Full Analysis Set 
The full analysis set (FAS) includes all patients for each group who have passed screening and are 
deemed to be eligible for this study.  All efficacy endpoints will be analyzed using FAS.  
10.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all enrolled patients who receive any study drug for each 
group.  Treatment compliance/administration and all clinical safety variables will be analyzed or 
summarized using the SAF. 
10.3.3. 
Pharmacokinetic Analysis Set 
The PK analysis set will include all patients who receive cemiplimab and have at least 
1 non-missing post-baseline measurement of cemiplimab concentration in serum. 
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10.3.4. 
Anti-Drug Antibody Analysis Set 
The ADA analysis set includes all treated patients who have received any cemiplimab and who 
have at least 1 post-dose ADA result. 
The NAb analysis set includes all patients who received any cemiplimab and who have at least 1 
non-missing result in the NAb assay. 
10.3.5. 
Biomarker Analysis Set 
The biomarker analysis set (BAS) includes all treated patients who received any cemiplimab and 
who have at least 1 sample assayed. 
10.4. 
Statistical Methods 
In general, the descriptive summary for continuous data will include the number of observations 
(n), mean, standard deviation, median, minimum and maximum.  In addition, the 25th percentile 
and the 75th 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. 
10.4.1. 
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 
10.4.2. 
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). 
10.4.3. 
Efficacy Analyses 
10.4.3.1. Primary Efficacy Analysis 
The primary endpoint for efficacy analyses is the ORR as determined by RECIST version 1.1 
(Eisenhauer 2009) or by the clinical and composite response criteria (see Section 8.2.2).  The ORR 
assessment for the primary analysis will be performed by an independent central review 
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committee.  The investigator-assessed ORR will be considered as a secondary analysis.  Efficacy 
analyses of Group 1 and Group 2 will be independent of each other. 
The primary analyses of efficacy for Group 1 and Group 2 are based on the binomial exact 
confidence interval approach, ie, whether or not the lower limit of 2-sided 95% confidence interval 
will exclude an historical control ORR that is not deemed clinically meaningful.  The 95% 
binomial exact confidence intervals using the Clopper-Pearson method (Clopper 1934) for 
observed ORRs is listed for Group 1 (Table 7) and for Group 2 (Table 8). 
10.4.3.2. Secondary Efficacy Analysis 
The secondary analysis of efficacy as measured by duration of response, PFS, and OS will be 
summarized by median and its 95% confidence interval by the Kaplan-Meier method. 
The CR rate will be summarized descriptively with 95% confidence interval.  Absence of residual 
BCC in patients with locally advanced BCC achieving a clinical response to cemiplimab, as 
measured by central review, will be summarized descriptively. 
10.4.3.3. Multiplicity Considerations 
Patients will be enrolled into 2 separate groups according to the stage of disease: metastatic BCC 
(Group 1) or unresectable locally advanced BCC (Group 2).  Statistical analyses of the primary 
endpoint 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).  There is 
no hypothesis test for secondary endpoints.  Therefore, statistical control of overall type I error for 
the whole study is not planned.  Unless specified otherwise, all efficacy endpoints will be 
summarized using 2-sided 95% confidence interval.   
10.4.4. 
Exploratory Analyses 
10.4.4.1. Subgroup Analyses 
Subgroup efficacy analyses may be performed based on the number of prior systemic therapy 
regimens, the degree of differentiation of the tumor (well, moderate, or poor), the presence or 
absence of human papillomavirus in the tumor, and the presence or absence of use of immune 
suppressive medications (eg, high dose steroids) to manage irAEs that may arise during the study. 
Subgroup efficacy analysis will also be performed based on the reason that a patient was deemed 
unlikely to benefit from further HHI therapy (progression/lack of response versus intolerance).  
Patients with stable disease will be included in the "lack of response" category for this analysis.  If 
a patient experiences both progression and intolerance, progression will be scored as the reason 
that the patient would be unlikely to benefit from further HHI therapy. 
In the subgroup of patients in Group 2 who experience objective responses, the number of patients 
who remain with unresectable BCC and the number of patients from whom BCC becomes 
resectable (complete gross resection) will be tabulated. 
10.4.4.2. Quality of Life and Skindex-16 Analysis 
The patient-reported outcomes and quality of life of patients will be repeatedly measured by the 
EORTC QLQ-C30 and the Skindex-16 at day 1 of each treatment cycle.  The change scores of the 
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QLQ-C30 and the Skindex-16 will be summarized descriptively at each post-baseline time point.  
The summary scores of the QLQ-C30 and the Skindex-16 will also be graphically depicted by 
longitudinal plots. 
10.4.5. 
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 and listings. 
10.4.5.1. 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 time from first dose of study drug to 105 
days after the last dose of study drug.   
 The post-treatment period is defined as the time starting 1 day after the on-treatment 
period. 
Treatment-emergent adverse events (TEAEs) are defined as AEs that are not present at baseline or 
represent the exacerbation of a pre-existing condition during the on-treatment period and 
treatment-related AEs that occurs any time after the first cemiplimab dose. 
Note regarding retreatment:  For patients who receive cemiplimab as retreatment, which starts 
more than 45 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 and the day before their first 
cemiplimab retreatment dose.  Cemiplimab retreatment that starts within 45 days after the last 
regular cemiplimab dose will be considered as regular cemiplimab treatment. 
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  Coding will be to lowest level terms.  The 
verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be listed. 
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. 
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Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by group. 
10.4.5.2. 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. 
10.4.5.3. 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. 
10.4.5.4. Treatment Compliance 
Treatment compliance will be defined in detail in the SAP and summarized by group. 
10.4.6. 
Analysis of Drug Concentration Data 
Summaries of study drug concentrations will be presented by nominal time point (ie, the time 
points specified in the protocol) and group. 
10.4.7. 
Analysis of Anti-Drug Antibody Data 
Formation of ADAs will be assessed in individual patients and per group as follows: 
 Possible correlation between changes in PK profile and the presence/absence of 
treatment-emergent anti-cemiplimab antibodies will be evaluated to identify a 
potential impact of treatment-emergent anti-cemiplimab antibodies on drug exposure 
 Possible correlation between AEs and the presence/absence of treatment-emergent 
anti-cemiplimab antibodies may be evaluated to identify a potential impact of 
treatment-emergent anti-cemiplimab antibodies on safety. 
Cases of ADA positivity will be listed and summarized as appropriate. 
10.4.8. 
Analysis of Biomarker Data 
Biomarker data will be analyzed using standard scientific methods and summarized by descriptive 
statistics and plot.  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. 
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10.4.8.1. 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 of control therapy vs. 
nivolumab 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 9): 
1. The actual number of tumor biopsies obtained and deemed evaluable is 60, 50, or 40. 
2. The PD-L1 expression level categorization results in PD-L1 negative/positive ratios of 
1:1 or 3:2. 
3. ORRs of 10% (PD-L1 negative) vs. 30% (PD-L1 positive) results in an odds ratio of 
3.857, and 10% (PD-L1 negative) vs. 25% (PD-L1 positive) results in 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 9: 
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 
10.5. 
Interim Analysis 
For regions where alpha spending is not required:  For this planned interim analysis on Group 1 
patients, 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.  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 1 patients, a 
2-sided alpha of 0.0001 will be allocated for interim analysis, and a 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 1 patients, the precision of ORR will be estimated by an adjusted and 
2-sided 99.99% exact confidence interval.  The unadjusted 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 1 patients, both adjusted 95.01% and unadjusted 95% exact confidence intervals will be 
reported. 
For other efficacy endpoints in Group 1 patients, only a 2-sided 95% exact confidence interval will 
be presented both at the interim and at the final analysis. 
  
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10.6. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
Definition of baseline:  
 Unless otherwise specified, the last assessment before the initial administration of 
cemiplimab will be considered the baseline evaluation 
General rules for handling missing data: 
 Unless otherwise specified, there will be no imputations for missing data 
 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 not evaluable by RECIST version 1.1 (Group 1; 
Appendix 1) or 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.  Duration of response 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 CRF assessment recorded by the investigator. 
10.7. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the clinical development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 16.1. 
 
 
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11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation, cleaning, correcting, releasing) will be maintained and stored at Regeneron. 
A medical coding plan will specify the processes and the dictionary used for coding.  All data 
coding (eg, AEs, baseline findings, medication, medical /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. 
11.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
 IWRS system – screening/enrollment, study drug supply 
 EDC system – data capture 
 Statistical Analysis System (SAS) – statistical review and analysis 
 Pharmacovigilance safety database 
 
 
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12. 
STUDY MONITORING 
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization monitor) will visit each site 
prior to enrollment of the first patient, and periodically during the study. 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. 
12.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
The investigator must keep all source documents on file with the 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. 
12.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on eCRFs within the EDC 
system by trained site personnel.  All required CRFs must be completed for each and every patient 
enrolled in the study.  After review of the clinical data for each patient, the investigator must 
provide an electronic signature.  A copy of each patient CRF casebook is to be retained by the 
investigator as part of the study record and must be available at all times for inspection by 
authorized representatives of the sponsor and regulatory authorities. 
Corrections to the 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 EDC system.  For corrections made via data queries, a reason for any alteration 
must be provided. 
 
 
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13. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
 Informing the sponsor of a planned inspection by the authorities as soon as 
notification is received, and authorizing the sponsor’s participation in the inspection 
 Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
 Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
 Taking all appropriate measures requested by the sponsor to resolve the problems 
found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities.  Conditions of study material storage are also subject to inspection.  In 
addition, representatives of the sponsor may observe the conduct of any aspect of 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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14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
14.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
14.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC.  A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand.  The ICF should be signed and dated by the patient and by 
the investigator or authorized designee who reviewed the ICF with the patient. 
 Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
 Patients who can understand but who can neither write nor read will have the ICF 
read to them in 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. 
14.3. 
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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14.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
 The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
 Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the 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. 
15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB/EC 
-approved amendment 
 
 
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16. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
16.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
16.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
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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17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF must be signed 
electronically by the investigator.  This signed declaration accompanies each set of patient final 
CRF that will be provided to the sponsor. 
17.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities.  The investigator must consult with the sponsor before discarding or 
destroying any essential study documents following study completion or discontinuation.  Records 
must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor and the relevant records will be transferred to a mutually 
agreed-upon destination. 
18. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
19. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
20. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 
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22. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Phase 2 Study of REGN2810, a Fully Human Monoclonal 
Antibody to Programmed Death-1, in Patients with Advanced Basal Cell Carcinoma who 
Experienced Progression of Disease on Hedgehog Pathway Inhibitor Therapy, or were Intolerant 
of Prior Hedgehog Pathway Inhibitor Therapy, 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) 
For the purposes of this study, patients should be re-evaluated for response every 9 weeks in cycles 
1-5, and every 12 weeks in cycles 6 – 9.  Confirmatory scans should also be obtained 4 weeks 
following initial documentation of objective response or progressive disease.  For patients in whom 
all target lesions are followed by radiologic imaging, it is acceptable to use RECIST 1.1 for all 
response assessments and composite response criteria are not required. 
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 
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can be measured reproducibly should be selected. A sum of the diameters (longest for 
non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters. 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. 
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 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 
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 
 
