A Randomized, Double-Blind, Multicenter, Phase 2 Study of Retifanlimab in Combination With INCAGN02385 (Anti-LAG-3) and INCAGN02390 (Anti-TIM-3) as First-Line Treatment in Participants With PD-L1-Positive (CPS ≥ 1) Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck
Phase: PHASE2
Conditions: Head and Neck Cancer
Sponsor: Incyte Biosciences International Sàrl

Official Title: 
A Randomized, Double-Blind, Multicenter, Phase 2 Study of 
Retifanlimab in Combination With INCAGN02385 (Anti–LAG-3) and 
INCAGN02390 (Anti–TIM-3) as First-Line Treatment in Participants 
With PD-L1–Positive (CPS ≥ 1) Recurrent/Metastatic Squamous Cell 
Carcinoma of the Head and Neck 
NCT Number: 
NCT05287113 
Document Date: 
Protocol INCAGN 2385-203 Am 2 Version 3 19 DEC 2023 
 
 
 

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TITLE PAGE 
Clinical Study Protocol 
 
INCAGN 2385-203 
A Randomized, Double-Blind, Multicenter, Phase 2 Study of 
Retifanlimab in Combination With INCAGN02385 (Anti–LAG-3) and 
INCAGN02390 (Anti–TIM-3) as First-Line Treatment in Participants 
With PD-L1–Positive (CPS ≥ 1) Recurrent/Metastatic Squamous Cell 
Carcinoma of the Head and Neck 
 
Product: 
INCAGN02385; INCAGN02390; retifanlimab (INCMGA00012) 
IND Number: 
 
EudraCT Number: 
2021-005775-39 
EU CT Number: 
2023-504270-38-00 
Phase of Study: 
2 
Sponsor: 
Incyte Biosciences International Sàrl 
Rue Docteur-Yersin 12 
1110 Morges, Switzerland 
Original Protocol: 
15 NOV 2021 
Version 1-BE: 
06 JUL 2022 
Version 1-FR: 
11 JUL 2022 
Version 1-KR: 
11 JUL 2022 
Version 1-TW: 
01 AUG 2022 
Version 1-DE: 
30 AUG 2022 
Amendment 1: 
04 NOV 2022 
Amendment 2: 
19 DEC 2023 
 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki (Brazil 2013) and conducted in adherence to the study Protocol, applicable Good Clinical Practices, and 
applicable laws and country-specific regulations, including WMO (Medical Research Involving Human Participants 
Act) and Clinical Trials Regulation (EU) No. 536/2014, in which the study is being conducted. 
The information in this document is confidential. No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without prior 
written consent. 

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INVESTIGATOR'S AGREEMENT 
I have read the INCAGN 2385-203 Protocol Amendment 2 (dated 19 DEC 2023) and agree to 
conduct the study as outlined. I agree to maintain the confidentiality of all information received 
or developed in connection with this Protocol. 
 
 
 
 
 
(Printed Name of Investigator) 
 
 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 

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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR'S AGREEMENT ................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................9 
1. 
PROTOCOL SUMMARY ..........................................................................................13 
2. 
INTRODUCTION ......................................................................................................22 
2.1. 
Background .................................................................................................................22 
2.1.1. 
Scientific Rationale for Inhibition of PD-(L)1, LAG-3, and TIM-3 in Human 
Cancer .........................................................................................................................22 
2.1.2. 
Treatment of Patients With Recurrent/Metastatic SCCHN ........................................23 
2.1.3. 
Anti–PD-1 Plus Anti–LAG-3 With or Without Anti–TIM-3 in SCCHN...................24 
2.1.4. 
Justification for Dose of INCAGN02385 and INCAGN02390 ..................................25 
2.1.4.1. 
INCAGN02385 Dose ..................................................................................................25 
2.1.4.2. 
INCAGN02390 Dose ..................................................................................................27 
2.1.5. 
Justification for Retifanlimab Dose ............................................................................28 
2.2. 
Benefit/Risk Assessment ............................................................................................29 
2.2.1. 
Retifanlimab Monotherapy .........................................................................................29 
2.2.2. 
INCAGN02385 Monotherapy ....................................................................................30 
2.2.3. 
INCAGN02390 Monotherapy ....................................................................................30 
2.2.4. 
Combinations of Retifanlimab, INCAGN02385, and INCAGN02390 ......................31 
2.2.5. 
Benefit/Risk Assessment During the COVID-19 Pandemic ......................................32 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................34 
4. 
STUDY DESIGN .......................................................................................................36 
4.1. 
Overall Design ............................................................................................................36 
4.2. 
Number of Participants ...............................................................................................36 
4.3. 
Overall Study Duration ...............................................................................................37 
4.4. 
Study Termination ......................................................................................................37 
5. 
STUDY POPULATION .............................................................................................38 
5.1. 
Inclusion Criteria ........................................................................................................38 
5.2. 
Exclusion Criteria .......................................................................................................39 
5.3. 
Lifestyle Considerations .............................................................................................43 
5.4. 
Screen Failures ............................................................................................................43 

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5.5. 
Replacement of Participants .......................................................................................43 
5.6. 
Data Safety Monitoring Board ....................................................................................43 
6. 
STUDY TREATMENT ..............................................................................................45 
6.1. 
Study Treatments Administered .................................................................................45 
6.2. 
Preparation, Handling, and Accountability ................................................................46 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................47 
6.4. 
Study Treatment Compliance .....................................................................................47 
6.5. 
Dose Modifications .....................................................................................................47 
6.5.1. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study 
Drugs ...........................................................................................................................47 
6.5.1.1. 
Procedures for Participants Exhibiting Drug-Related, Non–Immune-Related 
Adverse Events ...........................................................................................................48 
6.5.2. 
Management of Suspected Infusion Reactions ...........................................................49 
6.5.3. 
Procedures for Participants Exhibiting Immune-Related Adverse Events .................50 
6.5.4. 
Criteria for Permanent Discontinuation of Study Treatment ......................................56 
6.5.5. 
Treatment After Initial Evidence of Radiologic Disease Progression ........................56 
6.6. 
Concomitant Medications and Procedures .................................................................57 
6.6.1. 
Permitted Medications and Procedures ......................................................................57 
6.6.2. 
Restricted Medications and Procedures ......................................................................58 
6.6.2.1. 
Palliative Surgery and Radiation Therapy While on Study Treatment ......................58 
6.6.3. 
Prohibited Medications and Procedures .....................................................................59 
6.7. 
Treatment After the End of the Study .........................................................................60 
7. 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
WITHDRAWAL ........................................................................................................61 
7.1. 
Discontinuation of Study Treatment ...........................................................................61 
7.1.1. 
Reasons for Discontinuation .......................................................................................61 
7.1.2. 
Discontinuation Procedures ........................................................................................62 
7.2. 
Participant Withdrawal From the Study .....................................................................62 
7.3. 
Lost to Follow-Up.......................................................................................................63 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................64 
8.1. 
Administrative and General Procedures .....................................................................64 
8.1.1. 
Informed Consent Process ..........................................................................................64 
8.1.2. 
Screening Procedures ..................................................................................................65 

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8.1.3. 
Interactive Response Technology Procedure ..............................................................65 
8.1.4. 
Distribution of Reminder Cards ..................................................................................65 
8.1.5. 
Demographics and Medical History ...........................................................................65 
8.1.5.1. 
Demographics and General Medical History .............................................................65 
8.1.5.2. 
Disease Characteristics and Treatment History ..........................................................66 
8.1.6. 
Prior/Concomitant Medications Review.....................................................................66 
8.2. 
Efficacy Assessments .................................................................................................66 
8.2.1. 
Tumor Imaging per RECIST v1.1 ..............................................................................66 
8.2.1.1. 
Tumor Imaging During Screening ..............................................................................66 
8.2.1.2. 
Tumor Imaging During the Study...............................................................................67 
8.2.2. 
Health Economics .......................................................................................................67 
8.3. 
Safety Assessments .....................................................................................................67 
8.3.1. 
Adverse Events ...........................................................................................................67 
8.3.2. 
Physical Examinations ................................................................................................68 
8.3.3. 
Vital Signs ..................................................................................................................68 
8.3.4. 
Electrocardiograms .....................................................................................................69 
8.3.5. 
Eastern Cooperative Oncology Group Performance Status ........................................69 
8.3.6. 
Laboratory Assessments .............................................................................................69 
8.3.6.1. 
Urine Sample Collection .............................................................................................72 
8.3.6.2. 
Pregnancy Testing ......................................................................................................72 
8.3.6.3. 
Serology ......................................................................................................................72 
8.4. 
Pharmacokinetic and Immunogenicity Assessments ..................................................72 
8.4.1. 
Blood Sample Collection ............................................................................................72 
8.4.2. 
Immunogenicity (Antidrug Antibody) Assessments ..................................................73 
8.5. 
Pharmacodynamic and Translational Assessments ....................................................73 
8.5.1. 
Tumor Tissue Collection ............................................................................................74 
8.5.2. 
Whole Blood Correlative Flow Cytometry Assessments ...........................................74 
8.5.3. 
Whole Blood for PBMC Assessments ........................................................................74 
8.5.4. 
Plasma Correlative Assessments ................................................................................75 
8.5.5. 
Plasma cfDNA Assessments .......................................................................................75 
8.6. 
Unscheduled Visits .....................................................................................................75 
8.7. 
End of Treatment and/or Early Termination ..............................................................75 
8.8. 
Follow-Up ...................................................................................................................75 

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8.8.1. 
Safety Follow-Up ........................................................................................................75 
8.8.2. 
Post-Treatment Disease Follow-Up ............................................................................76 
8.8.3. 
Survival Follow-Up ....................................................................................................76 
9. 
ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................77 
9.1. 
Definition of Adverse Event .......................................................................................77 
9.2. 
Definition of Serious Adverse Event ..........................................................................78 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events .........79 
9.4. 
Reporting of Serious Adverse Events .........................................................................81 
9.5. 
Events of Clinical Interest ..........................................................................................82 
9.6. 
Emergency Unblinding of Treatment Assignment .....................................................83 
9.7. 
Pregnancy ...................................................................................................................83 
9.8. 
Warnings and Precautions ..........................................................................................84 
9.9. 
Product Complaints ....................................................................................................84 
9.10. 
Treatment of Overdose ...............................................................................................84 
10. 
STATISTICS ..............................................................................................................85 
10.1. 
Sample Size Determination ........................................................................................85 
10.2. 
Populations for Analyses ............................................................................................85 
10.3. 
Level of Significance ..................................................................................................87 
10.4. 
Statistical Analyses .....................................................................................................87 
10.4.1. 
Primary Analysis ........................................................................................................87 
10.4.2. 
Secondary Analysis ....................................................................................................88 
10.4.2.1. 
Objective Response Rate ............................................................................................88 
10.4.2.2. 
Disease Control Rate ..................................................................................................89 
10.4.2.3. 
Duration of Response .................................................................................................89 
10.4.2.4. 
Overall Survival ..........................................................................................................89 
10.4.3. 
Overall Efficacy Conclusions .....................................................................................89 
10.4.4. 
Safety Analyses ..........................................................................................................89 
10.4.5. 
Pharmacokinetic Analysis ..........................................................................................90 
10.4.6. 
Exploratory Analysis ..................................................................................................90 
10.5. 
Interim Analysis ..........................................................................................................91 
10.6. 
Multiplicity Control ....................................................................................................91 
10.7. 
Subgroup Analyses .....................................................................................................91 

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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................93 
11.1. 
Investigator Responsibilities .......................................................................................93 
11.1.1. 
Identification of the Coordinating Principal Investigator ...........................................94 
11.2. 
Data Management .......................................................................................................94 
11.3. 
Data Quality Assurance ..............................................................................................96 
11.4. 
Data Privacy and Confidentiality of Study Records ...................................................96 
11.5. 
Financial Disclosure ...................................................................................................97 
11.6. 
Publication Policy .......................................................................................................97 
11.7. 
Study and Site Closure................................................................................................98 
12. 
REFERENCES ...........................................................................................................99 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS AND DEFINITIONS ..........................................104 
APPENDIX B. TEST FOR LAG-3 EXPRESSION .................................................................106 
APPENDIX C. COVID-19 PANDEMIC MITIGATION STRATEGIES AND 
INSTRUCTIONS .....................................................................................................107 
APPENDIX D. PROTOCOL AMENDMENT SUMMARY OF CHANGES .........................110 
 
LIST OF TABLES 
Table 1: 
Primary and Secondary Objectives and Endpoints .....................................................13 
Table 2: 
Key Study Design Elements .......................................................................................14 
Table 3: 
Schedule of Activities .................................................................................................16 
Table 4: 
Schedule of Laboratory Assessments .........................................................................19 
Table 5: 
Schedule of Pharmacokinetic and Pharmacodynamic Assessments ..........................21 
Table 6: 
Objectives and Endpoints ...........................................................................................34 
Table 7: 
Exclusionary Laboratory Values ................................................................................40 
Table 8: 
Study Treatment Information .....................................................................................45 
Table 9: 
Management Guidelines for Drug-Related, Non–Immune-Related Adverse 
Events .........................................................................................................................48 
Table 10: Guidelines for Management of Suspected Infusion Reactions ...................................50 
Table 11: Guidelines for Management of Immune-Related Adverse Events .............................52 
Table 12: Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease ........................................................................................................................57 
Table 13: Eastern Cooperative Oncology Group Performance Status ........................................69 

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Table 14: Required Laboratory Analytes ....................................................................................71 
Table 15: Pharmacokinetic and Antidrug Antibody Sample Blood Sample Timing ..................73 
Table 16: Biomarker/Translational Sample Timing ...................................................................74 
Table 17: Sample Size Assumptions for Progression-Free Survival ..........................................85 
Table 18: Populations for Analyses ............................................................................................86 
Table 19: Endpoints and Analysis Populations ..........................................................................86 
Table 20: Evaluation and Censoring of Progression-Free Survival ............................................87 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................15 
Figure 2: 
INCAGN02385 Concentrations Over Time (Mean ± SE) After the First 
Dose and at Steady-State at Various Dose Levels ......................................................26 
Figure 3: 
Average Receptor Occupancy in Participants Infused With Various Doses of 
INCAGN02385 ...........................................................................................................26 
Figure 4: 
Frequency of Proliferating T Cells in the Blood of Participants Receiving 
Various Doses of INCAGN02385 ..............................................................................27 
Figure 5: 
INCAGN02390 Concentrations Over Time (Mean ± SE) After the First 
Dose and at Steady-State at Various Dose Levels ......................................................28 
Figure 6: 
Average Receptor Occupancy in Participants Infused With Various Doses of 
INCAGN02390 ...........................................................................................................28 
Figure 7: 
Multiplicity Graph for 1-Sided Alpha Reallocation Strategy .....................................91 
 

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LIST OF ABBREVIATIONS 
Abbreviations and 
Special Terms 
Definition 
ADA 
antidrug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBc 
antihepatitis B core 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BNP 
B-type natriuretic peptide 
cfDNA 
circulating free deoxyribonucleic acid 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL 
total systemic clearance 
CMH 
Cochran-Mantel-Haenszel test 
CNS 
central nervous system 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019 
CPK 
creatine phosphokinase 
CPS 
combined positive score 
CR 
complete response  
CrCl 
creatinine clearance 
CSR 
Clinical Study Report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTR 
Clinical Trial Regulation 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
ECD 
extracellular domain 
ECOG 
Eastern Cooperative Oncology Group 

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Abbreviations and 
Special Terms 
Definition 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment  
ESMO 
European Society for Medical Oncology 
Fc 
fragment crystallizable 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GLOBOCAN 
Global Cancer Incidence, Mortality, and Prevalence 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
HPV 
human papilloma virus 
HR 
hazard ratio 
HRT 
hormone-replacement therapy 
IB 
Investigator's Brochure 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
ICI 
immune-checkpoint inhibitor 
IEC 
independent ethics committee 
IFN-γ 
interferon gamma 
IgG 
immunoglobulin G 
IgG1 
immunoglobulin gamma 1 
IgSF 
immunoglobulin superfamily 
IHC 
immunohistochemistry 
INR 
international normalized ratio 
irAE 
immune-related adverse event 
IRB 
institutional review board 
IRR 
infusion-related reaction 
IRT 
interactive response technology  
ITT 
intent-to-treat 

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Abbreviations and 
Special Terms 
Definition 
KD 
equilibrium dissociation constant between the antibody and its antigen 
LAG-3 
lymphocyte-activation gene 3 
LDL 
low-density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
major histocompatibility complex 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NA 
not applicable 
NSAID 
nonsteroidal anti-inflammatory drug 
NSCLC 
non–small cell lung cancer 
ORR 
objective response rate  
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease  
PD-1 
programmed death 1  
PD-L1 
programmed death-ligand 1 
PD-L2 
programmed death-ligand 2 
PFS 
progression-free survival  
PK 
pharmacokinetic(s) 
PO 
orally 
PR 
partial response  
PT 
prothrombin time 
PTT 
partial thromboplastin time 
Q2W 
once every 2 weeks 
Q4W 
once every 4 weeks 
Q8W 
once every 8 weeks 
Q12W 
once every 12 weeks 
R/M 
recurrent/metastatic 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
RSI 
Reference Safety Information 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV2 
severe acute respiratory syndrome coronavirus 2 

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Abbreviations and 
Special Terms 
Definition 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SITC 
Society for Immunotherapy of Cancer 
SoA 
schedule of activities 
SoC 
standard of care 
SOP 
Standard Operating Procedure 
TCGA 
The Cancer Genome Atlas 
TCR 
T-cell receptor 
TEAE 
treatment-emergent adverse event 
TG 
treatment group 
TIL 
tumor-infiltrating lymphocyte 
TIM-3 
T-cell immunoglobulin and mucin domain-containing protein 3 
TnI 
troponin I 
TnT 
troponin T 
TPS 
tumor proportion score 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
WBC 
white blood cell 
WOCBP 
woman of childbearing potential 

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1. 
PROTOCOL SUMMARY 
Protocol Title: 
A Randomized, Double-Blind, Multicenter, Phase 2 Study of Retifanlimab in Combination With 
INCAGN02385 (Anti–LAG-3) and INCAGN02390 (Anti–TIM-3) as First-Line Treatment in 
Participants With PD-L1–Positive (CPS ≥ 1) Recurrent/Metastatic Squamous Cell Carcinoma of 
the Head and Neck. 
Protocol Number: INCAGN 2385-203 
Objectives and Endpoints: 
Table 1 presents the primary and secondary objectives and endpoints. 
Table 1: 
Primary and Secondary Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To determine the efficacy of the combinations of 
retifanlimab + INCAGN02385 (TG2) and 
retifanlimab + INCAGN02385 + INCAGN02390 
(TG3) compared with retifanlimab alone (TG1) in 
the overall study population.  
PFS, defined as the interval between the date of 
randomization and the earliest date of disease 
progression, based on investigator assessment per 
RECIST v1.1, or death due to any cause. 
Secondary 
To assess disease response per RECIST v1.1 in 
TG2 and TG3 compared with TG1. 
• Objective response, defined as having a CR or 
PR, determined based on investigator 
assessment per RECIST v1.1. 
• DOR, defined as the time from earliest date of 
disease response (CR or PR) until earliest date 
of disease progression, based on investigator 
assessment per RECIST v1.1, or death from 
any cause if occurring sooner than progression. 
• Disease control, defined as having CR, PR, or 
SD (≥ 6 months) as best response, based on 
investigator assessment per RECIST v1.1. 
To determine the OS of TG2 and TG3 compared 
with TG1. 
OS, defined as the interval between the date of 
randomization until death due to any cause.  
To determine the safety of TG2 and TG3 
compared with TG1. 
• AEs, assessed in body systems with symptoms, 
through physical examinations, changes in vital 
signs and ECGs, and through clinical 
laboratory blood sample evaluations. 
• Impact on-study treatment, assessed by 
treatment interruptions, dose delays, and 
withdrawal of study treatment due to AEs. 

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Overall Design: 
Table 2 presents the key study design elements. Further study details are presented after the 
table. 
Table 2: 
Key Study Design Elements 
Study Phase 
Phase 2 
Clinical Indication 
Recurrent or metastatic SCCHN that is PD-L1–positive (CPS ≥ 1) 
Population 
Male and female participants at least 18 years of age who have R/M SCCHN 
that is PD-L1–positive and systemic therapy–naive in the advanced disease 
setting 
Number of 
Participants 
Approximately 162 total participants will be enrolled and randomized to 
3 treatment groups (approximately 54 participants per group) 
Study Design 
Randomized, double-blind, multicenter study evaluating the efficacy and 
safety of TG2 (retifanlimab + INCAGN02385) and TG3 (retifanlimab + 
INCAGN02385 + INCAGN02390) compared with TG1 (retifanlimab alone) 
Estimated Duration 
of Study 
Participation 
Up to 28 days for screening, continuous treatment in consecutive 4-week 
cycles as long as participants have not met any criteria for discontinuation, and 
90 days for safety follow-up. Participants will be allowed to receive study 
treatment for a maximum of 2 years. It is estimated that an individual will 
participate for approximately 1 year. 
DSMB 
Yes (external) 
Coordinating 
Principal 
Investigator 
Robert Haddad, MD 
Treatment Groups and Duration: 
This is a randomized, double-blind, Phase 2 study to evaluate the efficacy and safety of the 
combination of retifanlimab plus INCAGN02385(TG2) and retifanlimab plus INCAGN02385 
and INCAGN02390 (TG3) compared with retifanlimab alone as first-line treatment in 
participants with PD-L1–positive and systemic therapy–naive R/M SCCHN. 
Approximately 162 participants will be randomized in a 1:1:1 ratio to 1 of the above treatment 
groups. At randomization, participants will be stratified based on the following factors: 
• LAG-3 expression status (determined centrally): positive (≥ 5%) versus negative 
(< 5%) 
• PD-L1 CPS (determined centrally): 1-19 versus ≥ 20 
• HPV p16 status (oropharyngeal only): p16-positive versus p16-negative; HPV p16 
status for participants without oropharynx cancer (eg, cancers of the oral cavity, 
hypopharynx, larynx) are considered HPV p16 negative. 
Study treatment will begin on Day 1. Randomized participants will continue study treatment in 
4-week cycles for up to 2 years or until discontinuation criteria are met. The duration for 
enrollment is expected to be approximately 12 months. 

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After 30 participants have been randomized and have received treatment for at least 4 weeks (at 
least 2 doses), an interim analysis of safety will be performed by an independent external DSMB. 
The study design schema is presented in Figure 1. The schedules of activities, laboratory 
assessments, and PK and PD assessments are presented in Table 3, Table 4, and Table 5, 
respectively. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
Figure 1: 
Study Design Schema 
 

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Table 3: 
Schedule of Activities 
Visit Day (Range) 
Screening 
Treatment 
EOT 
Safety 
Follow-Up 
Survival 
Follow-Up 
Notes 
Days 
–28 to –1 
Cycle 1 
Cycle 2+ 
Q8W 
(± 7 d) 
EOT +  
30 and 90 
days 
(± 7 d) 
Q12W 
(± 14 d) 
Day 1 
Day 8  
(± 2 d) 
Day 15  
(± 2 d) 
Day 1  
(± 3 d) 
Day 15 
(± 2 d) 
Administrative procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
See Section 8.1.1 for details. 
Contact IRT 
X 
X 
 
X 
X 
X 
 
X 
X 
 
See Section 8.1.3 for details. 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
See Section 5 for details. 
Demographics and general and 
disease medical history 
X 
 
 
 
 
 
 
 
 
 
See Section 8.1.5 for details. 
HPV p16 testing 
X 
 
 
 
 
 
 
 
 
 
Participants with primary oropharyngeal 
tumors must have known HPV status 
(determined locally; otherwise, request 
central testing per sponsor) prior to 
randomization. See Section 5.1 for 
details. 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Section 8.1.6 for details. 
Administer retifanlimab 
 
X 
 
 
X 
 
 
 
 
 
Retifanlimab administered on Day 1 of 
each cycle (Q4W). 
See Section 6.1 for details.  
Administer 
INCAGN02385/placebo 
 
X 
 
X 
X 
X 
 
 
 
 
Administered Q2W of each cycle. 
See Section 6.1 for details. 
*Following completion of the Cycle 1 
Day 1 INCAGN02390/placebo infusion, 
participants will be observed at the study 
site for 4 hours per Section 6.5.2. 
Administer 
INCAGN02390/placebo 
 
X* 
 
X 
X 
X 
 
 
 
 
Distribute reminder card 
 
X 
X 
X 
X 
X 
 
X 
X 
 
See Section 8.1.4 for details. 
Safety assessments 
AE assessments 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
See Section 8.3.1 for details. 
Physical examination/body 
weight/height 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Complete physical exam at screening; 
targeted physical thereafter. Height at 
screening only. Body weight at screening 
and Day 1 of each cycle. 
See Section 8.3.2 for details. 

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Table 3: 
Schedule of Activities (Continued) 
Visit Day (Range) 
Screening 
Treatment 
EOT 
Safety 
Follow-Up 
Survival 
Follow-Up 
Notes 
Days 
–28 to –1 
Cycle 1 
Cycle 2+ 
Q8W 
(± 7 d) 
EOT +  
30 and 90 
days 
(± 7 d) 
Q12W 
(± 14 d) 
Day 1 
Day 8  
(± 2 d) 
Day 15  
(± 2 d) 
Day 1  
(± 3 d) 
Day 15 
(± 2 d) 
Safety assessments (continued) 
Vital signs 
X 
X* 
 
X* 
X* 
X† 
 
X 
X 
 
See Section 8.3.3 for details. 
*On Cycle 1 Day 1, Cycle 1 Day 15, and 
Cycle 2 Day 1, vital signs will be 
monitored prior to each study drug 
infusion (−10 minutes) and 30 and 
60 minutes (± 10 minutes) following 
completion of the INCAGN02390/placebo 
infusion, and additionally as clinically 
indicated. 
†On Cycle 2 Day 15 and all subsequent 
study drug infusions, vital signs will be 
monitored prior to each study drug 
infusion (−10 minutes) and additionally as 
clinically indicated. 
12-lead ECG 
X 
X* 
 
 
X† 
 
 
X 
 
 
*Not required if screening assessment 
performed within 7 days of Cycle 1 
Day 1, unless clinical signs or symptoms 
are present. 
†Performed on Day 1 of Cycles 2 through 
5, and then on Day 1 of every fourth cycle 
(ie, Cycles 9, 13, etc.) thereafter. 
Additional ECGs during treatment should 
be performed if clinically indicated. 
All ECGs will be performed in triplicate. 
All ECGs should be checked and 
interpreted prior to dose administration. 
See Section 8.3.4 for details.  
ECOG status 
X 
X 
 
 
X 
 
 
X 
 
 
See Section 8.3.5 for details.  
Survival status 
 
 
 
 
 
 
 
 
 
X* 
*After documented disease progression, 
or the start of new anticancer therapy; 
contacts are approximately Q12W. 
See Section 8.8.3 for details.  