18F-fluorodeoxyglucose positron emission tomography (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: CLINICAL AND COMPOSITE RESPONSE CRITERIA 
FOR PATIENTS WITH LOCALLY ADVANCED BCC 
These criteria are designed primarily for patients in Group 2. This appendix describes clinical 
response criteria for externally visible lesions that can be measured bi-dimensionally using digital 
medical photography. This appendix also provides clinical and composite response criteria for 
disease that is measureable by both clinical response criteria and RECIST 1.1. 
Group 2 patients will be followed by digital medical photography. Group 2 patients 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 8.2.1 and Section 8.2.2 
for further information on imaging requirements for Group 2 patients.  
Response assessments occur every 9 weeks during cycles 1 – 5 and every 12 weeks during cycles 
6 – 9 and also as specified in follow-up schedule.  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. Guidelines for digital medical photography are provided in 
Appendix 5. 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-measureable 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 2 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 4. 
As such, when the decision is made to perform biopsy, at least 4 biopsy samples are obtained 
(biopsy of 2 separate areas, with 2 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 4 for biopsy details. 
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 
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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 central 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 5.3.3 ). Central reviews will be scheduled by the 
sponsor or designee, but will not be continuous or “real-time.” Clinical management decisions 
generally will be as per investigator response assessments and local pathology review. In the 
unlikely event that central 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) Patients in Group 1 with Externally Visible Tumors 
Regarding Group 1 (metastatic BCC), these patients will generally be followed by RECIST 1.1 
criteria (Appendix 1). It is possible that some patients in Group 1 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-measureable metastatic 
lesions (eg, bone metastases) would be followed as non-target lesions.  For any target lesions in 
Group 1 or Group 2 that are measured by digital medical photography, measurements will be 
bi-dimensional. 
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6) Patients in Group 2 with Deeply Invasive Tumors 
Regarding Group 2 (unresectable locally advanced BCC), tumor measurements for these patients 
will generally be performed with digital medical photography (bi-dimensional measurements).  
However, some patients in Group 2 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 in Group 2 or Group 1 that are measured by 
cross-sectional imaging (eg, MRI with gadolinium or CT with contrast), measurements will be 
unidimensional according to RECIST 1.1. 
Clinical Response Criteria for Externally Visible Tumors (for all patients with locally 
advanced BCC)  
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 
standardized digital photography (Appendix 5). In the absence of substantial change in lesion 
geometry, subsequent visit measurements should be performed in the same axes and the 
investigator should refer to the previous visit’s annotated photographs as a starting point to identify 
axis for measurement when making subsequent assessments. 
Clinical response criteria for externally visible tumor(s) require bi-dimensional measurements 
according to WHO criteria, and are as follows: 
 Complete response of externally visible disease (vCR): all target lesion(s) and 
non-target lesions 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 4). 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. 
B. New Lesions 
A new cutaneous lesion consistent with BCC 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 BCC. If a new cutaneous lesion 
is not biopsied or if the histology is inconclusive, it should be considered BCC and deemed cPD.  
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Overall Clinical Responses For Locally Advanced BCC 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 
For patients who have locally advanced BCC 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.  A Central Review Committee will review the results from 
independently evaluated radiological scans, photographs and clinical tumor biopsies (if 
performed) to derive overall composite responses as per the charter document for that committee. 
Clinical Response 
(Digital Medical 
Photography) 
RECIST 1.1 Response 
(Radiology) 
Composite (Overall): 
Clinical + RECIST 
Response 
cCR 
CR or NA 
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 
NA 
SD 
SD 
cPD 
Any 
PD 
Any 
PD 
PD 
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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 
D. Non-Target Lesions 
Measurements of non-target lesions are not required.  The presence, absence, or in rare cases 
unequivocal progression of these lesions should be noted throughout follow up. 
 
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APPENDIX 3: RECOMMENDED DOSE MODIFICATION OR DISCONTINUATION AND 
SUPPORTIVE CARE GUIDELINES FOR SPECIFIC STUDY DRUG RELATED 
ADVERSE EVENTS 
 
Section 7.3.2 provides the dose level reductions. 
Event(s) 
CTCAE 
v4.03 Grade 
Management/ 
cemiplimab Dosing 
Action/Supportive Care Guidelines 
Symptomsa 
Differential 
Diagnosis 
Colitis events 
 Bowel 
obstruction  
 Colitis  
 Colitis 
microscopic 
≤ Grade 1 
No change in dose 
 For diarrhea, treat symptomatically (loperamide, oral hydration, electrolyte 
substitution and ADA colitis diet). Endoscopy is recommended if symptoms 
persist. 
 Grade 1 diarrhea that persist for >1 week should be treated with the addition 
of oral diphenoxylate hydrochloride and atropine sulfate four times daily and 
budesonide 9 mg daily. 
Symptoms may 
include (but are 
not limited to): 
 Abdominal 
pain, cramping 
and/or bloating 
 Blood and/or 
mucus in stool 
with or without 
fever 
 Constipation 
 Diarrhea 
 Ileus 
 Nausea and/or 
vomiting 
 Peritoneal 
signs 
consistent with 
bowel 
perforation 
 Rectal 
bleeding  
 With or 
without fever 
All attempts 
should be made 
to rule out other 
causes such as 
metastatic 
disease, bacterial 
or parasitic 
infection, viral 
gastroenteritis, 
or the first 
manifestation of 
an inflammatory 
bowel disease by 
examination for 
stool leukocytes, 
stool cultures, 
and a 
Clostridium 
difficile titer. 
 Enterocolitis 
hemorrhagic  
 Gastrointestinal 
(GI) perforation 
 Necrotizing 
colitis 
Diarrhea: 
All patients who 
experience diarrhea 
should be advised to 
drink liberal 
quantities of clear 
fluids. If sufficient 
oral fluid intake is 
not feasible, fluid 
and electrolytes 
should be 
substituted via IV 
infusion. 
Grade 2 
Hold until ≤Grade 1.  
Resume at same 
dose level. May 
increase dosing 
interval by 1 week if 
it takes more than 
4 weeks for 
toxicities to resolve. 
 GI consultation and endoscopy is recommended to confirm or rule out colitis 
for grade 2 diarrhea that persists >1 week or grade 1-2 diarrhea with rectal 
bleeding (additional guidelines for the treatment of persistent colitis are 
provided below). 
 Grade 2 diarrhea should be treated with the addition of oral diphenoxylate 
hydrochloride and atropine sulfate four times daily and budesonide 9 mg 
daily. 
 Grade 2 diarrhea with diffuse ulceration and bleeding seen on endoscopy 
may require oral steroids with prolonged taper and represent an increased 
risk for the development of bowel perforation. Consider prophylactic 
antibiotics for opportunistic infections.  
 When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 In patients with Grade 2 enterocolitis, cemiplimab should be withheld and 
antidiarrheal treatment should be started. If symptoms are persistent for 
more than one week, systemic corticosteroids should be initiated 
(eg, 0.5 mg/kg/day of prednisone or equivalent). When symptoms improve 
to Grade 1 or less, corticosteroid taper should be started and continued over 
at least 1 month. 
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Event(s) 
CTCAE 
v4.03 Grade 
Management/ 
cemiplimab Dosing 
Action/Supportive Care Guidelines 
Symptomsa 
Differential 
Diagnosis 
Colitis events 
(continued) 
Grade 3–4 
Withhold 
cemiplimab 
 
Discontinue if 
unable to reduce 
corticosteroid dose 
to < 10 mg per day 
prednisone 
equivalent within 
12 weeks of toxicity 
 In patients with Grade 3 enterocolitis, cemiplimab will be permanently 
discontinued and treatment with systemic corticosteroids should be initiated 
at a dose of 1–2 mg/kg/day of prednisone or equivalent. When symptoms 
improve to Grade 1 or less, corticosteroid taper should be started and 
continued over at least 1 month. Consider prophylactic antibiotics for 
opportunistic infections. 
 
For Grade 3–4 diarrhea (or Grade 2 diarrhea that persists after initial steroid 
treatment),  
 Rule out bowel perforation. Imaging with plain films or computed 
tomography (CT) can be useful. 
 Consider consultation with gastroenterologist and confirmation biopsy with 
endoscopy. 
 Treat with intravenous (IV) steroids (methylprednisolone 125 mg) followed 
by high-dose oral steroids (prednisone 1–2 mg/kg once per day or 
dexamethasone 4 mg every 4 hours). When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 
4 weeks. Taper over 6–8 weeks in patients with diffuse and severe ulceration 
and/or bleeding. 
 If IV steroids followed by high-dose oral steroids does not reduce initial 
symptoms within 48–72 hours, consider treatment with infliximab at 
5 mg/kg once every 2 weeks. Discontinue infliximab upon symptom relief 
and initiate a prolonged steroid taper over 45–60 days. If symptoms worsen 
during steroid reduction, initiate a retapering of steroids starting at a higher 
dose of 80 or 100 mg followed by a more prolonged taper and administer 
infliximab. CAUTION: infliximab is contraindicated in patients with bowel 
perforation or sepsisb. 
 If symptoms persist despite the above treatment a surgical consult should be 
obtained. 
Patients with 
diarrhea should 
be carefully 
monitored for 
signs and 
symptoms of 
enterocolitis (such 
as diarrhea, 
abdominal pain, 
blood or mucus in 
stool, with or 
without fever) 
and of bowel 
perforation (such 
as peritoneal 
signs and ileus). 
In symptomatic 
patients, 
infectious 
etiologies should 
be ruled out, and 
if symptoms are 
persistent and/or 
severe, 
endoscopic 
evaluation should 
be considered. 
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Event(s) 
CTCAE 
v4.03 Grade 
Management/ 
cemiplimab Dosing 
Action/Supportive Care Guidelines 
Symptomsa 
Differential 
Diagnosis 
Endocrine events 
 Hyperthyroidism 
 Hypophysitis 
 Hypopituitarism  
Grade 1-2 
No change in dose 
 Monitor thyroid function or other hormonal level tests and serum 
chemistries more frequently until returned to baseline values. 
Symptoms may 
include (but not 
limited to): 
 Abdominal 
pain 
 Abnormal 
thyroid 
function tests 
and/or serum 
chemistries 
(Thyroid-
stimulating 
hormone 
increased 
[decreased], 
Free thyroxine 
increased, Tri-
iodothyronine 
increased.)  
 Arrhythmiasc 
 Cold or heat 
intolerance 
 Fatigue  
 Fever 
 Headache 
 Hypotensionc 
 Loss of 
appetite 
 Mental status 
and/or 
behavior 
changes 
 Nausea and/or 
vomiting  
 Unusual bowel 
habits 
 Vision 
disturbances 
 Weakness 
All attempts 
should be made 
to rule out other 
causes such as 
brain metastases, 
sepsis, and/or 
infection. An 
endocrinology 
consultation is 
recommended. 
Endocrine events 
 Hypothyroidism 
 Thyroid disorder 
 Thyroiditis 
Grade 3-4 
Hold until on stable 
replacement dose 
 
 Consider endocrine consultation. 
 Rule out infection and sepsis with appropriate cultures and imaging. 
 Replacement of appropriate hormones as required.  
Endocrine events 
 Adrenal 
insufficiency 
 Hypophysitis 
 Pan-
hypopituitarism 
Grade 1-4 
Hold until on stable 
replacement dose 
 Thyroid hormone and/or steroid replacement therapy to manage adrenal 
insufficiency. 
 If Grade 1–2 hypophysitis is considered, pituitary gland imaging should be 
considered (magnetic resonance imaging [MRIs] with gadolinium and 
selective cuts of the pituitary can show enlargement or heterogeneity and 
confirm the diagnosis). 
 Grade 3–4 hypophysitis with clinically significant adrenal insufficiency and 
hypotension, dehydration, and electrolyte abnormalities (such as 
hyponatremia and hyperkalemia) constitutes adrenal crisis. Hospitalization 
and IV methylprednisolone should be initiated. 
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Event(s) 
CTCAE 
v4.03 Grade 
Management/ 
cemiplimab Dosing 
Action/Supportive Care Guidelines 
Symptomsa 
Differential 
Diagnosis 
Eye event: 
Uveitis  
(iritis, iridocyclitis) 
Grade 1 
Discontinue 
cemiplimab if 
symptoms persist 
despite treatment 
with topical 
immunosuppressive 
therapy  
 Evaluation by an ophthalmologist is strongly recommended. 
 Treat with topical steroids such as 1% prednisolone acetate suspension and 
iridocyclitics. 
Symptoms may 
include (but are 
not limited to): 
 Blurred vision 
 Diffuse 
erythema and a 
prominent 
blush on the 
sclerae 
 Dryness of the 
eyes 
 Pain 
 Photophobia 
All attempts 
should be made 
to rule out other 
causes such as 
metastatic 
disease, 
infection, or 
other ocular 
disease (e.g., 
glaucoma or 
cataracts). 
Grade 2 
Discontinue 
cemiplimab if 
symptoms persist 
despite treatment 
with topical 
immunosuppressive 
therapy and do not 
improve to Grade 1 
within the 
retreatment period 
OR requires 
systemic treatment. 
 Evaluation by an ophthalmologist is strongly recommended. 
 Treat with topical steroids such as 1% prednisolone acetate suspension and 
iridocyclitics. 
Grade 3–4 
Discontinue 
cemiplimab. 
 Treat with systemic corticosteroids such as prednisone at a dose of 
1-2 mg/kg per day. When symptoms improve to ≤Grade 1, steroid taper 
should be started and continued over no less than 4 weeks. 
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Event(s) 
CTCAE 
v4.03 Grade 
Management/ 
cemiplimab Dosing 
Action/Supportive Care Guidelines 
Symptomsa 
Differential 
Diagnosis 
Hepatic events 
 Hepatitis  
 Hepatitis, 
Autoimmune 
Grade 1–2 
Withhold 
cemiplimab if there 
is a treatment-
emergent concurrent 
elevation of ALT 
and bilirubin that 
corresponds to an 
upward shift of 2 or 
more grades in both 
parameters. 
 Monitor liver function tests more frequently until returned to baseline 
values. 
Symptoms may 
include (but are 
not limited to): 
 Elevations in: 
o AST >2.5 × 
ULN 
o ALT >2.5 × 
ULN 
o Total 
bilirubin >1.5 
× ULN 
 Fever 
 Malaise 
 Upper quadrant 
abdominal pain 
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 3–4 
 Hold (and consider 
discontinuation of) 
cemiplimab when 
AST or ALT 
>5.0 times ULN 
and/or total bilirubin 
>3.0 times ULN. 
 Consider appropriate consultation and liver biopsy to establish etiology of 
hepatic injury, if necessary. 
 Treat with high-dose IV glucocorticosteroids for 24–48 hours. When 
symptoms improve to grade 1 or less, a steroid taper with dexamethasone 
4 mg every 4 hours or prednisone at 1–2 mg/kg should be started and 
continued over no less than 4 weeks.  
 If serum transaminase levels do not decrease 48 hours after initiation of 
systemic steroids, oral mycophenolate mofetil 500 mg every 12 hours may 
be given. Infliximab is not recommended due to its potential for 
hepatotoxicityb. 
 Several courses of steroid tapering may be necessary as symptoms may 
worsen when the steroid dose is decreased. 
Nausea 
 
≤Grade 1 
No change in dose 
 Nausea should be treated aggressively, and consideration should be given in 
subsequent cycles to the administration of prophylactic antiemetic therapy 
according to standard institutional practice. Patients should be strongly 
encouraged to maintain liberal oral fluid intake. 
 
 
Grade 2 
Hold until ≤Grade 1.  
Resume at same 
dose level. May 
increase dosing 
interval by 1 week if 
it takes more than 
4 weeks for 
toxicities to resolve. 
Grade 3 
Hold until <Grade 2. 
May increase dosing 
interval by 1 week 
for each occurrence.  
Discontinue if 
toxicities do not 
resolve within 
12 weeks.  
Grade 4 
Off protocol therapy 
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Event(s) 
CTCAE 
v4.03 Grade 
Management/ 
cemiplimab Dosing 
Action/Supportive Care Guidelines 
Symptomsa 
Differential 
Diagnosis 
Neutropenia 
≤Grade 1 
No change in dose 
For neutropenia, see general guidelines on hematologic toxicity in Table 2  
 
 
Grade 2 
No change in dose 
 
Grade 3 
No change in dose 
 
Grade 4 
See Table 2 
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Event(s) 
CTCAE 
v4.03 Grade 
Management/ 
cemiplimab Dosing 
Action/Supportive Care Guidelines 
Symptomsa 
Differential 
Diagnosis 
Pneumonitis events 
 Pneumonitis 
 Interstitial lung 
disease 
 Acute interstitial 
pneumonitis 
Grade 1 
 
Consider hold of 
therapy. cemiplimab 
may be continued 
with close 
monitoring. 
 Radiologic findings should be followed on serial imaging studies at least 
every 3 weeks. 
 Monitor for symptoms every 2–3 days. 
 Consider pulmonary consultation and/or bronchoscopy if clinically 
indicated. 
Symptoms may 
include (but are 
not limited to): 
 Abnormal 
breath sounds 
 Chest pain 
and/or 
tightnessc 
 Dyspneac 
 Dry cough 
 Fatigue 
 Fever 
 Hemoptysis 
All attempts 
should be made 
to rule out other 
causes such as 
metastatic 
disease, bacterial 
or viral 
infection. 
 
Grade 2 
Hold cemiplimab  
To rule out other causes such as infection: 
 Consider pulmonary consultation with bronchoscopy and 
biopsy/bronchoalveolar lavage (BAL). 
 Consider pulmonary function tests. 
 Follow radiologic findings on serial imaging studies every 1–3 days 
If the patient is determined to have study drug associated pneumonitis: 
 Monitor symptoms daily; consider hospitalization. 
 Treat with systemic corticosteroids at a dose of 1–2 mg/kg/day prednisone 
or equivalent. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks.  
 Treatment with cemiplimab may be resumed if the event improves to 
≤ Grade 1 within 12 weeks and corticosteroids have been reduced to the 
equivalent of methylprednisolone 10 mg by mouth daily or less. Repeat 
chest imaging monthly as clinically indicated. 
For Grade 2 pneumonitis that improves to ≤Grade 1 within 12 weeks, the 
following rules should apply: 
 First episode of pneumonitis: May increase dosing interval by one week in 
subsequent cycles. 
 Second episode of pneumonitis: Discontinue cemiplimab if upon 
rechallenge the patient develops a second episode of ≥ Grade 2 pneumonitis. 
 
Grade 3–4 
Discontinue 
cemiplimab. 
 Consider pulmonary function tests with pulmonary consult. 
 Bronchoscopy with biopsy and/or BAL is recommended. 
 Treat with IV steroids (2–4 mg/kg per day prednisone or equivalent). When 
symptoms improve to grade 1 or less, a high-dose oral steroid (1–2 mg/kg 
prednisone once per day or 4 mg dexamethasone every 4 hours) taper 
should be started and continued over no less than 4 weeks. 
 Add prophylactic antibiotics for opportunistic infections. 
 If IV steroids followed by high-dose oral steroids does not reduce initial 
symptoms within 48–72 hours, treat with infliximab at 5 mg/kg once every 
2 weeks. Discontinue infliximab upon symptom relief and initiate a 
prolonged steroid taper over 45–60 days. If symptoms worsen during steroid 
reduction, initiate a retapering of steroids starting at a higher dose of 80 or 
100 mg followed by a more prolonged taper and administer infliximab. 
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Event(s) 
CTCAE 
v4.03 Grade 
Management/ 
cemiplimab Dosing 
Action/Supportive Care Guidelines 
Symptomsa 
Differential 
Diagnosis 
Renal events 
 Nephritis 
 Nephritis 
autoimmune 
Grade 1  
Consider 
withholding 
cemiplimab if event 
does not improve 
with symptomatic 
treatment 
 Provide symptomatic treatment. 
 Monitor creatinine weekly; when it returns to baseline, resume routine 
creatinine monitoring per protocol. 
Symptoms may 
include (but not 
limited to): 
 Fatigue  
 High blood 
pressure  
 Increased 
serum 
creatinine 
 Swelling 
All attempts 
should be made 
to rule out other 
causes such as 
obstructive 
uropathy, 
progression of 
disease, or injury 
to other 
chemotherapy 
agents. A renal 
consultation is 
recommended. 
 Renal failure 
Grade 2  
Consider 
withholding 
cemiplimab.  
 Systemic corticosteroids at a dose of 1–2 mg/kg/day of prednisone or 
equivalent may be indicated. When symptoms improve to Grade 1 or less, 
corticosteroid taper should be started and continued over at least 1 month. 
 Consider prophylactic antibiotics for opportunistic infections. 
 Consider renal biopsy. 
 If elevations persist >7 days or worsen, treat as Grade 4. 
 Renal failure, 
Acute 
Grade 3-4  
Discontinue 
cemiplimab. 
 Renal consultation with consideration of ultrasound and/or biopsy as 
appropriate. 
 Monitor creatinine daily. 
 Treat with systemic corticosteroids at a dose of 1–2 mg/kg prednisone or 
equivalent once per day.  
 When symptoms improve to grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.  
 Discontinue cemiplimab if unable to reduce corticosteroid dose for irAEs to 
≤10 mg. 
 cemiplimab treatment may be restarted and the dose modified as specified 
in the protocol. 
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Event(s) 
CTCAE 
v4.03 Grade 
Management/ 
cemiplimab Dosing 
Action/Supportive Care Guidelines 
Symptomsa 
Differential 
Diagnosis 
Skin events 
 Dermatitis 
exfoliative 
 Erythema 
multiforme 
 Stevens-Johnson 
syndrome 
 Toxic epidermal 
necrolysis 
Grade 1–2 
No change in dose 
 Symptomatic treatment should be given such as topical glucocorticosteroids 
(eg, betamethasone 0.1% cream or hydrocortisone 1%) or urea-containing 
creams in combination with oral antipruritics (eg, diphenhydramine HCl or 
hydroxyzine HCl).  
 Treatment with oral steroids is at investigator discretion for Grade 2 events. 
 
All attempts 
should be made 
to rule out other 
causes such as 
metastatic 
disease, 
infection, or 
allergic 
dermatitis. 
If considered to be 
immune related, 
≥ Grade 3 or result 
in dose modification 
or discontinuation: 
Grade 3 
Hold cemiplimab. 
 
 Consider dermatology consultation and biopsy for confirmation of 
diagnosis. 
 Treatment with oral steroids is recommended, starting with 1 mg/kg 
prednisone or equivalent once per day or dexamethasone 4 mg four times 
orally daily. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. 
 Pruritus 
 Rash 
 Rash generalized 
 Rash maculo-
papular 
 Vitiligo 
Grade 4 
Permanently 
discontinue 
cemiplimab. 
 
 Dermatology consultation and consideration of biopsy and clinical 
dermatology photograph. 
 Initiate steroids at 1–2 mg/kg prednisone or equivalent. When symptoms 
improve to grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
For any severe (Grade 3-4) irAE, if symptoms worsen or do not improve on 
adequate corticosteroids within 48-72 hours, consider adding additional 
immunosuppressive agents (to be selected from agents such as: infliximab, 
cyclophosphamide, cyclosporine, mycophenolate mofetil). Referral of the 
patient to a specialized unit for assessment and treatment should be 
considered 
Thrombocytopenia ≤ Grade 1 
No change in dose 
 
 
 
 
Grade 2 
No change in dose 
 
 
Grade 3 
See Table 2 
 
 
Grade 4 
See Table 2 
 
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Event(s) 
CTCAE 
v4.03 Grade 
Management/ 
cemiplimab Dosing 
Action/Supportive Care Guidelines 
Symptomsa 
Differential 
Diagnosis 
Vomiting 
≤ Grade 1 
No change in dose 
 Vomiting should be treated aggressively, and consideration should be given 
in subsequent cycles to the administration of prophylactic antiemetic 
therapy according to standard institutional practice. Patients should be 
strongly encouraged to maintain liberal oral fluid intake. 
 
 
 
Grade 2 
Hold until ≤Grade 1. 
Resume at same 
dose level. May 
increase dosing 
interval by 1 week if 
it takes more than 
4 weeks for 
toxicities to resolve.  
 
Grade 3 
Hold until <Grade 2. 
May increase dosing 
interval by 1 week 
for each occurrence. 
 
Discontinue if 
toxicities do not 
resolve within 
12 weeks. 
 
Grade 4 
Off protocol therapy 
a The signs and symptoms may be associated with any of the diagnoses in the associated “Event(s)” column. 
b REMICADE (Infliximab) prescribing information 
c If symptoms indicate possible new or worsening cardiac abnormalities, additional testing and/or a cardiology consultation should be considered. 
 