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Table 3: 
Schedule of Activities (Continued) 
Visit Day (Range) 
Screening 
Treatment 
EOT 
Safety 
Follow-Up 
Survival 
Follow-Up 
Notes 
Days 
–28 to –1 
Cycle 1 
Cycle 2+ 
Q8W 
(± 7 d) 
EOT +  
30 and 90 
days 
(± 7 d) 
Q12W 
(± 14 d) 
Day 1 
Day 8  
(± 2 d) 
Day 15  
(± 2 d) 
Day 1  
(± 3 d) 
Day 15 
(± 2 d) 
Efficacy assessments 
Radiologic tumor assessments 
(CT and/or MRI of neck, CT 
of chest and CT or MRI of 
abdomen). Imaging of the 
pelvis is optional. Imaging is 
required with contrast unless 
contraindicated. 
X 
 
 
 
 
 
X* 
X 
X† 
 
*Imaging will be performed Q8W 
(± 7 days) for the first 12 months, then 
Q12W (± 7 days) thereafter. 
†Participants who discontinue for reasons 
other than radiographic PD should be 
assessed according to the imaging 
schedule (ie, Q8W for the first 12 months, 
then Q12W thereafter) until radiographic 
PD or the start of new anticancer therapy. 
See Section 8.2 for details. 
Brain MRI or CT 
X* 
 
 
 
 
 
X† 
X† 
X† 
 
*Screening brain imaging should be 
performed on all participants who have 
previous history of CNS metastasis or as 
clinically indicated (eg, based on clinical 
symptoms). On-study brain imaging will 
be performed only if the screening brain 
imaging was positive or as clinically 
indicated. 
†If indicated, brain imaging should occur 
at same time as disease assessment scans. 
Whenever feasible, contrast-enhanced 
brain MRI is preferred to CT. 
See Section 8.2 for details. 

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Table 4: 
Schedule of Laboratory Assessments 
Procedure 
Screening 
Treatment 
EOT 
Safety Follow-Up 
Notes 
Days 
–28 to -1 
Cycle 1 
Cycle 2+ 
EOT +  
30 and 90 days 
(± 7 d) 
Day 1 
Day 15  
(± 3 d) 
Day 1 
(± 3 d) 
Day 15  
(± 3 d) 
Local laboratory assessments 
Blood chemistries 
X 
X* 
X 
X 
 
X 
X† 
*Only required at Cycle 1 Day 1 if screening assessment was 
not performed within 7 days. 
† 30-day visit only. 
Hematology with differential 
X 
X* 
X 
X 
 
X 
X† 
Fasting lipid panel 
X 
 
 
X 
 
X 
 
Performed at screening, Cycle 2 Day 1, Day 1 of every third 
cycle thereafter (ie, Cycles 5, 8, etc), and EOT.  
Coagulation panel 
X 
 
 
X 
 
X 
 
Urinalysis 
X 
 
 
X 
 
X 
 
Thyroid function panel 
X 
 
 
X 
 
X 
 
Performed at screening, Day 1 of every even cycle (ie, 
Cycles 2, 4, etc), and EOT. 
Note: Participants may be administered study treatment in 
subsequent cycles after Cycle 1 Day 1 while thyroid test 
results are pending. 
Hepatitis screening 
X 
 
 
 
 
 
 
Results obtained within the last 3 months before Cycle 1 
Day 1 are acceptable. 
TnI or TnT monitoring 
X 
X* 
X 
X† 
X‡ 
X 
 
*Only required at Cycle 1 Day 1 if screening assessment was 
not performed within 3 days. 
†Cycles 2, 3, and 4 only. 
‡Cycles 2 and 3 only. 
Note: To be performed within 3 calendar days prior to dose 
administration and all labs should be checked prior to dose 
administration. 
Note: Day 15 labs should be checked as soon as possible. In 
case of high troponin, perform cardiac imaging via 
echocardiography with/without cardiac MRI. 

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Table 4: 
Schedule of Laboratory Assessments (Continued) 
Procedure 
Screening 
Treatment 
EOT 
Safety Follow-Up 
Notes 
Days 
–28 to -1 
Cycle 1 
Cycle 2+ 
EOT +  
30 and 90 days 
(± 7 d) 
Day 1 
Day 15  
(± 3 d) 
Day 1 
(± 3 d) 
Day 15  
(± 3 d) 
Local laboratory assessments (continued) 
HIV diagnostic testing 
HIV management testing (only 
applicable for participants known 
to be HIV-positive: HIV viral 
load, CD4+ cell count) 
X* 
 
 
X† 
 
X‡ 
X‡ 
*HIV antibodies diagnostic testing is required only if 
mandated by local health authorities or regulations. If a 
participant is known to be HIV-positive, HIV management 
testing (HIV viral load CD4+ cell count) is required at 
screening. 
†For participants with positive HIV only: within 7 days of 
Cycle 3 Day 1 and every odd numbered cycle (ie, C5, C7, etc) 
for the first year. Frequency may be reduced to every 3 months 
during the second year of treatment and during the follow-up 
period. 
‡For participants with positive HIV only: Final sample at the 
EOT visit or 30-day follow-up visit if no separate EOT visit is 
performed. 
Pregnancy testing (WOCBP only) 
X* 
X† 
 
X† 
 
X* 
X‡ 
*Serum pregnancy test; must be within 72 hours before the 
first dose of study treatment and at EOT (optional if 
participant is going to hospice). 
†Serum or urine pregnancy test before first dose and on Day 1 
of each cycle. 
‡Serum or urine pregnancy test will be performed monthly for 
6 months after the last dose of study treatment. 
See Appendix A for definition of WOCBP. 

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Table 5: 
Schedule of Pharmacokinetic and Pharmacodynamic Assessments 
Procedure 
Screening 
Treatment 
Safety 
Follow-Up 
Notes 
Days 
–28 to –1 
Cycle 1 
Cycles 2 and 3 
Cycle 4 
Cycle 6 
EOT + 
30 and 90 days 
(± 7 d) 
Day 1 
Day 8 
(± 1 d) 
Day 15 
(± 1 d) 
Day 1 
(± 1 d) 
Day 1 
(± 1 d) 
Day 1 
(± 1 d) 
Serum sample for PK 
 
X 
X 
X 
X* 
X 
X† 
X‡ 
*Cycle 2 Day 1 only 
†Samples for PK and ADA will 
continue to be collected on Day 1 of 
all even-numbered cycles (ie, 
Cycles 8, 10, etc). 
‡Samples for PK and ADA will be 
collected at EOT, 30-day, and 90-day 
follow-up visits. 
See Section 8.4 for details and 
Table 15 for timing. 
Serum sample for ADA 
 
X 
 
X 
X* 
X 
X† 
X‡ 
Plasma biomarker 
 
X 
X 
X 
X 
X 
 
 
See Table 16 for timing. 
Plasma cfDNA 
 
X 
 
 
X* 
 
 
 
See Table 16 for timing. 
*Collected at Cycle 3 Day 1 only. 
Whole blood for flow 
cytometry 
 
X 
X 
X 
X 
X 
 
 
See Table 16 for timing. Only to be 
collected for the first 75 participants 
randomized. 
Whole blood for PBMC 
 
X 
X 
X 
X 
X 
 
 
See Table 16 for timing. 
Tumor biopsy 
X* 
 
 
 
 
 
 
X† 
*Mandatory pretreatment tumor 
tissue collection (archival or fresh). 
LAG-3 and PD-L1 (CPS) expression 
status must be determined per central 
laboratory testing before 
randomization. 
†Optional fresh tumor biopsy at EOT 
for disease progression only. 
See Section 8.5.1 for details. 

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2. 
INTRODUCTION 
2.1. 
Background 
While antibodies directed toward the PD-(L)1 axis have revolutionized the treatment of cancer, 
the majority of patients either do not respond or lose response to these drugs. The mechanisms 
for failure of anti–PD-1 therapy are poorly understood, but in some cases are likely due to 
existence of additional checkpoint pathways that either abrogate a response when present or 
cause loss of response when induced. This study aims to evaluate the clinical and biological 
effects of blocking additional key checkpoint pathways, LAG-3 and TIM-3, which have been 
implicated in the lack of/loss of response to PD-1 inhibitors. 
This is a randomized, Phase 2 study to evaluate the efficacy and safety of the combination of 
retifanlimab and INCAGN02385 and the triplet combination of retifanlimab, INCAGN02385, 
and INCAGN02390 compared with retifanlimab alone in participants with systemic 
therapy–naive, metastatic or with unresectable, recurrent SCCHN whose tumors express PD-L1. 
Retifanlimab is a humanized, hinge-stabilized, IgG4κ monoclonal antibody that recognizes 
human PD-1. Retifanlimab contains a human IgG4 Fc domain to limit effector function while 
retaining neonatal Fc receptor binding to extend circulating half-life. Retifanlimab is designed to 
target PD-1–expressing cells, including T cells, and sustain/restore their effector function by 
blocking checkpoint inhibitory interactions between PD-1 and its 2 ligands, PD-L1 and PD-L2. 
Additional information regarding preclinical and in vitro experience with retifanlimab can be 
found in the retifanlimab IB. 
INCAGN02385 is an Fc-modified IgG1κ monoclonal antibody that binds to human LAG-3 with 
an estimated affinity (KD) of 1.7 nM and was chosen for clinical development based on its 
selectivity for human LAG-3 with no cross-reactivity to related IgSF proteins. INCAGN02385 
functions as a potent LAG-3 antagonist antibody via its ability to inhibit LAG-3 binding to MHC 
class II, leading to enhanced TCR signaling. Additional information regarding preclinical and 
in vitro experience with INCAGN02385 can be found in the INCAGN02385 IB. 
INCAGN02390 is a recombinant, aglycosylated fully human IgG1κ monoclonal antibody that 
binds to the ECD of the TIM-3 receptor. Antagonist TIM-3 antibodies have demonstrated 
enhanced antitumor activity in several mouse tumor models when combined with blockade of the 
PD-(L)1 pathway (Ngiow et al 2011, Sakuishi et al 2010). Additional information regarding 
preclinical and in vitro experience with INCAGN02390 can be found in the INCAGN02390 IB. 
2.1.1. 
Scientific Rationale for Inhibition of PD-(L)1, LAG-3, and TIM-3 in Human 
Cancer 
Significant focus has been placed on understanding the activity of the immune system within the 
tumor microenvironment and identification of mechanisms of tumor resistance to immune 
surveillance. Loss of CD8+ T-cell effector function has been one such proposed mechanism. 
This loss of function, or T-cell exhaustion, has been described to be due in part to the 
accumulation and increased diversity of inhibitory receptors, or checkpoints, on the cell surface 
of CD8+ T cells (Wherry 2011). 

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Recovery of function has been accomplished in an in vivo viral model of T-cell exhaustion by 
simultaneous blockade of PD-1 and LAG-3 (Blackburn et al 2009). Further, in murine models, it 
has been demonstrated that PD-1 and LAG-3 act synergistically to promote tumor immune 
escape, and simultaneous blockade of LAG-3 and PD-1 results in synergistic inhibition of tumor 
growth (Woo et al 2012). Evidence for synergy of anti–PD-1 and anti–TIM-3 was shown in an 
in vivo murine model of chronic infection resulting in T-cell exhaustion characterized by 
coexpression of TIM-3 and PD-1. Combined blockade of these 2 inhibitory receptors markedly 
improved CD8+ T-cell responses (Jin et al 2010, INCAGN02385 IB, INCAGN02390 IB). 
Early clinical evidence of the efficacy of these combinations in patients who have progressed on 
anti–PD-(L)1 therapy have been evolving. Blockade of the PD-(L)1 axis in combination with 
blockade of either LAG-3 or TIM-3 has resulted in only modest responses in patients who have 
progressed on anti–PD-1 therapy alone (Ascierto et al 2017, Davar et al 2018). Potentially, 
multiple checkpoint inhibitors are potentially required in order to restore antitumor T-cell 
effector function in situ. Evidence for this approach was presented by Kauffman and colleagues 
at SITC 2018 (Kaufmann et al 2018). In this study, the triple combination of antibodies directed 
against PD-1, TIM-3, and LAG-3 demonstrated enhanced tumor growth inhibition relative to 
inhibition of either PD-1 and LAG-3 or PD-1 and TIM-3 in a murine model. In addition, the 
combination of all 3 antibodies resulted in greater restoration of function to TILs isolated from 
patients with ovarian cancer. This suggests a requirement for inhibition of all 3 checkpoints in 
concert is more relevant for returning immune function and tumor growth inhibition. It could 
also be that the population of patients that have prior exposure to checkpoint inhibitors represent 
a very difficult-to-treat population. 
While no clinical data exist for combination blockade of PD-1, LAG-3, and TIM-3 in patients 
with SCCHN, recent clinical data have emerged that suggests promising efficacy and safety of 
the combination of PD-1– and LAG-3–directed agents in checkpoint inhibitor–naive solid tumor 
populations. The RELATIVITY-047 study, which was a Phase 3 trial evaluating the anti–LAG-3 
antibody relatlimab plus nivolumab versus nivolumab alone in previously untreated melanoma, 
demonstrated significantly longer PFS in the combination group (10.1 months [95% CI: 6.4, 
15.7] vs 4.6 months [95% CI: 3.4, 5.6]), with a manageable safety profile and without 
unexpected safety signals (Lipson et al 2021). Additionally, the anti–LAG-3 antibody fianlimab, 
when added to the anti–PD-1 antibody cemiplimab, resulted in an ORR of 63.6% in 
33 treatment-naive patients with advanced/metastatic melanoma (Hamid et al 2021), which is 
above the historical ORR of PD-1 monotherapy (Robert et al 2019). Lastly, the anti–LAG-3 
fusion protein etilagimod alpha in combination with pembrolizumab demonstrated an 
encouraging response rate of 45.8% in patients with PD-L1–positive (CPS ≥ 1) SCCHN who had 
previously received 1 line of platinum-based chemotherapy and were naive to PD(L)-1 treatment 
(Brana et al 2021). Taken together, these recently reported data provide experimental support for 
the combination of anti–PD-1 therapy with LAG-3 blocking agents in a checkpoint inhibitor–
naive population. 
2.1.2. 
Treatment of Patients With Recurrent/Metastatic SCCHN 
According to GLOBOCAN epidemiological estimates of incidence and mortality of cancer 
worldwide, in 2018, there were approximately 835,000 new cases of cancer arising from the lips, 
oral cavity, oropharynx, hypopharynx, and larynx, the primary tumor sites that generally 

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comprise SCCHN, with the number of deaths in the same year being approximately 431,000 
(Bray et al 2018). 
A large percentage of patients with SCCHN primarily present with locally advanced, stage III/IV 
disease that is initially treated with multimodal therapy including systemic treatment, radiation, 
and/or surgery. Patients who progress after initial definitive therapy require subsequent treatment 
for R/M disease; patients who initially present with metastatic disease generally receive the same 
therapy as those with recurrent disease after definitive treatment. 
For patients with recurrent unresectable or metastatic SCCHN, platinum-based chemotherapy 
(the EXTREME regimen) has been the standard first-line treatment for the last decade, 
conferring a median OS of around 10 months. In 2016, the PD-1 inhibitors nivolumab and 
pembrolizumab were approved by the FDA as second-line treatment for patients who had 
progressed after platinum-based therapy following positive data demonstrating improved OS of 
nivolumab/pembrolizumab over investigator's choice systemic therapy in this population. In 
2019, based on the results of the KEYNOTE-048 study, the approval of pembrolizumab as 
first-line therapy has changed the treatment paradigm for patients with R/M SCCHN (Burtness 
et al 2019, NCCN 2020). Pembrolizumab as monotherapy in patients with PD-L1–positive 
(CPS  1) tumors, or in combination with chemotherapy irrespective of PD-L1 status, 
demonstrated superior OS over the EXTREME regimen. 
The KEYNOTE-048 study included participants in the first-line setting of R/M SCCHN, 85% 
had PD-L1 CPS ≥ 1 and 21% had HPV p16-positive status. The response rate was 19% in 
participants with PD-L1 CPS  1 tumors (16.9% in all participants) for pembrolizumab 
monotherapy, and 36% when combined with platinum-based chemotherapy (Rischin et al 2019). 
An estimated 85% to 95% of patients with R/M SCCHN have no response to these treatments, or 
have a response that is followed by disease progression (Chow 2020), highlighting the need for 
alternative treatment strategies and for biomarkers predictive of response. 
Mechanisms of immune evasion in SCCHN and other cancer types include tumor cell adaptation, 
direct T-cell suppression via inhibitory cell surface receptors or soluble factors, decreased 
immune stimulation, and the recruitment of immuno-suppressive cell populations (Horton 
et al 2019, Kok 2020). 
For patients with R/M SCCHN who have progressed on anti–PD-1 therapy, there are limited 
therapeutic options. Those who progressed on or after PD-1 plus chemotherapy may be treated 
with single-agent chemotherapy, cetixumab, or other experimental therapies. Those whose 
disease progresses on PD-1 monotherapy may be eligible for treatment with platinum-based 
chemotherapy regimens or single-agent platinum chemotherapy, other single-agent 
chemotherapies, cetuximab, or other experimental treatments (NCCN 2020). 
2.1.3. 
Anti–PD-1 Plus Anti–LAG-3 With or Without Anti–TIM-3 in SCCHN 
While the role of LAG-3 in SCCHN is not fully characterized, there is a growing body of 
evidence that suggests that LAG-3 expression may play an important role in resistance to 
immune surveillance and potentially to PD-1 blockade. Analysis of LAG-3 expression in a 
TCGA dataset showed that among multiple solid tumors, SCCHN had considerably high 
expression of LAG-3 (Panda et al 2020). Further, an internal survey using a commercially 
available SCCHN cohort found that approximately 58% of patients have tumors that express 

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≥ 5% LAG-3 (data on file). LAG-3 expression is mainly restricted to T cells; in SCCHN, LAG-3 
has been shown to be expressed on tumor-infiltrating Tregs (Jie et al 2013), suggesting that that 
is may contribute to immunosuppression in the tumor microenvironment. LAG-3 expression may 
be expected to correlate with PD-L1 expression in SCCHN (Mishra et al 2016) and has been 
independently associated with poor prognosis (Deng et al 2016). LAG-3 expression has also 
been found to be enriched in HPV-positive SCCHN and other virally mediated tumors, 
suggesting that such a "T-cell–inflamed" phenotype may benefit from combined PD-1 and 
LAG-3 expression (Gameiro et al 2018). Given these findings, it is reasonable to hypothesize 
that dual blockade of both PD-1 and LAG-3 will result in improved clinical response relative to 
PD-1 inhibition alone in patients with SCCHN. 
Similar to LAG-3, the role of TIM-3 in SCCHN has not been fully elucidated, although there is 
accumulating evidence that it may contribute to immune suppression in the tumor 
microenvironment in this tumor histology. TIM-3 expression on tumor-infiltrating lymphocytes 
has been shown to be upregulated in response to PD-1 blockade on both murine and human 
T cells in freshly excised SCCHN tumors, suggesting that compensatory upregulation of TIM-3 
may represent a specific adaptive response that functions to sustain the exhaustion status of TIL 
in response to PD-1 blockade (Shayan et al 2016). TIM-3+ TILs also correlate with poorer OS 
and may be considered an independent prognostic factor of poor disease outcome (Yang 
et al 2021). Oweida et al (2018) demonstrated that TIM-3 is upregulated on CD8 T cells and 
Tregs in SCCHN tumors treated with radiotherapy and PD-L1 blockade and that treatment with 
an anti–TIM-3 antibody concurrently with anti–PD-L1 and radiotherapy led to significant tumor 
growth delay, enhanced T-cell cytotoxicity, decreased Tregs, and improved survival. Further, 
Galectin-9 expression by CD4+ T cells has been shown to be increased in patients with 
HPV-positive oral SCCHN, which in turn leads to expansion of TIM-3+ monocytes, further 
suppressing IFN-γ production from activated CD8+ T cells (Dong et al 2017). 
2.1.4. 
Justification for Dose of INCAGN02385 and INCAGN02390 
Doses for INCAGN02385 and INCAGN02390 were chosen based on safety, receptor 
occupancy, and pharmacodynamic data obtained from study results from INCAGN 2385-101 
and INCAGN 2390-101, respectively (INCAGN02385 IB, INCAGN02390 IB). In both cases, 
doses chosen were below the highest dose tested. 
2.1.4.1. 
INCAGN02385 Dose 
As of 21 MAR 2022, a total of 22 unique participants were enrolled and received at least 1 dose 
of INCAGN02385 IV at doses of 25, 75, 250, 350, and 750 mg Q2W in an open-label, 
nonrandomized, dose-escalation, and cohort-expansion study, INCAGN2385-101. All doses 
were well tolerated with no DLTs observed, and there were no treatment-related deaths. 
INCAGN02385 PK was independent of dose after the first dose and showed moderate to high 
interindividual variability (see Figure 2). At a dose of 350 mg Q2W (N = 2), the steady-state 
AUC was 29,500 µg/mL∙h. The dose of 350 mg Q2W was chosen for INCAGN02385 based on 
the results that the receptor on the surface of the cells was fully occupied at trough concentration 
(see Figure 3) and that pharmacodynamic markers supported this dose to be pharmacologically 
active as measured by an increase in peripheral T-cell activation observed in doses greater than 
250 mg. 

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Figure 2:
INCAGN02385 Concentrations Over Time (Mean ± SE) After the First Dose 
and at Steady-State at Various Dose Levels
Figure 3:
Average Receptor Occupancy in Participants Infused With Various Doses of 
INCAGN02385
0
1 0
2 0
3 0
4 0
5 0
0
2 0
4 0
6 0
8 0
1 0 0
D a y s
R e c e p to r o c c u p a n c y
C o h o rt  1  - 2 5  m g
C o h o rt  2  - 7 5  m g
C o h o rt  3  -  2 5 0  m g
C o h o rt  4  -  3 5 0  m g
C o h o rt  5  -  7 5 0  m g

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Figure 4: 
Frequency of Proliferating T Cells in the Blood of Participants Receiving 
Various Doses of INCAGN02385 
 
2.1.4.2. 
INCAGN02390 Dose 
As of 28 JUN 2022, a total of 40 unique participants were enrolled and received at least 1 dose of 
INCAGN02390 at doses of 10, 30, 100, 200, 400, 800, and 1600 mg Q2W in the open-label, 
nonrandomized, dose-escalation, and cohort-expansion study INCAGN 2390-101, evaluating 
monotherapy INCAGN02390. All doses were well-tolerated, no DLTs were observed, and there 
were no treatment-related deaths. INCAGN02390 showed supraproportional PK after the first 
dose from 30 mg to 800 mg Q2W and low interindividual variability on PK exposures (see 
Figure 5). At a dose of 400 mg Q2W, the mean steady-state AUC determined in 4 participants 
was 43,400 µg/mL∙h. The dose of 400 mg was chosen for INCAGN02390 based on the results 
that the TIM-3 receptor was fully occupied on the surface of circulating monocytes (see 
Figure 6). 

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Figure 5:
INCAGN02390 Concentrations Over Time (Mean ± SE) After the First Dose 
and at Steady-State at Various Dose Levels
Figure 6:
Average Receptor Occupancy in Participants Infused With Various Doses of 
INCAGN02390
2.1.5.
Justification for Retifanlimab Dose
Retifanlimab will be administered at 500 mg Q4W. The selection of this dose was based on 
modeling of clinical PK data from the first-in-human monotherapy study, INCMGA 0012-101, 
in which 219 participants were treated with both body weight-based doses and flat doses of
1 mg/kg Q2W, 3 mg/kg Q2W, 3 mg/kg Q4W, 10 mg/kg Q2W, 10 mg/kg Q4W, 375 mg Q3W, 
500 mg Q4W, and 750 mg Q4W (retifanlimab IB).
Pharmacokinetic data from Study INCMGA 0012-101 suggested that retifanlimab exposure 
increased in a dose-dependent manner with doses ranging from 1 mg/kg to 10 mg/kg (including 
flat doses of 375 mg to 750 mg). Full and sustained PD-1 receptor occupancy was observed with 
all doses studied on both PD-1 expressing CD4+ and CD8+ cells. The PK of retifanlimab
following IV administration was well-characterized by a 2-compartment linear disposition model 
with time-dependent elimination. A population PK model estimated typical retifanlimab CL 

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as 0.0127 L/h with a steady-state t½ of 18.4 days. Similar PK profiles were observed for the 
3 mg/kg Q2W and 500 mg Q4W doses. 
A simulation was conducted to investigate the use of weight-based and fixed doses for 
retifanlimab with the aim of targeting a steady-state trough concentration of approximately 
21 μg/mL, which is the median trough concentration for pembrolizumab 2 mg/kg Q3W 
(Freshwater et al 2017). The 500 mg Q4W regimen resulted in steady-state exposure that was 
similar to the 3 mg/kg Q2W regimen (Ctrough). In addition, full PD-1 receptor occupancy was 
observed on PD-1 expressing CD4+ and CD8+ cells with effects on circulating cytokines that are 
typical for a PD-1 inhibitor in all dose regimens of Study INCMGA 0012-101. Therefore, the 
500 mg Q4W dose was selected as a dose for further development in monotherapy treatments 
and combination treatment. For more information, refer to the retifanlimab IB. 
2.2. 
Benefit/Risk Assessment 
2.2.1. 
Retifanlimab Monotherapy 
Treatment directed at the PD-(L)1 axis is a promising approach to the diseases under study. 
Monoclonal antibodies against PD-1 have shown benefit for these and other indications, and 
safety of these agents has been well-characterized. 
Antibodies targeting the PD-1 pathway have demonstrated activity in a wide variety of cancer 
types (Sun et al 2020), and the available preclinical and clinical data from study participants 
suggest that the pharmacologic and clinical profile of retifanlimab should be consistent with 
experience with other drugs in this class (Chen et al 2019, Condamine et al 2019, Lakhani 
et al 2017, Maio et al 2021, Mehnert et al 2018, Mehnert et al 2019). Based on these 
observations, the benefit/risk for retifanlimab should also be favorable, provided efficacy 
objectives in the proposed study are met, since the intended populations have a very limited 
prognosis with available therapy. 
As of 23 SEP 2021, 660 participants have been treated with retifanlimab monotherapy across 
6 clinical studies, and the overall safety profile is consistent with those observed with other 
anti–PD-1 antibodies (retifanlimab IB). Preliminary efficacy was been demonstrated in multiple 
tumor types with durable RECIST v1.1 responses observed in NSCLC (Mehnert et al 2019), 
cervical cancer (Mehnert et al 2018), biomarker-unselected endometrial cancer (Mehnert 
et al 2018), sarcoma (Mehnert et al 2018), Merkel cell carcinoma (Grignani et al 2020), and 
microsatellite instability-high or deficient mismatch repair endometrial cancer (Berton-Rigaud 
et al 2020). Retifanlimab has also demonstrated a clinical profile consistent with the PD(L)-1 
class and across multiple solid tumor types that are known to be sensitive to PD-1 blockade 
(Maio et al 2021) with ORRs consistent with historical controls (melanoma ORR: 40.0%; 
TPS ≥ 50% NSCLC ORR: 34.8%; CPS ≥ 10 urothelial cancer ORR: 37.9%; renal cell carcinoma 
ORR: 23.5%). Given this, consistent clinical activity can be anticipated in patients with 
PD-L1–positive SCCHN. 
Combination of PD-1 inhibitors with inhibitors of other checkpoints is supported by substantial 
preclinical and clinical data. Also, dose-ranging for all individual components in the combination 
regimen under study has been completed as well as combination treatment with the selected 
doses; thus, the selected dose levels are not anticipated to produce unexpected or unmanageable 
toxicity. Based on results from studies combining PD-1 inhibitors with antibodies directed at 