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APPENDIX 4: GUIDELINES FOR BIOPSIES FOR LOCALLY 
ADVANCED BCC 
This appendix provides time points and research procedures for biopsies in patients with locally 
advanced BCC.  Because of the potential for sampling error with any single biopsy, 2 separate 
sites (preferably on the same target lesion) should be biopsied for any biopsy assessment.  
Regarding the required exploratory biopsies for Group 2, if the investigator feels that the biopsy 
creates an unacceptable safety risk for the patient or cannot be performed without interfering with 
the measurements of the target lesions, the biopsy requirement may be waived for an individual 
patient after communication with the Medical Monitor. 
Note in clarification:  Exploratory biopsies are not required for Group 1 patients (metastatic).  For 
Group 1 patients (metastatic disease) who have externally visible BCC lesions that are amenable 
to biopsy with minimal risk, exploratory biopsies (baseline, day 22, at progression) may be 
obtained at investigator discretion. 
Time Points: 
1. 
Baseline (required):  
The study inclusion criteria require that the sponsor be provided with archived pathology 
material that will be used for the purpose of confirmation of the diagnosis of BCC by central 
pathology review for all study patients. If the archived material is not sufficient for 
confirmation of diagnosis of BCC by central review, baseline “exploratory” biopsy material 
(required only for Group 2 patients) may be used for central pathologic confirmation only if 
it is determined that no other archived pathology material is available for confirmation of 
diagnosis BCC by central pathology review.  Remaining baseline tumor material can only be 
used for exploratory assessments after central pathology confirmation of diagnosis of BCC 
has been established. 
2. Baseline or at any scheduled response assessment (If needed to differentiate benign versus 
malignant area of skin):  
Areas of indeterminate-appearing tissue should be biopsied to distinguish malignant tissue 
versus benign process (eg, scarring, fibrosis). In circumstances in which biopsies are planned, 
it is preferred that these be performed on the day of a regularly-scheduled response 
assessment. 
3. On cycle 1 day 22 (±3 business days) for exploratory assessments, 2 biopsies (punch 
biopsies, 3 to 5 mm each) should be obtained, preferably from the same externally visible 
lesion from which the baseline biopsies were taken. Both samples will be provided to the 
sponsor for exploratory assessments. The cycle 1 day 22 samples are not intended for local 
pathology review. 
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4. At clinical complete response (required): Complete response status for externally visible 
lesions requires biopsy confirmation.  The number of biopsies that are needed to confirm 
complete response status depends on the baseline size of the lesion. 
Recommended Number of Biopsies to Establish Complete Response, Based on Baseline Size 
of Lesion 
Lesion size 
(cm2) 
Minimal Number Biopsy 
Samples to Establish CR 
≤4 
2 
>4 but ≤10 
4 
>10 but ≤25 
6 
>25 
8 
 
5. At progression (strongly encouraged): Two sites of externally visible progressing tumor 
should be biopsied.  
Research procedures for ALL biopsies: 
1. Where and How: 
The technique and sites of biopsies will be selected by the investigator based on the sizes and 
locations of lesions. Generally, biopsies will be 3 mm punches. Biopsies should not be taken 
at the perimeter of a lesion because this could interfere with measurement of bi-dimensional 
perpendicular diameters for response assessments. Whenever possible, biopsy sites should be 
≥5 mm from the edge of baseline lesional area. 
Note:  If the investigator deems that a biopsy ≥5mm from edge is not possible, then the 
requirement for an exploratory biopsy will be waived after communication with and approval 
from the medical monitor, due to the potential for the biopsy to confound tumor 
measurements if the biopsy is close to edge of the tumor. 
2. How many: 
For exploratory assessments:  2 biopsies of externally visible BCC will be obtained at 
baseline and again at cycle 1 day 22 (±3 business days).  These required biopsies for Group 2 
patients are called "Exploratory Biopsies" for the purposes of this study.  Two biopsies at 
time of progression should also be obtained. In the event that an investigator determines that 
clinical circumstances interfere with the ability to obtain the recommended number of 
minimal biopsies at baseline or cycle 1 day 22 (±3 business days), the monitor will be 
contacted to discuss the number of biopsies that can be reasonably obtained and this will not 
be deemed a protocol violation.  
For indeterminate-appearing tissue:  In addition to these biopsies for exploratory 
assessments, biopsies should be taken at baseline and at any response assessment if there is 
tissue that is indeterminate-appearing regarding presence of benign versus malignant tissue.  
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These optional biopsies are referred to as "Response Biopsies" (eg, in response to a clinical 
question), to distinguish from the required "Exploratory Biopsies" described above. When 
the decision is made to perform a “response biopsy” of a lesion (or an area of a lesion) to 
clarify benign versus malignant status, 4 biopsies should be taken. This approach will 
mitigate the possibility for sample error or misleading results with any 1 biopsy, because 
2 sites in the “indeterminate appearing” tissue will be selected. At each of the selected sites, 
2 biopsies should be performed that are approximately adjacent (1 for central review, 1 for 
local pathology review). As such, 4 biopsies would be performed (2 sites, with paired 
biopsies at each site:  1 for local pathology, and 1 for central = 4 total biopsies). 
When an investigator deems that biopsy of indeterminate-appearing tissue is warranted, 
4 biopsies is the recommended minimal number of biopsies.  If the area of 
indeterminate-appearing tissue is >10 cm2, the recommended number of biopsies to 
evaluate the presence or absence of tumor in indeterminate-appearing tissue is 6 (3 sites, 
each with paired biopsies at each site:  1 for central review, and 1 for local). 
To establish complete response:  the number of required biopsies is based on the baseline 
size of the lesion, as per the table above. 
3. Annotation and Photography 
The punch biopsies should be labeled (annotated) on the patient and photographed, such that 
on review of the photograph the following information is clear for each biopsy site: the study 
week and day of the biopsy (eg, Baseline, Cycle 1, Day 22, etc), the identifying number of 
the biopsy (because at least 2 sites would be biopsied), and which samples are for central 
review and which samples are for local review. The tumor will also be annotated with a skin 
pen to indicate the tumor perimeter and delimiters of the longest bi-dimensional 
perpendicular axes. All biopsies will be photographed and annotated, including the cycle 1 
day 22 biopsies that are for exploratory assessments. 
Annotated photographs must be uploaded into Canfield secure website (see Appendix 5). 
4. Disposition of Samples 
Biopsy samples required for exploratory assessments (baseline, cycle 1 day 22) will be 
provided to the sponsor. It is also strongly encouraged that biopsy samples at time of 
progression be obtained for exploratory assessments, and these should also be provided to the 
sponsor.  
For each site that is biopsied to clarify indeterminate tissue, the entire block for one biopsy 
sample (designated for central) must be submitted to the Central Laboratory as per the 
Laboratory Manual. Because each biopsy site is sampled twice (closely adjacent samples) 
when there is indeterminate-appearing tissue, the second sample may be used for local 
pathology review. If only 1 adequate (eg, interpretable by pathologist) sample is obtained at a 
biopsy site, it will be provided to the sponsor for central review to address the study 
objectives (Section 5.3.3 ). 
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5. Classification of Pathology Samples 
For response assessments in which biopsies were performed, pathology results guide the 
determination of the area of invasive BCC versus benign tissue. Residual squamous 
carcinoma in situ will not be deemed to be invasive cancer. A minute focus of residual BCC 
in an otherwise benign responding biopsy sample will not automatically supersede a 
determination of partial response. However, the best response that can be recorded if the 
pathology report demonstrates any residual BCC is partial response (not complete response). 
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APPENDIX 5: DIGITAL PHOTOGRAPHIC PROCEDURES 
Image Capture 
 Close-up view with millimeter scale of the target area of the BCC 
 Global view of the target BCC area 
Equipment 
 Camera: Canon SL1 with Ranging Lights  
 Lens: 60mm Canon Lens 
 Flash: Canfield TwinFlash RL 
 Millimeter scale attachment  
 Dedicated laptop with Canfield Capture Application (software includes capturing, 
viewing and transferring images) 
 Canfield Tracing and Analysis application 
 Standardized background material 
The supplied equipment is to be used exclusively for this study. No modification, adjustments, or 
repairs of the camera equipment are to be undertaken without the expressed instruction of Canfield 
Scientific, Inc. 
Canfield will provide each study site with the necessary hardware as well as technical support as 
needed. All supplied photographic equipment remains the property of the Sponsor.  
Proper Patient Preparation and Positioning: 
In these clinical photographs for the duration of the study, the only variable allowed to change is 
the skin condition itself. Therefore, anything extraneous to the condition (furniture, etc.) is to be 
eliminated from the photographic field, starting at the entry visit through the final visit. The 
necessity of good end-of-study photographs should be stressed to patients to ensure their 
cooperation. Lighting, framing, exposure, and reproduction ratios must be held constant. In the 
end, the images should read like a time-lapse movie.  
In the close up view, the area of interest is the individual target lesion itself. In the global view, 
the area of interest includes the target lesion as well as relevant anatomical landmarks, e.g. side of 
face, side of neck, upper torso, full view of shoulder, etc. Photographs should be taken with the 
camera positioned at the same vertical height as the center of area of interest. Further, all shots 
should be made with the axis of the camera lens perpendicular to the surface of area of interest 
when possible. Glancing shots where the camera lens is not perpendicular to the patient’s area of 
interest are to be avoided as these photographic angles may distort the image perspective yielding 
inaccuracies when measurement of lesions is performed on photos by central review. 
The supplied standardized background material is to be used. Do not use wrinkled or crimped 
material. 
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The Canfield Capture software controls the setting of the camera specific to the protocol. The lens 
is set for auto focusing. The close-up view is accomplished using the attached standardized mm 
scale. The global view is accomplished when the ranging lights converge on the target area. Any 
doubt as to the correctness of the photographic technique should result in an immediate re-shoot.  
At the baseline visit, a profile view (perpendicular to the skin’s plane) will also be obtained of 
each lesion to capture any projection above the skin.  For all lesions in which the baseline profile 
view demonstrates significant projection above the skin, defined as ≥15mm, the profile view will 
also be obtained at subsequent scheduled clinical assessments of response.  
For each global view and each close up view, an unannotated photograph must be taken 
followed by a manually annotated photograph. 
For response assessments, Canfield imaging software should be used to assure that the photograph 
is taken at the same position and angle as the Baseline photograph. The annotated image from the 
prior visit should be referenced on the laptop screen prior to making annotations on the new image. 
Photographic Procedures: 
1. Prior to capturing the patient images using the camera system, the photographer launches 
the Canfield Scientific Canfield Capture Application by selecting the icon from the 
desktop.  
2. The photographer either creates a New Patient for an initial visit or, for a return subject, 
highlights the appropriate existing Patient ID listed in the Canfield Capture database. The 
visit name (as per study schedule) is selected by the photographer and the image date is 
captured by the software. 
3. With the patient’s target area positioned correctly in front of the camera system, the 
Photographer adjusts the camera distance for accurate system focus. The first capture is a 
Close-up view of patient’s target BCC area(s) using the attached mm scale, consisting of 
one individual BCC lesion. The second capture is Global view of patient’s target BCC 
area(s), consisting of up to 2 individual BCC lesions. For the global view the camera is 
moved closer to or further away from the target until the 2 green ranging lights converge 
to become one dot. 
4. The Photographer captures the image and is then prompted to review image acceptability. 
The Photographer either accepts the image and moves on to the next capture or does not 
accept and recaptures the image.  
5. After capturing the series of non-annotated lesion(s), the Investigator will annotate the 
circumference and axes delimiters of lesion with supplied skin pen. If any biopsies are 
taken at this visit (eg, baseline, cycle 1 day 22, at any regularly scheduled visit, or at 
time of progression), each biopsy will also be annotated as per Appendix 4.  The 
annotated photo will include the largest area, including both palpable and visible 
components of the lesion, as outlined by the investigator.  Following the same 
procedure as the non-annotated image capture the site will capture the series of annotated 
lesion(s) images  
6. Following the session, the Photographer submits the images to Canfield. Upon exiting, 
the software automatically reads, checksums, encrypts, packages, and duplicates the data 
to submit to Canfield via internet or removable media submission.  
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a. Internet: A secure, validated, compliant web server set up at Canfield is used for 
secure transfer of study images by study sites. Images are to be transferred the day 
they are recorded. Only approved individuals by the Sponsor have access to 
the website.  
The application logs a record of this action to a local database and prompts the Photographer when 
completed.  
1. Upon completion of photography session, the Investigator will log in to the Canfield 
tracing application to annotate the lesion and the software will provide measurements 
(surface area, longest diameter, perpendicular diameter) of the lesion. 
2. Trained Canfield staff review the data files for technical quality and acceptability and 
communicate any comments to the site. 
3. At the end of the study, a copy of site specific patient images will be provided to each 
site. This is in addition to the Photography Result Reports available for printing from the 
Clinical Services Website after each session. Remote access to all images by the Sponsor 
is also provided.  
Any questions or problems regarding the photographic portion of this study are to be forwarded to 
the assigned Project Manager at Canfield Scientific. 
Canfield Scientific, Inc. 
4 Wood Hollow Rd 
Parsippany, NJ 07054 United States 
 
 
 
 
 
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APPENDIX 6: 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 7: CEMIPLIMAB PHARMACOKINETIC SAMPLING AND 
ASSESSMENT SCHEDULE 
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 2–5: day 1 
 
Preinfusion 
 
Within 10 min after end of infusion 
Cycles 6–9: day 1 
 
Preinfusion 
 
Within 10 min after end of infusion 
End of study (if progression during 
cycles 2-9) and follow-up visits 1,4, and 
7 
Anytime during the visit 
 
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APPENDIX 8: FACTORS TO CONSIDER IN ASSESSING THE 
RELATIONSHIP OF AES TO CEMIPLIMAB OR 
INFUSION PROCEDURE, STUDY PROCEDURE, OR 
COMBINATION TREATMENT 
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 
 are not a known response to cemiplimab or infusion procedure, study procedure, or 
combination treatment based upon pre-clinical data or prior clinical data 
Yes: 
 could not be explained by environmental factors or other treatment/s being 
administered 
 could not be explained by the patient’s disease state or clinical condition 
 follow a reasonable temporal sequence following the time of administration of the dose 
of 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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Signature of Sponsor’s Responsible Officers 
(Scientific/Medical Monitor, 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, in Patients with Advanced Basal Cell Carcinoma who Experienced 
Progression of Disease on Hedgehog Pathway Inhibitor Therapy, or were Intolerant of Prior 
Hedgehog Pathway Inhibitor Therapy 
Protocol Number: 
R2810-ONC-1620 
Protocol Version: 
R2810-ONC-1620 Amendment 4  
 
See appended electronic signature page 
Sponsor’s Responsible Scientific/Medical Monitor 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Representative 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead: 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician: 
 
                                        VV-RIM-00082550-1.0 Approved - 29 Jul 2019 GMT-5:00


Signature Page for VV-RIM-00082550 v1.0
Signature Page for VV-RIM-00082550 v1.0 Approved
ESig Approval
29-Jul-2019 17:52:13 GMT+0000
ESig Approval
29-Jul-2019 18:13:57 GMT+0000
ESig Approval
agement
29-Jul-2019 18:15:27 GMT+0000
ESig Approval
29-Jul-2019 18:43:57 GMT+0000
                                        VV-RIM-00082550-1.0 Approved - 29 Jul 2019 GMT-5:00

SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
STATISTICAL ANALYSIS PLAN 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.1 
July 2, 2013 
Title:  A Phase II Study of REGN2810, A Fully Human Monoclonal Antibody to Programmed 
Death-1 (PD-1), in Patients with Advanced Basal Cell Carcinoma Who Experienced Progression 
of Disease on Hedgehog Pathway Inhibitor Therapy, or Were Intolerant of Prior Hedgehog 
Pathway Inhibitor Therapy 
Protocol:  
R2810-ONC-1620 
Investigational product:  
Cemiplimab (REGN2810 [anti-PD-1 mAb]) 
Sponsor:  
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
Clinical Study Team Leader:  
Study Medical Director:  
Version: 2.0 
Date:  Feb 5, 2020 
VV-RIM-00099532-1.0 Approved - 07 Feb 2020 GMT-5:00
NCT03132636


Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1620 
Statistical Analysis Plan 
Feb 5, 2020 
CONFIDENTIAL 
Page 2 of 36 
SIGNATURE PAGE 
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. 
 
Author: 
See appended electronic signature page 
 
Study Biostatistician  
 
 
Approver: 
See appended electronic signature page 
 
Study Medical Director 
 
 
Approver: 
See appended electronic signature page 
 
Head of Biostatistics and Data Management or designee 
 
 
 
 
 
 
                                        VV-RIM-00099532-1.0 Approved - 07 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1620 
Statistical Analysis Plan 
Feb 5, 2020 
CONFIDENTIAL 
Page 3 of 36 
TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
ABBREVIATIONS AND DEFINITIONS ......................................................................................6 
1. 
OVERVIEW .................................................................................................................8 
1.1. 
Background/Rationale ..................................................................................................8 
1.1.1. 
Background ...................................................................................................................8 
1.1.2. 
Rationale .......................................................................................................................8 
1.2. 
Study Objectives ...........................................................................................................9 
1.2.1. 
Primary Objective .........................................................................................................9 
1.2.2. 
Secondary Objectives ...................................................................................................9 
1.2.3. 
Exploratory Objective (Group 2 only) ..........................................................................9 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................10 
1.2.5. 
Modifications from the Approved Statistical Analysis Plan ......................................10 
2. 
INVESTIGATION PLAN ..........................................................................................11 
2.1. 
Study Design ...............................................................................................................11 
2.2. 
Statisticial Hypothesis ................................................................................................12 
2.3. 
Sample Size and Power Considerations .....................................................................12 
2.4. 
Study Plan ...................................................................................................................14 
3. 
ANALYSIS POPULATIONS ....................................................................................15 
3.1. 
Full Analysis Set (FAS) ..............................................................................................15 
3.2. 
Safety Analysis Set (SAF) ..........................................................................................15 
3.3. 
PK Analysis Set (PKA) ..............................................................................................15 
3.4. 
Anti-Drug Antibody Set (ADA) .................................................................................15 
3.5. 
Biomarker Analysis Set (BAS) ...................................................................................15 
4. 
ANALYSIS VARIABLES .........................................................................................16 
4.1. 
Demographic and Baseline Characteristics ................................................................16 
4.2. 
Medical History ..........................................................................................................16 
4.3. 
Pre-Treatment/Concomitant Medications and Procedures .........................................16 
4.4. 
Efficacy Variable ........................................................................................................17 
4.4.1. 
Primary Efficacy Variable ..........................................................................................17 
4.4.2. 
Secondary Efficacy Variables .....................................................................................18 
1.4.3 
Exploratory Efficacy Variables ..................................................................................19 
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Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1620 
Statistical Analysis Plan 
Feb 5, 2020 
CONFIDENTIAL 
Page 4 of 36 
4.5. 
Safety Variables ..........................................................................................................19 
4.5.1. 
Adverse Events and Serious Adverse Events .............................................................19 
4.5.2. 
Adverse Events of Special Interest .............................................................................21 
4.5.3. 
Laboratory Safety Variables .......................................................................................21 
4.5.4. 
Vital Signs ..................................................................................................................21 
4.5.5. 
12-Lead Electrocardiography (ECG) ..........................................................................22 
4.5.6. 
Physical Examination Variables .................................................................................22 
4.6. 
Pharmacokinetic Variables and Anti-Drug Antibody Variables (ADA) ....................22 
4.6.1. 
Pharmacokinetic Variables .........................................................................................22 
4.6.2. 
Immunogenicity  Variables .........................................................................................22 
5. 
STATISTICAL METHODS .......................................................................................22 
5.1. 
Demographics and Baseline Characteristics ...............................................................23 
5.2. 
Medical History ..........................................................................................................23 
5.3. 
Prior/Concomitant Medications and Procedures ........................................................23 
5.4. 
Subject Disposition .....................................................................................................24 
5.5. 
Protocol Deviations ....................................................................................................24 
5.6. 
Measurement of Compliance ......................................................................................24 
5.7. 
Exposure to Investigational Product ...........................................................................25 
5.8. 
Analysis of Efficacy Variables ...................................................................................25 
5.8.1. 
Analysis of Primary Efficacy Variable .......................................................................25 
5.8.2. 
Analysis of Secondary Efficacy Variables .................................................................26 
5.8.3. 
Analysis of Quality of Life Variables .........................................................................26 
5.8.4. 
Subgroup Efficacy Analysis and Exploratory Efficacy Analysis ...............................27 
5.9. 
Analysis of Safety Data ..............................................................................................28 
5.9.1. 
Adverse Events ...........................................................................................................28 
5.9.2. 
Clinical Laboratory Measurements and Vital Signs ...................................................30 
5.9.3. 
Analysis of Vital Signs ...............................................................................................30 
5.9.4. 
Analysis of 12-Lead ECG ...........................................................................................30 
5.9.5. 
Physical Exams ...........................................................................................................31 
5.10. 
Analysis of Pharmacokinetic and Antibody Data .......................................................31 
5.10.1. 
Analysis of Pharmacokinetic Data ..............................................................................31 
5.10.2. 
Analysis of of Immunogenicity  Data .........................................................................31 
5.11. 
Analysis of Exploratory Biomarker Data ...................................................................32 
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Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1620 
Statistical Analysis Plan 
Feb 5, 2020 
CONFIDENTIAL 
Page 5 of 36 
6. 
DATA CONVENTIONS ............................................................................................32 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................33 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................33 
6.3. 
Definition of Study Day ..............................................................................................33 
6.4. 
Data Handling Convention for Missing Data .............................................................33 
6.5. 
Unscheduled Assessments ..........................................................................................34 
7. 
MULTIPLICITY CONSIDERATIONS .....................................................................34 
8. 
INTERIM ANALYSIS ...............................................................................................35 
9. 
SOFTWARE ...............................................................................................................35 
10. 
REFERENCES ...........................................................................................................36 
 
LIST OF TABLES 
Table 1: 
The 95% Binomial Exact Confidence Intervals for Observed ORR in 
Group 1 Given a Sample Size of 50 Patients (Based on 85% Power) ........................12 
Table 2: 
The 95% Binomial Exact Confidence Intervals for Observed ORR in 
Group 2 Given a Sample Size of 80 Patients (Based on 85% Power) ........................14 
 
 
                                        VV-RIM-00099532-1.0 Approved - 07 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1620 
Statistical Analysis Plan 
Feb 5, 2020 
CONFIDENTIAL 
Page 6 of 36 
ABBREVIATIONS AND DEFINITIONS 
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  
BMI 
Body mass index 
BOR 
Best overall response 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
CPK 
Creatine phosphokinase 
CR 
Complete response 
CRF 
Case report form  
CSR 
Clinical study report 
DLT 
Dose-limiting toxicities 
DCR 
Disease control rate 
dDCR 
Duration disease contral rate 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
East Cooperative Oncology Group 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOS 
End of study 
FAS 
Full analysis set 
FIH 
First-in-human 
HHI 
Hedgehog inhibitor 
ICH 
International Conference on Harmonisation 
irAE 
Immune-related adverse event 
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Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1620 
Statistical Analysis Plan 
Feb 5, 2020 
CONFIDENTIAL 
Page 7 of 36 
Abbreviation 
Definition of Term 
IWRS  
Interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NE 
Not evaluable  
NSCLC 
Non-small cell lung cancer 
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 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PKA 
PK analysis set 
PR 
Partial response 
PT 
Preferred term 
QLQ-C30 
Quality of Life Questionnaire Core 30 
RCC 
Renal cell cancer 
TILs 
Tumor-infiltrating lymphocytes 
TTR 
Time to response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Systems (software) 
SD 
Stable disease 
SI 
Standard international 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
WBC 
White blood cell 
WHODD 
WHO Drug Dictionary 
                                        VV-RIM-00099532-1.0 Approved - 07 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1620 
Statistical Analysis Plan 
Feb  5, 2020 
 
CONFIDENTIAL 
Page 8 of 36 
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 prior to the database lock. The 
SAP is intended to be a comprehensive and detailed description of strategy and statistical technique 
to be used to realize the analysis of data for R2810-ONC-1620 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. 
There are two groups in R2810-ONC-1620, Group 1 patients with metastatic BCC and Group 2 
patients with unresectable locally advanced BCC. Although enrolled in the same clinical trial,  the 
two groups are entirely distinct with different subjects, therefore, the statistical efficacy analysis 
of the two groups will be conducted independently and summarized separately. Thus, each group 
will be entitled to a separate alpha spend of 0.05.  Other analyses, including baseline 
characteristics, drug exposure, and safety data analysis, will be combined when deemed 
appropriate. 
1.1. 
Background/Rationale 
1.1.1. 
Background 
Basal cell carcinoma (BCC) is the most common malignancy in the United States. Virtually all 
BCCs are characterized by aberrant signaling of the hedgehog signaling pathway. Two hedgehog 
inhibitors (HHIs), vismodegib and sonidegib, were developed for treating BCC. ERIVANCE was 
a non-randomized phase 2 study that led to regulatory approval of vismodegib for the treatment of 
locally advanced and metastatic BCC. Vismodegib yielded overall response rates (ORRs) of 30% 
and 43% in metastatic and unresectable locally advanced BCC, respectively, in the original report 
(Sekulic 2012). At the 12-month update, median durations of response were 7.6 months for 
metastatic BCC and 9.5 months for locally advanced BCC (Sekulic 2015). Another orally available 
HHI, sonidegib, also has received regulatory approval for unresectable locally advanced BCC, 
based on demonstration of ORR of 43% (18 responses among 42 patients) in this population 
(Migden 2015). However, there is no approved agent for BCC patients who experienced 
progression of disease on HHI therapy, or who were intolerant of prior HHI therapy. 
1.1.2. 
Rationale 
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, cutaneous squamous cell carcinoma (CSCC), 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.  
 