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either LAG-3 (Ascierto et al 2017, Lipson et al 2021) or TIM-3 (Davar et al 2018), toxicity of 
these combinations is expected to be similar to single-agent PD-1. Additionally, based on 
available preclinical and clinical data, combination of PD-1 inhibitors with other immune-
checkpoint inhibitors may potentially provide responses in populations either unresponsive or 
who have lost response to PD-1 inhibitors. 
2.2.2. 
INCAGN02385 Monotherapy 
As of 21 MAR 2022, 22 participants with advanced malignancies have received INCAGN02385 
Q2W at doses of 25 mg (n = 4), 75 mg (n = 4), 250 mg (n = 4), 350 mg (n = 3), and 750 mg 
(n = 7) in Part 1 (dose-escalation) of Study INCAGN 2385-101 (INCAGN02385 IB). All 
participants had at least 1 TEAE. Treatment-emergent AEs related to INCAGN02385 occurring 
in more than 1 participant were fatigue (n = 7) and creatinine increase, lymphopenia, myalgia, 
pruritus, and tumor pain (n = 2 each). 
Eight participants had serious TEAEs; none of the serious TEAEs were considered by the 
investigator to be related to INCAGN02385. One participant (350 mg Q2W) had a TEAE 
leading to discontinuation of study drug (transient ischemic attack; not related to 
INCAGN02385). One participant (250 mg Q2W) had a fatal TEAE (failure to thrive), which was 
considered not related to INCAGN02385 by the investigator. 
An MTD was not reached for INCAGN02385, and there have been no DLTs. Enrollment in 
Part 1 of Study INCAGN 2385-101 is complete. 
2.2.3. 
INCAGN02390 Monotherapy 
As of 28 JUN 2022, 40 participants have been exposed to monotherapy INCAGN02390 in 
Study INCAGN 2390-101 at doses of 10, 30, 100, 200, 400, 800, and 1600 mg Q2W 
(INCAGN02390 IB). All participants had at least 1 TEAE. The most frequently reported TEAEs 
(≥ 15%) for INCAGN02390 monotherapy in participants with advanced or metastatic 
immunogenic solid tumors were anemia (35.0%); back pain (30.0%), fatigue (27.5%); decreased 
appetite, nausea, and pruritus (17.5% each); and abdominal pain, diarrhea, and hyponatremia 
(15.0% each). 
Eighteen participants (45.0%) had at least 1 serious TEAE, including pleural effusion 
(4 participants; 10.0%), acute respiratory failure (3 participants; 7.5%), and sepsis 
(2 participants; 5.0%). All other serious TEAEs were reported in 1 participant (2.5%) each. 
One participant (2.5%) had 1 fatal TEAE, multiple organ dysfunction syndrome due to disease 
progression, which was considered not related to study treatment. 
Six participants (15.0%) had at least 1 TEAE leading to discontinuation of study drug, including 
sepsis (2 participants [5.0%]) and acute respiratory failure, female genital tract fistula, impaired 
healing, pleural effusion, and supraventricular tachycardia (1 participant each; 2.5%). 
Infusion-related reactions included sponsor-predefined preferred terms indicating a diagnosis of 
IRRs or symptoms potentially associated with IRRs. One participant (2.5%) had an 
infusion-related TEAE, which was Grade 1 pyrexia. Immune-related AEs were identified using 
sponsor-predefined preferred terms based on the ICI class regardless of investigator's assessment 
of causality. Four participants (10.0%) had at least 1 immune-related TEAE, including adrenal 

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insufficiency, hypothyroidism, acute kidney injury, dermatitis, and pruritus in 1 participant 
(2.5%) each. 
The MTD of INCAGN02390 was not identified, and there were no DLTs. The RP2D of 
INCAGN02390 has been identified as 400 mg Q2W. There were no safety concerns identified 
with INCAGN02390 monotherapy. 
2.2.4. 
Combinations of Retifanlimab, INCAGN02385, and INCAGN02390 
INCAGN 2385-201 in an ongoing Phase 1/2 study evaluating the safety and preliminary efficacy 
of combinations of the Phase 1 doses of INCAGN02385 and INCAGN02390 described above 
together, as well as in combination with retifanlimab 500 mg Q4W. As of 28 JUN 2022, a total 
of 27 unique participants were enrolled and received at least 1 dose of INCAGN02385 IV at 
doses of 350 mg Q2W in combination with INCAGN02390 400 mg Q2W (N = 10) or 
INCAGN02390 400 mg Q2W + retifanlimab 500 mg Q4W (N = 17) in this open-label, 
nonrandomized, safety evaluation, and cohort-expansion study. During Phase 1 of 
INCAGN 2385-201, no DLTs were observed; 25 participants had at least 1 TEAE (9 participants 
who received the doublet and 16 participants who received the triple combination). 
For the doublet combination of INCAGN02385 and INCAGN02390, 9 participants (90.0%) had 
at least 1 TEAE. Five participants (50.0%) had serious TEAEs, which included asthenia, 
pancreatitis, dyspnea, hypoxia, rectal hemorrhage, vulval hemorrhage, vasculitis, COVID-19, 
sepsis, and pyrexia; only 1 of which (vasculitis) was considered related to both study agents by 
the investigator. One participant had a fatal TEAE of sepsis. Sepsis was related to the COVID-19 
infection and considered to not be related to study treatment. 
Infusion-related reactions included sponsor-predefined preferred terms indicating a diagnosis of 
IRRs or symptoms potentially associated with IRRs. One participant (10.0%) had an 
infusion-related TEAE, which was Grade 1 chills and was considered related to study treatment 
by the investigator. 
Immune-related AEs were identified using sponsor-predefined preferred terms based on the ICI 
class regardless of investigator's assessment of causality. Two participants (20.0%) had an 
immune-related TEAE, which were pancreatitis and vasculitis in 1 participant (10.0%) each. 
Pancreatitis was considered not related to study treatment, and vasculitis was considered related 
to study treatment by the investigator. 
There were no DLTs in Study INCAGN 2385-201. Enrollment in Phase 1, Part 1 of Study 
INCAGN 2385-201 has been completed. 
For the triplet combination of retifanlimab, INCAGN02385, and INCAGN02390, 16 participants 
(94.1%) had at least 1 TEAE. Three participants (17.6%) had serious TEAEs, which included 
pericardial effusion, myocarditis, acute respiratory failure, and pyrexia in 1 participant (5.9%) 
each. 
Two participants (11.8%) had TEAEs leading to discontinuation of study drug, which included 
pericardial effusion, myocarditis, and pneumonitis. 
No fatal TEAEs were reported after administration of INCAGN02385 in combination with 
INCAGN02390 and retifanlimab. 

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Immune-related AEs were identified using sponsor-predefined preferred terms based on the ICI 
class regardless of investigator's assessment of causality. Two participants (11.8%) had at least 
1 immune-related TEAE, which included myocarditis, pruritus, and pneumonitis in 1 participant 
(5.9%) each. All immune-related reactions were assessed as related to study treatment. 
Infusion-related reactions included sponsor-predefined preferred terms indicating a diagnosis of 
IRRs or symptoms potentially associated with IRRs. Four participants (23.5%) had at least 
1 infusion-related TEAE, which included pyrexia and IRR in 2 participants (11.8%) each and 
chills in 1 participant (5.9%). Two of these participants had infusion-related TEAEs considered 
related to study treatment, which was pyrexia in both participants. Chills was considered to not 
be related to study treatment by the investigator, and both events of IRR were considered related 
only to INCAGN02385. All infusion-related TEAEs were nonserious and Grades 1 or 2 in 
severity. 
There were no DLTs in Study INCAGN 2385-201. Enrollment in Phase 1, Part 2 of Study 
INCAGN 2385-201 has been completed. 
Overall, the preliminary toxicity profiles of the combination regimens, including the triplet 
combination of INCAGN02385, INCAGN02390, and retifanlimab, were consistent with those 
anticipated with checkpoints blockade with no safety signals based on those preliminary data. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of the study drugs retifanlimab, INCAGN02385, and INCAGN02390 may be 
found in the respective IBs (retifanlimab IB, INCAGN02385 IB, INCAGN02390 IB). 
2.2.5. 
Benefit/Risk Assessment During the COVID-19 Pandemic 
Participants to be enrolled into this study have recurrent or metastatic SCCHN and may be at 
higher risk for complications if they contract COVID-19. An ESMO multidisciplinary panel 
highlighted the importance of clinical cancer research to find better therapeutic options for 
participants even during the pandemic, including potential investigational therapies similar to 
immunotherapy with a known survival benefit (Curigliano et al 2020). Preliminary data released 
based on real-world data indicate that the use of immunotherapy either alone or in combination 
with chemotherapy does not appear to increase the risk of hospitalization upon COVID-19 
infection (Horn et al 2020) or cause an increased risk of mortality (Lee et al 2020). Effects of 
immune-checkpoint inhibitors on SARS-CoV2 infection is yet unknown. However, it has been 
reported that at early stages of SARS-CoV2 infection, CD8+ T-cell exhaustion and PD-1 
upregulation have been observed in patients (Riva et al 2020, Zheng et al 2020). Those findings 
may suggest the hypothesis that immune-checkpoint inhibitors may ameliorate the early phase of 
COVID-19 disease through the reactivation of T cells expressing PD-1 (Maio et al 2020). 
Conversely, potential risks of cytokine release syndrome, pneumonitis, or myocarditis related to 
immune-checkpoint inhibitors therapy, may represent a clinical issue and impact a course of 
COVID-19 disease (Maio et al 2020, Sullivan et al 2020). Considering the critical medical need 
for therapies in the setting of R/M SCCHN and the importance of continuing clinical cancer 
research even during the pandemic, and taking into account the lack of conclusive clinical data 
on the impact of immune-checkpoint inhibitors therapy on COVID disease course, the sponsor 
will implement additional guidance in this clinical study for participation in the study in the 
context of the COVID-19 pandemic and study treatment management in the event of SARS-
CoV2 infection (see Appendix C). 

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During the COVID-19 pandemic, additional risks to participants exist either related to going to a 
healthcare facility or as a result of study-related activities. The investigators will need to 
carefully assess both the benefit/risk and participant's available medical data (eg, performance 
status, past medical history, comorbidities) at screening in order to determine whether it is in the 
best interests of the potential participant to enroll and participate in the study. In addition, 
country-specific requirements will be followed with regard to COVID-19 testing as specified in 
Appendix C. 
Investigators will be warranted to follow-up with repeated tests during the study as per medical 
judgment and/or local practices, for enrolled participants who may be newly suspected of being 
exposed to or have symptoms of SARS-CoV2, or to demonstrate recovery. 
Participants will be monitored with safety procedures as described and with additional safety 
assessments as per SoC. Additional information regarding the flexibility of assessments/visits 
scheduling, where possible and warranted, and strategy for participant management during the 
dynamic pandemic as applicable are described in Appendix C. 

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3. 
OBJECTIVES AND ENDPOINTS 
Table 6 presents the objectives and endpoints. 
Table 6: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To determine the efficacy of the combinations of 
retifanlimab + INCAGN02385 (TG2) and 
retifanlimab + INCAGN02385 + INCAGN02390 
(TG3) compared with retifanlimab alone (TG1) in 
the overall study population.  
PFS, defined as the interval between the date of 
randomization and the earliest date of disease 
progression, based on investigator assessment per 
RECIST v1.1, or death due to any cause. 
Secondary 
To assess disease response using RECIST v1.1 in 
TG2 and TG3 compared with TG1. 
• Objective response, defined as having a CR or 
PR, determined based on investigator 
assessment per RECIST v1.1. 
• DOR, defined as the time from earliest date of 
disease response (CR or PR) until earliest date 
of disease progression, based on investigator 
assessment per RECIST v1.1, or death from 
any cause if occurring sooner than progression. 
• Disease control, defined as having CR, PR, or 
SD (≥ 6 months) as best response, based on 
investigator assessment per RECIST v1.1. 
To determine the OS of TG2 and TG3 compared 
with TG1. 
OS, defined as the interval between the date of 
randomization until death due to any cause.  
To determine the safety of TG2 and TG3 
compared with TG1.  
• AEs, assessed in body systems with symptoms, 
through physical examinations, changes in vital 
signs and ECGs, and through clinical 
laboratory blood sample evaluations. 
• Impact on-study treatment, assessed by 
treatment interruptions, dose delays, and 
withdrawal of study treatment due to AEs. 

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Table 6: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
Exploratory 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a randomized, double-blind, Phase 2 study to evaluate the efficacy and safety of the 
combination of retifanlimab plus INCAGN02385, and retifanlimab plus INCAGN02385 and 
INCAGN02390, compared with retifanlimab alone as first-line treatment in participants with 
PD-L1–positive, systemic therapy–naive, R/M SCCHN. 
Approximately 162 participants will be randomized in a 1:1:1 ratio (approximately 
54 participants per group) to 1 of the following treatment groups: 
• TG1: retifanlimab plus placebo (INCAGN02385) and placebo (INCAGN02390) 
• TG2: retifanlimab plus INCAGN02385 and placebo (INCAGN02390) 
• TG3: retifanlimab plus INCAGN02385 and INCAGN02390 
At randomization, participants will be stratified based on the following factors: 
• LAG-3 expression status (determined centrally): positive (≥ 5%) versus negative 
(< 5%) 
• PD-L1 CPS (determined centrally): 1-19 versus ≥ 20 
• HPV p16 status (oropharyngeal only): p16-positive versus p16-negative; HPV p16 
status for participants without oropharynx cancer (eg, cancers of the oral cavity, 
hypopharynx, larynx) is considered HPV p16 negative. 
The study design schema is shown in Figure 1. 
The study will include a 28-day screening period to determine eligibility, a treatment period in 
4-week cycles for up to 2 years or until discontinuation criteria are met, an EOT visit, and 30-day 
and 90-day safety follow-up visits. Tumor assessments will be performed at baseline and 
subsequently Q8W for the first year of treatment and Q12W thereafter by site investigator review 
according to RECIST v1.1. Safety will be evaluated from the time the participant signs the ICF 
until the 90-day safety follow-up regardless of the start of a new anticancer therapy. Study 
treatment will begin on Day 1. 
After 30 participants have been randomized and have received treatment for at least 4 weeks (at 
least 2 doses), an interim analysis of safety will be performed by an independent, external 
DSMB. Additional DSMB review of unblinded safety data will occur per the DSMB Charter. 
4.2. 
Number of Participants 
Approximately 162 participants will be randomized into the study (approximately 54 participants 
per group). Enrollment of participants whose tumors have low LAG-3 expression (ie, < 5%) will 
be capped at approximately 40% of the total. 

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4.3. 
Overall Study Duration 
The duration for enrollment is expected to be approximately 12 months. The study begins when 
the first participant signs the ICF. The end of the study is defined as the date of the last visit (last 
scheduled procedure shown in the SoA) of the last participant in the study (ie, globally). 
In the EU/EEA, the results of the study will be posted when the study is globally complete; this 
will ensure the data are robust, meaningful, and representative of all regions. Additionally, with 
the follow-up data complete, relevant statistical hypotheses can then be accurately and 
thoroughly evaluated. 
For this study, a participant is considered to have completed the study if they have finished both 
the treatment and survival follow-up periods. Study treatment will be provided for a maximum of 
2 years. 
Additional follow-up for OS may be conducted up to approximately 2 years after the 
randomization of the last participant or, if earlier, at the time which the Sponsor terminates the 
study. 
4.4. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract. The investigator is to notify the IRB/EC in writing of the 
study's completion or early termination, send a copy of the notification to the sponsor or 
sponsor's designee, and retain 1 copy for the site study regulatory file. 
The sponsor may terminate the study electively, if required by regulatory decision, or upon 
advice of the DSMB. If the study is terminated prematurely, the sponsor will notify the 
investigators, the IRBs and IECs, and the regulatory bodies of the decision and reason for 
termination of the study. Reduced data collection activities and procedures as per SoC for 
remaining participants on-study treatment may be performed for participants who wish to remain 
on study if they derive clinical benefit as per investigator. The DSMB will recommend 
termination of the study if warranted, as described in Section 5.6. 
In addition, further recruitment in the study or at a particular study site(s) may be stopped due to 
insufficient compliance with the protocol, GCP, and/or other applicable regulatory requirements; 
procedure-related problems; or the number of discontinuations for administrative reasons is too 
high. 

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5. 
STUDY POPULATION 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or participant safety. Therefore, 
adherence to the criteria as specified in the Protocol is essential. Prospective approval of Protocol 
deviations to recruitment and enrollment criteria, also known as Protocol waivers or exemptions, 
are not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Ability to comprehend and willingness to sign a written ICF for the study. 
2. Age 18 years or older (or as applicable per local country requirements), inclusive at the 
time of signing the ICF. 
3. Histologically or cytologically confirmed R/M SCCHN that is not amenable to therapy 
with curative intent (surgery and/or radiation therapy with or without chemotherapy). 
Participants who refuse potentially curative salvage surgery for recurrent disease are 
ineligible. 
a. Eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and 
larynx. 
b. Participants with primary tumors of the nasopharynx, sinonasal cavity, or salivary 
gland are excluded. 
c. Participants must not have received prior systemic therapy for R/M SCCHN. 
Note: Participants may have received prior adjuvant or neoadjuvant chemotherapy or 
chemotherapy as part of multimodal treatment for locally advanced disease. Systemic 
therapy given in the neoadjuvant/adjuvant setting must have been completed at least 
6 months prior to enrollment, with no evidence of disease progression within 6 months of 
completion of systemic treatment. 
Note: Participants enrolled will be eligible for first-line treatment with anti–PD-1 
monotherapy for R/M SCCHN (and would not require combination therapy with 
chemotherapy) at the discretion of the investigator. 
4. PD-L1 positive tumor status defined by CPS ≥ 1 per central laboratory determination. 
5. For participants with primary oropharyngeal tumors, documentation of HPV p16 status 
(positive or negative) based on local institutional standard is required. HPV p16 status is 
not required for other eligible SCCHN primary tumor sites. 
Note: If local p16 testing results are not available or cannot be assessed by the institution, 
a tumor tissue sample may be submitted for p16 testing at the designated central 
laboratory. The result must be available prior to randomization. Tissue requirements are 
detailed in the Laboratory Manual. 

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6. Participant must have at least 1 measurable tumor lesion per RECIST v1.1. 
Note: For the purpose of response assessment, a biopsied lesion may only be selected as a 
target lesion if postbiopsy imaging confirms that it still qualifies as a RECIST-defined 
measurable lesion, unless there are other lesions that qualify the participant for RECIST 
assessment. Further, lesions used for the purpose of response assessment must either a) 
not reside in a field that has been subjected to prior radiotherapy or b) have demonstrated 
clear evidence of radiographic progression since the completion of prior radiotherapy and 
prior to study enrollment. 
7. Availability of archival tissue for biomarker analysis from a core or excisional biopsy or 
willingness to undergo a fresh biopsy. 
Note: Biopsy should be from a tumor site that has not been irradiated following 
occurrence or recurrence of the lesion. Formalin-fixed archival specimens after the 
participant has been diagnosed with recurrent or metastatic disease, or a fresh biopsy 
sample, are required for central determination of LAG-3 and PD-L1 CPS status prior to 
randomization. 
8. ECOG performance status of 0 or 1. 
9. Willingness to avoid pregnancy or fathering children based on the criteria below: 
a. Male participants with reproductive potential must agree to take appropriate 
precautions to avoid fathering children from screening through 180 days after the last 
dose of study treatment and must refrain from donating sperm during this period. 
Permitted methods in preventing pregnancy (see Appendix A) should be 
communicated to the participants and their understanding confirmed. 
b. Female participants who are WOCBP must have a negative serum pregnancy test at 
screening and a negative serum or urine pregnancy test before the first dose on Day 1 
and must agree to take appropriate precautions to avoid pregnancy from screening 
through 180 days after the last dose of study treatment and must refrain from donating 
oocytes during this period. Permitted methods in preventing pregnancy (see 
Appendix A) should be communicated to the participants and their understanding 
confirmed. 
c. Female participants not considered to be of childbearing potential as defined in 
Appendix A are eligible. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Progressive or recurrent disease within 6 months of the last dose of systemic treatment 
for locally advanced SCCHN. 
2. Prior PD-(L)1, LAG-3, or TIM-3 directed therapy, or any other checkpoint inhibitor 
therapy, for SCCHN (in any disease setting) or any other malignancy. 
3. Treatment with anticancer therapies or participation in another interventional clinical 
study within 21 days before the first administration of study treatment (this includes 
curative radiation to the thorax or systemic anticancer therapies). 

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4. Presence of tumors that invade major blood vessels, as shown unequivocally by imaging, 
and with active bleeding. 
5. Less than 3-month life expectancy (based on investigator judgment). 
6. Participant has not recovered to ≤ Grade 1 or baseline from residual toxicities of prior 
therapy (with exceptions for anemia not requiring transfusion support, fatigue, or any 
grade of alopecia). 
7. Participant has not recovered adequately from toxicities and/or complications from 
surgical intervention before starting study treatment. 
8. Palliative radiation therapy administered within 1 week before the first dose of study 
treatment or radiation therapy in the thoracic region that is > 30 Gy within 6 months 
before the first dose of study treatment. 
Note: Participants must have recovered from all radiation-related toxicities, not require 
corticosteroids for this purpose, and not have had radiation pneumonitis. 
9. Known active CNS metastases and/or carcinomatous meningitis. Participants will be 
excluded if it has been < 4 weeks since radiation therapy was delivered to the CNS. 
Note: Participants with previously treated brain metastases may participate provided that 
they are stable (without evidence of progression by imaging for at least 4 weeks before 
the first dose of study treatment and any neurologic symptoms have returned to baseline), 
have no evidence of new or enlarging brain metastases or CNS edema, and have not 
required steroids for this purpose for at least 7 days before the first dose of study 
treatment. 
10. Participants with laboratory values at screening defined in Table 7. 
Table 7: 
Exclusionary Laboratory Values 
Laboratory Parameter 
Exclusion Criterion 
Hematology 
a. 
Platelets 
≤ 100 × 109/L 
b. 
Hemoglobin 
≤ 9 g/dL 
c. 
ANC 
≤ 1.5 × 109/L 
Hepatic 
d. 
ALT 
≥ 1.5 × ULN or ≥ 2.5 × ULN for participants with liver metastases 
e. 
AST 
≥ 1.5 × ULN or ≥ 2.5 × ULN for participants with liver metastases 
f. 
Total bilirubin 
≥ 1.5 × ULN or ≥ 2.5 × ULN if Gilbert's syndrome or liver metastasis 
Renal 
g. 
Calculated CrCl 
< 30 mL/min (calculated by Cockcroft-Gault equation) 
Coagulation 
h. 
INR or PT 
> 1.5 × ULN unless on therapeutic anticoagulants 

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Laboratory Parameter 
Exclusion Criterion 
i. 
aPTT 
> 1.5 × ULN unless on therapeutic anticoagulants 
Cardiac 
j. 
TnT or TnI 
> 2 × Institutional ULN. 
Participants with TnT or TnI levels between > 1 to 2 × ULN will be 
permitted if repeat levels within 24 hours are ≤ 1 × ULN.a 
Note: If the screening chemistry and hematology tests were conducted > 7 days before treatment initiation, they will 
need to be repeated on Day 1 before initiation of treatment to reconfirm eligibility. 
a If TnT or TnI levels are > 1 to 2 × ULN within 24 hours, the participant may undergo a cardiac evaluation and be 
considered for treatment following a discussion with the sponsor's medical monitor or designee. When repeat 
levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat 
levels beyond 24 hours are < 2 × ULN, the participant may undergo a cardiac evaluation and be considered for 
treatment following a discussion with the sponsor's medical monitor or designee. 
11. Has known active HBV or HCV infection, or risk of reactivation of HBV or HCV, 
defined as follows (testing must be performed to determine eligibility): 
a. Active HBV infection is defined by positive HBsAg and positive total anti-HBc 
results. 
Note: If HBsAg is negative AND HBcAb and/or HBsAb is positive, HBV-DNA will 
be evaluated; when HBV-DNA is negative, the participant can then be enrolled with 
close monitoring of HBV activities. 
b. Active HCV is defined as a positive HCV antibody result and quantitative HCV-RNA 
results greater than the lower limits of detection of the assay. 
Note: Participants positive for HCV antibody will be eligible if they are negative for 
HCV-RNA. Participants who have had definitive treatment for HCV are permitted if 
HCV-RNA is undetectable. 
Note: HBV-DNA and the following hepatitis B serology must be conducted prior to 
randomization: HbsAg, total anti-HBc, and anti-HBs. 
12. Participants who are known to be HIV-positive, unless all of the following criteria are 
met: 
a. CD4+ count ≥ 300/μL. 
b. Undetectable viral load. 
c. Receiving antiretroviral therapy that is not a potential risk for a drug-drug interaction 
with the assigned study drug. 
Note: Screening HIV antibody testing is required only if mandated by local health 
authorities or local regulations. 
13. Any known additional malignancy that is progressing or requires active treatment, or 
history of other malignancy within 3 years of the first dose of study treatment with the 
exception of cured basal cell or squamous cell carcinoma of the skin, superficial bladder 
cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other 
noninvasive or indolent malignancy, or cancers from which the participant has completed 
treatment > 2 years before randomization in this study and has been disease-free since 
completion of treatment with curative intent. 