                                        VV-RIM-00099532-1.0 Approved - 07 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1620 
Statistical Analysis Plan 
Feb  5, 2020 
 
CONFIDENTIAL 
Page 9 of 36 
Cemiplimab has been approved for CSCC in US, EU, Canada and Brazil. A safety database of 163 
patients with CSCC and 534 patients overall in clinical studies was used to inform the safety 
section of the labeling in the original filing. The safety database was later updated to 219 patients 
with CSCC and 591 patients overall.   
1.2. 
Study Objectives  
1.2.1. 
Primary Objective 
To estimate the clinical benefit of cemiplimab monotherapy for patients with metastatic BCC 
(Group 1) or with unresectable locally advanced BCC (Group 2), respectively, as measured by 
objective response rate (ORR) according to central review. 
1.2.2. 
Secondary Objectives 
 To estimate the ORR according to investigator review 
 To estimate the duration of response (DOR) and progression-free survival (PFS) by 
central and investigator review, and overall survival (OS)  
 To estimate the complete response (CR) rate by central review 
 To estimate the time to tumor response (TTR), disease control rate (DCR), and durable 
disease control rate (dDCR) by central and investigator review 
 To assess the safety and tolerability of cemiplimab 
 To assess the pharmacokinetics of cemiplimab (at selective sites only) 
 To assess the immunogenicity of cemiplimab 
 To assess the impact of cemiplimab on quality of life using EORTC QLQ-C30 and 
Skindex-16  
1.2.3. 
Exploratory Objective (Group 2 only) 
To explore the pharmacodynamic effects of cemiplimab in tumor biopsies obtained at baseline, 
during treatment, and at progression in BCC patients treated with cemiplimab and to assess 
predictive potential and correlation to clinical response for biomarkers of interest including but not 
limited to: 
 Tumor RNA expression 
 Number and distribution of TILs (CD8+ T cells, CD4+ T cells, T regulatory cells, and 
tissue permitting, other subtypes such as B cells, myeloid-derived cells, NK cells, etc.) 
                                        VV-RIM-00099532-1.0 Approved - 07 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1620 
Statistical Analysis Plan 
Feb  5, 2020 
 
CONFIDENTIAL 
Page 10 of 36 
 Expression levels (mRNA and/or protein) of PD-L1, GITR, and LAG-3, and possibly 
other check-point modulators 
 Mutations in known oncogenes and potential tumor neoantigens 
 Tumor mutation burden 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
Added TTR, DCR, and dDCR as secondary endpoints.  
1.2.5. 
Modifications from the Approved Statistical Analysis Plan 
This is the second version of the SAP, based on the study protocol of R2810-ONC-1620 
Amendment 4 dated July 29, 2019.  
The main changes from SAP 1.0 dated Nov 8, 2016 (based on original protocol) include:  
1. For the analysis of overall response rate in Group 1 (metastatic BCC), the statistical plan 
was revised so that the lower bound of the 95% confidence interval would exclude a 
clinically insignificant ORR of 15% in order to declare that the study treatment is 
effective. 
2. The dose of cemiplimab has been changed from 250 mg Q3W to 350 mg Q3W.  
3. Clarified the details of the timing of the data cut for the primary analysis for Group 2. 
Added an interim analysis for Group 1.  
4. Post treatment follow-up was extended for an additional 1 year, for a total of 
approximately 1.5 years after completion of the treatment at the end of extended 
follow-up (unless the patient enters retreatment).  
The following table outlines the main changes made to the SAP: 
                                        VV-RIM-00099532-1.0 Approved - 07 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1620 
Statistical Analysis Plan 
Feb  5, 2020 
 
CONFIDENTIAL 
Page 11 of 36 
SAP 1.0 (Nov 8, 2016) 
SAP 2.0 (current version) 
Protocol Amendment 
version and Rational 
The benchmarks for clinically 
meaningful response rates of 
Group 1 (metastatic BCC) 
was 10%.  
The benchmarks for clinically 
meaningful response rates of 
Group 1 (metastatic BCC) 
was changed to 15%. 
Change added in Protocol 
Amendment 2 (Mar 23, 
2017). The benchmark is 
more strigent based on FDA 
feedback.  
Planned dose of cemiplimab 
was 250 mg Q3W.  
Planned dose of cemiplimab 
was changed to 350 mg 
Q3W.  
Change added in Protocol 
Amendment 2 (Mar 23, 2017) 
based on modeling of 
exposure.  
No patient was enrolled prior 
to Protocol Amendment 2. 
Post-treatment follow-up was 
6 months.  
Post-treatment follow-up was 
extended for an additional 1 
year, for a total of 
approximately 1.5 years.  
Change added in Protocol 
Amendment 4 based on FDA 
feedback in order to increase 
stringency in capturing 
duration of response.  
No interim analysis 
Added an interim analysis for 
Group 1.  
Clarified the details of timing 
of the data cutoff for the 
primary analysis for Group 2 
Changes added in Protocol 
Amendment 4 in order to 
perform interim analysis of 
Group 1 at the time of 
primary analysis of Group 2.  
2. 
INVESTIGATION PLAN 
2.1. 
Study Design  
There are two study groups for this clinical trial, which will be analyzed independently. For each 
group, this is a phase II, non-randomized, multi-center pivotal trial evaluating the efficacy and 
safety of cemiplimab.  
 Group 1: Patients with metastatic BCC. These patients are required to have histologic 
confirmation of distant BCC metastases (e.g. lung, liver, bone, or lymph node). Group 
1 includes patients with both nodal metastatic and distant metastatic disease. 
 Group 2: Patients with unresectable locally advanced BCC. 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. 
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Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1620 
Statistical Analysis Plan 
Feb  5, 2020 
 
CONFIDENTIAL 
Page 12 of 36 
2.2. 
Statisticial Hypothesis 
For the primary endpoint of ORR, the following null hypothsis and alternative will be tested at 
2-sided significance level of 5% for Goup 1 and Group 2, respectively.  
Group 1: H0: ORR = 15% vs H1: ORR ≠ 15% 
Group 2: H0: ORR = 20% vs H1: ORR ≠ 20% 
2.3. 
Sample Size and Power Considerations   
Patients will be enrolled into 2 separate groups according to the stage of disease: metastatic BCC 
(Group 1) or unresectable locally advanced BCC (Group 2). The benchmarks for clinically 
meaningful response rates of >15% and >20% in metastatic and in unresectable locally advanced 
BCC, respectively, are consistent with published literature for BCC (Sekulic 2012, Migden 2015).  
For Group 1, 50 patients 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 5% if the true ORR is 34%.  
For Group 2, 80 patients are required to provide at least 85% power to reject a null hypothesis of 
an ORR of 20% at a 2-sided significance level of 5% if the true ORR is 35%. 
Given the sample sizes above, the non-clinically meaningful ORR of 15% for Group 1 will be 
excluded using the lower limit of 2-sided 95% CI if the observed ORR is 28% or more among 50 
patients (see Table 1); ie, the ORR for Group 1 is significantly different from 15%. The 
non-clinically meaningful ORR of 20% for Group 2 will be excluded using the lower limit of 
2-sided 95% CI if the observed ORR is 30.0% or more among 80 patients (see Table 2); ie, the 
ORR for Group 2 is significantly different from 20%. 
Table 1: 
The 95% Binomial Exact Confidence Intervals for Observed ORR in 
Group 1 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 
                                        VV-RIM-00099532-1.0 Approved - 07 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1620 
Statistical Analysis Plan 
Feb  5, 2020 
 
CONFIDENTIAL 
Page 13 of 36 
Number of Responders 
Observed ORR 
95%CI – lower 
95% CI – upper 
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 
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Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1620 
Statistical Analysis Plan 
Feb  5, 2020 
 
CONFIDENTIAL 
Page 14 of 36 
Table 2: 
The 95% Binomial Exact Confidence Intervals for Observed ORR in 
Group 2 Given a Sample Size of 80 Patients (Based on 85% Power) 
Number of Responders 
Observed ORR 
95%CI – lower 
95% CI – upper 
16 
0.200 
0.119 
0.304 
17 
0.212 
0.129 
0.318 
18 
0.225 
0.139 
0.332 
19 
0.237 
0.149 
0.346 
20 
0.250 
0.160 
0.359 
21 
0.263 
0.170 
0.373 
22 
0.275 
0.181 
0.386 
23 
0.287 
0.192 
0.400 
24 
0.300 
0.203 
0.413 
25 
0.312 
0.213 
0.426 
26 
0.325 
0.224 
0.439 
27 
0.338 
0.236 
0.452 
28 
0.350 
0.247 
0.465 
The sample sizes will be 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, and 84 patients for 
Group 2, for a total of 137 patients.  For each group, the actual minimum significant ORR at the 
end of study will be determined based on the final number of patients enrolled and treated. 
2.4. 
Study Plan 
After a screening period of up to 28 days, patients will receive up to 93 weeks of treatment. Each 
patient will receive a flat dose of 350 mg cemiplimab IV Q3W. Tumor assessments will be made 
at the end of each treatment cycle (5 treatment cycles of 9 weeks followed by 4 treatment cycles 
of 12 weeks). Extensive safety evaluations will occur on day 1 of each cycle, with routine safety 
evaluations to be conducted at each cemiplimab dosing visit.  
A patient will receive treatment until the 93-week treatment period is complete, or until disease 
progression (PD), unacceptable toxicity, withdrawal of consent, or confirmed CR. Patients with 
confirmed CR after a minimum of 48 weeks of treatment may elect to discontinue treatment and 
continue with all relevant study assessments (eg, efficacy assessments). Patients who discontinue 
study treatment due to PD should return to the clinic 30 days (range: 21 days to 42 days) after the 
last study treatment to complete the end-of-study (EOS) assessments. After the EOS visit, patients 
should be followed for survival status until death, loss to follow up, or study termination by the 
sponsor. 
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Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1620 
Statistical Analysis Plan 
Feb  5, 2020 
 
CONFIDENTIAL 
Page 15 of 36 
3. 
ANALYSIS POPULATIONS  
In accordance with guidance from the International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH 1998), the following populations sets will be used 
for statistical analysis.  
A patient is deemed eligible and enrolled after the patient completes the screening process and the 
first study drug dose is ordered in the 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 enrolled patients for each group who have passed screening 
and are deemed to be eligible for this study. All efficacy endpoints will be analyzed using the FAS 
by group.  
Note: In the interim analysis of Group 1, only patients with sufficient follow up will be included 
in the FAS (refer to Section 8 for interim analysis of Group 1).  
3.2. 
Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all enrolled patients who have received any cemiplimab for 
each group. Treatment compliance/administration and all clinical safety variables will be analyzed 
or summarized using the SAF.   
3.3. 
PK Analysis Set (PKA) 
The PK analysis set (PKA) will include all patients who have received any cemiplimab and have 
at least one non-missing post-baseline measurement of cemiplimab concentration in serum.  
3.4. 
Anti-Drug Antibody Set (ADA) 
The anti-drug antibody set (ADA) includes all patients who have received any cemiplimab and 
who have at least one post-dose ADA result. 
The NAb analysis set includes all patients who have received any cemiplimab and who have at 
least 1 non-missing result in the NAb assay. 
3.5. 
Biomarker Analysis Set (BAS) 
The biomarker analysis set (BAS) includes all patients who have received any cemiplimab and 
who have at least one sample assayed.  
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Regeneron Pharmaceuticals, Inc. 
Protocol: R2810-ONC-1620 
Statistical Analysis Plan 
Feb  5, 2020 
 