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14. Has active autoimmune disease requiring systemic immunosuppression with 
corticosteroids (> 10 mg/day of prednisone or equivalent) or immunosuppressive drugs 
within 2 years before the first dose of study treatment. 
15. Is on chronic systemic steroids (> 10 mg/day of prednisone or equivalent). 
Notes: 
a. Physiologic corticosteroid replacement therapy at doses > 10 mg/day of prednisone or 
equivalent for adrenal or pituitary insufficiency and in the absence of active 
autoimmune disease is permitted. 
b. Participants with a condition (eg, asthma or COPD) that requires intermittent use of 
bronchodilators, inhaled steroids, or local steroid injections may participate. 
c. Participants using topical, ocular, intra-articular, or intranasal steroids (with minimal 
systemic absorption) may participate. 
d. Brief courses of corticosteroids for prophylaxis (eg, contrast dye allergy) or study 
treatment-related standard premedication are permitted. 
16. Active infections (besides those described in Exclusion Criteria 11 and 12) requiring 
systemic antibiotics or antifungal or antiviral treatment (within 14 days before first dose 
of study treatment). 
Note: A participant with a positive test result for SARS-CoV2 infection at any time 
during screening should not be randomized until a negative antigen test is confirmed and 
any clinical symptoms (as applicable) have resolved. 
17. Evidence of interstitial lung disease or history of interstitial lung disease, or active, 
noninfectious pneumonitis. 
18. History of organ transplant, including allogeneic stem cell transplantation. 
19. Receiving probiotics as of the first dose of study treatment. 
20. History or presence of an abnormal ECG that, in the investigator's opinion, is clinically 
meaningful. Screening QTc interval > 460 milliseconds is excluded (corrected by 
Fridericia or Bazett formula). In the event that a single QTc is > 460 milliseconds, the 
participant may enroll if the average QTc for the 3 ECGs is ≤ 460 milliseconds. 
21. Has had a significant cardiac event within 6 months before the first dose of study 
treatment, including New York Heart Association Class III/IV, acute myocardial 
infarction (including severe/unstable angina), cardiomyopathy, coronary/peripheral artery 
bypass graft, symptomatic congestive heart failure, critical conduction delay, 
cerebrovascular accident or transient ischemic attack, or pulmonary embolism. 
Note: Medically-controlled arrhythmia is permitted. 
Note: Recovery from uncontrolled or Grade ≥ 3 hypertension to ≤ Grade 1 is required. 
22. Has received a live vaccine within 30 days of planned start of study treatment. 
Note: Examples of live vaccines include but are not limited to the following: measles, 
mumps, rubella, chicken pox/zoster, yellow fever, rabies, Bacillus Calmette–Guérin, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 

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vaccines and are allowed; however, intranasal influenza vaccines are live-attenuated 
vaccines and are not allowed. 
23. Known hypersensitivity to another monoclonal antibody that cannot be controlled with 
standard measures (eg, antihistamines and corticosteroids). 
24. Known allergy or hypersensitivity to any component of either retifanlimab, 
INCAGN02385, or INCAGN02390 study drug formulation (including excipients and 
additives). 
25. Women who are pregnant or breastfeeding. 
26. Any condition that would, in the investigator's judgment, interfere with full participation 
in the study, including administration of study treatment and attending required study 
visits; pose a significant risk to the participant; or interfere with interpretation of study 
data. 
27. The following participants are excluded in France: vulnerable populations according to 
article L.1121-6 of the French Public Health Code and adults under legal protection, or 
who are unable to express their consent per article L.1121-8 of the French Public Health 
Code. 
5.3. 
Lifestyle Considerations 
No restrictions are required. Participants should maintain a normal diet unless modifications are 
required to manage an AE such as diarrhea, nausea, or vomiting. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study treatment. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened after consultation with the sponsor and will receive a new participant number. 
Participants who rescreen must reconsent if more than 28 days have elapsed from the original 
consent date. 
Tests with results that fail eligibility requirements may be repeated once during screening if the 
investigator believes the result to be in error. For screening visit procedures, see Section 8.1.2. 
5.5. 
Replacement of Participants 
No participants will be replaced at any time during this study. 
5.6. 
Data Safety Monitoring Board 
After 30 participants have been randomized and have received treatment for at least 4 weeks (at 
least 2 doses), an interim analysis of safety will be performed by an independent, external 
DSMB. Enrollment will not be held during the safety interim analysis. 
The external DSMB will consist of qualified individuals who are not involved with the conduct 
of the study. Additionally, the DSMB will review safety data of the ongoing study at regular 
intervals as specified in the DSMB Charter. Such safety data will be summarized by treatment 

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group. The process by which the DSMB will make recommendations and decisions will be 
documented in the DSMB Charter. 

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6. 
STUDY TREATMENT 
6.1. 
Study Treatments Administered 
Table 8 presents the study treatment information. 
Table 8: 
Study Treatment Information 
 
Study Treatment 1 
Study Treatment 2 
Study Treatment 3 
Study treatment name: 
Retifanlimab 
(INCMGA00012) 
INCAGN02385/placebo 
INCAGN02390/placebo 
Dose formulation: 
Solution for infusion 
Solution for infusion 
Solution for infusion 
Unit dose strength(s)/ 
dose level(s): 
25 mg/mL in a glass vial 
for single use 
Dose level: 500 mg Q4W 
50 mg/mL 
Dose level: 350 mg Q2W 
50 mg/mL 
Dose level: 400 mg Q2W 
Route of 
administration 
IV (30-minute infusion 
with filter followed by 
10-minute flush) 
IV (30-minute infusion 
with filter followed by 
10-minute flush) 
IV (30-minute infusion 
with filter followed by 
10-minute flush) 
Packaging and labeling Study drug will be provided 
in a vial. 
Each vial will be labeled as 
required per country 
requirement. 
Study drug will be provided 
in a vial. 
Each vial will be labeled as 
required per country 
requirement. 
Study drug will be provided 
in a vial. 
Each vial will be labeled as 
required per country 
requirement. 
Status of treatment in 
participating countries: 
Investigational 
Investigational 
Investigational 
The order of administration of study drugs on Day 1 of each cycle should be retifanlimab, 
followed by INCAGN02385/placebo, followed by INCAGN02390/placebo. 
The order of administration of study drugs on Day 15 of each cycle should be 
INCAGN02385/placebo followed by INCAGN02390/placebo; retifanlimab is not 
administered on Day 15. 
As outlined in Table 8, infusions are 30 minutes each with a 10-minute flush followed by the 
next infusion. For additional details regarding infusion of study drugs, refer to the Pharmacy 
Manual. 
Study treatment will be administered for up to 2 years, or until discontinuation criteria are met 
(see Section 7.1.1). Study treatment may be administered ± 3 days of the scheduled Day 1 for 
each cycle (except for Cycle 1 Day 1, on which the study treatment will be administered 
specifically on Day 1) and ± 2 days of the scheduled Day 15 for each cycle. 
INCAGN02385/placebo and INCAGN02390/placebo doses should not be administered 
< 12 days apart. 
Before administration of study treatment, premedication with an antipyretic agent (eg, 
acetaminophen/paracetamol or ibuprofen) and a histamine blocker (eg, diphenhydramine) should 
be considered for participants who have had previous systemic reactions to protein product 
infusions or when recommended according to institutional policy. On Cycle 1 Day 1, Cycle 1 

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Day 15, and Cycle 2 Day 1, vital signs will be monitored prior to each study drug infusion 
(−10 minutes), as well as 30 and 60 minutes (± 10 minutes) following completion of the 
INCAGN02390/placebo infusion and additionally as clinically indicated. For subsequent study 
drug infusions (Cycle 2 Day 15 and beyond), vital signs will be monitored prior to each study 
drug infusion (−10 minutes) and additionally as clinically indicated. If the participant 
experiences an IRR, vital sign monitoring should continue at the specified timepoints for 
subsequent study drug infusions until no suspected IRR is observed. 
6.2. 
Preparation, Handling, and Accountability 
For detailed information concerning the reconstitution, preparation, and infusion of the study 
drugs, refer to the Pharmacy Manual. 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatments received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment, and only authorized site 
staff may supply or administer study treatment. All study treatment must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
The investigator (or designee) is responsible for study treatment accountability, reconciliation, 
and record maintenance (ie, receipt, reconciliation, and final disposition records). Inventory and 
accountability records must be maintained and readily available for inspection by the study 
monitor and are open to inspection at any time by any applicable regulatory authorities. The 
investigator or designee must maintain records that document: 
• Delivery of study drugs to the study site. 
• Inventory of study drugs at the site. 
• Participant use of the study drugs including vial counts from each supply dispensed. 
• Lot numbers and/or vial numbers (as applicable) of study drugs used to prepare the 
infusion solution. 
The investigational product must be used only in accordance with the Protocol. The investigator 
will also maintain records adequately documenting that the participants were provided the 
specified study drug. These records should include dates, quantities, and any available batch or 
serial numbers or unique code numbers assigned to the investigational product and study 
participants. 
Completed accountability records will be archived by the site. The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of the study drugs 
until verified by the study monitor (unless otherwise agreed to by the sponsor). At the conclusion 
of the study, the investigator or designee will oversee shipment of any remaining study drugs 
back to the sponsor or its designee for destruction according to institutional SOPs. If local 
procedures mandate on-site destruction of investigational supply, the site should (where local 
procedures allow) maintain the investigational supply until the study monitor inspects the 
accountability records in order to evaluate compliance and accuracy of accountability by the 

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investigative site. At sites where the study drugs are destroyed before monitor inspection, the 
monitors rely on documentation of destruction per the site SOP. 
Further guidance and information for the final disposition of unused study treatments are 
provided in the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
All participants will be centrally assigned to study treatment using an IRT. Full details will be 
provided in the IRT Manual. 
Study treatment will be dispensed at the study visits summarized in the SoA (see Table 3). 
Centralized randomization numbers within each stratum will be created for treatment 
assignment. Participants will be assigned to study treatment in accordance with the 
randomization schedule. Participants, investigators, the sponsor, and the study team will be 
blinded to treatment assignment. See emergency unblinding procedures in Section 9.6. 
A sponsor statistician who is not part of the study team will be unblinded and may provide 
summary aggregated data by treatment group to the DSMB, but individual participant data will 
remain blinded. 
6.4. 
Study Treatment Compliance 
Compliance with study treatment administration will be calculated by the sponsor based on study 
drug accountability and infusion records documented by the site staff and monitored by the 
sponsor/designee. 
6.5. 
Dose Modifications 
6.5.1. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study Drugs 
Individual decisions regarding dose modifications of study treatment should be made using 
clinical judgment in consultation with the medical monitor (whenever possible), taking into 
account relatedness of the AE to the study treatment and the participant's underlying condition. 
Adverse events that have a clear alternative explanation, or transient (≤ 72 hours) abnormal 
laboratory values without associated clinically significant signs or symptoms, may be exempt 
from dose-interruption rules. 
Safety concerns should be discussed with the sponsor immediately upon occurrence or awareness 
to determine if the participant should continue or discontinue study treatment. 
Dose modification of study drugs (INCAGN02385, INCAGN02390, and retifanlimab) is not 
permitted. If a dose-interruption is necessary for management of treatment-related TEAEs, study 
drugs will be reinitiated at the starting dose. 
Treatment with study drugs may be interrupted up to 4 weeks (28 days) to allow for resolution of 
toxicity, unless a longer interruption is approved by the sponsor. All study drugs should be 
interrupted at the same time for the same duration. Participants may resume treatment if no 
medical condition or other circumstance exists that, in the opinion of the investigator, would 
make the participant unsuitable for further participation in the study. The treating investigator 

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should contact the sponsor to discuss the case of any participant whose treatment has been 
delayed for more than 28 days before restarting the study treatment. 
Given the Q2W infusion schedule for INCAGN02385/placebo and INCAGN02390/placebo, if 
Day 15 infusions had to be delayed because of toxicity, the next dose of INCAGN02385/placebo 
and INCAGN02390/placebo can be resumed once the toxicity resolves as per protocol guidance: 
• If treatment is restarted < 2 weeks from the last treatment visit, resume 
INCAGN02385/placebo plus INCAGN02390/placebo only (that would be considered 
Day 15), then the subsequent treatment visit should occur 2 weeks later with the 
triplet (including retifanlimab) and continue per protocol schedule. 
• If treatment is restarted ≥ 2 weeks from last treatment visit, proceed with the triplet 
combination (ie, omit the Day 15 dose of the doublet INCAGN02385/placebo plus 
INCAGN02390/placebo) and continue per study schedule. 
Decisions regarding these dose interruptions and restart of study drugs will be made according to 
Section 6.5.1.1 for non-irAEs, Section 6.5.2 for suspected infusion reactions and Section 6.5.3 
for irAEs and, when needed, jointly by the investigator and medical monitor on a case-by-case 
basis. 
Dose interruptions are permitted in the case of medical or surgical events (eg, elective surgery, 
unrelated medical events). In such a case, study treatment should resume within 4 weeks of the 
scheduled interruption, unless otherwise discussed with the sponsor. Delayed study treatment 
administration in the case of logistical reasons not related to study therapy (eg, participant 
vacation, holidays) is permitted. In such a case, study treatment should resume within 3 to a 
maximum of 7 days of the scheduled interruption, unless otherwise discussed with the sponsor. 
For participants who have active, confirmed (positive results from an approved COVID-19 test) 
or presumed (test pending/clinical suspicion) SARS-CoV2 infection, guidelines in Appendix C 
should be followed. 
If treatment is permanently discontinued for toxicity, all 3 study drugs must be discontinued and 
the EOT visit should be conducted. 
6.5.1.1. 
Procedures for Participants Exhibiting Drug-Related, Non–Immune-Related 
Adverse Events 
The guidance presented in Table 9 should be followed as best practice for decisions regarding 
management of non-irAEs. 
Table 9: 
Management Guidelines for Drug-Related, Non–Immune-Related Adverse 
Events 
CTCAE Grade 
Suggested Modification for INCAGN02385, INCAGN02390, and Retifanlimab 
Grade 1 or Grade 2 
Continue treatment at the discretion of the investigator. 
Grade 3 
• Withhold treatment until resolution to ≤ Grade 1. 
• Permanently discontinue study treatment after third occurrence of toxicity, unless 
approved by the medical monitor to continue. 
Grade 4 
Permanently discontinue study treatment or discuss with medical monitor if treatment 
algorithm for CTCAE Grade 3 events (above) is appropriate. 

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6.5.2. 
Management of Suspected Infusion Reactions 
Immunotherapies have been associated with the occurrence of infusion reactions. Infusion or 
hypersensitivity reactions may be observed with administration of any foreign protein. 
Premedication with an antipyretic (eg, acetaminophen/paracetamol or ibuprofen) and a histamine 
blocker (eg, diphenhydramine) should be considered for participants who have had previous 
systemic reactions to protein product infusions or when recommended by institutional policy. 
Routine prophylaxis is not required. 
Participants should be monitored closely during the study drug infusion period and are required 
to remain at the study site on Cycle 1 Day 1 for safety observation for potential IRRs for at least 
4 hours after completion of the final infusion (INCAGN02390/placebo). From Cycle 2 onwards, 
participants may be required to stay at the investigator's discretion. 
Guidelines for management of suspected infusion reactions are provided in Table 10. 

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Table 10: 
Guidelines for Management of Suspected Infusion Reactions 
Grade 
Description 
Treatment 
Subsequent Infusions 
1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated. 
Monitor vital signs closely until 
medically stable. 
Premedication with an antipyretic 
(eg, acetaminophen/paracetamol) 
and a histamine blocker should be 
considered for participants who 
have had previous systemic 
reactions to protein product 
infusions or when recommended 
by institutional policy. 
2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 hours. 
First occurrence: Stop infusion 
and initiate appropriate medical 
measures (eg, IV fluids, 
antihistamines, NSAIDs, 
antipyretics, narcotics) per 
institutional preferences. 
Monitor vital signs until 
medically stable. 
If symptoms resolve within 
1 hour, infusion may be resumed 
at 50% of the original infusion 
rate. 
Subsequent occurrences (after 
recommended prophylaxis): 
Permanently discontinue study 
treatment. 
Premedicate at least 30 minutes 
before infusion with antihistamines 
(eg, diphenhydramine 50 mg PO) 
and an antipyretic 
(eg, acetaminophen/paracetamol 
500-1000 mg PO). 
Additional supportive measures 
may be acceptable (per 
institutional preference) but 
should be discussed with medical 
monitor. 
Next infusion should start at 50% 
of the original infusion rate. If no 
reaction, rate of infusion can be 
increase by 25% every 15 minutes 
until a rate of 100% has been 
reached. Subsequent infusions can 
begin at 100%. 
3 or 4 
Grade 3: Prolonged (ie, not 
rapidly responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (eg, renal 
impairment, pulmonary 
infiltrates). 
Grade 4: Life-threatening; 
pressor or ventilatory support 
indicated. 
Stop infusion and initiate 
appropriate medical therapy 
(eg, IV fluids, antihistamines 
NSAIDs, antipyretics, narcotics, 
oxygen, pressors, epinephrine, 
corticosteroids) per institutional 
preferences. 
Monitor vital signs frequently 
until medically stable. 
Hospitalization may be indicated. 
Permanently discontinue study 
treatment. 
Note: Per NCI CTCAE v5.0, appropriate resuscitation equipment should be available at the bedside and a physician 
readily available during the period of study treatment administration (NCI 2017). 
6.5.3. 
Procedures for Participants Exhibiting Immune-Related Adverse Events 
Adverse events of a potential immunologic etiology, or irAEs, may be defined as AEs of 
unknown etiology, associated with drug exposure and consistent with an immune phenomenon. 
Immune-related AEs may be predicted based on the nature of the compounds, their mechanism 
of action, and reported experience with immunotherapies that have a similar mechanism of 
action. Special attention should be paid to AEs that may be suggestive of potential irAEs. An 
irAE can occur shortly after the first dose or several months after the last dose of treatment. 

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If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxic, or other etiologic causes before labeling an AE as an irAE. 
General recommendations for the management of specific irAEs known to be associated with 
other PD-1 inhibitors (eg, pembrolizumab, nivolumab) are detailed in Table 11. Algorithms for 
evaluation of selected immune toxicities that have previously been attributed to PD-1 inhibitors 
and management guidelines for irAEs not detailed elsewhere in the protocol should follow the 
ASCO or ESMO Clinical Practice Guidelines (Haanen et al 2017, Schneider et al 2021). 
Continuous evaluation of toxicity events will be performed throughout the study to assess for any 
late-onset immune-related toxicities that occur up to a minimum of 90 days after the last dose of 
study drug. If warranted, enrollment of participants may be suspended until the sponsor, 
investigators, and DSMB have determined the appropriate course of action. 

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Table 11: 
Guidelines for Management of Immune-Related Adverse Events 
irAE 
Toxicity Grade or 
Conditions (CTCAE v5.0) 
Action Taken With Study Treatment 
Adverse Event Management With Corticosteroid and/or 
Other Supportive Care Therapies 
Pneumonitis 
Grade 1 
No action. 
None. 
Grade 2 
Withhold until ≤ Grade 1. 
• Administer systemic corticosteroids per local practice followed by 
taper. 
• Evaluate participants with suspected pneumonitis with radiographic 
imaging and initiate corticosteroid treatment. 
• Add prophylactic antibiotics for opportunistic infections. 
Grades 3 or 4, or recurrent 
Grade 2 
Permanently discontinue. 
Diarrhea/colitis 
Grade 1 
No action. 
None. 
Grades 2 or 3 
Withhold until ≤ Grade 1. 
• Consider prompt initiation of standard antidiarrheal agents and other 
necessary supportive care as needed (eg, oral and/or IV fluids). 
• Administer systemic corticosteroids per local practice followed by 
taper. 
• Consider prophylactic antibiotics per local practice. 
• Consider gastrointestinal consultation and performing endoscopy to 
rule out colitis. 
Grade 4 or recurrent Grade 3 
Permanently discontinue. 
AST/ALT elevation and/or 
increased total 
bilirubin/hepatitis 
Grade 1 
No action. 
• Administer systemic corticosteroids per local practice followed by 
taper. 
• Consider monitoring liver enzymes weekly (or more frequently) 
until liver enzyme value returns to baseline or is stable. 
• Consider monitoring total bilirubin, direct bilirubin, and alkaline 
phosphatase weekly (or more frequently) if needed. 
Grade 2 ALT or AST increase 
or 
Total bilirubin increases to 
> 1.5 × and up to 3 × ULN 
Withhold. 
Grades 3 or 4 ALT or AST 
increase 
or 
In participants with liver 
metastases with baseline 
Grade 2 elevation of AST or 
ALT, hepatitis with AST or 
ALT increases ≥ 50% and 
lasts ≥ 1 week 
or 
Total bilirubin increases to 
> 3 × ULN 
Permanently discontinue. 

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Table 11: 
Guidelines for Management of Immune-Related Adverse Events (Continued) 
irAE 
Toxicity Grade or 
Conditions (CTCAE v5.0) 
Action Taken With Study Treatment 
Adverse Event Management With Corticosteroid and/or 
Other Supportive Care Therapies 
Endocrinopathies 
• Type 1 diabetes mellitus 
• Hyperglycemia 
• Hyperthyroidism 
• Hypothyroidism 
• Adrenal insufficiency 
Grades 1 and 2 
No action if clinically appropriate. 
None. 
Grade 2 adrenal insufficiency  Withhold until ≤ Grade 1 or otherwise 
clinically stable 
Initiate treatment with HRT as clinically indicated. 
Grades 3 and 4 adrenal 
insufficiency 
Withhold until ≤ Grade 1 after 
corticosteroid taper to ≤ 10 mg/day 
prednisone or equivalent or is otherwise 
clinically stable. 
Initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a 
taper and HRT as clinically indicated. 
Grades 3 and 4 
hypothyroidism 
Withhold until ≤ Grade 2 or is otherwise 
clinically stable. 
Initiate thyroid replacement hormones (eg, levothyroxine or 
liothyronine) per SoC. 
Grades 3 and 4 
hyperthyroidism 
Withhold until ≤ Grade 2 or is otherwise 
clinically stable. 
Initiate symptomatic management. 
Grades 3 or 4 type 1 diabetes 
mellitus (or hyperglycemia) 
Withhold until ≤ Grade 1 or is otherwise 
clinically stable. 
Initiate treatment with antihyperglycemics as clinically indicated. 
Endocrinopathies 
• Hypophysitis 
Grade 1  
No action. 
None. 
Grade 2 (asymptomatic) 
Withhold until ≤ Grade 1. 
May restart study treatment after 
controlled by HRT. 
Administer hormonal replacement. 
Grade 2 (symptomatic; 
eg, headaches, visual 
disturbances) 
Withhold until ≤ Grade 1. 
May restart study treatment after 
controlled with HRT, if indicated, and 
steroid taper is complete. 
• Administer corticosteroids at initial dose of 1 to 2 mg/kg/day 
prednisone or equivalent followed by a taper, and initiate other 
HRTs as clinically indicated. 
• Consult with endocrinologist as needed. 
Grade 3 or 4 (symptomatic) 
• Permanent discontinuation should 
occur if after withholding study 
treatment, the toxicity does not 
resolve to ≤ Grade 1 within 12 weeks 
after last dose of study treatment, or 
if corticosteroid dose cannot be 
reduced to ≤ 10 mg prednisone or 
equivalent per day within 12 weeks. 
• Permanent discontinuation should 
take place earlier at the investigator's 
discretion if corticosteroids and/or 
HRT cannot balance the participant's 
pituitary function. 
• Administer corticosteroids at initial dose of 1 to 2 mg/kg/day 
prednisone or equivalent followed by a taper and initiate other HRTs 
as clinically indicated. 
• Consult with endocrinologist as needed. 

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Table 11: 
Guidelines for Management of Immune-Related Adverse Events (Continued) 
irAE 
Toxicity Grade or 
Conditions (CTCAE v5.0) 
Action Taken With Study Treatment 
Adverse Event Management With Corticosteroid and/or 
Other Supportive Care Therapies 
Nephritis with renal 
dysfunction 
Grade 1 
No action. 
None. 
Grade 2 increased blood 
creatinine 
Withhold until ≤ Grade 1. 
Administer corticosteroids per local practice followed by taper. 
Grade 3 or 4 increased blood 
creatinine 
Permanently discontinue.a 
Skin (eg, Stevens-Johnson 
syndrome, or toxic epidermal 
necrolysis) 
Grade 1 
No action. 
None. 
Grade 2 
No action. 
Manage with topical steroids with or without drug interruption. 
Grade 3b or persistent Grade 2 
(≥ 2 weeks) or suspected 
Stevens-Johnson syndromec 
Withhold until ≤ Grade 1. 
Study treatment can be resumed at same 
dose. 
• Administer corticosteroids per local practice followed by taper. 
• Additionally, oral antihistamines such as diphenhydramine or 
famotidine (per institutional preference) may be utilized as needed. 
• Should refer to dermatology if no resolution with these measures. 
Recurrent Grade 3d after 
resuming study treatment or 
Grade 4 rash or confirmed 
Grade 4 Stevens-Johnson 
syndromec or toxic epidermal 
necrolysise 
Permanently discontinue. 
• Initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed 
by a taper. 
• Refer to dermatology consult. 
Myocarditis 
Grade 2 
• Depending on severity of symptoms 
withhold until symptoms fully 
resolve and management with 
corticosteroids is complete. 
• Permanent discontinuation may take 
place earlier at the investigator's 
discretion. 
• Treatment with systemic corticosteroids should be initiated (initial 
dose of 1 to 2 mg/kg/day of prednisone or equivalent). Taper as 
appropriate. 
• Manage cardiac symptoms according to SoC and with guidance 
from cardiology. Consider cardiac MRI and myocardial biopsy for 
diagnosis. 
Grades 3 or 4 
Permanently discontinue. 
TnI or TnT increase 
All grades (including 
asymptomatic cases) 
Withhold until cardiac evaluation is 
completed, myocarditis is ruled out, and 
a cardiologist recommends that 
treatment may proceed. 
• Refer to cardiology consult and initiate diagnostic workup including 
ECG, echocardiogram (plus cardiac MRI as needed for diagnostic 
confirmation), and further relevant biological markers (eg, BNP, 
CPK) as per the cardiologist recommendation. 
• Confirmatory tests should be repeated within 24 hours 
− If troponin elevation is not confirmed within 24 hours in an 
asymptomatic participant, the dose delay may not be needed 
provided that the cardiac evaluation is completed and a 
cardiologist-recommended treatment may proceed. 
• If troponin elevation is confirmed, continue serial monitoring and 
consider initiating corticosteroids per cardiologist recommendation. 
Study treatment may resume when the cardiac evaluation is 
complete, myocarditis is ruled out, and a cardiologist recommends 
that treatment may proceed. 

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Table 11: 
Guidelines for Management of Immune-Related Adverse Events (Continued) 
irAE 
Toxicity Grade or 
Conditions (CTCAE v5.0) 
Action Taken With Study Treatment 
Adverse Event Management With Corticosteroid and/or 
Other Supportive Care Therapies 
Important nervous system 
events (eg, Guillain-Barre 
syndrome, autoimmune 
encephalitis, myasthenia 
gravis, autonomic 
neuropathy, or transverse 
myelitis) 
Grade 2 
Withhold until ≤ Grade 1. 
• Neurology consultation is recommended for all neurologic 
irAEs ≥ Grade 2. 
• Treatment with systemic corticosteroids should be initiated (initial 
dose of 1 to 2 mg/kg/day of prednisone or equivalent). Taper as 
appropriate. 
• For Grade 2 transverse myelitis, consider permanent discontinuation. 
• Manage symptoms according to SoC and with guidance from 
neurology. 
Grades 3 or 4 
Permanently discontinue. 
All other irAEs 
Grade 2 or Grade 3 based on 
severity and type of reaction 
Withhold until ≤ Grade 1. 
Based on severity of AE, administer corticosteroids. 
Recurrent Grade 3 or 
persistent Grade 2 and 
Grade 3 
Permanently discontinue. 
Grade 4 
Permanently discontinue. 
a If study drug(s) are implicated in the renal toxicity. 
b Participants with first onset of Grade 3 rash with desquamation, and/or mucosal involvement, requiring systemic steroids and not resolving or improving to ≤ Grade 1 within 
14 days must permanently discontinue study treatment. 
c Grade 3 Stevens-Johnson syndrome is defined as skin sloughing covering < 10% BSA with associated signs (eg, erythema, purpura, epidermal detachment, mucous membrane 
detachment). Grade 4 Stevens-Johnson syndrome is defined as skin sloughing covering 10% to 30% BSA with associated signs (eg, erythema, purpura, epidermal detachment, 
mucous membrane detachment). 
d Refers to single recurrence after first onset of Grade 3 that did not require systemic steroids and participant recovered and resumed study treatment. Investigators are required to 
define the medical term or type of "rash" as best as possible and not to enter in eCRFs the term generically as rash only. Severe skin rashes per CTCAE criteria are generally a 
rash that covers > 30% BSA and can be in the form of macules/papules or pustules; limiting self-care activities of daily living. 
e Toxic epidermal necrolysis is Grade 4 by definition and is defined as skin sloughing covering ≥ 30% BSA with associated symptoms (eg, erythema, purpura, epidermal 
detachment). 

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6.5.4. 
Criteria for Permanent Discontinuation of Study Treatment 
The occurrence of unacceptable toxicity not caused by the underlying disease will require that 
the study treatment be permanently discontinued. Unacceptable toxicity is defined as follows: 
• The occurrence of an AE that is related to study treatment that, in the judgment of the 
investigator or the sponsor's medical monitor, compromises the participant's ability to 
continue study-specific procedures or is considered to not be in the participant's best 
interest. 
• A persistent AE requiring a delay of therapy for more than 4 weeks (28 days) unless a 
greater delay has been approved by the sponsor. See exception for irAEs related to 
study treatment below. 
• An irAE that does not resolve within 12 weeks of the last dose of study treatment, or 
corticosteroids cannot be reduced to ≤ 10 mg/day prednisone or equivalent within 
12 weeks. 
See Section 7 for discontinuation procedures. 
6.5.5. 
Treatment After Initial Evidence of Radiologic Disease Progression 
Combinations of immunotherapeutic agents such as the combination of retifanlimab, 
INCAGN02385, and INCAGN02390 may produce antitumor effects by potentiating endogenous 
cancer-specific immune responses. The response patterns seen with such as approach may extend 
beyond the typical time course of responses seen with cytotoxic agents and can manifest as a 
clinical response after an initial increase in tumor burden or even the appearance of new lesions. 
If radiologic imaging shows PD, tumor assessment should be repeated ≥ 4 weeks later to confirm 
PD with the option of continuing treatment per below while awaiting radiologic confirmation of 
progression. If repeat imaging shows a reduction in the tumor burden compared with the initial 
scan demonstrating PD, treatment may be continued as per the treatment calendar. If repeat 
imaging confirms PD, participants will be discontinued from study therapy. In determining 
whether the tumor burden has increased or decreased, investigators should consider all target 
lesions as well as nontarget lesions. 
When feasible, participants should not be discontinued until PD is confirmed; however, the 
decision to continue study treatment after the first evidence of PD is at the investigator's 
discretion based on the clinical status of the participant as described in Table 12. Treatment 
should not continue beyond 2 years. 
Participants may receive study treatment while waiting for confirmation of PD if they are 
clinically stable as defined by the following criteria: 
• Absence of signs and symptoms (including worsening of laboratory values) 
indicating PD 
• No decline in ECOG performance status 
• Absence of rapid PD 
• Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 

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Participants who are eligible to continue treatment past progression should be reconsented prior 
to continuation of therapy. 
Table 12: 
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of PD  
Repeat imaging at 
≥ 4 weeks to 
confirm PD 
May continue study 
treatment at the 
investigator's 
discretion while 
awaiting 
confirmatory scan 
Repeat imaging at 
≥ 4 weeks to 
confirm PD if 
possible 
Discontinue 
treatment 
Repeat scan 
confirms PD  
No additional 
imaging required 
Discontinue 
treatment 
No additional 
imaging required 
NA 
Repeat scan shows 
SD, PR, or CR  
Continue regularly 
scheduled imaging 
assessments Q8W 
for the first year and 
Q12W thereafter 
Continue study 
treatment at the 
investigator's 
discretion 
Continue regularly 
scheduled imaging 
assessments Q8W 
for the first year and 
Q12W thereafter 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable per 
investigator's 
discretion 
6.6. 
Concomitant Medications and Procedures 
All concomitant medications and treatments (including over-the-counter or prescription 
medicines, vitamins, vaccines, and/or herbal supplements) must be recorded in the eCRF. Any 
medication received up to 28 days before the first dose of study treatment and up to 30 days after 
the last dose of study treatment, regardless of the start of a new anticancer therapy, will be 
recorded in the eCRF. Any addition, deletion, or change in the dose of these medications will 
also be recorded. Concomitant medications administered more than 30 days after the last dose of 
study treatment should be recorded for SAEs as defined in Section 9.3. Concomitant 
treatments/procedures that are required to manage a participant's medical condition during the 
study will also be recorded in the eCRF. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.6.1. 
Permitted Medications and Procedures 
All treatments that the investigator considers necessary for a participant's welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care, except those specifically defined as prohibited (see Section 6.6.3). 

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Recommended supportive measures for specific toxicities are described in Section 6.5.1. 
Permitted medications and procedures include the following: 
• The use of growth factors on a nonroutine basis (and following ASCO guidelines for 
cerebrospinal fluid use), anticoagulants, and transfusional support will be permitted. 
• Prior to administration of study treatment, premedication with an antipyretic (eg, 
acetaminophen/paracetamol or ibuprofen) and a histamine blocker should be 
considered for participants who have had previous systemic reactions to 
protein-product infusions or when recommended by institutional policy as described 
in Section 6.5.2. 
• The use of corticosteroids is permitted in the following situations: 
− Acute treatment for an AE. 
− Physiologic corticosteroid replacement therapy at doses < 10 mg daily of 
prednisone or equivalent for adrenal or pituitary insufficiency and in the absence 
of active autoimmune disease. 
− Participants with asthma who require intermittent use of bronchodilators, inhaled 
corticosteroids, or local corticosteroid injections. 
− Topical, ocular, intra-articular, or intranasal corticosteroids (with minimal 
systemic absorption). 
− Brief course of corticosteroids for prophylaxis (eg, < 3 weeks for contrast dye 
allergy), for study treatment-related premedication as per SoC, for chronic 
obstructive pulmonary disease exacerbation, or for treatment of nonautoimmune 
conditions (eg, delayed-type hypersensitivity reaction caused by a contact 
allergen). 
6.6.2. 
Restricted Medications and Procedures 
Use of systemic glucocorticoids is restricted to prophylaxis for contrast allergies for radiographic 
procedures or to modulate symptoms or treat an AE of suspected immunologic etiology as per 
Section 6.6.1. 
6.6.2.1. 
Palliative Surgery and Radiation Therapy While on Study Treatment 
Guidance regarding palliative surgery and radiation therapy while on study treatment is as 
follows: 
• Palliative radiation: any use of palliative radiation should not involve target lesions 
and should be discussed and agreed upon with the study medical monitor. Study 
treatment should be withheld for at least 1 week before, during, and 1 week after 
radiation. Participants should be closely monitored for any potential acute toxicity 
during and after receiving radiotherapy, and AEs should resolve to ≤ Grade 1 prior to 
resuming immunotherapy agents. 

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• Palliative surgical procedures: permitted for the underlying medical condition and 
management of symptoms but should not involve target lesions. Study treatment 
adjustments and safety washout periods should be discussed and agreed upon with the 
study medical monitor based on the extent and nature of surgery. 
Other restrictions and precautions include the following: 
• Study-related MRIs of the brain, if required, will be performed per the frequency 
specified in SoA (see Table 3). Investigators may obtain additional follow-up MRI 
scans as medically indicated. For other locally performed imaging, it is the local 
imaging facility's responsibility to determine, based on participant attributes 
(eg, allergy history, diabetic history, renal status), the appropriate imaging modality 
and contrast regimen for each participant. Imaging contraindications and contrast 
risks should be considered in this assessment. Participants with renal insufficiency 
should be assessed as to whether or not they should receive contrast and if so, what 
type and dose of contrast is appropriate. Specific to MRI, participants with severe 
renal insufficiency (ie, estimated GFR < 30 mL/min/1.73 m2) are at increased risk of 
nephrogenic systemic fibrosis. MRI contrast should not be given to this participant 
population. In addition, participants with surgically implanted devices 
(eg, pacemaker, deep brain stimulator, metallic implants) incompatible with MRI 
should not undergo such imaging techniques. The local imaging facility and 
investigator should determine the appropriate precautions or guidelines that should be 
instituted for participants with tattoos, body piercings, or other body art. The ultimate 
decision to perform an MRI in an individual participant in this study rests with the 
site radiologist, the investigator, and the standards set by the local ethics committee. 
6.6.3. 
Prohibited Medications and Procedures 
Medications or vaccinations specifically prohibited in the exclusion criteria (see Section 5.2) are 
not allowed during study treatment. If there is a clinical indication for any medication or 
vaccination specifically prohibited during the study, discontinuation from study treatment may 
be required. The investigator should discuss any questions regarding this with the medical 
monitor. The final decision on any supportive therapy or vaccination rests with the investigator 
and/or the participant's primary physician. However, the decision to continue the participant on 
study treatment requires the mutual agreement of the investigator, the medical monitor, and the 
participant. 
Participants are prohibited from receiving the following therapies during the screening, and study 
treatment of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy not specified in this 
Protocol. 
• Immunotherapy not specified in this Protocol. 
• Investigational agents other than retifanlimab, INCAGN02385, and INCAGN02390. 
• Curative radiation therapy or surgery. 
− Surgery or radiotherapy for tumor control is not permitted during the study 

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• Systemic immunosuppression for active autoimmune disease using 
immunosuppressive drugs or corticosteroids (> 10 mg daily of prednisone or 
equivalent), within 2 years before Day 1 of study treatment and throughout the study 
treatment period (with the exception of acute treatment for an AE; see Section 6.6.1). 
• Chronic use of systemic corticosteroids (> 10 mg daily of prednisone or equivalent). 
Exceptions for corticosteroid use are outlined in Section 6.6.1. 
• Live vaccines within 30 days before the first dose of study treatment, while 
participating in the study, and until 90 days after last dose of study drug. Examples of 
live vaccines include, but are not limited to, the following: measles, mumps, rubella, 
varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed; however, 
intranasal influenza vaccines are live-attenuated vaccines and are not allowed. 
• The use of probiotic dietary supplements. 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Participants may receive other medications that the investigator deems to be medically 
necessary. 
6.7. 
Treatment After the End of the Study 
Once a participant has discontinued study treatment, no further treatment will be provided in this 
study. Participants who discontinue study treatment will enter the follow-up period to be 
evaluated for safety and survival. Any participants entering the follow-up period for any reason 
other than PD will continue to be evaluated for disease status according to the scheduled 
assessments found in Table 3. 
In the event of early termination of the study, participants ongoing on-study treatment who are 
deriving clinical benefit (ie, do not have progressive disease) will be supplied with study drug 
through the 2-year treatment duration, until disease progression, or if any other treatment 
discontinuation criteria are met (eg, unacceptable toxicity, participant decision, physician 
decision), whichever occurs first. 

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7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
7.1.1. 
Reasons for Discontinuation 
Participants must be discontinued from study treatment for the following reasons: 
• Consent is withdrawn. 
Note: Consent withdrawn means that the participant has explicitly indicated that they 
do not want to be followed any longer; in this case, no further data, except data in 
public domain, may be solicited from or collected on the participant. Participants may 
choose to discontinue study treatment and remain in the study to be followed for 
progression and survival. 
• Confirmed or unequivocal PD per RECIST v1.1 as assessed by the investigator. 
Note: Guidance for treatment with immunotherapy beyond initial objective disease 
progression is provided in Section 6.5.5. 
• The participant is lost to follow-up as described in Section 7.3. 
• Further participation would be injurious to the participant's health or well-being, in 
the investigator's medical judgment. 
• Unacceptable toxicity as noted in Section 6.5. 
• The participant has received the maximum duration of 2 years of study treatment. 
• The investigator decides to discontinue the participant from study treatment. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
A participant may be discontinued from study treatment as follows: 
• If, during the course of the study, a participant is found not to have met eligibility 
criteria, the medical monitor, in collaboration with the investigator, will determine 
whether the participant should be withdrawn from study treatment. 
• If a participant is noncompliant with study procedures or study drug/treatment 
administration in the investigator's opinion, the sponsor should be consulted for 
instruction on handling the participant. 

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7.1.2. 
Discontinuation Procedures 
In the event that the decision is made to permanently discontinue the study treatment, the EOT 
visit should be conducted. Reasonable efforts should be made to have the participant return for 
the required follow-up visits. These visits are described in Table 3, Table 4, and Table 5. Each 
participant will be followed for 90 days for AE monitoring following cessation of study 
treatment. The last date of the last dose of study treatment and the reason for discontinuation of 
study treatment will be recorded in the eCRF. 
If a participant is discontinued from study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for discontinuation must be documented in the participant's medical 
record and the primary reason for discontinuation must be included in the eCRF. 
• The EOT visit should be performed and date recorded. 
• The status of the participant should be updated to EOT in the IRT. 
• Participants must be followed for safety until the time of the follow-up visit or until 
study treatment-related toxicities resolve, return to baseline, or are deemed 
irreversible, whichever is longest. 
If the participant discontinues study treatment and actively withdraws consent for collection of 
follow-up data, then no additional data collection should occur; however, participants will have 
the option of withdrawing consent for study treatment but continuing in the follow-up period of 
the study for safety/efficacy assessments. 
7.2. 
Participant Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
See Table 3, Table 4, and Table 5 for data to be collected at the time of study withdrawal and 
follow-up and for any further evaluations that need to be completed. 

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7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant's last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant's medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Administrative and General Procedures 
8.1.1. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 
− Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 
− Informed consent must be obtained using the IRB/IEC-approved version in a 
language that is native and understandable to the participant. A template will be 
provided by the sponsor or its designee. The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF template. The ICF must 
include a statement that the sponsor or its designee and regulatory authorities have 
direct access to participant records. 
− The ICF must contain all required elements and describe the nature, scope, and 
possible consequences of the study in a form understandable to the study 
participant. 
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the applicable 
requirements and regulations for the countries in which the study is being conducted 
as well as the IRB/IEC or study center. 
• The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection laws. The level of disclosure 
must also be explained to the participant. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must provide consent to the most current version of the ICF during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant. 
Participants who are rescreened are required to sign a new ICF if more than 28 days have elapsed 
from the original consent date. 

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8.1.2. 
Screening Procedures 
Screening is the interval between signing the ICF and the day the participant is randomized in the 
study (Cycle 1 Day 1). Screening may not exceed 28 days. Assessments that are required to 
demonstrate eligibility may be performed over the course of 1 or more days during the screening 
process. 
Procedures conducted as part of the participant's routine clinical management (eg, blood count, 
imaging study) and obtained before signing of the ICF may be used for screening or baseline 
purposes provided the procedure meets the Protocol-defined criteria and has been performed in 
the timeframe of the study (ie, within 28 days of Cycle 1 Day 1). If chemistry and hematology 
laboratory assessments were performed more than 7 days before Cycle 1 Day 1, then the tests 
must be repeated and eligibility confirmed before study treatment administration on Cycle 1 
Day 1. For participants who are randomized in the study, information associated with eligibility 
requirements must be entered into the appropriate eCRFs. 
Results from the screening visit evaluations will be reviewed to confirm eligibility before 
randomization or the administration of study treatment. Tests with results that fail eligibility 
requirements may be repeated once during screening if the investigator believes the results to be 
in error. For screening assessments that are repeated, the most recent available result before 
randomization will be used to determine eligibility. Treatment should start as soon as possible 
but no later than 3 days after the date of randomization. 
See Sections 5.4 and 5.5 for information regarding screen failures and replacement of 
participants, respectively. 
8.1.3. 
Interactive Response Technology Procedure 
Each participant will be identified in the study by a participant ID number, which is a 
combination of a country's abbreviation, the site ID, and the participant number. Site staff should 
contact the IRT to obtain the participant ID number during screening. Upon determining that the 
participant is eligible for randomization, the IRT will be contacted to obtain the blinded 
treatment assignment. Additionally, the IRT will be contacted at each study visit specified in 
Table 3. Additional details are provided in the IRT Manual. 
8.1.4. 
Distribution of Reminder Cards 
Participants will be provided with a reminder card at each visit. The reminder card will indicate 
the date/time of the next visit and will also provide any specific instructions, as applicable. 
8.1.5. 
Demographics and Medical History 
8.1.5.1. 
Demographics and General Medical History 
Demographic data and general medical history will be collected at screening by the investigator 
or qualified designee and will include year of birth/age, medical and surgical history, and current 
illnesses. The participant's history of tobacco and alcohol consumption use will also be collected. 
Medical history will include relevant medical or surgical treatment within the last 10 years that 
are considered to be clinically significant by the investigator. 

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8.1.5.2. 
Disease Characteristics and Treatment History 
A disease-targeted medical and treatment history will be collected at screening. Details regarding 
the participant's SCCHN history, including date of diagnosis, initial and current cancer stage, 
tumor histology, relevant disease characteristics, and prior treatments, including systemic 
treatments, radiation, and surgical procedures, will be recorded. At screening, PD-L1 expression 
(CPS) and HPV status (for oropharyngeal primary tumors) must be determined and documented. 
The combined positive score will be determined centrally for all participants prior to 
randomization; prior local CPS results may also be collected in the Case Report Form. HPV p16 
status is only required for participants with primary oropharyngeal tumors and may be 
determined locally (per the requirements in Section 5.1) or centrally if local testing is not 
feasible. 
8.1.6. 
Prior/Concomitant Medications Review 
The investigator or qualified designee will record medication, if any, taken within 28 days before 
the first dose of study treatment through the 30-days after the last dose of study treatment. 
Antibiotic use up to 2 months prior to the start of treatment will be collected. 
8.2. 
Efficacy Assessments 
Objective assessment of disease status is required using the evaluations per RECIST v1.1 
(Eisenhauer et al 2009). The investigator's assessment will be used to determine responses and 
will be recorded in the eCRF. 
Efficacy baseline assessments will be performed at screening, and further efficacy assessments 
will be performed throughout the study at the intervals defined in the SoA (see Table 3). Cycle 
delays should not interrupt the specified scan interval (see Section 8.2.1.2); thus tumor 
assessments and cycles may become out of sync. 
8.2.1. 
Tumor Imaging per RECIST v1.1 
The same imaging technique should be used for a participant throughout the study. All scans 
must be a contrast-enhanced CT or MRI, except in circumstances where there is a contrast 
allergy or with medical monitor approval. When the CT component of a positron emission 
tomography/CT scan uses higher energy and thinner slices (ie, of diagnostic quality), it may be 
acceptable with medical monitor approval. Images of the neck, chest, and abdomen are required 
for all participants. Additional imaging of other anatomical sites (eg, pelvis, brain), should be 
performed as applicable. 
8.2.1.1. 
Tumor Imaging During Screening 
Initial tumor imaging should be performed within 28 days before the first dose of study 
treatment. The site study team must review prestudy images to confirm that the participant has 
measurable disease per RECIST v1.1. For the purpose of response assessment, a biopsied lesion 
may only be selected as a target lesion if postbiopsy imaging confirms that it still qualifies as a 
RECIST defined measurable lesion, unless there are other lesions that qualify the participant for 
RECIST assessment. Further, lesions used for the purpose of response assessment must either a) 
not reside in a field that has been subjected to prior radiotherapy or b) have demonstrated clear 

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evidence of radiographic progression since the completion of prior radiotherapy and prior to 
study enrollment.. 
An MRI scan or CT of the brain will be performed at screening if there is a previous history of 
CNS metastasis or there are signs or symptoms suggesting that the participant has disease 
involvement in the CNS. 
Scans performed as part of routine clinical management are acceptable for use as the screening 
scan if they are of diagnostic quality and performed within 28 days before the first dose of study 
treatment. 
8.2.1.2. 
Tumor Imaging During the Study 
The first imaging assessment should be performed 8 weeks (± 7 days) after the first dose of study 
treatment and then Q8W (± 7 days) for 12 months and then Q12W (± 7 days) thereafter until PD 
is determined. Imaging assessments may be done more frequently if clinically indicated. Imaging 
should not be delayed for delays in cycle starts. 
Repeated brain imaging during the treatment phase will be performed only if the screening brain 
imaging was positive or as clinically indicated. If indicated, brain imaging should occur at same 
time (± 2 weeks) as disease assessment scans. Whenever feasible, contrast-enhanced brain MRI 
is preferred to CT. 
Per RECIST v1.1, response should be confirmed by a repeat radiographic assessment not less 
than 4 weeks from the date that the response was first documented. The scan for confirmation of 
response may be performed at the earliest 4 weeks after the first indication of response or at the 
next scheduled scan, whichever is clinically indicated. 
Imaging should continue to be performed until documented PD, the start of new anticancer 
treatment, withdrawal of consent, death, or the end of the study, whichever occurs first. A central 
imaging vendor will not be used in this study. 
8.2.2. 
Health Economics 
Not applicable; health economics parameters are not evaluated in this study. 
8.3. 
Safety Assessments 
See Section 6.5 for guidelines regarding the management of relevant laboratory or other safety 
assessment abnormalities. 
8.3.1. 
Adverse Events 
Adverse events will be monitored from the time the participant signs the ICF until at least 
90 days after the last dose of study treatment regardless of the start of a new anticancer therapy. 
Adverse events for randomized participants that begin or worsen after informed consent should 
be recorded on the Adverse Events Form in the eCRF regardless of the assumption of a causal 
relationship with the study treatment. Conditions that were already present at the time of 
informed consent should be recorded on the Medical History Form in the eCRF. Adverse events 
(including laboratory abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible rather than by individual underlying signs and symptoms. 

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Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate). The investigator and any qualified designees are responsible for detecting, 
documenting, and recording events that meet the definition of an AE or SAE and remain 
responsible for following-up on AEs that are serious, considered related to the study 
treatment/procedures, or that caused the participant to discontinue the study treatment. Care will 
be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and nonleading 
verbal questioning of the participant, such as "How are you feeling?" is the preferred method to 
inquire about AE occurrences. Adverse events may also be detected when they are volunteered 
by the participant during the screening process or between visits or through physical 
examinations, laboratory tests, or other assessments. The definition, reporting, and recording 
requirements for AEs are described in Section 9. 
All SAEs will be reported to the sponsor or designee within 24 hours. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
8.3.2. 
Physical Examinations 
Physical examinations must be performed by a medically qualified individual, such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits. Abnormalities identified after the first dose of study treatment constitute an AE if they 
are considered clinically meaningful, induce clinical signs or symptoms, require concomitant 
therapy, or require changes in study treatment. Investigators should pay special attention to 
clinical signs related to previous serious illnesses. 
At the screening visit, a comprehensive physical examination should be conducted. The 
comprehensive physical examination will include height and body weight, and assessment(s) of 
the following organ or body systems: skin; head, eyes, ears, nose, and throat; thyroid; lungs; 
cardiovascular system; abdomen; extremities; and lymph nodes; as well as a brief neurological 
examination. 
During the study, participants will be assessed by the investigator or medically qualified 
designee per institutional SoC. These assessments should be an evaluation as indicated by 
participant symptoms, AEs, or other findings and documented on the AE eCRF. Body weight 
will also be assessed on Day 1 of each cycle. 
8.3.3. 
Vital Signs 
Vital sign measurements (to be taken before blood collection for laboratory tests), include blood 
pressure, pulse, respiratory rate, and body temperature at each required assessment timepoint. 
Vital signs will be monitored before and/or after study drug infusions as per Table 3 and 
Section 6.1. Blood pressure and pulse will be taken with the participant in the recumbent, 
semirecumbent, or sitting position after 5 minutes of rest. Abnormal vital sign results identified 
after the first dose of study treatment constitute an AE if they are considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study treatment. 

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8.3.4. 
Electrocardiograms 
Triplicate 12-lead ECGs will be obtained as outlined in Table 3 at screening, Day 1 of Cycles 1 
through 5, on Day 1 of every fourth cycle beginning at Cycle 9, at EOT, and as clinically 
indicated. All 12-lead ECGs will be performed with the participant in a recumbent or 
semirecumbent position after 5 minutes of rest. 
All 12-lead ECGs will be performed using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTc intervals. Triplicate ECGs require 3 individual 
ECG tracings obtained as closely as possible in succession and up to approximately 2 minutes 
apart. The 12-lead ECGs will be interpreted by the investigator at the site to be used for 
immediate participant management. Additional 12-lead ECGs may be performed as clinically 
indicated to manage participant safety. The decision to include or exclude a participant or 
discontinue a participant from the study treatment based on an ECG flagged as "Abnormal, 
Clinically Significant" is the responsibility of the investigator, in consultation with the medical 
monitor, as appropriate. Clinically notable abnormalities that are considered clinically significant 
in the judgment of the investigator are to be reported as AEs. In the event that a single QTc is 
> 460 milliseconds at screening, the participant may enroll if the average QTc for the 3 ECGs is 
≤ 460 milliseconds or with approval from the medical monitor. For participants with an 
intraventricular conduction delay (QRS interval > 120 milliseconds) at screening, the JTc 
interval may be used in place of the QTc with medical monitor approval. In addition, the JTc 
interval should be used for all subsequent assessments. 
8.3.5. 
Eastern Cooperative Oncology Group Performance Status 
The ECOG performance status will be assessed at the timepoints indicated in Table 3 according 
to the criteria in Table 13. 
Table 13: 
Eastern Cooperative Oncology Group Performance Status 
Grade 
ECOG Performance Status 
0 
Fully active, able to carry on all predisease 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 self-care but unable to carry out any work activities; up and about more 
than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
Source: Oken et al 1982. 
8.3.6. 
Laboratory Assessments 
See Table 14 for the list of clinical laboratory tests to be performed and Table 4 for the timing 
and frequency. A certified laboratory local to the investigative site will perform all clinical 
laboratory assessments for safety (ie, blood chemistries, hematology assessments, coagulation 
tests, lipid panel, thyroid function, serology, pregnancy testing, and urinalysis). The investigative 
site will enter the laboratory results and laboratory normal ranges into the eCRF. Additional 

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testing may be required by the sponsor based on emerging safety data. Additional tests may also 
be performed if clinically indicated. 
Clinically significant abnormal laboratory findings are those that are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
participant's condition. All laboratory tests with values considered clinically significantly 
abnormal during participation in the study or within 30 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
Screening laboratory assessments must be performed within 28 days before Cycle 1 Day 1. If 
screening chemistry and hematology analyses are performed within 7 days before initial 
administration of study treatment, they do not need to be repeated on Cycle 1 Day 1. 
Laboratory sample collection on Cycle 1 Day 1 must be performed before study treatment 
administration. After Cycle 1, predose laboratory procedures can be conducted up to 72 hours 
before study treatment administration (within the 3-day study window), and results should be 
reviewed by the investigator or qualified designee and found to be acceptable before a new cycle 
of treatment is initiated. 

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Table 14: 
Required Laboratory Analytes 
Blood Chemistries 
Hematology 
Urinalysis 
Serology 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Amylase 
Bicarbonate, CO2 or HCO3 (if clinically 
indicated) 
Blood urea nitrogen or urea 
Calcium 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
Lipase 
Phosphate 
Potassium 
Sodium 
Total bilirubin (also direct bilirubin, if total 
bilirubin is elevated above ULN) 
Total protein 
Troponin (TnT or TnI) level (per local 
standard) 
Uric acid 
Complete blood count, including: 
• Hemoglobin 
• Hematocrit 
• Platelet count 
• Red blood cell count 
• WBC count 
 
Differential count, including: 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
 
Absolute values must be provided for: 
• WBC differential laboratory results 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Urobilinogen 
Microscopic examination (if blood 
or protein is abnormal) 
HBV screening and management (required): 
• HbsAg 
• Total anti-HBc 
• Anti-HBs 
• HBV-DNA 
 
When applicable per investigator discretion: 
• IgM anti-HBc 
 
HCV screening: 
• HCV antibody 
• HCV-RNA quantitative 
 
HIV antibodies only if mandated by local 
health authorities or local regulations. 
 