CONFIDENTIAL 
Page 16 of 36 
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) 
Baseline tumor characteristics variables include:  
 Anatomic site at earliest known diagnosis  
 Stage at initial diagnosis 
 TNM stage at initial diagnosis and screening 
 Metastatic status for Group 1 patients  
 Time from initial diagnosis to first dose  
 Time from most recent relapse/recurrence to first dose 
 Time on prior HHI therapy 
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. 
4.3. 
Pre-Treatment/Concomitant Medications and Procedures 
Medications/Procedures will be recorded from the time of informed consent until 105 days after 
the last study treatment. This also 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 to treat a study drug related AE. 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 
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Dictionary (WHODD). Patients will be counted once in all ATC categories linked to the 
medication. 
Prior cancer related 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 will be summarized.  
Pretreatment medications/procedures: non-study medications for which administration started and 
discontinued before a patient received the first dose of study drug.  
Concomitant medications/procedures: medications and other therapies that were onging at, or 
started between the first dose of study drug and 105 days after the last study drug, or started after 
105 days after the last study drug to treat a study drug related AE.  
Post treatment anti-cancer medications/procedures: anti-cancer medications and other anti-cancer 
therapies that started after initiation of the study drug.  
4.4. 
Efficacy Variable 
4.4.1. 
Primary Efficacy Variable 
The primary objective of the study is to estimate the ORR for mBCC (Group 1) or laBCC 
(Group 2) according to central review. Objective response rate (ORR) by central review is 
determined by the proportion of patients with best overall response of CR or PR based on central-
reviewed evaluation.  
Overall response is determined by RECIST version 1.1 for visceral lesions (Appendix 1 of the 
protocol), or by modified WHO criteria for skin lesions (Appendix 2 of the protocol), or by the 
composite response criteria for patients with both visceral and skin lesions (Appendix 2 of the 
protocol) at each time point at which a response assessment occurs. 
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.  
 Best overall response of SD must have met the response SD criteria at least once ≥ 39 
days (6 weeks – 3 days) after start of study treatment. Best overall 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. 
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 Patients with inoperable BCC at baseline who are rendered operable with clear 
margins will be deemed to have experienced PR.  
4.4.2. 
Secondary Efficacy Variables 
ORR by investigator assessment is determined by the proportion of patients with best overall 
response of CR or PR based on investigator-assessed evaluation..  
Duration of response (DOR) is determined for patients with BOR of CR or PR. DOR 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 (photographic or radiographic), 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.  
 Patients who do not have a documented tumor progression or death before initiation 
of new anti-cancer therapy will be censored at the last evaluable tumor assessment 
prior to or on  the date of new anti-cancer therapy.  
 Patients who do not have any evaluable post-baseline tumor assessment and do not 
die will be censored on the date of first study treatment.  
Progression-free survival (PFS) is measured from the start of treatment until the first date of 
recurrent or progressive disease (photographic or radiographic), 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.  
 Patients who do not have a documented tumor progression or death before initiation 
of new anti-cancer therapy will be censored at the last evaluable tumor assessment 
prior to or on  the date of new anti-cancer therapy.  
 Patients who do not have any evaluable post-baseline tumor assessment and do not 
die will be censored on the date of first study treatment. 
Overall survival (OS) is measured from the start of treatment until death due to any cause. Patients 
who do not die will be censored at the last date that patient is documented to be alive. As many 
patients may receive new anti-cancer therapy after disease progression, a sensitivity analysis of 
OS will be conducted by censoring patients at the first date of a new anti-cancer 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. 
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CR rate is determined by the proportion of patients with best overall response of CR (tumor biopsy 
confirmation is required for Group 2 patients).  
Disease control rate (DCR) is determined by the protion of patients with BOR of CR, PR, or SD.  
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 27 weeks (allowing tumor assessment made 1 
week earlier than week 27).   
Patient-reported quality of life are measured by the EORTC QLQ-C30 (Aaronson 1993) and 
Skindex-16 (Chren 2001) on day 1 of every cycle and at EOT.  
 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). 
 The scores for global and three domains of symptoms (4 items), functioning (5 items), 
and emotions (7 items) will be computed using the Skindex-16 scoring procedures 
(Chren 2001). 
 Change scores are defined as change of summary score of EORTC QLQ-C30 or 
Skindex-16 from day 1 of first treatment cycle. 
1.4.3 
Exploratory Efficacy Variables 
The following exploratory efficacy variables will be analyzed.  
 Association between efficacy and PD-L1 level  
 Association between efficacy and TMB 
4.5. 
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. 
4.5.1. 
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 after the last dose 
of study drug.  Prior to initiation of study drug, only the following categories of AEs should be 
reported on the AE CRF:  
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 SAEs 
 Non-SAEs 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 after the last dose of study 
treatment, regardless of relationship to study treatment, will be reported on the AE CRF.  
Additionally, any SAE or AE that the investigator believes may be related to study drug and that 
occurs later than 105 days after last dose of study drug should be reported. 
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 current 
version of the National Cancer Institute-Common Terminology Criteria for Adverse Events 
(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*.  
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 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. 
4.5.2. 
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 or greater immune-related toxicities (irAE) 
 An irAE of any grade in a patient previously treated with a PI 3-K inhibitor. 
Potential irAEs and Identified irAEs: Treatment-related TEAEs from the Sponsor Master List 
of Immune-Related PTs will be considered potential irAEs.  From the potential irAEs, the sponsor 
created a subsequent case definition for identified irAEs, defined as potential irAEs requiring 
treatment with corticosteroid or immunosuppressant, or potential irAEs that are immune-related 
endocrinopathies.   
4.5.3. 
 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; Potassium; Chloride; Carbon dioxide (bicarbonate); Calcium; 
Glucose; Albumin; Creatinine; Blood urea nitrogen (BUN); Urea; Aspartate aminotransferase 
(AST); Alanine aminotransferase (ALT); Alkaline phosphatase (ALP); Total bilirubin; Creatine 
phosphokinase (CPK) 
Hematology: Hemoglobin; White blood cells (WBCs); Platelet count; Differential: Neutrophils, 
Lymphocytes, Monocytes 
Urinalysis: Glucose; pH; Ketones; Blood; Specific gravity; Spot urine protein 
4.5.4. 
Vital Signs 
Vital signs will be collected according to Table 4, Table 5, and Table 6 of the protocol: Body 
temperature (oC); Resting systolic blood pressure and diastolic blood pressure (mmHg); Pulse 
(beats/minute); Respiratory rate (breaths/minute) 
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4.5.5. 
12-Lead Electrocardiography (ECG) 
A standard 12-lead ECG will be performed at time points according to Table 4, Table 5, and Table 
6 of the protocol.  On treatment days, ECG will be collected 30 minutes (±10 minutes) after the 
end of the infusion.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 (beat per minute; 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. 
4.5.6. 
Physical Examination Variables 
A thorough complete or limited physical examination will be performed at visits specified in Table 
4, Table 5, and Table 6 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 head and neck, lungs, heart, abdomen, 
lymph nodes, extremities, and skin, as well as a brief neurologic examination. Limited physical 
examination will include lungs, heart, abdomen, and skin. 
4.6. 
Pharmacokinetic Variables and Anti-Drug Antibody Variables 
(ADA)  
4.6.1. 
Pharmacokinetic Variables 
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 
4.6.2. 
Immunogenicity  Variables 
The immunogenicity variables are ADA status, titer, NAb status, and time-point/visit. Serum 
samples for ADA will be collected at the clinic visits specified in the table of events (Table 4, 
Table 5, and Table 6).   
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. 
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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 two-sided 95% confidence intervals will be summarized by the Kaplan-Meier method, unless 
otherwise specified. 
Statistical analysis for efficacy in Group 1 and Group 2 will be conducted independently.  
In order to describe ORR and DOR, the data cut for primary efficacy analysis will allow 
responding patients to be followed from onset of response for at least 6 months. For primary 
analysis, the last patient in a group will have the opportunity to be followed for approximately 57 
weeks, including 27 weeks (cycles 1 to 3) for response, plus an additional 30 weeks (cycles 4 to 
6) for DOR. If the last patient(s) has early EOS, the timing of data cut will be determined by the 
enrollment date of the last enrolled patient who remains on study (first dose + approximately 57 
weeks). 
An interim analysis of Group 1 patients will be performed at the time of the primary analysis for 
Group 2. For additional details, please see Section 8. 
An updated analysis of the response duration will be performed after all responding patients have 
been followed for a minimum of 12 months from onset of response. 
5.1. 
Demographics and Baseline Characteristics 
Patient demographics and baseline characteristics variables listed in Section 4.1 will be listed and 
summarized by group and combined. Reasons for Group 2 patients not being candidate for surgery 
or radiation will be listed and summarized.   
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 and summarized by group and combined. Listing of medical history 
will include SOC, PT, investigator verbatim and start and end dates Medical history will be 
summrerized by SOC and PT and  will be sorted by decreasing frequency of SOC followed by PT. 
5.3. 
Prior/Concomitant Medications and Procedures 
Prior medications and procedures will be listed and summarized by group and combined. Listing 
of prior cancer related medications will include generic name, ATC levels 2 and 4, start and end 
dates. Listing of prior cancer related radiotherapy will include type of radiation therapy, site of 
radiation, intent of treatment, start and end dates, and total dose. Listing of prior cancer related 
surgery will include type of procedure, date of surgery, and surgery location. The number and 
percentage of patients who received any prior cancer related medications, prior cancer related 
radiotherapy, or prior cancer related surgery will be summarized. The number and percentage of 
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patients who received any prior HHI therapy will also be summarized. Reasons for discontinuation 
of prior HHI therapy will also be listed and summarized.  
Concomitant medications and procedures will be listed and summarized by group and combined. 
Listing of concomitant medications will include generic name, ATC levels 2 and 4, indication, 
start and end dates, dose, route, frequency, and ongoing status. Concomitant medications will be 
summarized by ATC level 2 and ATC level 4. Concomitant procedures will be summarized by 
SOC and PT. 
Post treatment anti-tumort therapy will be listed. 
5.4. 
Subject Disposition 
Subject disposition will be listed and summarized by group and combined. The following 
summaries 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, date of end of study, and reasons for treatment and study 
discontinuation. 
5.5. 
Protocol Deviations 
Protocol deviations will be recorded in separate protocol deviation definition document which 
includes a listing of all patients with protocol deviations and the reason of deviation. 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 and combined. 
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. 
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The percentage of subjects who have <60%, 60-80%, 80-100%, and >100% compliance will be 
summarized for each group and combined. 
5.7. 
Exposure to Investigational Product 
Exposure to cemiplimab will be examined for each subject and the following variables will be 
summarized by group and combined: 
 The total number of cemiplimab doses administered  
 The total dosage of cemiplimab administered (mg) 
 Duration of treatment exposure (in weeks) calculated as the minimum of  
1. [date of last dose – date of first dose + 21 days based on Q3 weekly dosing 
schedule] / 7  
or  
2. [date of clinical data cut-off or date of death – date of first dose + 1] / 7 
 The number and percentage of patients exposed to cemiplimab will be presented by 
specific time points of interest (e.g., weeks 6, 12, 18, 24, 36, 72, 108) for each group 
and combined. The actual dose intensity (mg/week) = total dose received (mg) / 
duration of treatment exposure (week)  
 The relative dose intensity = actual dose intensity / planned dose intensity, 
 Planned dose intensity (mg/week) = planned dose (350 mg) / 3 
5.8. 
Analysis 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 (i.e., Group 1 and Group 2).  
The primary efficacy variable will be tested. All other efficacy variables will be summarized 
descriptively.   
5.8.1. 
Analysis of Primary Efficacy Variable 
The ORR according central review will 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.  
The primary analysis of efficacy is based on the exact binomial confidence interval approach of 
ORR. If the lower limit of 2-sided 95% exact bionomial confidence interval of observed ORRs 
excludes 15% for Group 1 or excludes 20% for group 2, the study treatment is deemed effective 
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for that group, respectively. For regions requiring alpha spending, details are provided in  
Section 8 for alpha adjustment due to interim analysis for Group 1.  
5.8.2. 
Analysis of Secondary Efficacy Variables 
ORR derived from the overall response that is based on investigator review 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 (for example, 6, 12, 18 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 (e.g., >=3 
months, >=6 months, >=12 months, >=18 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 (for example, 6, 12, 18 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 (for example, 6, 12, 18 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 (e.g., <2 
months, 2 to 4- months, 4 to 6- months, >=6 months).  
CR rate, DCR and dDCR will be summarized by group and the corresponding 2-sided 95% exact 
binomial confidence intervals will be derived using the Clopper-Pearson method.  