HIV management (if HIV-positive): 
• HIV viral load 
• CD4+ cell count 
Lipids 
Coagulation 
Pregnancy Testing 
Total cholesterol 
Triglycerides 
LDL 
HDL 
PT 
PTT or aPTT 
INR 
Human chorionic gonadotropin (serum or 
urine) 
Thyroid Function 
TSH 
T4 
fT4 
FT3/T3 as clinically indicated 
Note: Additional laboratory analytes used for management of AEs/SAEs, ruling out a diagnosis, or participant management are permissible during the study. 
Note: Alternative tests to the above may be conducted instead or in addition if they are the SoC in a particular region. 
Note: Additional tests may be required, as agreed upon by the investigator and sponsor, based on emerging safety data, or based on regional geographical differences, or depending 
on the extent of COVID-19 pandemic. Relevant test results will be documented in eCRFs. 

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8.3.6.1. 
Urine Sample Collection 
Urine will be collected as a predose sample at screening, Cycle 2 Day 1, every 3 cycles 
thereafter, and at EOT (see Table 4). A urine dipstick analysis will be performed. If clinically 
significant abnormalities are observed, further analysis, including microscopic analysis, should 
be performed as clinically indicated. The Laboratory Manual should be consulted for more 
complete instructions. 
8.3.6.2. 
Pregnancy Testing 
A serum pregnancy test will be required for all WOCBP during screening and at the EOT visit. 
The serum pregnancy test performed at screening must be performed within 72 hours before the 
first dose of study treatment; the test performed at EOT is optional if the participant is going to 
hospice. Serum or urine pregnancy tests will be performed locally as outlined in Table 4, as 
medically indicated (eg, in case of loss of menstrual cycle, when pregnancy is suspected), or per 
country-specific requirements (note that country-required urine pregnancy testing will be 
outlined and communicated to investigational sites under separate cover). If a urine pregnancy 
test is positive, the results should be confirmed with a serum pregnancy test. 
If the serum pregnancy test is negative after a urine test was positive, the investigator will assess 
the potential benefit/risk to the participant and determine whether it is in the participant's best 
interest to resume study treatment and continue participation in the study. 
If a pregnancy is confirmed by a serum pregnancy test, see Section 9.7 for reporting 
requirements. 
8.3.6.3. 
Serology 
Hepatitis and HIV (if applicable) screening assessments will be performed at the screening visit 
(see Table 4) to rule out hepatitis and HIV infection (see Section 5.2); required analytes are 
shown in Table 14. Generally, hepatitis and HIV tests should be performed early in the screening 
process due to the length of time needed to obtain the results. Additional tests may be performed 
if clinically indicated. 
Note: HIV testing is not required unless mandated by the local health authority. 
8.4. 
Pharmacokinetic and Immunogenicity Assessments 
8.4.1. 
Blood Sample Collection 
Pharmacokinetic and ADA samples will be obtained at the visits indicated in Table 5. Timing of 
blood samples for the measurement of serum concentrations and ADAs of retifanlimab, 
INCAGN02385, and INCAGN02390 is specified in Table 15. Predose is defined as within 
24 hours before administration of study treatment. For predose PK draws, contents of prior meals 
may be recorded. Adjustments to the timing of blood sampling may be made based on emerging 
PK data. The exact date and time of each PK blood draw will be recorded in the eCRF. 
Instructions for sample preparation and shipping will be provided in the Laboratory Manual. 

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Table 15: 
Pharmacokinetic and Antidrug Antibody Sample Blood Sample Timing 
Study Visit 
Assessment 
Timing of Sample 
Cycle 1 Day 1 
PK and ADA 
• Preinfusion samples for all 3 agents prior to retifanlimab infusion 
PK 
• Immediately after retifanlimab infusion (≤ 10 min) 
• Immediately after INCAGN02385 infusion (≤ 10 min) 
• Immediately after INCAGN02390 infusion (≤ 10 min) 
Cycle 1 Day 8 
PK 
Untimed PK sample 
Cycle 1 Day 15 
PK and ADA 
Preinfusion of INCAGN02385/placebo andINCAGN02390/placebo 
PK 
Untimed PK sample of retifanlimab 
Cycle 2 Day 1 
PK and ADA 
Preinfusion samples for all 3 agents prior to retifanlimab infusion 
Cycle 4 Day 1 
PK and ADA 
Preinfusion samples for all 3 agents prior to retifanlimab infusion 
Cycle 6 Day 1a 
PK and ADA 
Preinfusion samples for all 3 agents prior to retifanlimab infusion 
EOT, 30-day, and 
90-day safety follow-up 
PK and ADA 
Untimed sample 
a PK and ADA measurements will continue on Day 1 of all even-number cycles, for example, Cycle 8 Day 1, Cycle 10 Day 1, 
etc. 
8.4.2. 
Immunogenicity (Antidrug Antibody) Assessments 
Blood samples will be assessed for antibodies binding to retifanlimab, INCAGN02385, and 
INCAGN02390, and the titer of confirmed positive samples will be reported. Other analyses may 
be performed to verify the stability of antibodies to retifanlimab, INCAGN02385, and 
INCAGN02390 and/or further characterize the immunogenicity of study drug. 
The detection and characterization of antibodies to retifanlimab, INCAGN02385, and 
INCAGN02390 will be performed using a validated assay method by or under the supervision of 
the sponsor or designee. All samples collected for detection of antibodies to study drugs will also 
be evaluated for concentration to enable interpretation of the antibody data. Antibodies may be 
further characterized and/or evaluated for their ability to neutralize the activity of the study drug. 
8.5. 
Pharmacodynamic and Translational Assessments 
Whole blood, plasma, and tumor tissue will be collected for assessments as outlined in Table 4 
and Table 16 to investigate biomarkers relevant for participant stratification, as well as changes 
in the peripheral blood of participants given INCAGN02385 with or without INCAGN02390 in 
combination with retifanlimab. Biomarker assessments beyond those listed may be evaluated at 
the discretion of the sponsor using excess biomarker or PK samples. Analyses will be conducted 
by the sponsor or its designee. 
For information regarding handling/shipping of specimens, refer to the Laboratory Manual. 

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Table 16: 
Biomarker/Translational Sample Timing 
Biomarker Assessment 
Study Visit 
Timing of Sample 
Anytime 
Preinfusion 
Fresh tumor biopsy/archival tissue 
Screening 
X 
 
EOTa 
X 
 
• Whole blood for flow cytometryb 
• Whole blood for PBMC 
• Plasma biomarker 
Cycle 1 Day 1 
 
X 
Cycle 1 Day 8 
X 
 
Cycle 1 Day 15 
 
X 
Cycle 2, Cycle 3, and Cycle 4 Day 1 
 
X 
Plasma cfDNA 
Cycle 1 Day 1 
X 
 
Cycle 3 Day 1 
X 
 
a If discontinuing treatment for PD (optional). 
b First 75 participants only. 
8.5.1. 
Tumor Tissue Collection 
A baseline tumor tissue sample, either fresh or archival, is required for all participants at 
screening for central determination of LAG-3 and PD-L1 (CPS) expression status, and HPV p16 
status (as applicable) if not determined locally. Archived tissue is acceptable if there is adequate 
sample available (preferably at least 1 tissue block or 30 slides; see Laboratory Manual for 
specifics) and the sample was collected after the completion of the most recent systemic therapy, 
after the participant has been diagnosed with recurrent or metastatic disease, and less than 
12 months prior to the date of screening. Fine needle aspirates are not acceptable. LAG-3 
expression will be assessed by IHC using an investigative test at a central laboratory. The tumor 
sample will be assessed for PD-L1 expression at a central laboratory using the PD-L1 IHC 22C3 
pharmDx assay (Agilent Technologies, Carpinteria, CA) and may be used for assessment of the 
tumor microenvironment by IHC or RNA analysis. 
Tissue biopsy samples will also be used to investigate molecular signatures associated with 
response or resistance to treatment with the study drug. DNA and/or RNA may be extracted from 
these samples to perform somatic mutation analysis, epigenetic analysis, and gene expression 
analysis. Tissue may also be examined by histology and IHC or by exploratory methods to 
evaluate markers of immune cell populations, growth, signaling, apoptosis, etc. that may be 
associated with safety, response, or resistance to treatment with the study drug. 
8.5.2. 
Whole Blood Correlative Flow Cytometry Assessments 
Whole blood correlative samples will be analyzed by flow cytometry to identify relevant changes 
in cell populations or in various markers expression by cell populations with treatment. Receptor 
occupancy for LAG-3, TIM-3, and PD-1 may be assessed by flow cytometry in a retrospective 
manner, following completion of the final study analysis. Other assays relevant to the objectives 
of the study may be performed based upon emerging data. 
8.5.3. 
Whole Blood for PBMC Assessments 
Whole blood PBMC samples will be analyzed by DNA and/or RNA profiling or similar methods 
to identify cell populations and changes in cell populations or expression by cell populations 

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with treatment. RNA analysis may include expression analysis by RNASeq or RNAscope 
analysis for specific gene expression. Immune cell subsets function may also be assessed using 
ex vivo restimulation assays. Other assays relevant to the objectives of the study may be 
performed based upon emerging data. 
8.5.4. 
Plasma Correlative Assessments 
A number of tumor and immune response–derived proteins can be shed from tumors or activated 
normal cells and released into the blood. Correlation of presence and abundance of certain 
proteins with clinical response may identify new approaches for predictive biomarkers in blood. 
Plasma analytes may include cytokines and other markers of inflammation and immune status, 
tumor markers, and markers of metabolism and nutritional status. Other assays relevant to the 
objectives of the study may be performed based on emerging data. 
8.5.5. 
Plasma cfDNA Assessments 
A sample of plasma will be collected for possible analysis of mutations identified in tumor 
biopsies using tumor circulating DNA. 
8.6. 
Unscheduled Visits 
Unscheduled study visits may occur at any time if medically warranted, including scheduled 
cycle visits in which a study treatment hold is indicated for toxicity purposes. Any assessments 
performed at those visits should be recorded in the eCRF. 
8.7. 
End of Treatment and/or Early Termination 
Once a participant permanently discontinues all study treatment (whether the participant is 
withdrawing from the study early or the participant has completed the study treatment period), 
the EOT visit should be conducted. If the EOT visit coincides with a regular study visit, the EOT 
evaluations will supersede those of that scheduled visit, and the data should be entered in the 
EOT visit in the eCRF. All EOT assessments should be completed within 3 days of the decision 
to discontinue study treatment. Should EOT visit occur ≤ 21 days after the final dose of study 
treatment, a separate 30-day safety follow-up visit is required and should be conducted according 
to Table 3, Table 4, and Table 5. The participant should be encouraged to return for the safety 
follow-up visits. If the EOT visit occurs > 21 days after the last dose of study treatment, only a 
single EOT/30-day safety follow-up visit is required, and all unique assessments for the EOT and 
30-day follow-up visit will be performed once. 
8.8. 
Follow-Up 
8.8.1. 
Safety Follow-Up 
The safety follow-up period starts once the participant discontinues study treatment. 
Approximately 30 days (± 7 days) and 90 days (± 7 days) after the EOT, participants are to 
attend a clinic visit for safety evaluation. Adverse events and SAEs must be reported up until 
1) at least 90 days after the last dose of study treatment regardless of the start of a new anticancer 
therapy or 2) until toxicities resolve, return to baseline, or are deemed irreversible, whichever is 
longer. 

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Reasonable efforts should be made to have the participant return for the follow-up visits and 
report any AEs that may occur during this period. If the participant cannot return to the site for 
the safety follow-up visit, the participant should be contacted by telephone or other methods of 
communication for assessment of any AEs; this contact should be documented in the source. 
If a participant is scheduled to begin a new anticancer therapy before the planned 30-day safety 
follow-up visit, the safety follow-up visit should be performed before a new anticancer therapy is 
started. Once a new anticancer therapy has been initiated, the participant will move into the 
survival follow-up period. 
8.8.2. 
Post-Treatment Disease Follow-Up 
Participants who discontinue study treatment for a reason other than disease progression will 
move into the disease status follow-up period and should be assessed by radiologic imaging to 
monitor disease status Q8W (± 7 days) from the first 12 months following the start of study 
treatment, and then Q12W (± 7 days) thereafter. Every effort should be made to collect 
information regarding disease status until: 
• The start of new anticancer therapy 
• Disease progression 
• Death 
• The end of the study 
8.8.3. 
Survival Follow-Up 
Once a participant has received the last dose of study treatment, has confirmed disease 
progression, or starts a new anticancer therapy, the participant moves into the survival follow-up 
period. The participant should be contacted by telephone, email, or visit at least Q12W 
(± 14 days) to assess for survival status until death, withdrawal of consent, the end of the study, 
or the participant is lost to follow-up, whichever occurs first. 
For participants who do not intend to return to the study investigator for their ongoing care, 
follow-up should be maintained by phone contact, participant records, and public 
records/databases at intervals of no longer than 12 weeks (± 14 days). Participants may be 
contacted for survival status at any time during the course of the study to support planned 
survival analyses. 
Participants may withdraw their consent at any time from any or all portions or periods of the 
study. Participants who withdraw consent for treatment and/or imaging are encouraged to remain 
on the noninvasive survival follow-up portion of the study. The procedures associated with this 
phase may be only telephone contacts to assess survival status and the current state of the 
participant's SCCHN. The noninvasive nature and societal benefit of survival follow-up should 
be explained to the participant by the site staff, particularly when discontinuing treatment and 
imaging. 

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9. 
ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
9.1. 
Definition of Adverse Event 
Adverse Event Definition 
• An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or 
not it is considered drug-related. 
• An AE can therefore be any unfavorable or unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
treatment. 
Additional Guidance for Events Meeting the Adverse Event Definition 
• Any safety assessments (eg, ECG, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the investigator 
(ie, not related to progression of underlying disease) are to be reported as an AE. 
• Abnormal laboratory test results are to be reported as an AE if they are considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes in 
study treatment. Whenever possible, a diagnosis (eg, anemia, thrombocytopenia) should be recorded 
in the eCRF rather than the abnormal laboratory test result (eg, low hemoglobin, platelet count 
decreased). 
• Exacerbation of a chronic or intermittent pre-existing condition/disease, including either an increase 
in the frequency and/or intensity of the condition, is to be reported as an AE. 
• New conditions detected or diagnosed after the start of study treatment administration are to be 
reported as an AE. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction are to be reported as 
an AE. 
• Signs and/or symptoms from dose administration errors of a study treatment (eg, overdose) or a 
concomitant medication are to be reported as an AE. 
• "Lack of efficacy," "disease progression," or "failure of expected pharmacological action" will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
• A condition that leads to a medical or surgical procedure (eg, endoscopy, appendectomy) will be 
reported as an AE if it occurs after obtaining informed consent. If the condition is present before 
entering the study, then it should be captured as medical history. 
• Pre-existing diseases or conditions with expected fluctuations in signs or symptoms should be 
reported as an AE only if the investigator judges the fluctuation to have worsened more than 
expected during study participation. 

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9.2. 
Definition of Serious Adverse Event 
If an event is not an AE per the definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death due 
to progression of disease). 
A serious adverse event is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term "life-threatening" in the definition of "serious" refers to an adverse drug experience that 
places the participant, in the opinion of the initial reporter, at immediate risk of death from the adverse 
experience as it occurs. This does not include an adverse drug experience that, had it occurred in a 
more severe form, might have caused death. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician's office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether hospitalization occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment or planned surgery (eg, stent replacement, hip surgery) is not 
considered an SAE. 
Hospitalization for medical interventions in which no unfavorable medical occurrence occurred 
(ie, elective procedures or routine medical visits) are not considered SAEs.  
d. Results in persistent or significant disability/incapacity 
• The term "disability" means a substantial disruption of a person's ability to conduct normal life 
functions. This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (eg, sprained ankle), that may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Is an important medical event 
An important medical event is an event that may not result in death, be immediately life-threatening, or 
require hospitalization but may be considered serious when, based on appropriate medical judgment, 
the event may jeopardize the participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in the above definition. Examples of such events include new invasive or 
malignant cancers (excluding the disease[s] under study), intensive treatment in an emergency 
department or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. Secondary malignancies should 
always be considered SAEs. 

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9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse 
Events 
Adverse Event and Serious Adverse Event Recording 
• An AE/SAE that begins or worsens after informed consent is signed should be recorded on the 
Adverse Event Form in the eCRF. AEs/SAEs should be reported for randomized participants, but 
only SAEs need to be reported for screen failure participants. For randomized participants, 
conditions that were present at the time informed consent was given should be recorded on the 
Medical History eCRF. For detailed information refer to the eCRF guidelines. 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory reports, and diagnostic reports) related to the event. 
• The investigator (or delegate) will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the investigator to send photocopies of the participant's medical records 
in lieu of completing the Adverse Event Form in the eCRF. 
• There may be rare instances when copies of medical records for certain cases are requested. In this 
case, all participant identifiers, with the exception of the participant number, will be redacted by the 
site staff on the copies of the medical records before submission. These records can be submitted to 
Incyte Pharmacovigilance by email/fax per the contact information listed in the Study Reference 
Manual. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will 
be documented as the AE/SAE. When a clear diagnosis cannot be identified, each sign or symptom 
should be reported as a separate AE/SAE. 
To the extent possible, each AE/SAE should be evaluated to determine the following: 
• The severity grade (CTCAE v5.0 Grade 1 to 5). See below for further instructions on the assessment 
of intensity. 
• Whether there is at least a reasonable possibility that the AE is related to the study treatment: 
suspected (yes) or not suspected (no). See below for further instructions on the assessment of 
causality. 
• The start and end dates, unless unresolved at the final safety follow-up visit. 
• The action taken with regard to study treatment as a result of the AE/SAE(s). 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per the SAE definition provided in Section 9.2. 
• The action taken with regard to the event. Note: If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on the Adverse Event Form, and the treatment 
should be specified on the appropriate eCRF (eg, Prior/Concomitant Medications, Procedures and 
Non-Drug Therapy). 

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Assessment of Intensity 
The severity of AEs will be assessed using CTCAE v5.0 Grades 1 through 5. If an event is not 
classified by CTCAE, the severity of the AE will be graded according to the scale below to estimate the 
grade of severity. 
The investigator will make an assessment of intensity for each AE and SAE reported during the study 
and assign it to 1 of the following categories: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment 
not indicated. 
• Grade 2: Moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate 
activities of daily living. 
• Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. 
• Grade 4: Life-threatening consequences; urgent treatment indicated. 
• Grade 5: Fatal. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study treatment and each occurrence 
of each AE/SAE. If appropriate, the relationship to each study drug must be assessed, and the 
relationship to the combination may be assessed as well. 
• A "reasonable possibility" of a relationship conveys that there are medical facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled out. 
• The investigator will use clinical judgment to determine the possibility of a relationship. 
• The investigator will also consult the RSI in the IBs in making his/her assessment. 
• Alternative causes, such as underlying or concurrent disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration, will be 
considered and investigated. 
• For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• With regard to assessing causality of SAEs: 
− There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report. However, the causality assessment is one of the criteria 
used when determining regulatory reporting requirements. Therefore, it is very important that 
the investigator always make an assessment of causality based on the available information 
for every event before the initial transmission of the SAE. 
− The investigator may change his/her opinion of causality in light of follow-up information and 
submit the updated causality assessment. 

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Follow-Up of Adverse Events and Serious Adverse Events 
• The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the sponsor to elucidate the nature 
and/or causality of the AE or SAE as fully as possible. This may include additional laboratory tests 
or investigations, histopathological examinations, or consultation with other health care 
professionals. 
• Once an AE is detected, it should be followed in the AE eCRFs until it has resolved or until it is 
judged to be permanent; assessment should be made at each visit (or more frequently if necessary) of 
any changes in severity, the suspected relationship to the study treatment, the interventions required 
to treat the event, and the outcome. 
• When the severity of an AE changes over time for a reporting period (eg, between visits), each 
change in severity will be reported as a separate AE. 
• Updated SAE information will be recorded in the originally completed eCRF and reported to Incyte 
Pharmacovigilance (in the SAE EDC CRF) until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up. 
• Any updated SAE data (including SAEs being downgraded to nonserious) will be submitted to the 
sponsor (or designee) within 24 hours of receipt of the information. 
9.4. 
Reporting of Serious Adverse Events 
Regardless of suspected causality (eg, relationship to study treatment or study procedures), all 
SAEs occurring after the participant has signed the ICF through at least 90 days after the last 
dose of study treatment, regardless of the start of a new anticancer therapy, must be reported to 
the sponsor (or designee) within 24 hours of learning of its occurrence unless otherwise specified 
by the Protocol. The investigator will submit any updated SAE data to the sponsor (or designee) 
within 24 hours of it being available. 
Investigators are not obligated to actively seek SAE information after the safety follow-up visit 
or 90 days after the last dose of study treatment. If the investigator learns of any SAE, including 
a death, at any time during the disease status follow-up or survival status follow-up period, and 
he/she considers the event to be reasonably related to the study treatment or study participation, 
the investigator must notify the sponsor (or designee) within 24 hours of becoming aware of the 
event. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and irAEs (as defined in Section 6.5.3) will be followed 
until resolution, stabilization, the event is otherwise explained, or the participant is lost to 
follow-up (as defined in Section 7.3). 
Prompt notification by the investigator to the sponsor regarding an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a study 
treatment under clinical investigation are met. 
If the SAE is not documented in the RSI of the IB for any of the study drugs (new occurrence; 
refer to retifanlimab IB, INCAGN02385 IB, and INCAGN02390 IB) and is thought to be related 
to the study treatment, the sponsor or its designee may urgently require further information from 
the investigator for expedited reporting to health authorities. The sponsor or its designee may 
need to issue an Investigator Notification to inform all investigators involved in any study with 

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the same drug that this SAE has been reported. Suspected unexpected serious adverse reactions 
will be collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC, EU CTR No. 536/2014, and FDA 21 CFR Part 312 or as 
per national regulatory requirements in participating countries. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate, according to local requirements. 
Serious Adverse Event Reporting 
• Information about all SAEs is collected and recorded on the Adverse Event Form in the eCRF. 
• The investigator must report within 24 hours of learning of its occurrence any SAE via the EDC 
system (primary method) or by completing the Serious Adverse Event Report Form in English (only 
if the EDC system is not available. The contact information for Incyte Pharmacovigilance by 
email/fax is listed in the Study Reference Manual or as per the Incyte Reference Guide for 
Completing the Serious Adverse Event Report Form). 
• In circumstances where the EDC system is not accessible for reporting SAE information (initial 
and/or follow-up SAE information) to the sponsor within 24 hours, refer to the Incyte Reference 
Guide for Completing the Serious Adverse Report Form. Once the EDC system is functional, the 
SAE report should be retrospectively added to the EDC system and follow-up should be completed 
through the EDC. The original copy of the Serious Adverse Event Report Form and the email or 
facsimile confirmation sheet must be kept at the study site (refer to the Incyte Reference Guide for 
Completing the Serious Adverse Report Form or Study Reference Manual for details and for the 
email address or fax number). 
• Follow-up information is also recorded in the eCRF and transmitted to Incyte Pharmacovigilance via 
the EDC system. The follow-up report should include information that was not provided previously, 
such as the outcome of the event, treatment provided, action taken with study treatment because of 
the SAE (eg, dose reduced, interrupted, or discontinued), or participant disposition (eg, continued or 
withdrew from study participation). Each recurrence, complication, or progression of the original 
event should be reported as follow-up to that event, regardless of when it occurs. 
9.5. 
Events of Clinical Interest 
No specific AEs are expected to be sent to the sponsor within an expedited manner aside from 
the AEs that meet the seriousness category as described in Section 9.4. 
Immune-related AEs will be identified by investigator assessment as well as using sponsor-
predefined preferred terms based on the ICI class regardless of investigator's assessment of 
causality. Both investigator assessed and sponsor-assessed irAEs will be summarized. 

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9.6. 
Emergency Unblinding of Treatment Assignment 
In a medical emergency, if knowledge of the treatment assignment is necessary to determine 
optimal medical management of the participant, the procedure for emergency unblinding is 
provided in the IRT Manual. This option may be used only if the participant's well-being requires 
the investigator to be aware of the participant's treatment assignment. If a participant's treatment 
assignment is unblinded, the sponsor or its designee must be notified immediately by telephone. 
If an investigator, the site personnel performing assessments, or a participant is unblinded, then 
the participant must discontinue study treatment unless there are ethical reasons to have the 
participant remain on the study treatment. In these cases, the investigator must obtain specific 
approval from the sponsor's (or its designee's) medical monitor for the participant to continue in 
the study. 
9.7. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that the study 
treatment may have interfered with the effectiveness of a contraceptive medication or method. 
When a pregnancy has been confirmed in a participant during maternal or paternal exposure to 
study treatment, the following procedures should be followed in order to ensure safety: 
• The study treatment must be interrupted immediately (female participants only). 
• If the female participant is no longer pregnant and meets the treatment continuation 
criteria within 28 days of the scheduled start of a cycle, study treatment may be 
resumed after approval has been received from the sponsor's medical monitor. 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy Form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
Data on fetal outcome are collected for regulatory reporting and drug safety evaluation. 
Follow-up should be conducted for each pregnancy to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications, by following until the first 
well-baby visit. Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported 
by the investigator to the sponsor or its designee. Pregnancy follow-up information should be 
recorded on the same form and should include an assessment of the possible causal relationship 
to the sponsor's study drug to any pregnancy outcome, as well as follow-up to the first well-baby 
visit or the duration specified in local regulations, whichever is later. Refer to the Incyte 
Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy of a study participant must be recorded on the 
Serious Adverse Event Report Form and submitted to the sponsor or its designee. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, or ectopic pregnancy) are considered SAEs (if occurring in the study participant) and 
must be reported as described in Section 9.4. If an abnormal pregnancy outcome is reported in a 
study participant's partner, the event should be reported to the sponsor on the Clinical Trial 
Pregnancy Form. 

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9.8. 
Warnings and Precautions 
Special warnings or precautions for the study treatment, derived from safety information 
collected by the sponsor or its designee, are presented in the IBs. Additional safety information 
collected between IB updates will be communicated in the form of Investigator Notifications. 
Any important new safety information should be discussed with the participant during the study 
as necessary. If new significant risks are identified, they will be added to the ICF. 
9.9. 
Product Complaints 
The sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor. All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 
The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint via email or other written communication to the sponsor contact or respective 
manufacturer as noted in the packaging information. Any AE associated with a product 
complaint should be recorded as described in Section 9.3. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 
9.10. 
Treatment of Overdose 
For retifanlimab, a dose > 1500 mg within a 24-hour time period will be considered an overdose. 
In the event of an overdose of retifanlimab, the following should occur: 
• Appropriate supportive treatment should be provided if clinically indicated. 
• The investigator should contact the medical monitor immediately and closely monitor 
the participant for any AEs/SAEs and laboratory abnormalities per Section 9.3. 
• The quantity of the excess dose as well as the duration of the overdose should be 
documented in the eCRF. 
Decisions regarding dose interruptions will be made by the investigator in consultation with the 
medical monitor based on the clinical evaluation of the participant. 
There has been no clinical experience with overdose of INCAGN02385 or INCAGN02390. 
Treatment of overdose should consist of general supportive measures. 

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10. 
STATISTICS 
This section outlines the statistical analysis strategy and procedures for this study. If changes are 
made to primary efficacy and safety and/or secondary efficacy hypotheses or the statistical 
methods related to those hypotheses after the study has begun, but before the final database lock, 
the Protocol will be amended, consistent with ICH E9 (1998) and ICH E9 (R1; 2021). The 
detailed statistical analyses will be documented in the Statistical Analysis Plan. 
10.1. 
Sample Size Determination 
The sample size calculation is based on the primary endpoint of PFS. Approximately 
162 participants will be randomized in a 1:1:1 ratio into TG1:TG2:TG3. The study is 
event-driven and will be complete after approximately 94 PFS events have been observed 
between TG1 and TG2 or between TG1 and TG3 (approximately 140 PFS events across the 
3 treatment groups). Based on a target of 94 PFS events for all participants at the final analysis 
between TG1 and TG2 or between TG1 and TG3 (approximately 140 PFS events across the 
3 treatment groups), which is expected to occur about 20 months from the start of enrollment, the 
study has approximately 80% power to detect an HR of 0.6 at an overall alpha level of 5% 
(1-sided) favoring one of the combination therapies with the assumption of study parameters as 
specified in Table 17 for PFS. 
The sample size and power calculations were performed in R package "gsDesign." 
Table 17: 
Sample Size Assumptions for Progression-Free Survival 
Variable 
Assumptions 
Median PFS in TG1 (All participants) 
3 monthsa 
Randomization ratio 
1:1:1 
Assumed HR (All participants) 
0.6 
Enrollment duration 
12 months 
Follow-up for PFS  
8 months 
Assumed annual dropout rate 
1% 
a Burtness et al 2019. 
10.2. 
Populations for Analyses 
Table 18 presents the populations for analysis. 

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Table 18: 
Populations for Analyses 
Population 
Description 
ITT 
All randomized participants. Treatment groups for this population are 
determined according to the treatment they have been assigned at the time of 
randomization. 
The ITT population will be used for the summary of demographics, baseline 
characteristics, participant disposition, and analyses of all efficacy data. 
Safety 
The safety population includes all randomized participants who receive at 
least 1 dose of study treatment. Treatment groups for this population will be 
determined according to the actual treatment the participant received 
regardless of assigned treatment at the time of randomization. 
All safety analyses will be conducted using the safety population.  
PK/pharmacodynamic 
evaluable 
The PK evaluable population will include all participants who received at 
least 1 dose of study treatment and provided at least 1 postdose serum sample 
(1 PK measurement). 
The pharmacodynamic evaluable population will include all participants who 
received at least 1 dose of study treatment and provided at least 1 postdose 
plasma sample (1 pharmacodynamic measurement). 
ADA 
The ADA-evaluable population comprises all participants who received at 
least 1 dose of study treatment and provided at least 1 ADA postdose sample. 
Table 19 shows how the analysis population is associated with the endpoints. 
Table 19: 
Endpoints and Analysis Populations 
Primary/Secondary 
Endpoint 
Population 
Hypothesis 
Population-Level 
Summary Metric 
PFS 
ITT 
Hypothesis 1: TG3 is superior to 
TG1 with respect to PFS in all 
participants 
Hypothesis 2: TG2 is superior to 
TG1 with respect to PFS in all 
participants 
HR 
OS 
ITT 
NA 
HR 
Objective response  
ITT 
NA 
ORR difference 
Disease control  
ITT 
NA 
DCR difference 
DOR 
ITTa 
NA 
Median DOR 
AEs 
Impact on study treatment 
Safety 
NA 
Rate  
a Responder subpopulation. 

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10.3. 
Level of Significance 
For the primary endpoint, the overall 1-sided alpha level will be strongly controlled 10%, with an 
initial 1-sided alpha allocation for each hypothesis at 5% (refer to SAP). The detailed 
multiplicity control will be specified in the Protocol Section 10.6. Unless otherwise stated, all 
CIs provided will be reported at a 95% confidence level. 
10.4. 
Statistical Analyses 
10.4.1. 
Primary Analysis 
Progression-free survival, defined as the time from the date of randomization to the date of the 
first documented progression or death due to any cause, whichever occurs first. Progression-free 
survival will be based on investigator assessment per RECIST v1.1. Survival data will be 
analyzed by the Kaplan-Meier method, treating participants with no observed death or disease 
progression as censored. Censoring for PFS will follow the primary analysis algorithm outlined 
in Table 20, which is based on regulatory guidelines (FDA 2015). 
Table 20: 
Evaluation and Censoring of Progression-Free Survival 
Situation 
Primary Analysis 
Sensitivity Analysis 1 
Sensitivity Analysis 2 
No valid postbaseline 
response assessments in 
the absence of death 
prior to first scheduled 
tumor assessment 
Censored at date of 
randomization 
Censored at date of 
randomization 
Censored at date of 
randomization 
Progression 
documented between 
scheduled visits 
Progressed at date of 
first overall response of 
PD 
Progressed at date of 
first overall response of 
PD 
Progressed at date of 
first overall response of 
PD 
Death before first PD 
assessment 
Progressed at date of 
death 
Progressed at date of 
death 
Progressed at date of 
death 
No PD and no death; 
new anticancer 
treatment is not 
initiated 
Censored at last disease 
assessment 
Censored at last disease 
assessment 
Censored at last disease 
assessment if still on 
study therapy; 
progressed at treatment 
discontinuation 
otherwise 
No PD and no death; 
new anticancer 
treatment is initiated 
Censored at last disease 
assessment before new 
anticancer treatment 
Censored at last disease 
assessment before new 
anticancer treatment 
Progressed at date of 
new anticancer 
treatment 
No PD and no death; 
after ≥ 2 missed disease 
assessments 
Censored at last disease 
assessment prior to the 
≥ 2 missed disease 
assessment 
Censored at last disease 
assessment 
Censored at last disease 
assessment 

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Table 20: 
Evaluation and Censoring of Progression-Free Survival (Continued) 
Situation 
Primary Analysis 
Sensitivity Analysis 1 
Sensitivity Analysis 2 
PD or death 
documented after 
≤ 1 missed disease 
assessment 
Progressed at date of 
documented PD or 
death 
Progressed at date of 
documented PD or 
death 
Progressed at date of 
documented PD or 
death 
PD or death 
documented after 
≥ 2 missed disease 
assessments 
Censored at last disease 
assessment prior to the 
≥ 2 missed disease 
assessment 
Progressed at date of 
documented PD or 
death 
Progressed at date of 
documented PD or 
death 
The stratified log-rank test will be used to compare PFS between treatment groups in the ITT at a 
1-sided 5% significance level, stratified for LAG-3 expression status (≥ 5% vs < 5%), PD-L1 
CPS (1%-19% vs ≥ 20%), and HPV p16 status (p16-positive vs p16-negative, oropharyngeal 
only). The strata identified in the randomization process will be used for the analysis. 
The HR and its 95% CI will be estimated based on the stratified Cox regression model using the 
same stratification factors as for the log-rank test with Efron's method accounting for ties in 
event times (1977). 
Kaplan-Meier curves for PFS will be presented by treatment groups. The Kaplan-Meier estimate 
of median PFS will be presented with its 95% CI. The 95% CI will be calculated using the 
generalization of Brookmeyer and Crowley's method (1982) with log-log transformation 
(Klein and Moeschberger 1997). 
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment at which PD was not documented and the assessment when PD is 
documented. In order to evaluate the robustness of the PFS endpoint per RECIST v1.1 based on 
investigator review, 2 sensitivity analyses with a different set of censoring rules will be 
performed. For the first sensitivity analysis, participants who miss more than 1 disease 
assessment are not handled differently from participants who miss 0 or 1 disease assessment 
(ie, the status depends on if there is PD or death). 
The second sensitivity analysis handles participants who discontinue treatment or initiate an 
anticancer treatment subsequent to discontinuation of study-specified treatments differently from 
the primary analysis. The censoring rules for these 2 sensitivity analyses are also summarized in 
Table 20. Within each analysis, if a participant meets multiple criteria for censoring, the 
censoring criterion that occurs earliest will be applied. 
10.4.2. 
Secondary Analysis 
10.4.2.1. Objective Response Rate 
Objective response is a key secondary objective and will be determined by investigator 
assessment per RECIST v1.1. Objective response rate is defined as the proportion of participants 
with a CR or PR as best objective response. 
The stratified CMH test will be used for comparison of ORR between treatment groups in the 
ITT population. The strata identified in the randomization process will be used for the analysis. 

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Estimates of ORR along with its exact 95% CIs using the Clopper-Pearson method will be 
computed for each treatment group. The odds ratio and its 95% CIs calculated from the stratified 
CMH test will also be presented. 
10.4.2.2. Disease Control Rate 
Disease control rate is defined as the proportion of participants with a CR, PR, or SD 
(≥ 6 months) as the best objective response based on investigator assessment per RECIST v1.1. 
The stratified CMH test will be used for comparison of DCR between treatment groups in the 
ITT population. The strata identified in the randomization process will be used for the analysis. 
Estimates of DCR along with its exact 95% CIs using the Clopper-Pearson method will be 
computed for each treatment group. The odds ratio and its 95% CIs calculated from the stratified 
CMH test will also be presented. 
10.4.2.3. Duration of Response 
Duration of response is a key secondary objective defined as the time from earliest date of 
disease response (CR or PR) until earliest date of disease progression as determined by 
investigator assessment per RECIST v1.1, or death from any cause, if occurring sooner than 
progression. Participants with no observed death or disease progression will be censored. 
Censoring for DOR will follow the algorithm outlined in Table 20. If a participant meets 
multiple criteria for censoring, the censoring criterion that occurs earliest will be applied. 
Kaplan-Meier estimation of median DOR and its 95% CIs will be presented by treatment group 
for participants who achieve an objective response. 
10.4.2.4. Overall Survival 
Overall survival is defined as the time from the date of randomization to the date of death due to 
any cause. The primary efficacy analysis comparing the 2 treatment groups will be a stratified 
log-rank test at an allocated overall 1-sided level of significance. The stratification will be based 
on the randomization stratification factors listed in Section 4.1 and based on the ITT population 
according to the randomized treatment group and strata assigned at randomization. Kaplan-Meier 
curves, medians, and 95% CIs of the medians will be presented for each treatment group. The 
HR for OS will be calculated, along with its 95% CI, from a stratified Cox model using the same 
stratification factors as for the log-rank test with Efron's likelihood approximation to account for 
ties in event times. Participants without documented death at the time of analysis will be 
censored at the date of last known contact. Analysis using the restricted mean survival time 
method may be conducted for OS to account for the possible nonproportional hazards effect. 
10.4.3. 
Overall Efficacy Conclusions 
The overall efficacy conclusions from the study will be based on the totality of the efficacy 
endpoint analysis. 
10.4.4. 
Safety Analyses 
Safety analyses will be conducted for the safety population. 

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All TEAEs, clinical laboratory measurements, vital sign measurements, and ECG values will be 
summarized by treatment group. Quantitative safety variables and their changes from baseline 
(laboratory, vital signs, and ECG values) will be summarized with descriptive statistics. 
Abnormal values outside of established ranges will be flagged and tabulated based on predefined 
criteria. 
Measures of exposure (eg, days of exposure, dose modification, dose intensity) of study drug 
will be summarized descriptively. 
Adverse events will be coded by the MedDRA dictionary and severity of AEs will be based on 
the NCI CTCAE v5.0 using Grades 1 through 5. A TEAE is defined as an AE either reported for 
the first time or worsening of a pre-existing event after first dose of study drug and within 
90 days of the last dose. The number and percentage (%) of participants reporting any TEAEs, 
any serious TEAEs, any Grade 3 or higher TEAEs, any treatment-related TEAEs, any 
treatment-related serious TEAEs, any treatment-related Grade 3 or higher TEAEs, any fatal 
TEAEs, and any TEAEs leading to treatment interruption/discontinuation will be tabulated by 
MedDRA system organ class and preferred term. Data listings will include all AEs regardless of 
their timing to study drug administration. Adverse events of clinical interest will be summarized 
as detailed in the SAP. 
The clinical laboratory data will be analyzed using summary statistics; no formal treatment group 
comparisons are planned. In addition, distributions of key laboratory parameters may be plotted 
over time; these values will also be classified into CTCAE toxicity grades when applicable and 
tabulated. 
Descriptive statistics and mean change from baseline will be determined for vital signs at each 
assessment time. The abnormal values for participants exhibiting vital sign abnormalities will be 
listed. 
The abnormal values for participants exhibiting ECG abnormalities will be listed. 
10.4.5. 
Pharmacokinetic Analysis 
10.4.6. 
Exploratory Analysis 

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10.5. 
Interim Analysis 
No formal efficacy interim analysis is planned for this study. However, DSMB-related activities 
are routinely conducted. One interim analysis to review safety will occur as outlined in 
Section 5.6. 
10.6. 
Multiplicity Control 
The study uses the graphical method of Maurer and Bretz (Maurer and Bretz 2013) to strongly 
control type I error for multiple hypotheses. A graphical display of the plans for reallocation of 
alpha is displayed in Figure 7 using the initial 1-sided alpha allocation for each hypothesis in the 
ellipse representing the hypothesis. The weights for reallocation from each hypothesis to the 
others are represented in the boxes on the lines connecting the hypothesis. The detailed 
information for each hypothesis about the bounds and boundary properties for the final analysis 
for different alpha level due to the alpha reallocation will be tabulated in SAP. 
Figure 7: 
Multiplicity Graph for 1-Sided Alpha Reallocation Strategy 
 
10.7. 
Subgroup Analyses 

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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
11.1. 
Investigator Responsibilities 
• The Protocol, Protocol amendments, ICF, IB, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC and health authorities before the study is 
initiated. In accordance with EU CTR No. 536/2014, the sponsor will be responsible 
for submitting all documents in participating countries. 
• The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements, the 
policies and procedures established by the IRB/IEC, and institutional requirements. 
• Any amendments to the Protocol will require approval from both health authorities 
and IRB/IEC before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to study participants. 
• The investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
− Providing oversight of the conduct of the study at the site and adherence to GCP, 
IRB/IEC requirements, institutional requirements, and applicable laws and 
country-specific regulations. 
− Ensuring study-site compliance with the requirements of EU CTR No. 536/2014. 
• Adhering to the Protocol as described in this document and agreeing that changes to 
the Protocol procedures, with the exception of medical emergencies, must be 
discussed and approved, first, by the sponsor or its designee and, second, by the 
IRB/IEC. Each investigator is responsible for enrolling participants who have met the 
specified eligibility criteria. 
• Retaining records in accordance with all local, national, and regulatory laws but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
− The investigator must not destroy any records associated with the study without 
receiving approval from the sponsor. The investigator must notify the sponsor or 
its designee in the event of accidental loss or destruction of any study records. If 
the investigator leaves the institution where the study was conducted, the sponsor 
or its designee must be contacted to arrange alternative record storage options. 

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− All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations. 
The sponsor will retain the original eCRF data and audit trail. 
11.1.1. 
Identification of the Coordinating Principal Investigator 
A coordinating principal investigator will be appointed by the sponsor before the end of the 
study. As part of his or her responsibilities, the coordinating principal investigator will review 
the final CSR. Agreement with the final CSR will be documented by the dated signature of the 
coordinating principal investigator. 
11.2. 
Data Management 
Data management will be performed in a validated EDC system. The investigator will be 
provided with access to an EDC system so that an eCRF can be completed for each participant. 
The site will be provided with eCRF completion guidelines for instructions on data entry in the 
eCRF. The study monitor will reference the Monitoring Plan in order to ensure that each issue 
identified is appropriately documented, reported, and resolved in a timely manner in accordance 
with the plan's requirements. Other data outside the EDC system required in the study conduct of 
the Protocol such as documents or results transmitted to the sponsor via a central laboratory or 
specialized technical vendors and, as designated by the sponsor, will have their own data flow 
management plans, study charters, or biomarker plans, as applicable. 
The sponsor (or designee) will be responsible for: 
• Managing the integrity of the data and the quality of the conduct of the study, such as 
ensuring that study monitors perform ongoing source data verification to confirm that 
data entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved Protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• Managing and reconciling the data generated, and/or collected including documents 
and results such as laboratory or imaging data analyzed centrally by a designated 
vendor of the sponsor. 
The investigator will be responsible for: 
• Recording, or ensuring the recording of, all relevant data relating to the study in the 
eCRF. 
• Delivering, or ensuring the delivery of, all other results, documents, data, know-how, 
or formulas relating to the study to the sponsor or designee electronically and/or 
centrally (eg, laboratory data, imaging data, biomarker data, photographs, diary data), 
or as otherwise specified in the Protocol. 

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• Maintaining adequate and accurate source documents and trial records that include all 
pertinent observations on each of the site's trial participants. Source data should be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, should not obscure the original entry, and should be 
explained if necessary (eg, via an audit trail). Source data are in general all 
information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source 
documents (original records or certified copies). 
• Verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 
• Maintaining accurate documentation (source data) that supports the information 
entered in the eCRF, or sent to a central vendor designated by the sponsor, or as 
described in other study and data flow manuals. 
− Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed and 
available at the investigator's site. Examples of source documents are original 
documents, data, and records (eg, hospital records; electronic hospital records; 
clinical and office charts; laboratory notes; memoranda; participants' diaries or 
evaluation checklists; pharmacy dispensing records; recorded data from 
automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiches; photographic negatives; microfilm or 
magnetic media; x-rays; participants' files; and e-records/records kept at the 
pharmacy, at the laboratories and at medico-technical departments involved in the 
clinical trial). 
− Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, 
depending on the study. Current applicable medical records must be available. 
• Sending participants' data, either as unique samples, or copies, or photographs, to be 
evaluated centrally or analyzed centrally, or both, by a qualified vendor designated by 
the sponsor. 
• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring: Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan. The 
investigator must allow the study monitors to review any study materials and 
participant records at each monitoring visit. 

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− Auditing: Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct. The 
investigator must allow the auditors to review original source records and study 
documentation for all participants. 
− Regulatory inspection: Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product. The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other 
study-related documents. The investigator must immediately notify the sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection. 
11.3. 
Data Quality Assurance 
The sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations). The sponsor or designee is responsible for the data management of this 
study, including quality checking of the data. Further, monitoring details describing strategy, 
including definition of study-critical data items and processes (eg, risk-based initiatives in 
operations and quality such as risk management and mitigation strategies and analytical 
risk-based monitoring), methods, responsibilities, and requirements, including handling of 
noncompliance issues, Protocol deviations, and monitoring techniques (eg, central, remote, or 
on-site monitoring) are provided in the monitoring plan. 
Quality tolerance limits will be predefined in the operational manual or equivalent to identify 
systematic issues that can impact participants' safety, efficacy results and analysis, and/or 
reliability of study results. These predefined parameters will be monitored during the study and 
can be adjusted during the study upon data review. Important deviations from the quality 
tolerance limits and remedial actions taken, including reporting to IRBs/IECs and health 
authorities if applicable, will be summarized in the CSR. 
11.4. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data protection laws 
and regulations. The investigator and the sponsor or its designee are responsible for ensuring that 
personal information is handled in accordance with local data protection laws (including but not 
limited to HIPAA and GDPR) as applicable, and the sponsor operates comprehensive data 
privacy and data security programs that are applicable to this study. Appropriate notice, or notice 
consent (as may be required by each applicable jurisdiction), for collection, use, disclosure, 
and/or transfer (if applicable) of personal information must be obtained in accordance with local 
data protection laws. Appropriate data protection terms that comply with applicable laws will be 
included in relevant study agreements. 
To ensure confidentiality of records and protect personal data, participant names will not be 
supplied to the sponsor or its designee. Only the participant number will be recorded in the 
eCRF; if the participant's name appears on any other document (eg, laboratory report), it must be 
obliterated on the copy of the document to be supplied to the sponsor or its designee. Study 

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findings stored on a computer will be stored in accordance with appropriate technical and 
organizational measures as required by local data protection laws. 
 In the event of a data breach involving participant data, the sponsor or its designee will follow 
the sponsor's incident response procedures. The precise definition of a data breach varies in 
accordance with applicable law but may generally be understood as a breach of security leading 
to the accidental or unlawful destruction, loss, alteration, unauthorized disclosure of, or access to, 
personal data. In accordance with its incident response procedures, the sponsor will assess the 
breach to consider its notification and remediation obligations under applicable law. 
11.5. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 CFR Part 54 – Financial Disclosure by Clinical Investigators (ie, "covered 
studies") are required to submit a completed Clinical Investigator Financial Disclosure form that 
sufficiently details any financial interests and arrangements that apply. For the purpose of this 
regulation, "clinical investigator" is defined as any investigator or subinvestigator who is directly 
involved in the treatment or evaluation of research participants, including the spouse and each 
dependent child of the clinical investigator or subinvestigator. These requirements apply to both 
US and foreign clinical investigators conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Investigator Financial Disclosure Form. During a covered clinical study, any 
changes to the financial information previously reported by a clinical investigator must be 
reported to the sponsor or its designee. At the conclusion of the covered clinical study, the 
clinical investigators will be reminded of their obligations. In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
11.6. 
Publication Policy 
By signing the study Protocol, the investigator and his/her institution agree that the results of the 
study may be used by the sponsor, Incyte Biosciences International Sàrl (Incyte), for the 
purposes of national and international registration, publication, and information for medical and 
pharmaceutical professionals. Study results will be published in accordance with applicable local 
and national regulations. If necessary, the authorities will be notified of the investigator's name, 
address, qualifications, and extent of involvement. The terms regarding the publication of study 
results are contained in the agreement signed with the sponsor or its designee. A signed 
agreement will be retained by the sponsor or its designee. 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 

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Authorship will be determined in line with International Committee of Medical Journal Editors 
authorship requirements. 
11.7. 
Study and Site Closure 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the Protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines. 
• Inadequate recruitment of participants by the investigator. 
• Discontinuation of further study treatment development. 

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12. 
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS AND DEFINITIONS 
Definitions 
WOCBP: A woman who is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below) 
Women in the following categories are not considered WOCBP: 
• Premenarchal 
• Premenopausal with 1 of the following:a 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
• Postmenopausal 
− A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. 
o A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range is required. 
− Females on HRT and whose menopausal status is in doubt will be required to use 1 of the nonhormonal, 
highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment. 
For male participants of reproductive potentialb 
The following methods during the Protocol-defined timeframe in Section 5.1 are highly effective: 
• Use of a male condom plus partner use of an additional contraceptive method when having penile-vaginal 
intercourse with a woman of childbearing potential who is not currently pregnant 
• Vasectomy with medical assessment of the surgical success (verified by site personnel's review of the 
participant's medical records) 
• Sexual abstinencec 
− Abstinence from penile-vaginal intercourse 
The following are not acceptable methods of contraception: 
• Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method. 
• Male condom with cap, diaphragm, or sponge with spermicide. 
• Male and female condom used together. 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal 
intercourse or use a male condom during each episode of penile penetration. 

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For female participants who are WOCBP 
The following methods during the Protocol-defined timeframe in Section 5.1 that can achieve a failure rate of less 
than 1% per year when used consistently and correctly are considered as highly effective birth control methods: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation.d 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulationd 
− oral 
− injectable 
− implantablee 
• Intrauterine devicee 
• Intrauterine hormone-releasing systeme 
• Bilateral tubal occlusione 
• Vasectomized partnere,f 
• Sexual abstinencec 
a Documentation can come from the site personnel's review of the participant's medical records, medical examination, or medical 
history interview. 
b If the male participant has a partner with childbearing potential, the partner should also use contraceptives. 
c In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the 
participant. 
d Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may reduce the 
efficacy of the contraception method. 
e Contraception methods that in the context of this guidance are considered to have low user dependency. 
f Vasectomized partner is a highly effective method of avoiding pregnancy provided that partner is the sole sexual partner of the 
WOCBP study participant and that the vasectomized partner has received medical assessment of the surgical success. 
Source: Clinical Trials Facilitation and Coordination Group (2020). 

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APPENDIX B. TEST FOR LAG-3 EXPRESSION 
The IHC assay for LAG-3 expression was developed and validated at Neogenomics laboratories. 
Summary of LAG-3 Assay 
Assay category 
Lab developed test 
Reagent category 
Research use only 
Assay type 
Semiquantitative IHC 
Analyte name 
Anti–LAG-3 antibody 
Analyte clone 
L4-PL33 
Analyte manufacturer 
Enzo Life Sciences 
Intend use of the assay 
Determine LAG-3 status in FFPE tumor 
samples of human SCCHN 
Assay intended to be used on specimen type 
FFPE tissue 
Assay cut-off 
≥ 5% 
Assay accuracy at cut-off 
97.2% 
Prevalence of positivity in SCCHN (5% cut-off) 
58% 

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APPENDIX C. COVID-19 PANDEMIC MITIGATION STRATEGIES AND 
INSTRUCTIONS 
The COVID-19 global pandemic presents challenges to the ongoing conduct of clinical studies. 
In line with regulatory guidance regarding clinical study execution during the pandemic, the 
sponsor has issued the following Protocol considerations to ensure participant safety is 
maintained and adequate benefit/risk analyses are applied relative to the completion of study 
procedures and maintaining the investigational product supply chain. 
Recognizing the dynamic nature and flexibility required to manage the impact of the pandemic 
on this clinical study, additional details will be incorporated into respective study manuals and 
site-specific monitoring plans as applicable, with institutional requirements as warranted, and 
communicated to the investigative sites as needed. Relevant test results will be documented in 
the eCRF, and applicable changes to the ICF will be made and monitored. 
Given the critical medical need for alternative treatments for patients in the setting of 
recurrent/metastatic cancer and the importance of continuing cancer research, a positive 
COVID-19 screening test should not result in definitive exclusion. Participants with a positive 
COVID-19 test during screening may be reassessed for eligibility in the study only after 
normalization of their COVID-19 screening test and clinical recovery as per the investigator's 
evaluation. 
SARS-CoV2 Infection and Participation in the Study 
Benefit/risk assessment in the context of the COVID-19 pandemic is provided in Section 2.2.5. 
During the COVID-19 pandemic, additional risks to participants exist either related to going to a 
healthcare facility or as a result of study-related activities. It is at the investigator's discretion to 
balance the risk/benefit while considering the participant's safety, existing comorbidities, and 
current malignancy. In addition, country-specific requirements are to be followed with regard to 
COVID-19 testing. 
A participant who fails screening due to COVID-19 infection may repeat the screening process 
upon recovery and COVID test normalization. 
Study Site Visits 
If local travel restrictions, isolation requirements, or the investigator's benefit/risk assessment 
determines it to be unsafe for participants to attend study visits at the investigational site, the site 
staff may elect to pursue the following: 
• In order to minimize participant risk, study visits may be conducted via telemedicine 
modalities (phone or video) or as per site institutional guidelines. At a minimum, a 
review of AEs and concomitant medications must be completed. On-site visits should 
be conducted whenever feasible and are required for administration of study 
treatment. The participant may also be asked to undergo additional safety laboratory 
assessments. 