The duration of response and the best percentage change from baseline in target lesions will be 
presented by swimmer plot and waterfall plot respectively.  
5.8.3. 
Analysis of Quality of Life Variables 
Subject disposition rates: 
The subject disposition by group for all patient-reported outcomes (PRO) assessment timepoints 
will be provided:  
 The number of subjects with PRO assessment expected; a PRO assessment is 
expected as long as the subject is alive and on treatment 
 The number and % of subjects with PRO assessment not expected due to progression  
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 The number and % of subjects with PRO assessment not expected due to death 
 The number and % of subjects with PRO assessment not expected due to other 
reasons 
The subject disposition by treatment group by PRO assessment timepoint will also be provided 
graphically. 
PRO completion rates: 
PRO instrument completion rate at each PRO assessment timepoint will be reported for the 
EORTC QLQ-C30 (Physical function, role function, and global health status) and Skindex-16 
(Emotions, Symptoms, and Fuctioning). Completion rate will be calculated among subjects who 
are expected to have PRO assessments. The following will be provided: 
 The number and % of subjects meeting at least the minimum requirements for scoring 
of the instrument; these requirements are as follows: 
 EORTC QLQ C30: at least one subscale can be calculated 
 Skindex-16: at least one domain can be calculated 
The completion rates by treatment group at each PRO assessment timepoint will also be provided 
graphically. 
Descriptive analyses: 
The quality of life of patients will be repeatedly measured by the EORTC QLQ-C30 and 
Skindex-16 at the day 1 of each treatment cycle and end of treatment visit. The change scores of 
each component of QLQ-C30 and Skindex-16 will be summarized descriptively at each 
post-baseline time point. The summary scores of each component of QLQ-C30 and Skindex-16 
will also be graphically depicted by longitudinal plots. Partial missing data in QLQ-C30 and 
Skindex-16 will be addressed by the scoring algorithm, no additional imputations will be 
conducted for missing data.  
Additional analysis of PROs will be performed and the details will be included in a separate PRO 
SAP. 
5.8.4. 
Subgroup Efficacy Analysis and Exploratory 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) 
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 geographical region (North American, Europe and Rest of World) 
 number of prior systemic therapies (1, >1) 
 prior HHI (Progression/Lack of Response, Intolerant) 
 histologic subtype (Nodular, Infiltrative, Other) 
However, due to small sample sizes, the subgroup analysis will be exploratory in nature.  
In Group 2 patients who experience objective responses, the number of patients who remain with 
unresectable BCC and the number of patients from whom BCC becomes resectable (complete 
gross resection) will be tabulated. 
5.9. 
Analysis of Safety Data 
The analysis of safety and tolerance will be performed on the SAF. 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 . 
Period of observation: The observation period will be divided into three segments: pre-treatment, 
on-treatment and post-treatment.  
 The pre-treatment period is defined as the time between when the subjects give 
informed consent and before the start of cemiplimab treatment.  
 The on-treatment period it is defined as the time from the first dose of cemiplimab up 
to 105 days after the last dose of cemiplimab; 
 For patients who started cemiplimab as re-treatment more than 45 days after the 
last dose of regular cemiplimab treatment, the on-treatment period ends at the 
earlier day of 105 days after the last dose of regular cemiplimab or 1 day before 
the first dose of cemiplimab re-treatment; 
 For patients who started cemiplimab re-treatment within 45 days of their last 
regular cemiplimab treatment, the re-treatment is considered as a part of the 
regular treatment. That is, the on-treatment period ends at 105 days after the last 
dose of cemiplimab re-treatment;  
 For patients who started new anti-cancer systemic therapy, the on-treatment 
period ends at the earlier day of 105 days after the last dose of regular cemiplimab 
or 1 day before the first dose of new anti-cancer systemic therapy.  
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 The post-treatment period is defined as the time starting one day after the end of 
on-treatment period. 
Definitions:  
 Pre-treatment AEs are defined as AEs that developed during the pre-treatment period 
and are not treatment-emergent as defined below. 
 Treatment-emergent AEs (TEAEs) are defined as AEs that developed or worsened 
during the on-treatment period and treatment-related AEs that occur during 
post-treatment period. 
 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 TEAEs will include: TEAEs, Treatment related TEAEs, Serious TEAEs, 
Treatment-related Serious TEAEs and treatment-emergent AESI. For TEAEs, the following will 
be summarized: 
 The number and proportions of patients reporting at least 1 TEAE, presented by SOC 
and PT 
 TEAEs by severity (CTCAE, latest available version), presented by SOC and PT 
 Grade ≥3 TEAEs by SOC and PT 
 TEAEs related to treatment, presented by SOC and PT 
 Grade ≥3 treatment-related TEAEs by SOC and PT 
 TEAEs leading to permanent treatment discontinuation, presented by SOC, PT and 
CTCAE NCI 
 TEAEs leading to death, presented by SOC and PT 
 IRR by SOC, PT and CTCAE NCI 
 Treatment-emergent potential irAEs based on sponsor list by SOC, PT and NCI and 
by Composite term, PT and NCI 
 Treatment-emergent identified irAEs based on sponsor list by SOC, PT and NCI and 
by Composite term, PT and NCI 
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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. 
For TEAE listings, the following variables will be displayed:  
 Verbatim Term, SOC, PT 
 AE start date and end date (and corresponding study day) 
 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: none, medication, procedure/surgery 
 Outcome 
Pre-treatment AEs and post-treatment AEs will be listed separately.  
5.9.2. 
Clinical Laboratory Measurements and Vital Signs 
Listings of laboratory measurements will include laboratory values, normal ranges, grade (if 
applicable), collection date, and visit. For numeric lab variables and change from baseline to each 
visit will be summarized.  
Summary tables for worst laboratory values during on-treatment period with NCI CTCAE all 
grade and grade ≥ 3 will be generated. Shift tables from baseline to wosrt post-treatment NCI 
CTCAE grade during on-treatment period will be generated.  
5.9.3. 
Analysis of Vital Signs 
Vital signs (pulse, sitting blood pressures, and temperature) 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 if appliable, QRS interval, and Ventricular 
rate) will be listed and summarized by Baseline and change from Baseline to each scheduled 
assessment time with descriptive statistics. 
ECG status (i.e. 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.  
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5.9.5. 
Physical Exams 
Physical examination findings at baseline as well as post-baseline 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-traetment period will be summized. 
5.10. 
Analysis of Pharmacokinetic and Antibody Data 
5.10.1. 
Analysis of Pharmacokinetic Data  
Concentration of cemiplimab in serum 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 and Ctrough, 
will be presented as individual values with descriptive statistics. 
5.10.2. 
Analysis of of Immunogenicity  Data 
The immunogenicity variables described in Section 4.6.2 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: 
Anti-drug antibody response categories and titer categories that will be assessed are as follows: 
 Pre-existing immunoreactivity, defined as either an ADA positive response in the 
cemiplimab ADA assays 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. 
 Persistent Response-Treatment-emergent ADA positive response with two or more 
consecutive ADA positive sampling time points, separated by at least 12-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. 
 The treatment-emergent responses will be further characterized as Persistent, 
Indeterminate, or Transient 
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 Treatment boosted ADA response, defined as a positive response in the cemiplimab 
ADA assay post first dose that is greater than or equal to 9-fold over baseline titer 
levels, when baseline results are positive. 
 Titer value category (Titer Range) 
 Low (titer <1,000) 
 Moderate (1,000≤ titer ≤10,000) 
 High (titer >10,000) 
 NAb response in ADA positive patients  
Listing of all ADA titer levels will be provided for treatment-emergent and treatment-boosted 
ADA response patients. 
Potential association between immunogenicity variables and systemic exposure to cemiplimab 
will be explored by treatment groups.  Plots of cemiplimab concentrations may be provided for 
analyzing the potential impact of ADA response status, titer and on PK.  
Potential association between ADA/immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period:  
Infusion related reactions (serious or severe and lasting 24 hours or longer) 
Hypersensitivity  
Anaphylaxis 
Potential association between immunogenicity variables and efficacy endpoints may be explored 
(e.g. scatter plot or spaghetti plot). 
5.11. 
Analysis of Exploratory Biomarker Data  
Descriptive statistics of ORR will be provided by PD-L1 expression levels (for example, PD-L1 
expression <1% vs PD-L1 expression >=1%). Descriptive statistics of TMB will be provided by 
patients’ clinical efficacy data.  
Description of statistical methods that will be used for additional biomarker data analyses will be 
provided in a separate Biomarker Analytical Plan.  
6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
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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 unevaluable 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. 
Definition of Study Day 
Study day 1 is the day of patient receiving frist dose of cemiplimab. Study day –1 is the day 
before patient receiving first dose of cemiplimab. There is no Day 0. 
For events prior to the first day a patient receiving cemiplimab treatment, the study day is 
defined as date of the date of event - first dose of cemiplimab; for events on or after the first dose 
of cemiplilmab, the study day is defined as date of event - date of the first dose of cemiplimab 
+1. 
6.4. 
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. 
AE suspected to be caused by cemiplimab If AE suspected to be caused by cemiplimab is missing, 
the AE relationship will be imputed as related.  
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6.5. 
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 worst post-basline values 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. 
7. 
MULTIPLICITY CONSIDERATIONS 
Patients will be enrolled into 2 separate groups according to the stage of disease: metastatic BCC 
(Group 1) or unresectable locally advanced BCC (Group 2). 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. A separate type I error of 5% is 
applied to Group 1 and Group 2, respectively. Therefore, statistical control of overall type I error 
for the whole study is not planned.  
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8. 
INTERIM ANALYSIS 
An interim analysis of Group 1 patients will be performed at the time of the primary analysis for 
Group 2. All Group 1 patients enrolled on or prior to the cutoff date will be included in the safety 
analysis. In order to describe ORR and DOR, Group 1 patients who have the opportunity to be 
followed from onset of response for at least 6 months will be included in the efficacy analysis. 
Because responses may emerge slowly in BCC patients (Falchook 2016), and the primary endpoint 
results are not known prior to data cut, the convention in this study will be that all patients will 
have the opportunity for at least 6 months to develop response. Given the tumor assessment 
schedule (every 9 weeks from cycle 1 to 5, and every 12 weeks from cycle 6 to 9), the interim 
analysis for Group 1 will only include Group 1 patients who have the opportunity to be followed 
for approximately 57 weeks, including 27 weeks (cycles 1 to 3) for response, plus an additional 30 
weeks (cycles 4 to 6) for DOR. If the last patient(s) has early EOS, the timing of data cut will be 
determined by the enrollment date of the last enrolled patient who remains on study (first dose + 
approximately 57 weeks). 
For regions where alpha spending is not required: For this planned interim analysis on Group 1 
patients, 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. 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. At the time of the final 
analysis for Group 1 patients, 95% exact confidence intervals will be reported. 
For regions where alpha spending is required: For this interim analysis on Group 1 patients, a 
2-sided alpha of 0.0001 will be allocated for interim analysis, and a 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 1 patients, the precision of ORR will be estimated by an adjusted and 
2-sided 99.99% exact confidence interval. The unadjusted 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 1 patients, both adjusted 95.01% and unadjusted 95% exact confidence intervals will be 
reported. 
For other efficacy endpoints in Group 1 patients, only a 2-sided 95% exact confidence interval will 
be presented both at the interim and at the final analysis. 
9. 
SOFTWARE 
All statistical analyses will be done using SAS Version 9.4 or above. 
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10. 
REFERENCES 
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. 
Chren, M. M.; Lasek, R. J.; Sahay, A. P. & Sands, L. P. (2001), 'Measurement properties of 
Skindex-16: a brief quality-of-life measure for patients with skin diseases.', J Cutan Med Surg 
5(2), 105--110. 
Clopper, C. & Pearson, E. S. (1934), 'The use of confidence or fiducial limits illustrated in the 
case of the binomial', Biometrika, 404--413. 
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. 
Falchook GS, Leidner R, Stankevich E, Piening B, Bifulco C, Lowy I, Fury MG. Responses of 
metastatic basal cell and cutaneous squamous cell carcinomas to anti-PD1 monoclonal antibody 
REGN2810. J Immunother Cancer 2016;4:70. 
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. 
Migden, M. R.; Guminski, A.; Gutzmer, R.; Dirix, L.; Lewis, K. D.; Combemale, P.; Herd, R. 
M.; Kudchadkar, R.; Trefzer, U.; Gogov, S.; Pallaud, C.; Yi, T.; Mone, M.; Kaatz, M.; Loquai, 
C.; Stratigos, A. J.; Schulze, H.-J.; Plummer, R.; Chang, A. L. S.; Cornélis, F.; Lear, J. T.; 
Sellami, D. & Dummer, R. (2015), 'Treatment with two different doses of sonidegib in patients 
with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, 
double-blind phase 2 trial.', Lancet Oncol 16(6), 716--728. 
Sekulic, A.; Migden, M. R.; Lewis, K.; Hainsworth, J. D.; Solomon, J. A.; Yoo, S.; Arron, S. T.; 
Friedlander, P. A.; Marmur, E.; Rudin, C. M.; Chang, A. L. S.; Dirix, L.; Hou, J.; Yue, H.; 
Hauschild, A. & , E. R. I. V. A. N. C. E. B. C. C. i. (2015), 'Pivotal ERIVANCE basal cell 
carcinoma (BCC) study: 12-month update of efficacy and safety of vismodegib in advanced 
BCC.', J Am Acad Dermatol 72(6), 1021--6.e8. 
Sekulic, A.; Migden, M. R.; Oro, A. E.; Dirix, L.; Lewis, K. D.; Hainsworth, J. D.; Solomon, J. 
A.; Yoo, S.; Arron, S. T.; Friedlander, P. A.; Marmur, E.; Rudin, C. M.; Chang, A. L. S.; Low, J. 
A.; Mackey, H. M.; Yauch, R. L.; Graham, R. A.; Reddy, J. C. & Hauschild, A. (2012), 'Efficacy 
and safety of vismodegib in advanced basal-cell carcinoma.', N Engl J Med 366(23), 2171--2179. 
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