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• In order to support investigator oversight of participant safety and disease 
management, the participant may be asked to undergo some laboratory tests or study 
procedures at a local laboratory or facility closer to the participant's residence rather 
than at the investigational site. In this case, the study physician will provide the 
participant with the list of parameters to be checked. These tests should be performed 
in certified laboratories. 
• Some tests, such as ECG or CT scan assessments, may require longer windows of 
time to perform due to the COVID-19 pandemic and may be performed outside the 
regularly scheduled visit window or may be conducted at the next scheduled visit. It 
is the investigator's responsibility to check with the facility (if performed at a 
different facility) that the data will be obtained and available for evaluation. General 
procedures performed outside of protocol parameters will be captured as protocol 
deviations due to COVID-19. 
Study Treatment Management in the Event of SARS-CoV2 Infection 
If a participant develops a SARS-CoV2 infection, the event should be reported as SAE (if it 
meets the SAE definition requirements) and appropriate medical intervention provided. 
Postbaseline COVID-19 testing should follow country-specific requirements depending on the 
extent of COVID19-pandemic, local institutional guidance, or investigator's clinical judgment. 
For participants who are diagnosed with COVID-19 during the study (positive COVID-19 test) 
or presumed affected by SARS-CoV2 infection (test pending/clinical suspicion), study treatment 
should be delayed until COVID-19 test normalization and clinical recovery. Before restarting 
treatment, the study medical monitor should be notified with the participant's condition, that is, 
the participant should be afebrile for 72 hours and SARS-CoV2–related symptoms (if any) 
should have recovered for a minimum of 72 hours. 
Safety monitoring following COVID-19 infection should be implemented as per institutional 
guidance or clinical judgment (eg, coagulation factors). Concomitant medication administered 
for treatment of SARS-CoV2 infection should be carefully considered for potential drug-drug 
interactions and recorded in the EDC. 
COVID-19 Vaccination 
Participants may receive a COVID-19 vaccine. COVID-19 vaccination will be captured in the 
eCRF as a concomitant medication. Vaccination on the day of study treatment administration is 
not recommended. Administration of study treatment may be delayed to ensure vaccination is 
completed. 
Clinical Study Monitoring 
Study monitoring visits could be postponed; however, the site monitor and sponsor will continue 
to employ off-site monitoring practices such as routine communication methods (eg, phone calls, 
emails, video visits) with the sites to get information on trial progress, participant status, and 
information on issue resolution. The study monitor may remotely review data entered into the 
EDC for accuracy and completeness if allowed by the national regulatory body, investigational 
site, and/or in compliance with local authorities. 

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Reimbursement of Additional Expenses 
The sponsor will reimburse for any extraordinary expenses, keeping appropriate documentation 
as evidence (eg, travel expenses for local laboratory visits, cost of local laboratory tests). 

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APPENDIX D. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Version 1-BE 
06 JUL 2022 
Version 1-FR 
11 JUL 2022 
Version 1-KR 
11 JUL 2022 
Version 1-TW 
01 AUG 2022 
Version 1-DE 
30 AUG 2022 
Amendment 1 
04 NOV 2022 
Amendment 2 
19 DEC 2023 
Amendment 2 (19 DEC 2023) 
Overall Rationale for the Amendment: 
The primary purpose of the amendment is to update the statistical section, to clarify select 
eligibility criteria, to update select management guidelines for immune-related adverse events, to 
revise the guidance for resumption of treatment after a Day 15 dose delay, and to include the 
requirements set forth in the new Regulation EU No 536/2014 of the European Parliament and of 
the Council, as well as to harmonize the Protocol prior to transition to CTR. Additional changes 
are summarized below. 
1. Title Page 
Description of change: Removed EudraCT Number; added EU CT Number. 
Rationale of change: Update was initiated by Protocol template and regulations. 
2. Section 1, Protocol Summary (Table 2: Key Study Design Elements) 
Description of change: Updated Coordinating PI. 
Rationale for change: Current Coordinating PI elected to disaffiliate from study. 
3. Section 1, Protocol Summary (Table 1: Primary and Secondary Objectives and 
Endpoints); Section 3, Objectives and Endpoints (Table 6: Objectives and 
Endpoints) 
Description of change: Revised secondary endpoint from "dose reductions" to "dose 
delays." 
Rationale for change: To update endpoint description as dose reductions are not 
applicable to the study. 
4. Section 1, Protocol Summary; Section 4.1, Overall Design; Section 4.2, Number of 
Participants 
Description of change: Removed acronym "TPS" from references to LAG-3 expression. 
Rationale for change: LAG-3 expression is being evaluated on immune cells in the 
tumor microenvironment and not on tumor cells. 

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5. Section 1, Protocol Summary (Table 3: Schedule of Activities) 
Description of change: Added an "X" to Cycle 1 Day 15 and Cycle 2+ Day 15 columns 
for "Contact IRT" activity. 
Rationale for change: To correct prior omission on the Schedule of Activities, as the 
IRT will dispense the study drug at these visits. 
6. Section 1, Protocol Summary (Table 4: Schedule of Laboratory Assessments); 
Section 5.1, Inclusion Criteria (Criterion #9b); Section 8.3.6, Laboratory 
Assessments (Table 14: Required Laboratory Analytes); Section 8.3.6.2, Pregnancy 
Testing 
Description of change: Added text to include "serum or" where only urine pregnancy 
testing is specified. 
Rationale for change: Serum testing is more accurate than urine testing for detecting 
threshold levels of human chorionic gonadotropin. 
7. Section 4.3, Overall Study Duration 
Description of change: Updated the definition of "end of the study" with regard to 
primary endpoint and overall study completion. Added text to clarify when results will 
post, as well as when follow-up for OS could occur. 
Rationale for change: Clarification of key study milestones for data collection and 
public disclosure. 
8. Section 5.1, Inclusion Criteria (Criterion #6); Section 8, Tumor Imaging During 
Screening; Section 8.2.1.1, Tumor Imaging During Screening 
Description of change: Updated language to clarify criteria for assessing a previously 
biopsied lesion as a target lesion prior to randomization. 
Rationale for change: To provide specifications to ensure that postbiopsied imaging is 
done, and the tumor remains qualified per RECIST. 
9. Section 5.2, Exclusion Criteria (Criterion #11); Section 8.3.6, Laboratory 
Assessments (Table 14: Required Laboratory Analytes) 
Description of change: Added a note, as well as specific tests, to clarify that HBV 
testing will be required at the screening visit (prior to randomization). 
Rationale for change: Clarification of HBV testing. 
10. Section 5.2, Exclusion Criteria (Criterion #16) 
Description of change: Updated SARS-CoV2 test from PCR to antigen testing. 
Rationale for change: Research shows that antigen testing for SARS-CoV2 is more 
accurate when determining results. 
11. Section 6.1, Study Treatment Administered 
Description of change: Updated minimum interval for INCAGN02385/placebo and 
INCAGN02390/placebo doses from 14 days to 12 days. 
Rationale for change: To align with Day 15 visit window of ± 2 days. 

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12. Section 6.5.1, Criteria and Procedures for Dose Interruptions and Adjustments of 
Study Drugs 
Description of change: Revised the maximum duration for a Day 15 treatment delay 
from 4 weeks to 2 weeks, which would be before the visit must be skipped, and Day 1 of 
the subsequent treatment cycle should be conducted. 
Rationale for change: To allow a maximum delay of 2 weeks before dose administration 
with the anti–PD-1 antibody; this will enable the required dose intensity with a class of 
agent with established clinical activity in participants with R/M SCCHN. 
13. Section 6.5.2, Management of Suspected Infusion Reactions (Table 10: Guidelines 
for Management of Suspected Infusion Reactions) 
Description of change: Updated guidelines to permanently discontinue study treatment 
in a participant with a Grade 3 or 4 infusion reaction. 
Rationale for change: To ensure that treatment is not resumed in participants who had a 
Grade ≥3 IRR. 
14. Section 6.5.3, Procedures for Participants Exhibiting Immune-Related Adverse 
Events (Table 11: Guidelines for Management of Immune-Related Adverse Events) 
Description of change: Updated guidelines to allow participants to resume study 
treatment following improvement of Grade 3 and Grade 4 hyper- and hypothyroidism 
events. 
Rationale for change: To be consistent with clinical practice guidelines, participants will 
resume study treatment when adequate symptom control and/or thyroid hormone-
replacement is achieved (ie, Grade 2 or better). 
15. Section 6.5.3, Procedures for Participants Exhibiting Immune-Related Adverse 
Events (Table 11: Guidelines for Management of Immune-Related Adverse Events) 
Description of change: Updated guidelines to allow participants with an increase in 
serum troponin (ie, TnT or TnI) to resume study treatment following cardiologist 
evaluation. 
Rationale for change: To allow for a cardiology recommendation to determine whether 
it is appropriate to resume treatment after relevant evaluations for potential myocarditis 
are performed. 
16. Section 8.1.1, Informed Consent Process; Section 8.3.1, Adverse Events 
Description of change: References to "legally authorized representative" were deleted. 
Rationale for change: EU CTR No. 536/2014 defines "legally authorized 
representative" in the context of incapacitated persons and minors; these participants are 
not eligible for this study. 
17. Section 8.3.6, Laboratory Assessments (Table 14: Required Laboratory Analytes) 
Description of change: Added thyroid function tests. 
Rationale of change: Precision and details for assessments. 

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18. Section 9.4, Reporting of Serious Adverse Events; Section 11.1, Investigator 
Responsibilities 
Description of change: Added EU CTR No. 536/2014 and FDA 21 CFR Part 312 to list 
of applicable requirements for SAE reporting. 
Rationale for change: To include the current EU and US regulation requirements. 
19. Section 10, Statistics 
Description of change: Added statement to outline the statistical analysis strategies and 
procedures with regard to future Protocol amendments. 
Rationale for change: To confirm the Protocol will be consistent with key statistical 
parameters (ie, primary and/or secondary efficacy and safety hypotheses and statistical 
methods related to hypotheses). 
20. Section 10.1, Sample Size Determination 
Description of change: Updated the number of PFS events required for the final analysis 
to align with the Statistical Analysis Plan. 
Rationale for change: To harmonize the study Protocol and the Statistical Analysis Plan. 
21. Section 10.2, Populations for Analysis (Table 18: Populations for Analyses) 
Description of change: Added an ADA-evaluable population. 
Rationale for change: To define a population of study participants that are evaluable for 
ADA analysis. 
22. Section 10.3, Level of Significance 
Description of change: Added details for the level of significance. 
Rationale of change: Clarification. 
23. Section 10.4.1, Primary Analysis (Table 20: Evaluation and Censoring of 
Progression-Free Survival) 
Description of change: Updated scenarios. Removed scenario, "No baseline tumor 
assessments"; added scenario, "No valid postbaseline response assessments in the 
absence of death prior to the first scheduled tumor assessment." 
Rationale for change: To clarify censoring methodology. 
24. Section 10.7, Subgroup Analysis 
Description of change: Added an additional subgroup analysis by region (North 
America, EU, or Asia). 
Rationale for change: Added subgroup by region to the analysis. 
25. Incorporation of administrative changes. Other regulatory guidance and administrative 
changes have been incorporated throughout the Protocol and are noted in the redline 
version of the amendment. 

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Amendment 1 (04 NOV 2022) 
Overall Rationale for the Amendment: 
The primary purpose for this amendment is to add eligibility criteria for serum troponin as well 
as monitoring and management guidelines for troponin elevations; to update the management of 
suspected irAEs; to clarify certain study assessments; and to incorporate changes requested by 
regulatory authorities; to incorporate country-specific amendments. Additional changes are 
summarized below. 
1. Section 1, Protocol Summary (Table 2: Key Study Design Elements) 
Description of change: Added coordinating principal investigator. 
Rationale for change: To update the coordinating principal investigator field in the 
table. 
2. Section 1, Protocol Summary; Section 2.1.2, Treatment of Patients With 
Recurrent/Metastatic SCCHN; Section 2.2.1, Retifanlimab Monotherapy; Section 3, 
Objectives and Endpoints (Table 6: Objective and Endpoints); Section 4.1, Overall 
Design; Section 5.1, Inclusion Criteria (Inclusion Criterion 4); Section 10.4.6, 
Exploratory Analysis; Section 10.7, Subgroup Analysis 
Description of change: Deleted the "%" after CPS. 
Rationale for change: To conform to the accepted method for referencing CPS. 
3. Section 1, Protocol Summary; Section 4.1, Overall Design 
Description of change: Updated HPV p16 stratification factor description to clarify that 
participants without oropharynx cancer are considered HPV p16 negative. 
Rationale for change: To add clarity to stratification factor. 
4. Section 1, Protocol Summary (Table 3: Schedule of Activities); Section 6.1, Study 
Treatments Administered; Section 6.5.2, Management of Suspected Infusion 
Reactions; Section 8.3.3, Vital Signs 
Description of change: Added safety observation period following Cycle 1 Day 1 
infusion and pre- and postinfusion vital sign monitoring for potential IRRs. 
Rationale for change: To increase participant monitoring for potential IRRs during and 
after administration of study drugs. 
5. Section 1, Protocol Summary (Table 3: Schedule of Activities); Section 8.2.1, Tumor 
Imaging per RECIST v1.1 
Description of change: Clarified imaging modality requirements; added additional text 
to SoA to indicate that contrast-enhanced images are required unless contraindicated. 
Rationale for change: To specify the study imaging requirements. 

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6. Section 1, Protocol Summary (Table 3: Schedule of Activities); Section 8.3.4, 
Electrocardiograms 
Description of change: Added additional serial ECGs to include Day 1 of each cycle 
through Cycle 5. 
Rationale for change: Additional cardiac safety monitoring added based on data from 
other LAG-3 targeting agents. 
7. Section 1, Protocol Summary (Table 4: Schedule of Laboratory Assessments); 
Section 5.2, Exclusion Criteria (Table 7: Exclusion Laboratory Values); 
Section 6.5.3, Procedures for Participants Exhibiting Immune-Related Adverse 
Events (Table 11: Guidelines for Management of Immune-Related Adverse Events); 
Section 8.3.6, Laboratory Assessments (Table 14: Required Laboratory Analytes) 
Description of change: Added troponin monitoring through Cycle 4, or longer as 
needed, as well as management guidelines for elevated troponin. An exclusion of 
participants with high troponin levels at baseline was also added. 
Rationale for change: Additional cardiac safety monitoring added based on data from 
other LAG-3 targeting agents. 
8. Section 1, Protocol Summary (Table 5: Schedule of Pharmacokinetic and 
Pharmacodynamic Assessments); Section 8.4 (Table 15: Pharmacokinetic and 
Antidrug Antibody Sample Blood Sample Timing) 
Description of change: Added additional PK and ADA timepoint at 90-day safety 
follow-up visit. 
Rationale for change: To further characterize the long-term study drug exposure and 
potential immunogenicity. 
9. Section 2.2.1, Retifanlimab Monotherapy; Section 2.2.2, INCAGN02385 
Monotherapy; Section 2.2.3, INCAGN02390 Monotherapy; Section 2.2.4, 
Combinations of Retifanlimab, INCAGN02385, and INCAGN02390 
Description of change: Updated clinical data summaries for retifanlimab monotherapy, 
INCAGN02385 monotherapy, INCAGN02390 monotherapy, and combinations of 
retifanlimab, INCAGN02385 and INCAGN02390. 
Rationale for change: To align the clinical data summaries with the current version(s) of 
the IB(s). 
10. Section 5.1, Inclusion Criteria (Inclusion Criterion 3) 
Description of change: Added a note to indicate that participants enrolled will be 
eligible for first-line treatment with anti–PD-1 monotherapy for R/M SCCHN (and would 
not require combination therapy with chemotherapy) at the discretion of the investigator. 
Rationale for change: To ensure that potential participants who require chemotherapy, 
per investigator judgment, are not enrolled. 
11. Section 5.1, Inclusion Criteria (Inclusion Criterion 6) 
Description of change: Updated to specify the conditions under which lesions used for 
response assessment can be used for biopsy. 

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Rationale for change: To clarify the criteria for using a potential target lesion for the 
study-required tissue biopsy. 
12. Section 5.1, Inclusion Criteria (Inclusion Criterion 7) 
Description of change: Updated to specify the conditions under which lesions, which 
have been previously irradiated, can be used for biopsy. 
Rationale for change: To clarify the criteria for obtaining the study-required biopsy 
from a lesion which has previous been treated with radiation. 
13. Section 5.2, Exclusion Criteria (Exclusion Criterion 11) 
Description of change: Exclusion criterion was updated to refine and clarify the 
definition of HBV infection. 
Rationale for change: To clarify the exclusion criterion for HBV infection. 
14. Section 5.2, Exclusion Criteria (Exclusion Criterion 13) 
Description of change: Updated the exception for participants with a history of other 
malignancy within 3 years of first dose of study treatment to include cancers from which 
the participant has completed treatment > 2 years before randomization in this study and 
has been disease-free since completion of treatment with curative intent. 
Rationale for change: Clarification of exclusion criterion 13. 
15. Section 5.2, Exclusion Criteria (Exclusion Criterion 27) 
Description of change: Exclusion criterion 27 has been added for vulnerable populations 
and adults under legal protection. 
Rationale for change: To address a regulatory requirement in France. 
16. Section 6.1, Study Treatment Administered 
Description of change: Added text regarding dose administration window for Day 15 
and minimum interval between INCAGN02385/placebo and INCAGN02390/placebo 
doses. 
Rationale for change: To clarify the Day 15 dose administration window and minimum 
dose administration interval. 
17. Section 6.1, Study Treatment Administered 
Description of change: Premedication guidance for IRR prophylaxis was updated to 
reflect the allowance for any antipyretic and any histamine blocker discussed in 
Section 6.5.2. 
Rationale for change: To allow for investigator discretion when administering 
preinfusion IRR prophylaxis. 
18. Section 6.5.1, Criteria and Procedures for Dose Interruptions and Adjustments of 
Study Drugs 
Description of change: Updated to allow for longer interruption of treatment to allow for 
resolution of toxicity when approved by sponsor. 
Rationale for change: To provide additional flexibility regarding the duration of 
treatment interruptions. 

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19. Section 6.5.1, Criteria and Procedures for Dose Interruptions and Adjustments of 
Study Drugs 
Description of change: Added guidance for whether to resume or skip a Day 15 visit in 
the event that the dose has been held for toxicity. 
Rationale for change: To provide specific parameters regarding whether to resume or 
skip the Day 15 visit if the dose has been held for toxicity, depending on the duration of 
the hold. 
20. Section 6.5.1, Criteria and Procedures for Dose Interruptions and Adjustments of 
Study Drugs 
Description of change: Updated to require discontinuation of all 3 study drugs in the 
event that treatment is terminated due to toxicity. 
Rationale for change: To ensure that the 3 treatment groups are evaluated using only the 
assigned combination of study drugs, so as to not confound the endpoint comparing the 
treatment arms versus the retifanlimab control. 
21. Section 6.5.1.1, Procedures for Participants Exhibiting Drug-Related, 
Non–Immune-Related Adverse Events (Table 9: Management Guidelines for 
Drug-Related, Non-Immune Related Adverse Events) 
Description of change: Updated to correct the study drug names. 
Rationale for change: Correction of an administrative/editorial error in the table. 
22. Section 6.5.3, Procedures for Participants Exhibiting Immune-Related Adverse 
Events (Table 11: Guidelines for Management of Immune-Related Adverse Events) 
Description of change: Revised the guidelines for ALT/AST and nephritis events. 
Rationale for change: To apply permanent treatment discontinuation criteria to Grade 3 
events. 
23. Section 6.6.1, Permitted Medications and Procedures; Section 6.6.2, Restricted 
Medication and Procedures; Section 6.6.3, Prohibited Medications and Procedures 
Description of change: Included additional guidance and requirements regarding 
permitted, restricted, and prohibited medications and procedures. 
Rationale for change: To provide additional specific details regarding medications and 
procedures which are permitted, restricted, and prohibited during study participation. 
24. Section 6.7, Treatment After the End of the Study 
Description of change: Added a statement to clarify that participants will be supplied 
with study medication for up to 2 years total if the study is terminated early. 
Rationale for change: To clarify the availability of study medication to participants if 
the study is terminated early. 
25. Section 8.1.5.2, Disease Characteristics and Treatment History 
Description of change: Corrected statement regarding local determination of CPS. 
Rationale for change: To update the statement to be consistent with the protocol 
requirements for central determination of tumor CPS status. 
26. Section 8.5.1, Tumor Tissue Collection 

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Description of change: Included additional criteria regarding submission of archival 
tissue for baseline tumor tissue requirement. 
Rationale for change: To further specify the requirements for archival tumor tissue. 
27. Section 8.5.2, Whole Blood Correlative Flow Cytometry Assessments 
Description of change: Clarified the timing of receptor occupancy analysis. 
Rationale for change: To specify that an analysis of receptor occupancy, if performed, 
will occur following completion of the final study analysis. 
28. Section 8.8.2, Post-Treatment Disease Follow-Up 
Description of change: Clarified the timing of post-treatment imaging for participants 
that have been discontinued from study treatment for reasons other than disease 
progression. 
Rationale for change: To further clarify the timing requirements for post-treatment 
imaging. 
29. Section 9.5, Events of Clinical Interest 
Description of change: Added methods for identification and analysis of irAEs. 
Rationale for change: To clarify how irAEs will be summarized and reported for the 
study. 
30. Section 10.4.5, Pharmacokinetic Analysis 
Description of change: Added section regarding PK analysis. 
Rationale for change: To clarify how PK will be analyzed for the study. 
31. Incorporation of administrative changes. Other regulatory guidance and administrative 
changes have been incorporated throughout the Protocol and are noted in the redline 
version of the amendment. 

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Version 1-DE (30 AUG 2022) 
Overall Rationale for the Amendment: 
The primary purpose for this amendment is to address health authority comments. 
1. Section 5.1, Inclusion Criteria 
Description of change: Added a note to indicate that participants enrolled will be 
eligible for first-line treatment with anti–PD-1 monotherapy for R/M SCCHN (and would 
not require combination therapy with chemotherapy) at the discretion of the investigator. 
Rationale for change: To ensure that potential participants who require chemotherapy, 
per investigator judgment, are not enrolled. 
2. Incorporation of administrative changes. Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 

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Version 1-TW (01 AUG 2022) 
Overall Rationale for the Amendment: 
The primary purpose for this amendment is to address health authority comments. 
1. Section 1, Protocol Summary (Table 3: Schedule of Activities); Section 6.1, Study 
Treatments Administered; Section 6.5.2, Management of Suspected Infusion 
Reactions; Section 8.3.3, Vital Signs 
Description of change: Added safety observation period following Cycle 1 Day 1 
infusion and pre- and postinfusion vital sign monitoring for potential IRRs. 
Rationale for change: To ensure that study participants are properly monitored for 
potential IRRs during and after administration of study drugs. 
2. Section 1, Protocol Summary (Table 3: Schedule of Activities); Section 8.3.4, 
Electrocardiograms 
Description of change: Added additional serial ECGs to include Day 1 of each cycle 
through Cycle 5. 
Rationale for change: Additional cardiac safety monitoring is justified based on 
emerging data from other LAG-3 targeting agents. 
3. Section 1, Protocol Summary (Table 4: Schedule of Laboratory Assessments); 
Section 5.2, Exclusion Criteria (Table 7: Exclusion Laboratory Values); 
Section 6.5.3, Procedures for Participants Exhibiting Immune-Related Adverse 
Events (Table 11: Guidelines for Management of Immune-Related Adverse Events); 
Section 8.3.6, Laboratory Assessments (Table 14: Required Laboratory Analytes) 
Description of change: Added troponin monitoring through Cycle 4, or longer as 
needed. An exclusion of participants with high troponin levels at baseline was also added. 
Rationale for change: Additional cardiac safety monitoring is justified based on 
emerging data from other LAG-3 targeting agents. 
4. Incorporation of administrative changes. Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 

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Version 1-KR (11 JUL 2022) 
Overall Rationale for the Amendment: 
The primary purpose for this amendment is to address health authority comments. 
1. Section 5.2, Exclusion Criteria (Criterion #13) 
Description of change: Updated the exception for participants with a history of other 
malignancy within 3 years of first dose of study treatment to include cancers from which 
the participant has completed treatment > 2 years before randomization in this study and 
has been disease-free since completion of treatment with curative intent. 
Rationale for change: Clarification of exclusion criterion #13. 
2. Incorporation of administrative changes. Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 

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Version 1-FR (11 JUL 2022) 
Overall Rationale for the Amendment: 
The primary purpose for this amendment is to address health authority comments. 
1. Section 6.5.1.1, Procedures for Participants Exhibiting Drug-Related, 
Non–Immune-Related Adverse Events (Table 9: Management Guidelines for 
Drug-Related, Non-Immune Related Adverse Events) 
Description of change: Updated to correct the study drug names. 
Rationale for change: Correction of an administrative/editorial error in the table. 
2. Section 6.5.3, Procedures for Participants Exhibiting Immune-Related Adverse 
Events (Table 11: Guidelines for Management of Immune-Related Adverse Events) 
Description of change: Revised the guidelines for ALT/AST and nephritis events. 
Rationale for change: To apply permanent treatment discontinuation criteria to Grade 3 
events. 
3. Section 6.7, Treatment After the End of the Study 
Description of change: Added a statement to clarify that participants will be supplied 
with study medication for up to 2 years if the study is terminated early. 
Rationale for change: To clarify the availability of study medication to participants if 
the study is terminated early. 
4. Section 8.5.2, Whole Blood Correlative Flow Cytometry Assessments 
Description of change: Updated to clarify the timing of receptor occupancy analysis. 
Rationale for change: To specify that an analysis of receptor occupancy, if performed, 
will occur following completion of the final study analysis. 
5. Incorporation of administrative changes. Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 

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Version 1-BE (06 JUL 2022) 
Overall Rationale for the Amendment: 
The primary purpose for this amendment is to address comments from the Belgium Health 
Authority. 
1. Section 1, Protocol Summary (Table 3: Schedule of Activities); Section 6.1, Study 
Treatments Administered; Section 8.3.3, Vital Signs 
Description of change: Added pre- and post-infusion vital sign monitoring for potential 
IRRs. 
Rationale for change: To ensure that study participants are properly monitored for 
potential IRRs during and after administration of study drugs. 
2. Section 1, Protocol Summary (Table 3: Schedule of Activities); Section 8.3.4, 
Electrocardiograms 
Description of change: Added additional serial electrocardiograms to include Day 1 of 
each cycle through Cycle 5. 
Rationale for change: Additional cardiac safety monitoring is justified based on 
emerging data from other LAG-3 targeting agents. 
3. Section 1, Protocol Summary (Table 4: Schedule of Laboratory Assessments); 
Section 5.2, Exclusion Criteria (Table 7: Exclusion Laboratory Values); 
Section 6.5.3, Procedures for Participants Exhibiting Immune-Related Adverse 
Events (Table 11: Guidelines for Management of Immune-Related Adverse Events); 
Section 8.3.6, Laboratory Assessments (Table 14: Required Laboratory Analytes) 
Description of change: Added troponin monitoring through Cycle 4, or longer as 
needed. An exclusion of participants with high troponin levels at baseline was also added. 
Rationale for change: Additional cardiac safety monitoring is justified based on 
emerging data from other LAG-3 targeting agents. 
4. Incorporation of administrative changes. Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 

Signature Page for VV-CLIN-018190 v5.0
Signature Page for VV-CLIN-018190 v5.0
Approval Task
r
 Clinical Operations
20-Dec-2023 08:28:35 GMT+0000
Approval Task
 Hematology Oncology Clinical
Development
20-Dec-2023 13:47:17 GMT+0000
Approval Task
Approver
 Clinical Research Scientist
20-Dec-2023 13:53:26 GMT+0000
Approval Task
 Hematology/Oncology Clinical
Development
20-Dec-2023 13:57:19 GMT+0000
Approval Task
Approver
 Biostatistics
20-Dec-2023 15:36:48 GMT+0000